Cytomegalovirus (CMV) Retinitis Workup

Updated: Feb 11, 2019
  • Author: Michael Altaweel, MD, FRCSC; Chief Editor: Andrew A Dahl, MD, FACS  more...
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Approach Considerations

CMV viremia can be detected via polymerase chain reaction (PCR), antigen assays, or culture and is usually, but not invariably, present in patients with end-organ disease, even when the CD4 count is low. Serum tests to detect CMV via antigen detection, culture, or PCR are not recommended for diagnosis of CMV end-organ disease because of their poor positive predictive value [55] A negative serum or plasma PCR assay result also does not rule out CMV end-organ disease.

CMV DNA is detected in the vitreous in approximately 80% of patients with CMV retinitis, but in serum in only 70%, with the remaining cases diagnosed via clinical criteria plus response to therapy. [56, 57] CMV PCR can be particularly useful in assessing CSF or vitreous or aqueous humor specimens; a positive result is highly suggestive that CMV infection is the cause of end-organ disease. However, PCR assays are not standardized; therefore, sensitivity, specificity, and interassay comparability are not clearly delineated.

The presence of serum antibodies to CMV is not diagnostically useful, although a negative immunoglobulin G antibody level indicates that CMV is unlikely to be the cause of the disease process.

A dilated fundus examination performed by a skilled and experienced ophthalmologist is a prerequisite for diagnosis and has a 95% positive predictive value. [58] In rare cases, diagnosis may be difficult, and PCR of aqueous or vitreous specimens for CMV and other pathogens, especially herpes simplex virus, varicella zoster virus, and toxoplasmosis, can be useful for establishing the diagnosis.


Laboratory Studies

CD4 count

The CD4 count is a marker of immune dysfunction in patients infected with HIV. [59] Patients may be asymptomatic with CMV retinitis; therefore, ophthalmic screening frequency is based on CD4 count. [60, 61]

  • CD4 >50 cells/μL - Little risk; screening examination every 6 months if CD4 50-100 cells/μL; screen yearly if CD4 >100 cells/μL; if antiretroviral therapy has recently been initiated, immune recovery CMV retinitis is possible, even in cases with CD4 >50 cells/μL, and therefore surveillance would be more frequent when starting treatment [34]
  • CD4 < 50 cells/μL - Up to 35% incidence of CMV retinitis; median time to diagnosis of CMV retinitis is 13 months; screen every 3 months [62]

The CD8+ T-lymphocyte count is also predictive of CMV retinitis in patients with AIDS. The risk for retinitis appears higher when the CD8+ T-lymphocyte count is below 520 cells/mm3. The CD8+ T-lymphocyte count is of no additional and independent predictive value if the CD4+ T-lymphocyte count is already known.

The above screening regimen was used prior to the routine use of HAART. The frequency of examinations likely will be modified by assessing viral load, result of CMV DNA capture, CD4 count, and response to treatment.


A PCR test can be qualitative or quantitative. Specimens can be obtained from blood buffy coat, semen, or urine. Detection of CMV in the blood by DNA PCR is most predictive of developing CMV disease but has poor positive predictive value. [63, 64] Patients with AIDS who test positive have a 60% chance of developing CMV end-organ disease. [65, 66] Responders to ganciclovir prophylaxis convert to PCR-negative with treatment. In case series, survival is increased 2.4 times at 12 months when PCR shows a treatment response. DNA PCR analysis is increasingly applied to ocular fluids. [18, 67, 68]

PCR-based analysis of vitreous humor offers high diagnostic specificity and sensitivity. Vitreous sampling is usually reserved for patients with atypical lesions, for individuals in whom disease is not responsive to treatment, or for patients for whom a vitreous biopsy would carry little added risk (eg, those already scheduled to undergo vitrectomy for retinal detachment repair).

Viral load

Increased viral load can be a predictor of development of CMV end-organ disease.

HIV test

HIV testing should be performed in any patient with an unclear medical history, any patient with systemic signs and symptoms of AIDS, or any patient who is making his or her first visit to the physician.

Complete blood cell count with differential

Complete blood cell (CBC) count with differential is important in evaluation for causes of immunosuppression and in assessment for adverse effects of ganciclovir use.

Blood urea nitrogen and creatinine

Blood urea nitrogen (BUN) and creatinine baseline assessment and serial measurements are used to evaluate for side effects of foscarnet or cidofovir use. They can also be used to evaluate systemic inflammatory status and to monitor for potential sepsis.


