AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Cytomegalovirus (CMV) is a ubiquitous DNA virus that infects the majority of the adult population. In the immunocompetent host, infection is generally asymptomatic or limited to a mononucleosislike syndrome. Like many other herpesviruses, CMV remains latent in the host and may reactivate if host immunity is compromised.

In immunocompromised individuals, primary infection or reactivation of latent virus can lead to opportunistic infection of multiple organ systems. In the eye, CMV most commonly presents as a viral necrotizing retinitis with a characteristic ophthalmoscopic appearance. Untreated CMV retinitis inexorably progresses to visual loss and blindness.

Multiple antiviral agents, delivered locally, systemically, or in combination, are currently in use to delay or arrest the progress of the disease. In addition, highly active antiretroviral therapy (HAART) for HIV infection has revolutionized the treatment of CMV retinitis by allowing immune reconstitution in many individuals.

Pathophysiology

Clinical CMV infection can affect multiple organ systems, including the skin (eg, rashes, ulcers, pustules), lungs (eg, interstitial pneumonitis), gastrointestinal tract (eg, colitis, esophagitis), peripheral nerves (eg, radiculopathy and myelopathy), the brain (eg, meningoencephalitis), and the eye (eg, retinitis, optic neuritis).

Frequency

United States

CMV is ubiquitous, infecting 50-80% of the adult population. Clinically evident disease is found almost exclusively in immunosuppressed individuals. Prior to HAART, CMV occurred in 25-40% of all AIDS patients and was the most common opportunistic infection in AIDS patients with a CD4 count below 50 cells/mL. While HAART has decreased the incidence of CMV retinitis by 55-83%, the decline in AIDS-related mortality has led to an increase in the number of patients with CMV disease.

CMV retinitis remains a leading cause of visual loss in patients with AIDS and is increasing in organ transplant recipients as the number of those procedures performed each year increases.

International

The frequency of disease in other developed countries is equivalent. The incidence of CMV in developing countries mirrors the spread of the HIV virus and the availability of antiretroviral medications.

Mortality/Morbidity

CMV retinitis frequently results in considerable loss of visual acuity, and, without treatment, it almost universally leads to blindness. Severe visual loss primarily occurs from the direct spread of retinitis into the posterior pole, affecting central vision, or from retinal detachment (RD) secondary to multiple retinal breaks in the peripheral, necrotic retina.

Early and aggressive treatment with antiviral medication for both CMV and HIV, combined with improved surgical techniques for RD repair, has helped to improve the visual outcomes in these patients.

• Untreated CMV leads to progressive visual loss and eventual blindness.
• Retinal detachment occurs in up to 29%.
• Retinitis permanently destroys the retina; lesions change appearance with treatment but do not become smaller.
• If the CD4 count is less than 100 cells/mL, CMV retinitis will develop in 20-30% of patients over a year, although retinitis typically develops if the CD4 count is reduced below 50 cells/mL. Of these patients, 5-10% develop other systemic infections (eg, pneumonitis, colitis, esophagitis).
• With the advent of HAART and immune reconstitution, some patients suffer from a relatively new condition known as immune recovery uveitis (IRU). IRU occurs when the poor immune response of an immunocompromised individual is suddenly increased as the patients restored immune system recognizes and reacts to viral antigens in the retina. This reaction can lead to several complications, including uveitis, leading to hypotony, cataract, and glaucoma; epiretinal membrane (ERM); and cystoid macular edema (CME).

Sex

Although the incidence of CMV retinitis is the same among men and women, the prevalence is higher in men than in women because of the higher prevalence of AIDS in men. The prevalence of CMV retinitis in the heterosexual community has been steadily increasing.

Age

The age of most individuals developing CMV retinitis is 20-50 years.

CLINICAL

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History

Presenting symptoms vary depending on the location of retinal involvement. Posterior lesions present with diminished visual acuity. More peripheral lesions initially can be asymptomatic. Floaters often are noted if significant vitritis is present. The eye usually is white and quiet.

