Cytomegalovirus (CMV) retinitis primarily affects immunocompromised individuals. It causes full-thickness retinal necrosis and viral inclusion bodies are seen in infected cells. Patients present with painless vision loss or may be asymptomatic. It is diagnosed based on characteristic fundal appearances, often demonstrating white, wedge-shaped areas of necrosis with associated retinal haemorrhages. Treatment options include intravenous, oral or intravitreal antiviral therapy. Important complications are retinal detachment and immune recovery uveitis.
Aetiology & Epidemiology
Cytomegalovirus (CMV) is an enveloped double-stranded DNA virus that is a member of the human herpes virus family (human herpes virus 5) (1). Its spread is via saliva, breast milk, sexual contact and organ transplantation (2). An estimated 50-60% of the UK population is seropositive for CMV (3).
In primary CMV infection, the viral genome is incorporated into the host cell nucleus, transcription of which results in the production of viral particles. In the bone marrow, when CD34+ myeloid precursors are infected, DNA-binding proteins inhibit the transcription of viral particles and therefore the virus is not detected by the immune system; this is the basis of latent infection. These progenitors differentiate into monocytes and tissue macrophages, that may be activated as part of the response to intercurrent infection; this results in transient transcription of CMV viral particles. This process is regulated in immunocompetent individuals, preventing the development of serious CMV infection. In immunocompromised individuals, the consequences of reactivation can be severe (2).
Of the ocular manifestations of CMV infection, CMV retinitis is the most common, with anterior uveitis and corneal endotheliitis among the other observed complications.
CMV retinitis occurs most commonly in immunocompromised individuals, as a result of decreased T-cell function. Risk factors for infection include AIDS secondary to HIV, organ transplantation, and immunosuppressive drug therapy, including intravitreal steroids (4). CD4+ count of <50 cells/microlitre has been demonstrated to be the single most important risk factor (5).
Introduction of combination antiretroviral therapy has led to a reduction in incidence and visual morbidity of HIV-related CMV retinitis (4).
CMV reaches the eye via haematogenous spread (6).
Full-thickness retinal necrosis, including of the retinal pigment epithelium (RPE), is seen on microscopy. Inflammation of the affected retina may be limited, but necrosis is typically widespread across infected cells. Infected cells are enlarged and viral inclusion bodies are seen in their nucleus and cytoplasm. CMV infection can persist in the RPE following treatment, and reactivation characteristically occurs at the edge of scars from previous active retinitis (7). Areas of necrosis are eventually replaced by atrophic scar tissue, which is transparent and underlying retinal pigmental epithelium stippling is seen (8).
There are 3 characteristic clinical patterns of CMV retinitis on fundoscopy: fulminant, indolent and frosted-angiitis types.
Fulminant type (or ‘bushfire’ type): white, well-demarcated wedge-shaped segments of necrosis associated with haemorrhages, commonly termed ‘pizza pie’ appearance, which typically extends along the vascular arcades
Indolent type (or ‘granular’ type): small, white, granular dot-shaped lesions with few retinal haemorrhages, shows slow progression and begins within the peripheral retina.
Frosted-angiitis type: retinal vasculitis with associated perivascular exudates (9).
The typical presentation is of painless visual loss with or without floaters, although active retinitis may be asymptomatic (9). Visual impairment is a result of retinal necrosis involving the macula or optic nerve (10, 11). Blindness can occur secondary to retinal detachment, cataract, or formation of epiretinal membrane (12).
Diagnosis of CMV retinitis is made on the basis of characteristic fundal appearance, in an individual deemed clinically susceptible (4). Differential diagnoses include necrotising retinitis due to herpes simplex or varicella zoster viruses, toxoplasmosis gondii or syphilis (9). If there is doubt about the diagnosis, polymerase chain reaction (PCR) testing can be used on samples of aqueous to detect viral DNA (13). HIV serology should also be performed if HIV status is unknown (9).
