|Figure 1. Retinal Zones. One disc diameter is approximately 1,800 µm.1-3|
CMVR has been associated with the human immunodeficiency virus infection since the 1980s.16 CMVR occurs in 15 to 40 percent of acquired immune deficiency syndrome patients.5 The advent of highly active antiretroviral therapy (HAART) in the 1990s has reduced the incidence of CMVR by 90 percent in the United States.9,17 HAART has reduced the rate of CMVR-associated rhegmatogenous retinal detachments by 60 percent.5
CMVR typically occurs when CD4+ T-cell counts fall below 50 cells/µl, and rarely occurs at counts above 100 cells/µl.2,9 Immune recovery uveitis refers to intraocular inflammation that occurs in HIV-positive patients with prior, inactive CMVR, in whom the CD4+ counts rise above 100 cells/µl. IRU occurs in up to 63 percent of patients with prior CMVR.18
Uveitic manifestations of IRU include vitritis; vitreomacular traction; cystoid macular edema; epiretinal membrane; papillitis; neovascularization; proliferative vitreoretinopathy; and RRD.17,18 The vitritis and CME of IRU can be treated with periocular or intravitreal triamcinolone, but with caution, so as to avoid recurrence.2 Systemic CMV manifestations include encephalitis; esophagitis; colitis; pneumonitis; hepatitis; leukopenia; and arthralgia. Systemic CMV disease occurs in about 25 percent of patients with CMVR.5
CMVR can also occur in non-HIV patients, but is much less common. In a recent comprehensive review of 178 HIV-negative patients with CMVR, factors that contributed to relative immunosuppression included age over 60 years (33.1 percent); leukemia (19.7 percent); systemic autoimmune disease (19.1 percent); organ transplantation (15.2 percent); lymphoma (7.9 percent); diabetes mellitus (6.1 percent); and multiple myeloma (1.7 percent).19 CMVR has been described in nine patients with Good syndrome.19,20 Among 105 HIV-negative CMVR patients on immunosuppressives, CMVR was found in patients on corticosteroids (65.7 percent); cyclophosphamide (31.4 percent); azathioprine (16.2 percent); methotrexate (14.3 percent); cyclosporine (12.4 percent); tacrolimus (10.5 percent); mycophenolate (7.6 percent); and fludarabine (6.7 percent).19 CMVR can also occur following periocular or intraocular corticosteroid injection.4,13,19-22 IRU can also occur in HIV-negative patients with prior CMVR, but
|Figure 2: Color fundus photograph of the right eye of an HIV-positive 35-year-old female. The hemorrhage and vascular sheathing suggests fulminant CMVR. Encroachment of the CMVR into the superotemporal macular area suggests Zone 1 involvement. The border opacification at 9 o’clock matches the standard peripheral photograph of severe (4+) border opacification; this is active retinitis. The CMVR involves approximately 25 percent of the retina surface of the right eye. This patient died of AIDS soon after this photograph was taken.|
Many patients with CMVR are asymptomatic, as the retinitis often begins in the peripheral retina. Screening for CMVR is indicated for all HIV-positive patients with a CD4+ count less than 100 cells/µl.2,5
Classical CMVR is a slowly progressive necrotizing retinitis that may affect the posterior pole and periphery, and may be unilateral or bilateral. White intraretinal infiltrates are often seen along the vascular arcades and are associated with necrotic areas and retinal hemorrhages. CMVR progression leads to retinal atrophy. Anterior segment inflammation with or without keratic precipitates is often present. Optic atrophy is a common late manifestation.2,5
CMVR can be classified into indolent or fulminant CMVR. Indolent CMVR consists of granular retinal opacification with visible choroidal details with no hemorrhage and no vascular sheathing. Fulminant (edematous) CMVR consists of dense confluent retinal opacification of necrotizing retinitis and hemorrhages with no atrophic areas.3
CMVR assessment should include grading of the area of retina involvement into three zones (See Figure 1). Zone 1 is the area 3,000 µm from the fovea and 1,500 µm from the optic disc. Zone 2 is from Zone 1 to the vortex veins. Zone 3 is the remaining retina up to the ora serrata.1,23 In HIV-positive patients, the majority of CMVR is peripheral (i.e., Zone 1-sparing; 61 to 71 percent of eyes) with only a minority involving Zone 1 (i.e., 29 to 39 percent of eyes).17,24 CMVR assessment should also include estimation of the percentage of the total retinal surface area affected by the CMVR (e.g., <10 percent, 10 to 24 percent, 25 to 50 percent, >50 percent) since this has implications regarding the risk of retinal detachment.24
|Figure 3. Fundus autofluorescence photograph of the same patient from figure 2. Intense, confluent hyperautofluorescence temporal to the macula corresponds to the advancing, active edge of retinitis. Mottled hyper- and hypoautofluorescence peripheral to the area of active retinitis corresponds to a large area of previously infected, but not necrotic, atrophic retina.8|
CMVR borders can be graded based on photographs. Mild (1+) is where the CMVR border is faint and does not obscure the choroid. Moderate (2+) is where the CMVR border consists of isolated areas of denser retinal whitening which partially obscures the choroid. Marked (3+) is confluent retinal whitening, partially obscuring the choroid. Severe (4+) is where the border opacification is so dense that the choroid cannot be seen, indicating active retinitis.3,7 Screening has revealed that 42.9 percent of CMVR eyes have 1+ opacification; 28.6 percent have 2+ opacification; 4.7 percent have 3+ opacification; and 23.8 percent have 4+ opacification.24 Figures 2 and 3 show color and fundus autofluorescence montages of active CMVR in an HIV-positive patient.