• Active CMV retinitis usually is found in conjunction with immunosuppression, whether from AIDS, leukemia, or use of chemotherapy. These points are important in evaluating the patient history. Rarely, CMV retinitis is the first presenting manifestation of AIDS.
• Natural history
• • CMV retinitis is a slowly progressive disease, requiring weeks to months to involve the entire retina. Vision is lost with involvement of the posterior pole (macula or optic nerve) or retinal detachment.
  • Initial reports described CMV retinitis as an end-stage disease, which indicated a life expectancy of 6 weeks. With the use of antiviral medications, the average survival after diagnosis ranged from 5.5-8 months. The advent of HAART has prolonged survival to years in some instances, and it has allowed discontinuation of medications targeted against CMV retinitis if clinical resolution occurs and the immune status recovers (reflected by a CD4 count of >100 cells/mL).
• After initiation of therapy, some advance of the leading edge of retinitis may be noted. This usually is not a treatment failure but rather the revealing of an area of subclinical infection that was not previously evident.

Physical

Patients with suspected CMV retinitis should have a complete ocular examination of both eyes. A careful examination should include the following:

• Carefully check and record the patient's best corrected visual acuity as a baseline. Check for visual field defects that could represent optic nerve damage, RD, or CNS disease from AIDS-related brain diseases (eg, encephalitis, stroke, CNS lymphoma). Ocular motility should be assessed as part of a cranial nerve examination. Pupils should be checked for a relative afferent pupillary defect indicating optic nerve involvement.
• External examination of the lids and adnexa should be performed for other AIDS associated findings, such as Kaposi sarcoma or lymphoma.
• A thorough slit lamp examination should show a white and quiet conjunctiva. A red hot eye in an immunocompromised patient should alert the clinician to another possible diagnosis. Fine, stellate keratitic precipitates (KP) characteristic of CMV may be seen on the corneal endothelium. Uveitis may be present in the anterior chamber and, if severe, may require treatment. The level of vitritis can be assessed in the anterior vitreous and may be important for monitoring response to treatment or the occurrence of IRU.
• A dilated fundus examination with indirect ophthalmoscopy is essential for assessing the location and extent of retinal involvement as well as for evaluating for retinal breaks or detachment. Retinal lesions have several characteristics, as follows:
• • Lesions that present posteriorly appear along retinal vessels as large areas of thick white infiltrate accompanied by retinal hemorrhage described as "pizza pie" or "cheese pizza" in appearance.
  • The peripheral type of lesion demonstrates a more granular appearance with satellite lesions and less hemorrhage. Behind the advancing border is necrotic retina with mottled pigmentation from hyperplasia of the retinal pigment epithelium (RPE).
  • Lesions usually begin peripherally and spread posteriorly in a contiguous fashion. However, multiple unconnected lesions are frequent, and involvement of the posterior pole with minimal peripheral disease is possible.
  • Retinitis follows the nerve fiber layer.
  • Retinitis produces wide areas of necrosis, scarring, and atrophy.
  • Even severe retinitis is usually accompanied by minimal vitritis in the immunocompromised patient. If HAART is instituted and immune reconstitution occurs, then IRU with severe anterior and posterior uveitis may occur.
  • Extensive vascular sheathing, often described as frosted branch angiitis, is a known but uncommon appearance.
  • Retinal vascular occlusion/nonperfusion can be seen on fluorescein angiogram.
• Peripheral holes and tears frequently occur in areas of necrosis.
• Rate of progression of untreated retinitis is 250-350 µm per week. Skip lesions can occur.
• Serial examinations may be necessary at early stages to distinguish CMV retinitis from HIV retinopathy with multiple cotton-wool spots.
• Optic neuritis can develop without apparent retinitis.
• Most patients with CMV retinitis will initially present with unilateral disease. Untreated, the immunocompromised patient has a 50% risk of developing disease in the contralateral eye within 6 months. This is reduced to 20% with antiviral treatment and further reduced with HAART.

Causes

Any immunosuppression due to disease or medication may allow clinical CMV infection to develop.

• Acquired immune deficiency syndrome
• Leukemia, lymphoma, and aplastic anemia
• Use of immunosuppressive chemotherapy
• Organ transplant recipients

