Purpose
To review the cases of viral retinitis after intravitreal steroid administration at a single center, to estimate the incidence, and to propose risk factors for its occurrence.
Design
Retrospective, observational case series.
Methods
Seven hundred thirty-six intravitreal triamcinolone (IVTA) injections were administered in the clinic and operating room by 3 retina specialists at a single academic medical center between September 2002 and November 2008. Inclusion criteria were simply a history of 1 or more IVTA injections during the period. The overall incidence of viral retinitis after IVTA injection was calculated. Subsequently, a chart audit was performed to estimate the number of patients with immune-altering conditions who had received IVTA during the period, and the incidence within this subgroup was calculated.
Results
Viral retinitis developed after IVTA injection in 3 patients, yielding an overall incidence of 3 in 736 or 0.41%. An estimated 334 injections were administered to patients with an immune-altering condition, including diabetes. All 3 of the patients in whom viral retinitis developed after IVTA injection possessed abnormal immune systems, yielding an incidence rate of 3 in 334 or 0.90% within this subgroup.
Conclusions
Our high reported incidence for this potentially devastating complication can be attributed to multiple factors, including coexisting medical immunocompromising comorbidities, a higher dose with a longer duration of local immunosuppression in the vitreous, multiple injections, as well as previous viral retinitis. Caution with a high index of clinical suspicion and frequent follow-up is advised in patients receiving IVTA injection with potentially immune-altering conditions, even after apparent immune recovery.
Viral retinitis is a devastating condition with disastrous consequences. Depending on the etiologic agent and immune status of the victim, the infection often can progress rapidly to involve the entire retina, including the macula, ultimately leading to severe loss of vision. Cytomegalovirus (CMV) was the first viral retinitis to be described and remains the most common etiologic agent. It generally affects severely immunocompromised patients, such as human immunodeficiency virus (HIV)-positive individuals with CD4 T-lymphocyte counts of less than 50 cells/mm 3 or, rarely, those with iatrogenic immunosuppression after chemotherapy, organ transplantation, or systemic corticosteroids for other indications. In their Focal Points module, Goldstein and associate indicate that acute retinal necrosis (ARN) was initially reported by Urayama and associates in 1971, and is most common in young immunocompetent adults. Freeman and associates demonstrated herpes group virus in endoretinal biopsy specimens in the acute phase of the disease, with varicella zoster virus or herpes simplex virus being the usual culprits. Patients left untreated can experience contralateral eye involvement within 1 month in up to one third of cases. More recently, a highly destructive, rapidly progressive variant of ARN that occurs solely in severely immunocompromised individuals has been described. Progressive outer retinal necrosis syndrome is caused by the same viruses as ARN, and leads to rapid involvement of the central and peripheral retina by full-thickness necrosis, ultimately leading to severe vision loss as a result of retinal detachment or optic atrophy. Although the virulence and rate of destruction of viral retinitis can vary, prompt, appropriate treatment is the key to a favorable visual outcome. However, the therapeutic agents used often are associated with frequent and severe systemic side effects, namely bone marrow suppression and nephrotoxicity. Patients, especially those who are immunocompromised, often require lifelong prophylaxis with these toxic agents to avoid recurrent infections in the same and contralateral eye.
In recent years, case reports have surfaced identifying immunocompetent patients in whom viral retinitis developed after the administration of intravitreal steroids. As the popularity of intravitreal triamcinolone acetonide (IVTA) injection and the indications for its use have grown over the years, deleterious side effects such as elevated intraocular pressure, posterior subcapsular cataracts, vitreous hemorrhage, and endophthalmitis have become well known to ophthalmologists, and intravitreal steroids often are avoided in patients deemed to be at higher risk of these complications. Viral retinitis, however, has received far less attention as a potential consequence of the medication. In 2005, Saidel and associates first described CMV retinitis (diagnosed by vitreous fluid polymerase chain reaction [PCR]) 4 months after IVTA injection in a patient treated for clinically significant macular edema resulting from diabetes. Delyfer and associates reported 2 immunocompetent patients in whom CMV retinitis developed after IVTA use for exudative age-related macular degeneration in one case and macular edema resulting from a central retinal vein occlusion in the second case. The cases were diagnosed via anterior chamber paracentesis and PCR. A recent paper by Ufret-Vincenty and associates presented a patient diagnosed with CMV retinitis (by clinical appearance) after placement of a fluocinolone acetonide (Retisert; Bausch and Lomb Inc., Rochester, New York, USA) implant for vitreitis and macular edema secondary to Behçet disease. The patient had not received systemic immunosuppressive medication for 5 months before the development of retinitis. Other articles have described ARN resulting from presumed herpes simplex virus (on the basis of positive serum antibody results) after IVTA injection in previously immunocompetent patients, although PCR was not performed on aqueous or vitreous fluid ( Table 1 ).
