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Ophthalmology and Visual Sciences

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Cytomegalovirus (CMV) Retinitis:

36-year-old Indian male with HIV and decreasing visual acuity

Arpitha Muthialu, MD, and James C. Folk, MD

December 18, 2006

History of Present Illness: 36-year-old East Indian male with progressive decrease in vision the right eye (OD) for 6 months. The vision is generally depressed, with no discrete scotomas.

Past Ocular History: None known to the patient.

Medical History: Patient has Acquired Immunodeficiency Syndrome (AIDS) with Humun Immunodeficiency Virus (HIV) transmitted through intercourse with a prostitute. The last known CD4 count was 9 cells/mm3. Patient also has a history of Tuberculosis.

Medications: The patient was very recently placed on Highly Active Antiretroviral Therapy (HAART) and anti-tuberculosis therapy.

Family History: The patient’s wife is also HIV+ due to transmission from the patient.

Social History: The patient denies any other sexual contacts since his diagnosis of HIV+.

Physical Exam:

  • General: Thin appearing patient in no acute distress
  • Visual Acuity, without correction: Right eye (OD)--light perception; Left eye (OS)--20/30
  • Extraocular Motility: Full, both eyes (OU)
  • Intra-ocular pressure: Normal, OU
  • Pupils: Grossly positive Relative Afferent Pupillary Defect (RAPD +), OD (not quantified at the time)
  • External and anterior segment examination:
    • OD -- Fine keratic precipitates, 1+ aqueous cells with flare, 1+ vitreous cells, clear crystalline lens
    • OS -- Normal exam
  • Dilated fundus exam (DFE):
    • OD -- A large subfoveal irregular patch of retinal necrosis appearing as a white, fluffy lesion with overlying retinal hemorrhages. A few scattered necrotic spots perifoveally (see Figure 1). Mild optic disc pallor is noted.
    • OS -- Normal macula, vessels, and periphery.
Figure 1: Cytomegalovirus (CMV) retinitis, OD. White, fluffy retinal necrosis with overlying retinal hemorrhages.

Course: In summary, this is a 36-year-old patient with AIDS, low CD4 count of 9 cells/mm3, recently placed on HAART therapy with progressive decrease in visual acuity in the right eye for the past 6 months. Associated ocular findings include vitritis and patchy area(s) of retinal necrosis with irregular borders and overlying retinal hemorrhages. The patient’s history, symptoms, and signs are consistent with CMV retinitis OD. With the very recent initiation of HAART, the patient has not had much time to build up an immune response. In addition to the role that appropriate HAART therapy will play in fighting CMV, the patient also underwent induction therapy with intravenous ganciclovir therapy. It is thought that an intravitreal ganciclovir injection may also be helpful in this patient given the location of the lesion.

Discussion: CMV retinitis (CMVR) remains one of the most common opportunistic ocular infections of patients with AIDS. It is a disease of profound immunosuppression that occurs primarily in patients with CD4 T-lymphocyte counts of 50 cells/mm3 or less. Although advances in antiretroviral therapy, such as highly active anti-retroviral therapy (HAART), have significantly reduced the incidence of this disease, active CMVR in patients with higher T-cell counts can occur through the deletion of CMV-specific CD4 memory cells or blunted T-cell response.

HAART is a combination of two nucleoside reverse transcriptase inhibitors and at least one protease inhibitor or nonnucleoside reverse transcriptase inhibitor. The combination has proven to significantly reduce the number of plasma HIV messenger RNA copies and to increase the number of CD4+ T lymphocytes. Since the use of HAART, the incidence of CMVR has declined by 50% to 80%. The strongest predictor for CMVR in the pre-HAART era was the absolute CD4 count, and the risk was directly correlated with lower CD4 counts.

Clinical features  

Symptoms of blurred vision, floaters, and flashes of light are highly variable and depend on the location and size of the lesion and on the immune status of the host.