DIFFERENTIALS

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WORKUP

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Lab Studies

• The CD4 count is a marker of immune dysfunction in patients infected with HIV. Patients may be asymptomatic with CMV retinitis; therefore, ophthalmic screening frequency is based on CD4 count.
• • CD4 >50 cells/mL - Little risk; screening examination every 6 months if CD4 50-100 cells/mL; screen yearly if CD4 >100 cells/mL
  • CD4 <50 cells/mL - Up to 35% incidence of CMV retinitis; median time to diagnosis of CMV retinitis is 13 months; screen every 3 months
  • 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.
• CMV DNA capture
• • A polymerase chain reaction (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. Patients with AIDS who test positive will have more than a 60% chance of developing CMV end-organ disease.
  • Responders to ganciclovir prophylaxis convert to PCR negative with treatment. Compared to nonresponders, survival is increased 2.4 times at 12 months.
• Viral load: Increased viral load can be a predictor of development of CMV end-organ disease.
• HIV test
• Complete blood count (CBC) with differential is important in evaluation for causes of immunosuppression and in assessment for side effects of ganciclovir use.
• Blood urea nitrogen (BUN) and creatinine baseline assessment and serial measurements are used to evaluate for side effects of foscarnet or cidofovir use.

Imaging Studies

• Ultrasound is used for evaluation of retinal detachment, particularly if vitritis obscures adequate fundus visualization.
• Fluorescein angiogram - Assessment for areas of ischemia
• Chest x-ray - Assessment for concurrent Pneumocystis pneumonia

Other Tests

• 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 vitritis

Procedures

• Ganciclovir implant
• • This intravitreal implant releases ganciclovir at a steady state for up to 8 months.
  • The implant provides treatment of CMV retinitis in 1 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 include vitreous hemorrhage, retinal detachment, hypotony, and endophthalmitis.
  • After 8 months, if still required, a second implant may be placed. The first implant can be left in place or removed.
• Fomivirsen implant: Fomivirsen is not used as a primary therapy but is approved for cases not responding to other therapies.
• Vitreoretinal surgery
• • Retinal detachment repair is required in 5-50% of patients with CMV retinitis (depending on the trial).
  • Multiple small holes in several areas of the retina are often responsible for the retinal detachment. These occur at the junction of healthy and necrotic retina.
  • Primary repair with vitrectomy, air-fluid exchange, endolaser, and silicone oil tamponade has improved surgical outcome.
• Laser photocoagulation: Small peripheral retinal detachments can be repaired with laser photocoagulation.
• Intravitreal injections of ganciclovir, foscarnet, or cidofovir
• • These injections offer high levels of intraocular drug for short periods of time.
  • They are useful in acute vision-threatening cases when rapid drug delivery is needed prior to instituting longer term therapy.
  • Risks of intravitreal injection include hemorrhage, RD, and endophthalmitis.

Histologic Findings

The healthy retina is sharply demarcated from infected retinal cells, which show edema, pathognomonic cytomegalic inclusions, and few surrounding inflammatory cells (consistent with a compromised immune response). 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.

Staging

CMV retinitis is described by the stage and zone of involvement.

• Stage
• • Active retinitis - 3 general patterns
    1. Hemorrhagic - Large areas of retinal hemorrhage on a background of whitened, necrotic retina
    2. Brush fire - Yellow-white margin of slowly advancing retinitis at the border of atrophic retina
    3. 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.
• Zone of involvement
• • 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 2 and 3 are the most common sites of initial retinal involvement.
• Progression - Spread of retinitis usually is along the leading edge, although skip lesions can occur. Progression occurs at a rate of 250-350 µm per week if untreated.

TREATMENT

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Medical Care

An internist or infectious disease specialist coordinates medical care. Ophthalmic assessment is required on a regular basis, with frequency dependent on existence of CMV retinitis and on CD4 count. The immunosuppressed individual requires evaluation for other opportunistic infections and surveillance for side effects of prescribed medications.

• Highly active antiretroviral therapy
• • This treatment regimen has altered the long-term management of CMV retinitis. Because the antiviral medications used to treat CMV are virustatic, it was necessary for patients to continue their use for the rest of their lives. The advent of HAART with consequent recovery of immune function allows individuals to discontinue their CMV therapy if the process has resolved adequately with initial antiviral treatment. As long as the CD4 count remains elevated, there is little risk of disease recurrence.
  • Intravenous or oral therapy can be discontinued, or a scheduled implant replacement can be delayed indefinitely.
  • Careful monitoring of both immune status and ophthalmic findings are necessary to prevent retinal damage from an asymptomatic recurrence.

Surgical Care

Individuals with CMV retinitis commonly require surgical intervention, whether for repair of a retinal detachment or for intravitreal instillation of ganciclovir by injection or implantation.

