Cytomegalovirus Retinitis Associated With Intravitreal Dexamethasone Implant Injection

Abstract

Purpose: To describe an immunocompetent patient with cytomegalovirus (CMV) retinitis after dexamethasone implant injection and review previously documented cases. Methods: A review of case reports and literature was performed. Results: A 75-year-old man presented with acute decreased vision in the left eye. He had a vitrectomy and membrane peeling for an epiretinal membrane with recurrent cystoid macular edema and was receiving intravitreal dexamethasone implant injections at an outside hospital. The visual acuity in the left eye was hand motions, and an examination found patchy retinal whitening with hemorrhages. Aqueous polymerase chain reaction was positive for CMV. The laboratory evaluation was negative for immunodeficiencies. He was treated successfully with intravitreal and oral antivirals; however, his vision remained poor at most recent follow-up. A literature review found 8 previous cases of CMV retinitis after dexamethasone implant injection, although most had underlying immune dysregulation. Conclusions: CMV retinitis after intravitreal dexamethasone implant injection is rare. Awareness of this complication is essential because of the risk for devastating blindness.

Introduction

Cytomegalovirus (CMV) retinitis is a rare manifestation of CMV infection with the potential to cause blindness. It tends to occur in immunocompromised individuals, including neonates, bone marrow or solid organ transplant recipients, patients with AIDS caused by HIV, or those with underlying malignancy, systemic immunosuppressive therapy, or primary immunodeficiencies. ¹ CMV retinitis has also rarely been reported after intravitreal injection of corticosteroids, including triamcinolone. ² However, there are limited studies of its incidence after injection of longer duration corticosteroid implants, including the intravitreal dexamethasone implant (Ozurdex, Allergan).

We present a rare case of an immunocompetent patient who developed CMV retinitis after dexamethasone implant injection. Also, a comprehensive literature review was performed to identify previously reported cases of CMV retinitis associated with the intravitreal dexamethasone implant.

Case Report

A 75-year-old man presented with 4 days of painless decreased vision in the left eye. He denied previous medical conditions, including diabetes mellitus (DM), autoimmune conditions, recent surgeries, and past hospitalizations. His ocular history was notable for primary open-angle glaucoma requiring a trabeculectomy in the right eye and placement of glaucoma drainage devices in the left eye 5 years previously. He also had pars plana vitrectomy and membrane peeling for an epiretinal membrane (ERM) in the left eye. Because of persistent, recurrent cystoid macular edema, he had been receiving intravitreal dexamethasone implant injections every 8 weeks at an outside hospital. His most recent injection was 2 months before presentation.

The visual acuity (VA) was 20/20 OD and hand motions (HM) OS. An anterior segment examination of the right eye showed a superior trabeculectomy but was otherwise unremarkable. A slitlamp examination of the left eye showed 2 glaucoma tubes without exposure, inferior keratic precipitates, 2+ anterior chamber (AC) cells, and 1+ vitreous cells. The dilated fundus examination was notable for diffuse, patchy whitening in the macula and zone 2 midperiphery, with scattered areas of hemorrhage (Figure 1). The dexamethasone implant was not visualized. Optical coherence tomography showed full-thickness necrosis with hyperreflectivity of the inner retina, loss of the outer retina, and disorganization (Figure 2A). An AC paracentesis was performed. Given the concern for viral etiology, intravitreal ganciclovir and foscarnet were injected. The patient was also started empirically on valganciclovir 900 mg twice per day and trimethoprim/sulfamethoxazole 800-160 mg twice per day.

Figure 1.

Fundus photograph of the left eye at presentation shows diffuse granular areas of whitening and a hemorrhage in the macula and posterior pole that extend to the midperiphery.

Figure 2.

Optical coherence tomography of the retina of the left eye at presentation and follow-up. (A) The left eye has full-thickness necrosis of the macula and disorganization of the retinal layers. (B) At the follow-up, the left eye had significant subfoveal and macular atrophy, although there was no evidence of active retinitis.

A laboratory evaluation was notable for a normal complete blood count, a comprehensive metabolic panel including glucose and hemoglobin A_1c, as well as negative treponemal antibodies, HIV, and QuantiFERON-TB Gold. Serum CMV immunoglobulin M (IgM) and IgG were found to be elevated. Aqueous viral polymerase chain reaction (PCR) was negative for herpes simplex viruses 1/2, varicella zoster virus, and toxoplasmosis and was positive for CMV, confirming the diagnosis of CMV retinitis.

The patient received 3 additional intravitreal injections of ganciclovir and foscarnet and was continued on valganciclovir 900 mg daily for 2.5 months, at which point he appeared quiescent and was transitioned to valganciclovir 450 mg daily for 4 additional months. At the most recent follow-up 18 months after presentation, he appeared stable without evidence of recurrence of the retinitis, although his VA remained poor at HM, likely due to significant macular atrophy after the necrosis (Figure 2B).

