CMV Retinitis

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Article initiated by:

Brad Ballard, MD

All contributors:

Lucas Kim, Brad Ballard, MD, Vinay A. Shah M.D., Priya Sharma, Koushik Tripathy, MD (AIIMS), Joobin Khadamy, MD, FEBO, Daniel F. Kiernan, MD, FACS, Alan Palestine, MD, Jessica Shantha, MD, Marissa Larochelle, MD, Jonathan C. Tsui, MD, Neelakshi Bhagat, MD, FACS, Grant M. Comer M.D.

Assigned editor:

Marissa Larochelle, MD, Neelakshi Bhagat, MD, FACS

Review:

Assigned status Up to Date

 by Neelakshi Bhagat, MD, FACS on December 17, 2024.

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Contributing Editors:	add

CMV Retinitis

ICD-10

[1]25.9

MedlinePlus

000665

MeSH

D017726

Disease Entity

Cytomegalovirus (CMV) Retinitis is an acquired immunodeficiency syndrome (AIDS)-related opportunistic infection that can lead to blindness. CMV retinitis occurred with higher frequency prior to the advent of antiretroviral therapy, but has since been decreasing in well-developed countries, although still remains a prevalent condition in developing countries. It is a viral retinitis that can also be seen in patients who are immunosuppressed for other reasons aside from AIDS.

Disease

Cytomegalovirus (CMV) retinitis is an important ocular AIDS associated illness. It is a full thickness retinal infection that can lead to necrosis and retinal breaks and detachments.

Etiology

CMV retinitis is caused by cytomegalovirus, a double stranded DNA virus in the herpes viridae family. It is often associated with HIV/AIDS and was extremely rare prior to the AIDS epidemic. It is also associated with severe immunosuppression from chemotherapy and autoimmune conditions requiring immunomodulators. With the advent of antiretroviral therapies, the incidence of CMV retinitis has decreased by 90% in AIDS population.

Risk Factors

Risk factors include HIV, CD4 count less than 50, or severe systemic immunosuppression. Recent reports have also demonstrated that local ocular immunosuppression can be a risk factor for CMV Retinitis. There have also been case reports of CMV retinitis in the absence of immunosuppression.

General Pathology

Infected cells show pathognomonic cytomegalic inclusions with large eosinophilic intracellular bodies. Electron microscopy can show the typical virus particles within infected cells. Histopathology shows full-thickness retinal necrosis that is eventually replaced by atrophic scar tissue, coagulative vasculitis, and choroiditis.

Pathophysiology

CMV reaches the retina hematogenously and infects the vascular endothelium which then spreads to the retinal cells. Impaired CD4 cell function permits uncontrolled CMV replication.

Primary prevention

CMV retinitis has dropped in incidence and prevalence since the advent of HAART. The incidence has declined 55-99% and the odds of progression has reduced by 50% with HAART. Survival has improved from 0.65 years to greater than 1 year.

Patients with CD4 counts less than 50 cells/mm³ should be seen at least every 3 months to screen for CMV retinitis, as active retinitis is typically asymptomatic.

Diagnosis

Diagnosis is largely clinical based upon the classic retinal findings and an immunosuppressive condition such as HIV; however, polymerase chain reaction (PCR) analysis of the vitreous or aqueous can further support the diagnosis. Differentiation from acute retinal necrosis/ARN is vital as treatment is different.

Comparison of cytomegaloviral retinitis and acute retinal necrosis

History

Patients present with decreased visual acuity and floaters. Some may present with flashing lights (photopsias) or blind spots (scotomata). One study showed 54% were asymptomatic.

Physical examination

Physical exam shows yellow white retinal lesions that often start in the periphery and follow the vasculature centripetally. However, it can start in the posterior segment. The classic findings are retinal hemorrhages with a whitish, granular appearance to the retina. Each lesion has the most activity in the borders. Vitreous signs of inflammation may be minimal as most patients are severely immunosuppressed. Very early CMV may resemble cotton wool spots, but with lesions larger than 750 µm, CMV must be considered. Three typical patterns have been described: a granular pattern, a fulminant/hemorrhagic appearance, or "frosted branch" angiitis.

Rhegmatogenous retinal detachment occurs in approximately one-third of patients when greater than 25% of the retina is involved. The presence of concurrent keratic precipitates in a stellate fashion can also suggest CMV uveitis.

Signs

CMV retinitis can present as: 1. Fulminant - hemorrhagic necrosis on white/yellow cloudy retinal lesions. They may be centered around vasculature. 2. Granular - Found more often in the retinal periphery with little to no necrosis and hemorrhage. 3. Perivascular - The classic "frosted branch" angiitis showing white lesions surrounding the retinal vessels.

Symptoms

Most patients are asymptomatic, but may have floaters, flashes (photopsias), blind spots (scotomata). Pain and photophobia are uncommon.

Clinical diagnosis

The clinical diagnosis is made on history and classic retinal findings.