The retinitis begins as small, white perivascular retinal infiltrates or dot-blot hemorrhages. The classic lesion is a hemorrhagic necrotizing retinitis that follows the retinal vasculature. When fluffy retinal infiltrates and necrosis are associated with scattered hemorrhages, this creates what has been called the "scrambled eggs and ketchup" appearance of severe CMVR. Clusters of small white dots representing retinal infiltration may precede the leading edge of the lesion as it advances. Large areas of necrosis can lead to retinal tears and detachment, ending in blindness within 4 to 6 months. Another form of CMVR is a white granular geographic lesion that clears centrally as it enlarges, leaving a quiet central area of retinal atrophy and mottled retinal pigment epithelium—this has also been described as a "brush-fire" pattern. Because the retinitis advances at a relatively slow rate, it is important to observe these patients carefully, ideally with serial photography, to detect progression. CMVR is categorized as a standard measure by the most posterior extent of the lesions into Zone 1, Zone 2, and Zone 3. The risk of retinal detachments may be up to 50% at 1 year after onset of active CMV retinitis.

Other uncommon forms of ocular CMV disease include isolated iritis and frosted branch angitis. Systemically, CMV can also cause esophagitis, colitis, pneumonitis, and sinusitis in immunocompromised patients.

Treatment

Before the advent of HAART, patients with CMVR could expect induction anti-CMV drug therapy followed by lifelong maintenance therapy to suppress retinitis and to prevent or postpone the otherwise inevitable loss of vision.

HAART has been shown to prolong the disease-free interval as much as threefold for patients with existing CMVR. Additionally, anti-CMV maintenance therapy has been safely withdrawn from patients with prolonged immune recovery resulting from HAART. Treatment regimen should be based on degree of ocular involvement, location of retinitis, current and expected immune status, underlying medical conditions, access to medical care, and lifestyle preferences. For antiretroviral-naïve patients about to begin HAART, the goal should be to stabilize the retinitis while awaiting recovery of the immune system.

In the United States, four medications are currently approved for treatment of CMV retinitis: ganciclovir, foscarnet, cidofovir, and valganciclovir. Treatment of CMV retinitis may prolong the survival of patients with AIDS.

Ganciclovir is a useful first-line therapy intravenously (IV). Oral ganciclovir has poor absorption and is used for maintenance or in conjunction other therapy. In 80-90% of patients, IV administration of ganciclovir or foscarnet twice daily (induction therapy) (5mg/kg) for 21 days initially halts retinal-cell necrosis and reduces viral recovery from urine and blood. After 2-3 weeks of induction therapy, patients are usually switched to maintenance therapy with daily intravenous infusions. Intravitreal ganciclovir allows high doses in the eye and decreases systemic complications by allowing lower systemic concentrations administered with intravitreal injections. Intraocular ganciclovir also helps to prevent progression when the macula or optic nerve is threatened. Intravitreal ganciclovir is given as 1mg in 0.1mL twice weekly in active CMV retinitis and once weekly for maintenance. Commercially available intraocular ganciclovir implants do seem to be useful for prolonged medication delivery to the intravitreal space, but these need replacing regularly. Foscarnet is useful in patients with either resistance to ganciclovir or systemic toxicity (see chart below for systemic toxicities of these antiviral drugs).

Once patients are on HAART, caution must be taken within the first 6 months of HAART initiation because of susceptibility to recurrent retinitis. After reconstitution of the immune system and a CD4 count greater than 100 cells/mm 3 for 6 consecutive months, anti CMV maintenance therapy can be withdrawn.

Recurrence and Resistance

Relapse of retinitis is a sign of worsening function of the immune system, inadequate intraocular drug levels, or development of resistance to the agent used. Reinduction with the same or a different anti-CMV agent can reestablish control, however the interval between relapses progressively shortens.