• Retinal detachment due to CMV retinitis
• • This condition occurs in 5-29% of eyes in various case series. High incidence of bilaterality exists.
  • Repair is most successful with vitrectomy, endolaser, scleral buckle, and silicone oil endotamponade.
  • A total reattachment rate of 76% exists; macular attachment occurs in 90%. Mean postoperative visual acuity is 6/18.
  • Prophylactic laser for the other eye with CMV did not prevent retinal detachment.
• Intravitreal ganciclovir implant
• • 1 µg/h sustained release with life span of 8 months - Study of immediate versus deferred therapy
    • Deferred - 15 days to progression
    • Immediate - 226 days to progression, only 5 of 14 progressed
    • Retinal detachment rate 11% (13-26% in IV treatment group)
    • Within 6 months, 50% develop CMV retinitis in fellow eye.
  • Pros
    • Less systemic toxicity
    • Better effect versus CMV in implanted eye
    • Can use AZT concomitantly
    • No indwelling catheter
    • Implant is useful if intolerant of systemic ganciclovir or if progression continues despite intravenous treatment.
  • Cons
    • Sixty-seven percent developed CMV in the fellow eye versus 0-15% rate in intravenous treatment group.
    • No systemic effect for CMV organ disease
• Intravitreal ganciclovir injection
  • Delayed progression of disease
  • Topical anesthesia
  • Short half-life - Injection is required twice per week.
  • Increased risk of endophthalmitis, retinal detachment, and vitreous hemorrhage

Consultations

Infectious disease specialist

• Evaluation of general medical condition - Assessment for other end-organ sequelae of CMV infection (pneumonitis, gastroenteritis); evaluation for other opportunistic infections
• Evaluation for criteria sufficient to meet the diagnosis of AIDS
• Assessment of confirmatory lab tests
• Institution of systemic therapy (for CMV retinitis and for AIDS)
• General internist, hematologist, and/or oncologist referral if CMV retinitis is associated with immunosuppression for non–HIV-related reasons

MEDICATION

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A number of different antiviral medications are available for the treatment of CMV retinitis. Routes of delivery and adverse effect profiles vary significantly, so treatment programs are tailored to individual patients and their response to treatment. Current therapies use an induction dose to halt active disease followed by a lower maintenance dose that must be continued indefinitely unless immune recovery occurs. In recent years, several developments have drastically improved the quality of life for patients with CMV retinitis.

HAART therapy, as previously mentioned, has allowed immune recovery that, in turn, allows discontinuation of anti-CMV medication. This often obviates the need for multiple implant procedures or the long-term dose related adverse effects of anti-CMV medications.

Valganciclovir, a prodrug of ganciclovir that possesses excellent oral bioavailability and antiviral activity, has been shown to be effective in both the induction phase and the maintenance phase of CMV retinitis treatment. It is available in convenient once daily or twice daily dosing. Valganciclovir has largely replaced other treatments since it avoids the need for frequent IV infusions and long-term IV access ports.

Neupogen (granulocyte colony stimulating factor) can be used in conjunction with valganciclovir in patients experiencing neutropenia. This has helped to lessen one of the most common treatment terminating adverse effects of a very convenient and useful medication.

Foscarnet and cidofovir are effective alternatives in the treatment of CMV retinitis. However, because of their adverse effect profiles and the lack of an orally bioavailable form, they have become second-line treatments. Intravitreal implants are used less frequently but are still needed in patients who have reactivation of retinitis despite systemic treatment or in those who cannot tolerate systemic treatment.

At this time, primary treatment generally consists of induction with either valganciclovir (900 mg PO bid for 2-3 wk) or ganciclovir (5 mg/kg IV bid for 2-3 wk) followed by maintenance with valganciclovir (900 mg PO qd) until the CD4 count is above 100 cells/mL.

Finally, IRU has added a new postscript to the treatment of CMV retinitis. Treatment options are varied, and close follow-up by an experienced ophthalmologist is needed to guard against vision-threatening complications.

Drug Category: Antivirals

Direct action is to inhibit the DNA polymerase of CMV, preventing viral replication.

Drug Category: Antisense medications

Inhibit viral replication by interfering with the regulation of viral gene expression.

Drug Category: Colony stimulating factors

Stimulation of stem cells to produce differentiation, proliferation, and increased functional activity of neutrophils, monocytes, eosinophils, and macrophages.

FOLLOW-UP

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Further Inpatient Care

• Placement of long-term intravenous access for medication delivery

Further Outpatient Care

• Ophthalmic follow-up care depends on stage of disease (ie, active vs atrophic retinitis), and CD4 count.