Active(a) and healed (b) CMV retinitis From Tripathy K, Mittal K, Venkatesh P, Bakhshi S, Chawla R. Treatment of unilateral zone I cytomegalovirus retinitis in acute lymphoblastic leukemia with oral valganciclovir and intravitreal ganciclovir. Oman J Ophthalmol [serial online] 2017 [cited 2018 Dec 2];10:250-2. Available from: http://www.ojoonline.org/text.asp?2017/10/3/250/215997

Retinal Zones of CMV retinitis

• Zone 1- 1 disc diameter surrounding the disc and 2 disc diameter around the fovea: immediately sight threatening
• Zone 2- Anterior to zone 1 and posterior to vortex vein ampullae
• Zone 3- Peripheral to Zone 2

Diagnostic procedures

Diagnostic procedures can include aqueous or vitreous tap to test for CMV and other herpes viruses.

Laboratory test

In cases of unknown retinitis, aqueous or vitreous tap and PCR analysis for CMV can be done. Serologic antibodies for CMV have not been shown to be helpful in diagnosis CMV retinitis-- a positive CMV antibody titer reflects prior exposure but does not diagnose the retinitis specifically, and a negative CMV antibody titer does not completely eliminate the chance of CMV retinitis, as patients who are immunosuppressed may not mount appropriate titers. The pooled incidence of blood CMV load <400 copies/mL has been reported to be 62% , ranging from 13% to 91%.

Differential diagnosis

Early CMV can resemble cotton wool spots. It may be confused with HIV retinopathy, which is actually more common the CMV retinitis. HIV retinopathy occurs in 50-70% of patients and is characterized by intraretinal hemorrhages, cotton wool spots, and microaneurysms. For small lesions that are hard to differentiate from cotton wool spots, serial exams should be performed, which will show enlargement of the CMV lesions. Immunosuppression should be treated like a spectrum; some patients are more immunosuppressed than other individuals. For cases of minor immunosuppression, CMV retinitis may present as acute retinal necrosis (ARN) syndrome but follows a chronic course similar to CMV retinitis, which may cause misdiagnosis.

Syphilitic hemorrhagic necrotizing retinitis can mimick CMV retinitis; all patients should undergo treponemal testing.

A patient with CMV retinitis (A) who was treated with oral Letermovir and corticosteroid. After one month, there is no new active retinitis, but chorioretinal atrophy is evident (B). (Courtesy of J. Khadamy)

Management

Management is largely medically based with intravenous (IV), oral, and intravitreal anti-viral medications. Topical corticosteroids can be used to treat anterior chamber inflammation. Management also hinges on HAART in HIV positive patients.

Patients should be started on high dose induction therapy, which is followed by continuous maintenance therapy until CD4 counts increase, HAART is therapeutic, and CMV retinitis shows no progression.

General treatment

There are at least 8 options for therapy of CMV retinitis.

1. Oral valganciclovir
2. Intravenous ganciclovir
3. Intravenous foscarnet
4. Intravenous Cidofovir
5. Intraocular ganciclovir device
6. Intravitreal ganciclovir
7. Oral leflunomide
8. Oral letermovir
    

Major Drug Toxicities

Valganciclovir/Ganciclovir	Myelosuppression  -  Concomitant use of Granulocyte-Monocyte Colony Stimulating Factor (GM-CSF) can help reduce this risk. Thrombocytopenia occurs in 5-10% of patients. Potentially embryotoxic (discontinue nursing).
Foscarnet	Renal dysfunction with electrolyte abnormalities. Increased risk of seizures. Anemia.
Cidofovir	As high as 50% of patients taking cidofovir may experience ocular hypotony and anterior uveitis. Renal dysfunction.

Medical therapy

First line therapy is generally oral valganciclovir, which is a pro-drug of ganciclovir. The induction dose is 900 mg twice daily for 21 days followed by maintenance of 900 mg daily. Valganciclovir has increased bioavailability compared to oral ganciclovir and does not require IV administration, making it a favorite for patients and doctors alike. However, the cost of therapy is high and patient compliance can be a problem especially in developing countries. Should be avoided if hemoglobin is <8gm%,  absolute neutrophil count is less than 500 cells/µL, and the platelet count is less than 25,000/µL.

IV ganciclovir is given at 5 mg/kg twice daily for two to three weeks as induction therapy then followed by daily 5 mg/kg infusions. This can be quite cumbersome to patients.

Foscarnet is given at 90 mg/kg twice daily for two weeks followed by maintenance therapy of 90-120 mg/kg daily through IV infusion.

Cidofovir has a longer half life and can be administered weekly during induction followed by bi-weekly maintenance therapy. The dose is 5 mg/kg weekly during induction, and 5 mg/kg every other week during maintenance. Cidofovir can cause severe nephrotoxicity, so is typically given with saline hydration and high-dose probenecid therapy.

Oral ganciclovir can be considered for maintenance therapy but regression and involvement of fellow eye is more frequent.

Intravitreal ganciclovir, foscarnet, or cidofovir can be considered for short-term management.

