CASE STUDY

It Still Happens Today: Bilateral Frosted Branch Angiitis in Cytomegalovirus Retinitis

Prompt use of antivirals spared vision in a noncompliant patient.

RUWAN A. SILVA, MD ∙ THOMAS A. ALBINI, MD ∙ HARRY W. FLYNN, Jr., MD

Cytomegalovirus (CMV) retinitis remains by far the most common opportunistic infection in AIDS patients.¹ Though the era of highly active antiretroviral therapy (HAART) has likely attenuated its incidence, the disease remains quite pertinent as 20% of individuals continue to fail antiviral therapy.² A further consideration is the virus& tropism for the retina: Despite documented systemic CMV infection (manifested as mononucleosis, pneumonitis, colitis, and myelitis), retinitis accounts for 85% of all CMV disease.³ Active retinal lesions generally take one of three forms: (1) granular (generally peripheral) disease; (2) fulminant retinal necrosis; or (3) perivascular disease.

Of these, perivascular disease appears to be the least common variant, the florid presentation of which is termed frosted branch angiitis (FBA). We report a case of bilateral CMV retinitis notable for its striking appearance as bilateral FBA and its regression after a course of antiviral therapy.

CASE REPORT

A 38-year-old, African-American, HIV-positive female (CD4 = 6) presented in October 2009, complaining of blurry vision in her right eye for several days. Her initial visual acuity was 20/70 in the right eye and 20/20 in the left eye. The posterior-segment exam (Figure 1) demonstrated peripheral retinal necrosis and hemorrhage consistent with CMV retinitis of the right eye. The patient was admitted for treatment with intravenous ganciclovir (5 mg/kg IV bid) and begun on HAART. However, the patient left against medical advice (AMA) after seven days of treatment.

Figure 1. Fundus photos demonstrating fulminant CMV retinitis and early perivascular disease in the superior periphery, with cotton wool spots in the macula of the right eye (A). Posterior pole of the left eye appears normal (B).

She was lost to follow-up until December 2009, when she was examined for blurry vision in both eyes. Visual acuity was 20/40 in the right eye and 20/25 in the left eye. The CMV retinitis had now progressed to both eyes (Figure 2).

Figure 2. Progression of fulminant CMV retinitis to involve all four quadrants of the right eye with perivascular disease encroaching upon the fovea and optic nerve (A). Early temporal retinal necrosis of the left eye (B).

The patient was restarted on induction intravenous ganciclovir and HAART but again left AMA after six days of treatment. She returned in February 2010 complaining of worsening vision in both eyes. Visual acuity at that time was 20/60 in the right eye and 20/20 in the left eye, with the posterior-segment examination (Figure 3) demonstrating FBA and fulminant CMV retinitis in both eyes. The patient was again admitted and restarted on HAART therapy and intravenous ganciclovir for 14 days. She also received six intravitreal injections of ganciclovir (2,000 μg) and foscarnet (1,200 μg) in each eye. After induction, the patient was transitioned to oral valganciclovir (900 mg po daily) and discharged on HAART.

Figure 3. Fulminant CMV retinal necrosis and frosted branch angiitis in both eyes (A and B).

As of April 2010, her retinitis appeared quiescent, though trace vitritis in the left eye (presumed immune reconstitution uveitis) was noted (Figure 4). Her vision was stable at 20/40 in both eyes.

Figure 4. Regressed CMV retinitis with diffuse retinal atrophy and pigmentary changes superiorly and prominent intraretinal crystalline deposits temporally OD (A). Diffuse peripheral retinal atrophy with regressing perivascular disease in all four quadrants and regressing granular disease superotemporally and inferonasally OS. Mild vitritis is also present (B).

DISCUSSION

First described in the Japanese literature in 1976, FBA of any etiology remains a rare clinical entity. The initial report was somewhat prescient, as approximately 75% of reported cases occur in Japan, with only 18 cases ever reported in the US — only seven of which appeared secondary to CMV retinitis.^4-10 It seems the here-presented case mimics prior literature in that the patient is both female and exhibited bilateral disease, traits that are predominant in 61% and 75% of reported cases, respectively.¹¹

The precise pathogenesis of FBA depends on the under lying disease in which it manifests, with at least three variants suggested.¹² CMV likely elicits periphlebitis via either a type 3 hypersensitivity reaction affecting immune-complex deposition or CMV viral particles themselves producing angiitis.⁶ Evidence of the former stems from reports of FBA regressing with use of immunosuppressants,¹¹ while the very pathogenesis of CMV retinitis itself suggests the latter. CMV virion particles circumvent the inner blood-retina barrier through endocytosis by retinal endothelial cells.