| Authors | Dose (mg/0.1 mL) | Indication for IVTA | Cause | Diagnosis Confirmation | Interval to Retinitis | Medical Comorbidities |
|---|---|---|---|---|---|---|
| Saidel and associates | 4 | CSME | CMV | Vitreous PCR | 4 mos | NIDDM |
| Toh and associates | 4 | Exudative AMD (w/ PDT) | HSV | Serum IgG and IgM | 5 mos | None |
| Aggermann and associates | 4 | CME resulting from CRVO | HSV | Serum IgG | 3 wks | None |
| Delyfer and associates | 20 | Exudative AMD (w/ PDT) | CMV | AC PCR | 3 mos | NIDDM |
| Delyfer and associates | 8 × 3 | CME resulting from CRVO | CMV | AC PCR | 3 mos | NIDDM |
| Ufret-Vincenty and associates | Retisert × 2 | CME/vitreitis resulting from Behçet disease | CMV | Clinical | 5 mos after Retisert no. 2 | Behçet disease |
| Sekiryu and associates | 4 | CME resulting from BRVO | CMV | AC PCR | 7 mos | NIDDM |
| Park and associates | 4 | CME resulting from CRVO | CMV | AC PCR | 4 mos | None |
Although reports of viral retinitis after IVTA injection have begun to surface in the literature, no information on the incidence of this potentially severe complication exists. Furthermore, minimal discussion of risk factors predisposing individuals to viral retinitis after IVTA injection has been presented. Our purpose was to review the cases of viral retinitis after intravitreal steroid administration at a single center, to estimate the incidence, and to propose risk factors for its occurrence. Following are 3 cases of primary or reactivated viral retinitis that developed after IVTA injection from our institution in patients with immune-altering medical comorbidities.
Methods
We retrospectively reviewed the charts of patients from our institution who had received IVTA injections from 3 retina specialists from September 2002 through November 2008. No patients received IVTA at our institution before 2002. All cases were included, regardless of diagnosis code or indication for the treatment. The most common diagnoses were cystoid macular edema, macular edema, and diabetic macular edema. Settings for the injections included the clinic and operating room. The overall incidence of this complication was calculated as the number of viral retinitis cases divided by the total number of IVTA injections administered. Subsequently, a chart audit was performed to estimate the number of patients with altered immunity who had received IVTA during the period. Responsible conditions included diabetes mellitus (DM), HIV or acquired immunodeficiency syndrome, or use of long-term oral steroids or steroid-sparing immunomodulatory or chemotherapeutic agents.
Results
A total of 736 IVTA injections were administered over this period. Viral retinitis subsequently developed in 3 patients. The overall incidence of viral retinitis after IVTA injection at our institution was 3 in 736 patients, or 0.41%. Of the 736 total injections, an estimated 334 were administered to patients with an immune-altering condition, including diabetes. All 3 of the patients at our center in whom viral retinitis developed after IVTA injection possessed abnormal immune systems. The calculated incidence of viral retinitis after IVTA injection among this subgroup at our institution was 3 in 334 patients, or 0.90%. Table 2 describes the clinical data for the 3 patients. The mean age of the patients in whom viral retinitis developed was 59.3 years (range, 43 to 73 years). Two were male and 1 was female. Indications for IVTA injection were macular edema from various causes. The patients received either 1 or 2 injections, and the dose of IVTA administered was 20 mg/0.1 mL in all 3 cases. Two patients previously had undergone vitrectomy. The mean interval to the development of retinitis after the final IVTA injection was 16 weeks (range, 10 to 26 weeks).
| Age (yrs) | Medical Comorbidities | Indication for IVTA | No. of Injections | Dose (mg/0.1 mL) | Previous Vitrectomy | Interval to Retinitis (wks) | Cause | Diagnosis Confirmation | Prior Retinitis | VA before IVTA Injection | VA after Retinitis |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 62 | NIDDM | CME from BRVO | 2 | 20 | Yes | 26 | CMV | Vitreous PCR | None | 20/200 | 20/400 |
| 43 | HIV | CME from IRU | 1 | 20 | No | 13 | CMV | Prior CMV retinitis, clinical appearance | CMV | 20/40 | 20/40 |
| 73 | Metastatic ovarian cancer receiving chemotherapy | IRF from ERM | 1 | 20 | Yes | 10 | VZV | Response to treatment | None | 20/200 | 20/400 |
Patient 1 was a diabetic male who received IVTA injection for recurrent macular edema secondary to a branch retinal vein occlusion that had been refractory to grid laser and anti–vascular endothelial growth factor therapy. Six months after a second IVTA injection during a vitrectomy with epiretinal membrane peel, the patient sought treatment for 3+ anterior chamber cell, keratic precipitates, vitreitis, and foci of retinal whitening and hemorrhage in the supertemporal and inferotemporal periphery ( Figure 1 ). Although initial vitreous biopsy results yielded negative cultures and PCR for CMV, herpes simplex virus, and varicella zoster virus, a clinical diagnosis of ARN was made and valacyclovir 1 g 3 times daily was initiated. However, progressive worsening of the retinitis led to retinal detachment requiring vitrectomy with endolaser and silicone oil. Repeat PCR analysis of vitreous fluid at this time produced positive results for CMV, and therapy was switched to valganciclovir 900 mg twice daily. CD4 T-lymphocyte count was 307 cells/μL, with no history of immunodeficiency other than diabetes. Valganciclovir was continued for 6 more weeks, at which time all retinitis lesions were healed.
Patient 2 was an HIV-positive man with a history of CD4 counts of less than 50 cells/μL and CMV retinitis, after which highly active antiretroviral therapy was instituted. Within months, his CD4 count had risen to 325 cells/μL and macular edema and vitreitis had developed, leading to a diagnosis of immune recovery uveitis. Because no CMV lesions were present, the maintenance dose of valganciclovir 450 mg twice daily was discontinued and IVTA injection was administered for the macular edema. The patient returned 3 months later with 3+ vitreous cell and apparent reactivation of CMV retinitis despite a CD4 count of 417 cells/μL ( Figure 2 ). Valganciclovir was begun at treatment dose of 900 mg twice daily, and therapy currently is ongoing.