Other options for therapy are oral leflunomide and oral letermovir. These therapies are using much less often but have been effective in patients that are experiencing side effects of other medications. Maribavir, a director UL97 inhibitor, has also demonstrated efficacy in treating resistant strands which may be a forthcoming viable systemic treatment option.

Drug	Induction Dose	Maintenance Dose	Major Toxicity
Valganciclovir	900 mg PO BID for 21 days	900 mg daily	Myelosuppression
Ganciclovir	5 mg/kg IV BID for 14 to 21 days	5 mg/kg IV daily	Myelosuppression
Foscarnet	90 mg/kg IV BID for 14 days	90-120 mg/kg IV daily	Renal dysfunction, electrolyte abnormalities, seizures
Cidofovir	5 mg/kg IV weekly for 14 days	5 mg/kg IV every other week	Hypotony, anterior uveitis, nephrotoxicity (give saline hydration and probenecid concurrently)

In patients with immediately sight-threatening lesions (lesions close to the macula or optic nerve head), intravitreal injection of ganciclovir (2mg in 0.1 mL injection) or foscarnet (2.4 mg in 0.1 mL injection) or fomvirsen 330 micrograms, or cidofovir 20micrograms with concurrent systemic therapy can be done.

CMV retinitis can be become drug resistant the longer the duration of treatment lasts. Resistance can be caused by immunosuppression after organ or hematopoietic stem cell transplants, where specifically ganciclovir and valganciclovir resistance have been reported.

Medical follow up

Depending on the medication used, complete blood counts, chemistries, and intraocular pressure checks will be needed. Dilated eye exams should be performed at least weekly initially, then 2 weeks after induction therapy, followed by monthly thereafter while the patient is on anti-CMV treatment. Fundus photographs can be helpful to detect early relapse.

Patients should be followed in an appropriate HIV clinic with CD4 counts and viral load studies.

Surgery

The only initial surgical management involves intravitreal placement of intraocular ganciclovir devices. They have a relatively low risk profile and can last 6-8 months. They afford no protection to the fellow eye, however. In addition these implants are not readily available.

Surgery can also be performed for complications of retinitis that include rhegmatogenous retinal detachments.

Surgical follow up

Look for complications of silicone oil especially cataract and glaucoma. Many patients are one-eyed and silicone oil may need to be left for long duration.

Complications

The most serious complication of therapy for CMV retinitis, besides those listed above due to medications is immune recovery uveitis (IRU). As the CD4 counts rise with HAART, it is presumed that reactions to CMV antigens cause anterior or intermediate uveitis. Cystoid macular edema and epiretinal membranes are also potential complications of IRU. Posterior capsular cataracts, proliferative vitreoretinopathy, and optic nerve neovascularization are possible complications as well. HAART therapy can also unmask CMV retinitis in a patient without prior CMV disease (unmasking CMV-immune recovery retinitis (IRR)) or can cause worsening of known CMV retinitis (paradoxical CMV-IRR).

CMV retinitis that involves > 25% of the retina can lead to rhegmatogenous retinal detachments from breaks that occur near thin, necrotic retina. Peripheral anterior retinal lesions are associated with increased risk of retinal detachment, due to the anterior adherence of the vitreous base.

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 diagnosis of CMV retinitis.

Prognosis for patients with or without HIV infection, corticosteroid immunosuppression, and other risk factors all have similar visual outcomes. The strongest factor associated with poorer visual outcomes for all patients is retinal detachment. 

Additional Resources

• Turbert D, Janigian RH. Cytomegalovirus Retinitis. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/cytomegalovirus-retinitis-list. Accessed March 07, 2019.

References

16. Vertes D, Snyers B, DePotter. Cytomegalovirus retinitis after low-dose intravitreous triamcinolone acetone in an immunocompetent patient: a warning fotr the widespread use of intravitreal corticosteroids. Int Ophthalmol 2010; 30 (5): 595-7.
17. Schneider EW, Elner SG, van Kuijk FJ, et al. Chronic Retinal Necrosis: Cytomegalovirus necrotizing retinitis associated with panretinal vasculopathy in non-HIV patients. Retina 2013; 33 (9): 1791-9.
18. Print: Wills Eye Manual. Sixth Edition. Section 12.9: Cytomegalovirus Retinitis. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
19. Basic and Clinical Science Course. Section 9: Intraocular Inflammation and Uveitis.  Ocular Involvement in AIDS. 2010: AAO.
20. Basic and Clinical Science Course. Section 12: Retina and Vitreous. 2010: AAO.
21. Goldberg DE, et al. HIV-Associated Retinopathy in the HAART Era. Retina: The Journal of Retinal and Vitreous Diseases. 2005: 25;5. 634-49.
22. Jacobson MA. Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis. In: UpToDate, Bartlett JG and Mitty J (Ed), UpToDate, Waltham, MA. (Accessed on May 16, 2015).
23. Jacobson MA. Treatment of AIDS-related cytomegalovirus retinitis. In: UpToDate, Bartlett JG and Mitty J (Ed), UpToDate, Waltham, MA. (Accessed on May 16, 2015).