Imaging Studies

See the list below:

  • Ultrasonography is used to evaluate for retinal detachment, particularly if vitreitis obscures adequate fundus visualization.
  • Fundus photography and fluorescein angiography - Assessment for areas of retinitis and ischemia
  • Chest radiography - Assessment for concurrent Pneumocystis pneumonia or possible pneumonitis

Other Tests

See the list below:

  • Fluorescent treponemal antibody absorption (FTA-ABS) test or microhemagglutination-Treponema pallidum (MHA-TP) - Serologic testing for infection with syphilis, a differential diagnosis for CMV retinitis

  • Serum toxoplasma titer - Differential diagnosis for retinitis with vitreitis



Ganciclovir implant   [69]

No longer available in the United States, this intravitreal implant released ganciclovir at a steady state for up to 8 months. [70] The implant provided treatment of CMV retinitis in one eye only. No systemic effect occurs. The initial implant usually is placed in the inferotemporal quadrant. It may be visualized through a dilated pupil. Possible complications included vitreous hemorrhage, retinal detachment, hypotony, and endophthalmitis. [71, 72]  After 8 months, if still required, a second implant may be placed. The first implant can be left in place or removed. [73]

Vitreoretinal surgery

Retinal detachment repair is required in 5-50% of patients with CMV retinitis (depending on the trial). [74] Multiple small holes that have resulted from vitreous contraction or direct retinal necrosis are often responsible for the retinal detachment. These occur at the junction of healthy and necrotic retina.

Primary repair with vitrectomy, fluid-air exchange, endolaser, and silicone oil tamponade has improved surgical outcome. [75, 76, 77, 78] A second surgery is performed to remove the silicone oil in 4-6 months if the retina remains stable. Oil removal is associated with a risk of redetachment.

Laser photocoagulation

Small peripheral retinal detachments can be repaired with laser photocoagulation.

Intravitreal injections of ganciclovir, foscarnet,  [79] or cidofovir  [80]

These injections offer high levels of intraocular drug for short periods of time. [81] Ganciclovir and foscarnet are given once or twice per week; cidofovir is given once every 5-6 weeks. They are useful in acute vision-threatening cases when rapid drug delivery is needed prior to instituting longer-term therapy or if the response to intravenous therapy is poor and/or the patient is intolerant to systemic therapy.

Risks of intravitreal injection include hemorrhage, retinal detachment, and endophthalmitis.

Intravitreal cidofovir can cause idiosyncratic iritis and hypotony. The risk of iritis can be reduced from 70% to 18% if oral probenecid is given. Iritis can be treated with topical steroids and cycloplegia. A 20% asymptomatic reduction in intraocular pressure is nearly universal; however, only 1% develop vision changes due to profound hypotony. Given the increased side effect profile, cidofovir is typically reserved until after ganciclovir and foscarnet are attempted.

Fomivirsen is a fourth-line drug that is no longer available in the United States.


Histologic Findings

The healthy retina is sharply demarcated from infected retinal cells, which show edema, cytomegalic inclusions, necrosis, and few surrounding inflammatory cells (consistent with a compromised immune response). CMV-infected cells contain eosinophilic cytoplasmic and nuclear viral inclusion bodies giving an "owl's eye" appearance on hematoxylin and eosin staining (see image below).

Intranuclear inclusions (arrows) found in cytomega Intranuclear inclusions (arrows) found in cytomegalovirus retinitis. Referred to as owl's eye because of the dark intranuclear inclusion surrounded by a clear halo.

Infected cells lyse, leaving an area of full-thickness necrosis and releasing virus particles that infect adjacent retinal cells. The histopathology correlates well with the clinical picture of a posteriorly advancing edge of active disease with formerly active areas undergoing necrosis, scarring, and atrophy. [82, 83]



CMV retinitis is described by the stage and zone of involvement. [84, 85, 86]


Active retinitis - 3 general patterns, as follows:

  • Hemorrhagic - Large areas of retinal hemorrhage on a background of whitened, necrotic retina
  • Brush fire - Yellow-white margin of slowly advancing retinitis at the border of atrophic retina
  • Granular - Found in the periphery; focal white granular lesions without associated hemorrhage

Necrotic stage - End result of all patterns of active retinitis is the progression to necrosis. Retinal tears or holes can develop in these areas.

Geographic patterns and anatomy

The retina can be divided into specific zones that may have prognostic value. These zones are as follows:

  • Zone 1 - Within 1500 µm of the optic nerve or 3000 µm of the fovea
  • Zone 2 - From zone 1 to equator, at vortex vein ampullae
  • Zone 3 - From zone 2 to the ora serrata
  • Zone 1 lesions are considered immediately sight threatening.
  • Zone 2 and 3 are the most common sites of initial retinal involvement.

Several studies have shown significant posterior pole involvement. [87] Retinitis that spreads from zone to zone usually moves along the leading edge, although skip lesions can occur. Progression occurs at a rate of 250-350 µm/wk if untreated. [88]