In/Out Patient Meds

• Medications described in the prior section are used on an outpatient basis after initiation in-hospital. See Medication.

Deterrence/Prevention

• CMV retinitis occurs in immunocompromised individuals. Treatment of underlying disorders can prevent the development of retinitis. Prevention practices to reduce the transmission of HIV would concomitantly reduce the incidence of CMV retinitis.

Complications

• Untreated retinitis will progress to blindness, from retinal necrosis, optic nerve involvement, or retinal detachment.
• CMV retinitis can relapse despite ongoing treatment. Drug levels need to be assessed. Reinduction, a change in medication, combination drug therapy, or an ocular implant are alternatives for management.
• Drug resistance
• • Resistance to ganciclovir, foscarnet, or cidofovir can occur since these drugs are administered long term. The chance of this occurring increases with time. In a study of 76 newly diagnosed patients treated for CMV retinitis with intravenous ganciclovir, resistant isolates were obtained from blood or urine samples in 5.4% of patients at 3 months, 11.4% of patients at 6 months, and 27.5% of patients at 9 months.
  • Management of drug resistance leading to reactivation of CMV retinitis or occurrence in the other eye involves combination therapy. Ganciclovir and foscarnet are synergistic and may be combined in intravenous or intravitreal therapy.
• Retinal detachment is a potential complication of CMV retinitis, with a 1-year risk of 5-50%. Repair requires laser photocoagulation or vitrectomy with silicone oil tamponade.

Prognosis

• Untreated retinitis will progress to blindness, from retinal necrosis, optic nerve involvement, or retinal detachment. Of treated patients, 80-95% will respond, with resolution of intraretinal hemorrhages and white infiltrates. If treatment is discontinued and the individual is still immunocompromised (ie, CD4 <50), then the retinitis will recur in 100%. Prior to the advent of HAART, 50% of patients would experience recurrence within 6 months despite maintenance therapy. This rate is reduced if the CD4 count is elevated.
• If a retinal detachment occurs, repair with vitrectomy and silicone oil tamponade will result in at least a 70% reattachment rate.

Patient Education

• Visual symptoms that require a repeat examination are vision loss, development of a visual field defect, new floaters, and photophobia.
• Provide education on the following:
• • Medication use and possible side effects
  • Education on care of long-term intravenous access site
  • Education on HIV transmission

MISCELLANEOUS

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Medical/Legal Pitfalls

• Ophthalmic examination: Because CMV retinitis is a clinical diagnosis, evaluation by a retina specialist is recommended to distinguish this disease from other signs of HIV retinopathy such as nerve fiber layer infarcts.
• HIV testing: If CMV retinitis is found in an individual who is not known to be HIV positive, then this test should be performed after an informed consent is obtained.
• Follow-up examinations: A number of factors will determine the frequency of follow-up examinations, including the stage of CMV retinitis and the CD4 count. It is important to adhere to this schedule to avoid missing progression or recurrence of disease.
• Cessation of therapy: If the CD4 count rises dramatically and CMV retinitis therapy is stopped, it is important to maintain a frequent examination schedule and counsel the individual appropriately regarding the chance of recurrence if the CD4 count starts to decrease once again.

Special Concerns

• Most issues of special concern relate to the underlying disorder. Infection with HIV can be transmitted to offspring. The systemic medications used for CMV retinitis should be avoided during pregnancy. The ganciclovir implant would be a preferable route of medication administration if the disease manifestation is restricted to the eye.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  White granular retinitis with intraretinal hemorrhage.
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Media file 2:  Early necrosis at periphery.
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Media file 3:  Attenuation of vessels in area affected by retinitis.
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Media file 4:  Retinitis typically starts in the midperiphery and can progress in a "brush fire" pattern.
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Media file 5:  Progression of retinitis toward the optic nerve.
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Media file 6:  Frosted branch angiitis.
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Media file 7:  Inactive cytomegalovirus retinitis.
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Media file 8:  Cytomegalovirus papillitis.
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Media file 9:  Intranuclear inclusions (arrows) found in cytomegalovirus retinitis. Referred to as owl's eye because of the dark intranuclear inclusion surrounded by a clear halo.
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Media file 10:  Retinal detachment due to peripheral tear in area of necrosis.
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REFERENCES

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