The differential diagnoses for CMVR is shown in Table 1.5 Most of these conditions can be differentiated from CMVR clinically, but retinitides mediated by HHV family members (e.g., CMV, herpes simplex virus and varicella zoster virus) may be more difficult to distinguish clinically.5,6
|Table 1. Differential Diagnoses of Cytomegalovirus Retinitis|
|Infective causes||Non-infective causes|
|Acute retinal necrosis (ARN)||Behçet’s disease|
|Progressive (outer) retinal necrosis (PORN)||Primary vitreoretinal lymphoma (PVRL)|
|Herpes simplex virus retinitis|
|Subacute sclerosing panencephalitis (SSPE)|
An aqueous tap for polymerase chain reaction-based testing can distinguish between CMV, HSV and VZV infection. An anterior chamber tap typically provides 50 to 150 µl of fluid. A vitreous tap provides 300 µl of fluid. Among 178 HIV-negative CMVR eyes, 71.8 percent had their diagnosis of CMVR confirmed by PCR.19 PCR for toxoplasmosis could also be requested if there is a concern.25 It should be noted that the sensitivity of PCR-based testing falls if the sample is obtained following the initiation of anti-viral therapy.4
Serial fundus photography and wide-angle fluorescein angiography can be helpful in the management of patients with CMVR. Wide-angle imaging, in particular, can demonstrate peripheral ischemia, which may require pan-retinal photocoagulation.26 In HIV-negative CMVR patients, an occlusive vasculopathy was reported in 47 of 199 eyes—or nearly one in four cases.19
RRD occurs in about 20 to 30 percent of HIV-infected CMVR patients, and occurs most often in areas of prior retinal necrosis.2,5,27 The risk of RRD increases as the amount of peripheral retina affected by the CMVR increases.2 For post-CMVR RRD, a retina reattachment rate of 86 percent can be achieved with a 360 degree encircling band, vitrectomy, endolaser and silicone oil injection.5,28
|Table 2. Systemic Antivirals|
|Drug||Route||Dosage & Timing||Side Effects (by %) and Comments|
|900 mg b.i.d. for three weeks (induction); 900 mg daily (maintenance)||Diarrhea (38%), nausea (23), neutropenia (10), anemia (12), thrombocytopenia (2)|
|Ganciclovir||Intravenous||5 mg/kg q12h for two to three weeks (induction); 5 mg/kg/day (maintenance)||Granulocytopenia (33), neurologic dysfunction, abnormal liver function, thrombocytopenia. |
|Foscarnet||Intravenous||90 mg/kg b.i.d. for two to three weeks|
(induction); 90 mg/kg daily (maintenance)
|Nephrotoxicity, neutropenia, anemia,|
hypocalcemia, Mg2+, PO4- abnormalities. Consider saline loading.