Conclusions

CMV is a double-stranded DNA herpesvirus that establishes latency in leukocytes. Although there is 60% seroprevalence in the United States, clinical manifestations are rare and primarily occur in the setting of an immunocompromised status, including HIV and severe systemic immunosuppression. ¹ CMV retinitis classically presents with decreased vision, with the fundus examination demonstrating peripheral granular yellow–white retinal lesions with adjacent retinal hemorrhages, often in a centrifugal pattern. Significant visual impairment can occur as a result of retinal necrosis involving the macula or optic nerve, and there may be associated retinal detachment. ¹

The diagnosis is primarily clinical but may be substantiated by a positive aqueous CMV PCR, which has been shown to be an accurate marker corresponding to active disease. ³ Treatment aims include the preservation of vision and a decreased risk for CMV-related visual complications. Typical agents include intravenous and intravitreal ganciclovir and foscarnet, intravenous cidofovir, and oral valganciclovir, which may be effective, although drug resistance can occur and lead to worse clinical outcomes. ⁴ Addressing the underlying immunodeficiency through immune reconstitution is also essential for long-term disease control, including treatment of HIV or the cessation of immunosuppressant agents, if possible.

Although CMV retinitis typically occurs in immunosuppressed patients, it very rarely occurs in immunocompetent patients. DM has been found to be associated with CMV retinitis. ⁵ Although the pathophysiology remains unknown, circulating CMV levels have been reported to be higher in patients with diabetes. ⁶ It has been hypothesized that diabetic vasculopathy or a breakdown of the blood–retinal barrier in the setting of diabetic macular edema (DME) may facilitate entry of CMV into the retina and thereby promote the development of retinitis. ² This may be exacerbated by administration of local immunosuppressant medications for DME, including intravitreal corticosteroids.

Intravitreal triamcinolone acetonide (IVTA) is a common agent used to treat macular edema that results from a variety of causes, including diabetes. The US Food and Drug Administration approved the dexamethasone implant in 2009 for the treatment of macular edema after branch or central retinal vein occlusion (CRVO), with expansion of its use for DME in 2014. It is thought to be relatively safe and efficacious, with the common side effect of elevated intraocular pressure (IOP), with 1 study finding that, in general, the IOP increase did not require surgical intervention. ⁷ It provided an alternative for the shorter-acting IVTA and the very long-lasting fluocinolone acetonide implant (Retisert, Bausch + Lomb), which requires surgical placement and releases corticosteroids at a constant rate over a 3-year period.

Although CMV retinitis after administration of injection of intravitreal corticosteroids is uncommon, it can occur, possibly as a result of the prolonged local immunosuppression. One study reported that 3 (0.41%) of 746 patients who received IVTA developed viral retinitis. ² The primary risk factor appeared to be an abnormal underlying immune system given that the 3 patients in that study who developed CMV retinitis had diabetes, HIV, or were receiving chemotherapy, with neither the dose of IVTA nor the presence or absence of previous vitrectomy appearing to affect the incidence of the disease. Multiple injections resulting in greater time with local immunosuppression has been hypothesized as increasing the risk for CMV retinitis, although this has not been comprehensively investigated. Similarly, few studies have investigated the development of CMV retinitis after injection of the dexamethasone implant, which may result in even longer local immunosuppression and an increased risk for viral infection from the implant’s prolonged release of intravitreal corticosteroids.

A literature review through PubMed with various permutations of the search terms “cytomegalovirus retinitis”, “CMV”, “dexamethasone implant”, “dexamethasone”, and “Ozurdex” yielded 8 previously reported cases in the English language, 9 including the patient presented in this report (Table 1).^6,8–15 The average age was 66.9 years, and 6 (66.7%) of the 9 patients were men. The reasons for the initial dexamethasone implant varied and included macular edema caused by CRVO (n = 1), noninfectious panuveitis (n = 3), DM (n = 2), ERM (n = 1), age-related macular degeneration (off-label; n = 1), and a dislocated intraocular lens (n = 1). Of note, 5 (55.5%) of the 9 patients had underlying diabetes or another immune dysfunction, including taking immunosuppressant medications, and 2 patients (22.2%) had no known immunosuppression but had chronic idiopathic panuveitis, suggestive of immune dysregulation. One patient had diabetes and idiopathic panuveitis. Only 2 patients, including our patient, had neither diabetes nor systemic immune dysregulation, with the dexamethasone implant as the potential source of local immunosuppression.

Table 1.

Literature Review of Cytomegalovirus Retinitis After Intravitreal Dexamethasone Implant Injection.