In the future, fundus photography could be used as a screening modality for at-risk individuals (14). It is also sometimes recommended in the monitoring of response to treatment (9).
Fundus autofluorescence has been shown to reveal characteristic appearances in CMV retinitis; areas of active retinitis and haemorrhage may exhibit hypoautofluorescence, and the advancing peripheral edge of retinitis lesions may show hyperautofluorescence (15). Fluorescein angiography may show leakage, nonperfusion and blocking defects due to haemorrhages (16). However, the clinical value of fundus autofluorescence and angiography is yet to be demonstrated and does not commonly form a routine part of the work up for this condition (4).
Effective antiretroviral therapy against CMV retinitis was first developed in the 1980s. Intravenous ganciclovir was the first agent developed (4). The currently available antiretroviral intravenous options include ganciclovir, foscarnet and cidofovir. Ganciclovir and foscarnet are also effective and available as intravitreal therapy. Oral valganciclovir is another form of systemic therapy that is used, which has the advantage of allowing outpatient treatment. An important side effect of this treatment is bone marrow suppression, thus monitoring is warranted (9). Studies have demonstrated that treatment with intra-ocular ganciclovir implant is superior to intravenous ganciclovir therapy, however comes with the disadvantage of not simultaneously treating disease in the contralateral eye (17). Oral leflunomide and oral letermovir are further therapeutic options available, although are less commonly used and usually reserved for those experiencing side effects from the other more conventional treatments (18, 19). If antiretroviral treatment is indicated, it should be initiated two weeks after CMV treatment, to reduce the risk of immune recovery uveitis – see below (9).
Retinal detachment is a significant cause of vision loss in CMV retinitis (4). Typically this is rhegmatogenous detachment secondary to multiple small retinal breaks in areas of necrosis. The risk is increased with lesion size and bilateral disease (20). Treatment usually involves pars plana vitrectomy and silicone oil or gas tamponade (16). Twenty percent of cases of rhegmatogenous retinal detachment due to CMV retinitis go on to develop proliferative vitreoretinopathy (PVR), which has a poor prognosis (7).
A second significant complication is immune recovery uveitis. This can occur when anti-retroviral therapy is initiated in patients who are HIV-positive, particularly in individuals with a T cell count below 50 cells/microlitre. Re-activation of T cell function results in a paradoxical increase in intraocular inflammatory immune activity (21). This manifests as anterior segment and vitreous inflammation, and may include uveitis, cystoid macular oedema and the formation of epiretinal membranes. The phenomenon is seen in up to 40% of HIV-positive individuals with CMV retinitis. It is treated with steroids (2).
- Jabs DA, Ahuja A, Van Natta ML, Lyon AT, Yeh S, Danis R. Long-term outcomes of cytomegalovirus retinitis in the era of modern antiretroviral therapy. Ophthalmology. 2015;122(7):1452–63.
- Carmichael A. Cytomegalovirus and the eye. Eye. 2012 Feb;26(2):237-40.
- Cytomegalovirus Steering Group. SABTO report of the Cytomegalovirus Steering Group [Internet]. GOV.UK. Department of Health and Social Care; 2012 [cited 2023Feb3]. Available from: https://www.gov.uk/government/publications/sabto-report-of-the-cytomegalovirus-steering-group
- Port AD, Orlin A, Kiss S, Patel S, D’Amico DJ, Gupta MP. Cytomegalovirus retinitis: a review. Journal of Ocular Pharmacology and Therapeutics. 2017 May 1;33(4):224-34.
- Sugar EA, Jabs DA, Ahuja A, Thorne JE, Danis RP, Meinert CL, Studies of the Ocular Complications of AIDS Research Group. Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. American journal of ophthalmology. 2012 Jun 1;153(6):1016-24.
- Holland GN. AIDS and ophthalmology: the first quarter century. American Journal of Ophthalmology. 2008 Mar 1;145(3):397-408.