|Cidofovir||Intravenous||5 mg/kg once a week for two to three weeks (induction); 3 to 5 mg/kg alternate weeks (maintenance)||Iritis (50), ocular hypotony. Probenecid and IV hydration reduces nephrotoxicity. |
Treatment of CMVR
Treatment options for CMVR vary. Systemic options are shown in Table 2. Local options are shown in Table 3.2,5,29
The gold standard for the treatment of CMVR, in both HIV-positive and HIV-negative patients, is systemic antiviral therapy.15,17 Systemic therapy is generally preferred both because it reduces overall morbidity and because it generally works, with nearly three-quarters of patients achieving a post-treatment vision of 20/40 or better.17 First-line treatment for both HIV-positive and HIV-negative patients with CMVR includes either intravenous ganciclovir or oral valganciclovir.5,15
If an HIV-positive patient’s CD4+ count cannot be elevated with HAART, systemic antiviral therapy may need to become lifelong. This typically requires placement of a permanent indwelling venous catheter. If the CD4+ count can be kept above 100 cells/µl for three to six months, anti-CMV treatment typically can be stopped. Oral valganciclovir is as effective as IV ganciclovir, and allows patients to be maintained without long-term intravenous access.5
|Table 3. Local Antivirals|
|Drug||Route||Dosage & Timing||Comments|
|Ganciclovir||Intravitreal||2 mg twice a week (induction*);|
2 mg weekly (maintenance)15, 30
|5 mg weekly, high-dose possible.31|
|Foscarnet||Intravitreal||2.4 mg, one to two times a week (induction); 2.4 mg weekly|
|Cidofovir||Intravitreal||20 µg every five to six weeks32||Long-acting. Give oral probenecid 2 g two hours before injection, and 1 g two hours and eight hours after injection. Hypotony and iritis risks are lower with a 10-µg dose. |
|Fomivirsen||Intravitreal||Two doses 330 µg (0.05 ml), two weeks apart (induction); 330 µg monthly (maintenance)||No longer available in the United States. Reports of peripheral retinal toxicity and inflammation. |
|Sustained-release implant||1 µg per hour for eight months||No longer available.5, 29|
CMV resistance to ganciclovir can occur with long-term antiviral therapy.5,25 When ganciclovir resistance does occur, treatment options include the use of systemic foscarnet, or use of adjunctive high-dose intravitreal antiviral foscarnet or ganciclovir.31,33 Combination intravenous ganciclovir/foscarnet or oral valganciclovir plus intravenous foscarnet is more effective than monotherapy in resistant CMVR.5 While a 2-mg intravitreal injection of ganciclovir maintains therapeutic vitreous levels for up to seven days,34,15 use of intravitreal injections alone has been associated with worse visual acuity outcomes—at least in HIV-positive patients.2,35
As many CMVR patients are initially asymptomatic, screening for CMVR is recommended. CMVR progresses approximately 250 µm per week.2,37 Currently no laboratory marker exists that predicts the occurrence of CMVR.5 Clinical examination by a fellowship-trained retina specialist diagnosed CMVR in 15.5 percent of HIV-positive patients with CD4+ counts <100 cells/µl (i.e., 16 out of 103 patients). Fundus photography mediated telescreening is less successful, with a lower pick-up rate of 5.8 percent (i.e., six out of 103 patients). Use of ultra-widefield retinal imaging may improve the success rate of telescreening.24
In conclusion, CMVR is a sight-threatening infection caused by a member of the HHV family.5,6,9 Both HIV and CMVR are more common in the developing world.9-11,38 The gold-standard in CMVR therapy is systemic antiviral medication (e.g., valganciclovir).17 But due to cost, CMVR is still treated by intravitreal antivirals alone (e.g., ganciclovir) in many settings.13,31,32,36 REVIEW
Dr. Yeung is a uveitis and ocular immunology fellow at the National Eye Institute, Bethesda, Md. Dr. Downes is a cornea fellow at The Casey Eye Institute, Oregon Health Science University, Portland, Ore. Dr. Sen is the director of the uveitis and ocular immunology fellowship program at the NEI and has a joint appointment as a clinical professor in the Department of Ophthalmology at George Washington University, Washington, D.C. Dr. Cunningham is the director of the Uveitis Service at California Pacific Medical Center, San Francisco; an adjunct clinical professor of ophthalmology at Stanford University School of Medicine; a research associate at the Francis I. Proctor Foundation, UCSF School of Medicine, San Francisco; and a partner in the West Coast Retina Medical Group, San Francisco.
Correspondence should be directed to Dr. Sen at firstname.lastname@example.org. This work was supported by the NEI Intramural Research Program.
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