More common presentations of full-thickness fulminant retinal necrosis are comprised of subsequent cell-to-cell horizontal transmission and Müller glia-mediated vertical transmission of CMV.¹³

FBA, however, may result from an exudative response to the initial mechanism of viral retinal access: replicating within, disrupting microtubule support for, and, consequently, inducing apoptosis in retinal vascular endothelial cells. HIV viral endotheliopathy, associated with impaired endothelial function as well as elevated levels of tumor necrosis factors, may also be a contributing factor.^14,15

Because of the aggressive nature of FBA in the setting of CMV retinitis, prompt antiviral induction therapy with consideration of intravitreal delivery in fovea or optic nerve threatening disease (particularly in resistant viral strains) should be administered.¹⁶ Given its aforementioned virulence, prognosis for CMV retinitis is generally guarded, with full-thickness necrosis leaving patients vulnerable to retinal holes, retinal detachments and, ultimately, severe vision loss. In FBA, other complications include macular scarring, vascular occlusions and epiretinal membrane formation.¹¹

Despite interrupted treatment, this patient responded quite well to her most recent therapy with excellent visual outcome in this usually devastating ocular infection. RP

REFERENCES

1. Munoz A, Schrager LK, Bacellar H, et al. Trends in the incidence of outcomes defining acquired immunodeficiency syndrome (AIDS) in the Multicenter AIDS Cohort Study: 1985-1991. Am J Epidemiol 1993;137:423-438.
2. Holland GN, Tufail A, Jordan MC. Cytomegalovirus diseases. In: Pepose JS,Holland GN, Wilhelmus KR, eds. Ocular Infection & Immunity. St.Louis: Mosby, 1996;1088-1129.
3. Gallant JE, Moore RD, Richman DD, et al. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. J Infect Dis. 1992;166:1223-1227.
4. Browning DJ. Mild frosted branch periphlebitis. Am J Ophthalmol.1992;114:505-506.
5. Geier SA, Nasemann J, Klauss V, et al. Frosted branch angiitis in a patient with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1992;113:203-205.
6. Kleiner RC, Kaplan HJ, Shakin JL, et al. Acute frosted retinal periphlebitis. Am J Ophthalmol. 1988;106:27-34.
7. Mansour AM, Li HK. Frosted retinal periphlebitis in the acquired immunodeficiency syndrome. Ophthalmologica 1993;207:182-186.
8. Spaide RF, Vitale AT, Toth IR, Oliver JM. Frosted branch angiitis associated with cytomegalovirus retinitis. Am J Ophthalmol 1992;113:522-528.
9. Sugin SL, Henderly DE, Friedman SM, et al. Unilateral frosted branch angiitis. Am J Ophthalmol 1991;111:682-685.
10. Vander JF, Masciulli L. Unilateral frosted branch angiitis. Am J Ophthalmol. 1991;112:477-478.
11. Walker S, Iguchi A, Jones NP. Frosted branch angiitis: a review. Eye (Lond) 2004;18:527-533.
12. Kleiner RC. Frosted branch angiitis: clinical syndrome or clinical sign? Retina. 1997;17:370-371.
13. Rao NA, Zhang J, Ishimoto S. Role of retinal vascular endothelial cells in development of CMV retinitis. Trans Am Ophthalmol Soc. 1998;96:111-123.
14. Cohen OJ, Kinter A, Fauci AS. Host factors in the pathogenesis of HIV disease. Immunol Rev. 1997;159:31-48.
15. Harooni M, Lashkari K, Freilich JM, Schepens CL. Cytomegalovirus retinitis. Int Ophthalmol Clin. 1996;36:131-140.
16. Desatnik HR, Foster RE, Lowder CY. Treatment of clinically resistant cytomegalovirus retinitis with combined intravitreal injections of ganciclovir and foscarnet. Am J Ophthalmol. 1996;122:121-123.