Author a /Year	Age/Sex	Time From Injection to Symptoms (Mo)	Previous Implant Injection?	Ocular Conditions	Systemic Disease	VA at Presentation w/ Retinitis	Treatment	FU (Mo)	VA at Last FU	Visual Outcomes
Vannozzi 8 (2016)	54/M	3.0	No	CME from CRVO	HTN; mild hyperhomocysteinemia w/ methylenetetrahydrofolate reductase gene mutation; 2 y mycophenolate mofetil for presumed retinal vasculitis	LP	IV ganciclovir (250 mg 2× daily for 3 wk) followed by oral valganciclovir (900 mg 2× daily for 8 wk); mycophenolate mofetil discontinued; refused intravitreal injection	9	LP	Iris neovascularization; inferior RD
Thrane 9 (2016)	67/M	0.5	Yes	CME from chronic bilateral idiopathic panuveitis	None	20/120	IV ganciclovir followed by oral valganciclovir	4	20/120	Complicated by iris neovascularization & superotemporal RD
Dogra 10 (2018)	60/M	2.0	No	DME; implant inserted at time of cataract extraction	Diabetes, s/p renal transplant for renal failure on azathioprine & tacrolimus	CF	Intravitreal ganciclovir ×3; IV ganciclovir followed by oral valganciclovir (450 mg daily ×3 months, renally dosed)	9	20/80	No recurrence of infection
Kim 11 (2019)	60/F	2.0	No	Noninfectious panuveitis	None	NS	Diagnostic vitrectomy with 1× intravitreal ganciclovir injection; 2 mo oral valganciclovir medication	20	NS	Improvement in inflammation
Witmer 12 (2021)	71/F	3.5	Yes	CME after sx for dislocated IOL 1 y prior	Diabetes	20/400	Intravitreal ganciclovir ×5; oral valganciclovir	1	20/70	Lesions healing
Chaudhry 13 (2021)	80/F	3.5	Yes	AMD	None	20/1200	Vitrectomy; intravitreal foscarnet ×1; valganciclovir 450 mg 2× daily (renally dosed) for 2 mo	2	20/200	No recurrence of infection
Šulavíková 14 (2022)	75/M	3.5	No	DME	Diabetes; chronic myeloid leukemia on imatinib	20/63	Vitrectomy; acyclovir 400 mg 5× per day	1	20/160	Reduction in inflammation; improvement in vision
Kim 15 (2023)	60/M	3.0	No	Noninfectious panuveitis	Diabetes	20/60	Valganciclovir; biweekly foscarnet injections; PPV with biopsy	3.5	20/60	Reduced CMV counts; decreased vision attributed to PCO
Shoji b (2023)	75/M	2.0	Yes	ERM w/ CME	None	HM	Intravitreal ganciclovir and foscarnet ×4, valganciclovir 900 mg daily ×2.5 mo, then 450 mg daily ×4 mo	15	HM	No recurrence of infection, but vision remained limited by retinal atrophy

Abbreviations: AMD, age-related macular degeneration; CF, counting fingers; CME, cystoid macular edema; CMV, cytomegalovirus; CRVO, central retinal vein occlusion; DME, diabetic macular edema; ERM, epiretinal membrane; FU, follow-up; HM, hand motions; HTN, hypertension; IOL, intraocular lens; IV, intravenous; LP, light perception; NS, not specified; PCO, posterior capsular opacification; PPV, pars plana vitrectomy; RD, retinal detachment; s/p, status post; sx, surgery.

^aFirst author only.

^bPatient in the current study.

The onset of symptoms occurred an average of 2.6 months after injection. Interestingly, 44.5% of patients had previously received the dexamethasone injection without complication. This may suggest that the blood–retinal barrier breakdown caused by their underlying disease had progressed over time or that prolonged immunosuppression resulting from multiple implant injections increases the risk for retinitis. Also notable is that 1 patient received bilateral dexamethasone implant injections but developed CMV retinitis in 1 eye only, further suggesting that the underlying retina function might contribute to the development of retinitis.

Outcomes were poor, with the VA ranging from 20/70 to light perception at the most recent follow-up. Five of the 9 patients had worse or the same VA compared with the VA at presentation (average follow-up 7.5 months).

In conclusion, CMV retinitis in immunocompetent patients is rare. This report highlights an unusual case of CMV retinitis in an immunocompetent patient after dexamethasone implant injection. To our knowledge, this is only the second case reported in an immunocompetent patient. CMV retinitis can occur after a dexamethasone implant in patients with an underlying immunocompromised status, those with limited immune dysfunction such as DM, or those without significant medical conditions and may be an underreported or underrecognized risk of intravitreal dexamethasone implant administration. Increased awareness of this complication after implant injection is essential for physicians and providers because of the poor outcomes and potentially devastating blindness resulting from CMV retinitis. Careful patient selection and appropriate counseling of the risks and benefits should occur before the injection, and patients should be carefully monitored for potential complications after each implant injection.