Diagnosis: Cytomegalovirus (CMV) Retinitis

EPIDEMIOLOGY

  • 40-100% of the general population are seropositive for CMV
    • Seroprevalence among lower socioeconomic groups, residents of developing countries, and homosexual men can exceed 90%
  • Activation of disease occurs more in the immunocompromised population
  • In healthy individuals the virus becomes dormant
  • The majority of CMV retinitis cases are found in patients with AIDS, and retinitis accounts for 75-85% of CMV-related disease
  • With the advent of HAART, there is a 75% reduction in the number of new cases of CMV retinitis

SIGNS

  • Traditionally, 3 patterns of active lesions have been described:
    • Hemorrhagic - with a predominance of retinal hemorrhage interspersed with retinal necrosis ("scrambled eggs with ketchup")
    • "Brush fire" - with progressively expanding yellow-white margin surrounding necrotic retina
    • Granular - with a central atrophic area surrounded by punctate white granular satellite lesions without retinal hemorrhage
  • Locations of lesions mapped using a zone grading system (Zone 1-3 posterior to anterior)
  • Full thickness retinal necrosis can lead to rhegmatogenous retinal detachments
  • Rarely, more anterior findings may include vitritis, anterior segment cell and flare, or fine KP
  • Rarely, papillitis (4%)

SYMPTOMS

  • Presenting symptoms depend on the location of the retinal lesions (small peripheral lesions may be asymptomatic)
    • Decreased visual acuity (76%)
    • Floaters (49%)
    • Photopsia (16%)
    • Eye pain (7%)
    • Scotomas (3%)

TREATMENT

  • Key to effective treatment is the improvement of the immune status of the patient, especially institution of multidrug anti-HIV therapy for the HIV+ patient (protease inhibitors plus nucleoside analogues)
  • Small peripheral lesions may be observed without other treatment
  • Anti-CMV therapy includes:
    • Ganciclovir (IV induction with 5mg/kg twice daily for 14-21 days followed by maintenance regimen) - can cause leukopenia
    • Intravitreal ganciclovir (1mg in 0.1ml twice weekly for active disease and once weekly for maintenance)
    • Sustained-release intraocular implant is also available
    • Foscarnet intravitreal injection weekly - can cause renal toxicity and electrolyte problems
    • Cidofovir is a newer agent, not recommended as first-line therapy - can cause uveitis, hypotony, or renal failure

Differential Diagnoses for CMV Retinitis:

  • Necrotizing herpetic retinopathy
    • Acute Retinal Necrosis (ARN)
    • Progressive Outer Retinal Necrosis (PORN)
  • Ocular syphilis- neuroretinitis, perineuritis, retrobulbar optic neuritis, papillitis, retinal vasculitis, necrotizing retinitis
  • Toxoplasmic Retinochoroiditis
  • HIV retinopathy/Cotton Wool Spots
  • Lymphoma

References

  1. Jacobson MA. Treatment of Cytomegalovirus Retinitis in Patients with the Acquired Immunodeficiency Syndrome. New England Journal of Medicine. 1997;337(2):105-115.
  2. Opremcak EM et al. "Ocular Involvement in AIDS: Management". Intraocular Inflammation and Uveitis. (Section 9: Basic and Clinical Science Course. 2006-2007). San Francisco: American Academy of Ophthalmology, 2006: 250-253. 
  3. Regillo C et al "Cytomegalovirus Infection" In: Retina and Vitreous (Section 12: Basic and Clinical Science Course 2006-2007). San Francisco: American Academy of Ophthalmology, 2006:192-193. 
  4. Scholz M, Doerr HW, Cinati J. Human Cytomegalovirus Retinitis: Pathogenicity, Immune Evasion and Persistence. Trends in Microbiology. 2003; 11(4): 171-178.
  5. See RF, Rao NA. Cytomegalovirus Retinitis in the Era of Combined Highly Active Antiretroviral Therapy. Opthalmol Clin N. Am. 2002; 529-536.
  6. Wiegand TW, Young LHY. Cytomegalovirus Retinitis. Int Ophthalmol Clin. 2006 Spring;46(2):91-110.

Suggested Citation Format: Muthialu A, Folk JC. Cytomegalovirus (CMV) Retinitis: 36-year-old Indian male with HIV and decreasing visual acuity. EyeRounds.org. December 18, 2006 ; Available from: http://webeye.ophth.uiowa.edu/eyeforum/cases/61-CMV-Cytomegalovirus-Retinitis-HIV.htm, 2006

last updated: 12-18-2006; minor update 5-16-2016
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