- Cytomegalovirus retinitis: Pathophysiology – American Academy of … [Internet]. Focal Points Snippet Detail. American Academy of Ophthalmology; [cited 2023Feb3]. Available from: https://www.aao.org/focalpointssnippetdetail.aspx?id=bc891841-b847-4210-a66b-2bb28d1ef1bf
- Whitcup SM. Acquired Immunodeficiency Syndrome. Whitcup and Nussenblatt’s Uveitis: Fundamentals and Clinical Practice. 2021 Mar 31:145.
- Steffen J, Rice J. Cytomegalovirus: Clinical features and management. Eye Health. 2020 Mar 30;33(108):79.
- Holland GN, Vaudaux JD, Jeng SM, Yu F, Goldenberg DT, Folz IC, Cumberland WG, McCannel CA, Helm CJ, Hardy WD, UCLA CMV Retinitis Study Group. Characteristics of untreated AIDS-related cytomegalovirus retinitis. I. Findings before the era of highly active antiretroviral therapy (1988 to 1994). American journal of ophthalmology. 2008 Jan 1;145(1):5-11.
- Holland GN, Shuler JD. Progression rates of cytomegalovirus retinopathy in ganciclovir-treated and untreated patients. Archives of Ophthalmology. 1992 Oct 1;110(10):1435-42.
- Thorne JE, Holbrook JT, Jabs DA, Kempen JH, Nichols C, Meinert CL, Studies of Ocular Complications of AIDS Research Group. Effect of cytomegalovirus retinitis on the risk of visual acuity loss among patients with AIDS. Ophthalmology. 2007 Mar 1;114(3):591-8.
- Smith IL, Macdonald JC, Freeman WR, Shapiro AM, Spector SA. Cytomegalovirus (CMV) retinitis activity is accurately reflected by the presence and level of CMV DNA in aqueous humor and vitreous. The Journal of infectious diseases. 1999 May 1;179(5):1249-53.
- Jirawison C, Yen M, Leenasirimakul P, Chen J, Guadanant S, Kunavisarut P, Patikulsila D, Watanachai N, Ausayakhun S, Heiden D, Holland GN. Telemedicine screening for cytomegalovirus retinitis at the point of care for human immunodeficiency virus infection. JAMA ophthalmology. 2015 Feb 1;133(2):198-205.
- Yeh S, Forooghian F, Faia LJ, Weichel ED, Wong WT, Sen HN, Chan-Kai B, Witherspoon SR, Lauer AK, Chew EY, Nussenblatt RB. Fundus autofluorescence changes in cytomegalovirus retinitis. Retina (Philadelphia, Pa.). 2010 Jan;30(1):42.
- Kozak I, McCutchan JA, Freeman WR. HIV-associated infections. InRetina 2013 Jan 1 (pp. 1441-1472). WB Saunders.
- Musch DC, Martin DF, Gordon JF, Davis MD, Kuppermann BD, Ganciclovir Implant Study Group. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. New England Journal of Medicine. 1997 Jul 10;337(2):83-90.
- Turner N, Strand A, Grewal DS, Cox G, Arif S, Baker AW, Maziarz EK, Saullo JH, Wolfe CR. Use of letermovir as salvage therapy for drug-resistant cytomegalovirus retinitis. Antimicrobial agents and chemotherapy. 2019 Mar;63(3):e02337-18.
- Avery RK, Mossad SB, Poggio E, Lard M, Budev M, Bolwell B, Waldman WJ, Braun W, Mawhorter SD, Fatica R, Krishnamurthi V. Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation. 2010 Aug 27;90(4):419-26.
- Yen M, Chen J, Ausayakhun S, Kunavisarut P, Vichitvejpaisal P, Ausayakhun S, Jirawison C, Shantha J, Holland GN, Heiden D, Margolis TP. Retinal detachment associated with AIDS-related cytomegalovirus retinitis: risk factors in a resource-limited setting. American journal of ophthalmology. 2015 Jan 1;159(1):185-92.
- Holland GN. Immune recovery uveitis. Ocular Immunology and Inflammation. 1999 Jan 1;7(3-4):215-21.