CLINICAL SCIENCES Noninfectious Associated With Intravitreal Triamcinolone

Daniel B. Roth, MD; Janet Chieh, BA; Marc J. Spirn, MD; Stuart N. Green, MD; David L. Yarian, MD; Nauman A. Chaudhry, MD

Background: of triamcinolone has ously undergone . Four eyes had a layered hy- been advocated to treat exudative macular diseases such popyon. All 7 eyes had an anterior chamber cellular reac- as macular and choroidal neovascularization. tion and vitritis. Visual acuity ranged from 20/400 to hand movements. The first 6 patients were treated for presumed Objective: To describe 7 patients who developed a clini- endophthalmitis with vitreous cultures and intravitreal in- cal picture simulating endophthalmitis after intravitreal jections of antibiotics. All 6 cultures were negative for any triamcinolone injection. organisms, and the eyes resolved their inflammatory re- sponse, with recovery to preinjection visual acuity or bet- Methods: Intravitreal triamcinolone injections were per- ter. The seventh patient was treated with topical predniso- formed to treat refractory cystoid macular edema or dif- lone without antibiotic therapy, and the inflammation fuse macular edema associated with diabetic retinopa- resolved, with resolution of the macular edema seen be- thy, macular pucker, branch retinal vein occlusion, or fore the intravitreal triamcinolone injection. pseudophakia. One patient received an injection in an attempt to treat exudation associated with occult cho- Conclusion: It may be appropriate to closely observe non- roidal neovascularization. infectious, toxic endophthalmitis in patients treated with intravitreal triamcinolone before assuming it to be in- Results: Preinjection visual acuity ranged from 20/50 to fectious, especially in the absence of eye pain. 20/400. An extensive inflammatory response developed 1 to 2 days after injection in all 7 eyes. Five eyes had previ- Arch Ophthalmol. 2003;121:1279-1282

YSTOID MACULAR edema and well tolerated,13,14 and it has been (CME) is a common cause advocated recently as treatment for refrac- of compromised central vi- tory CME.15-18 Intravitreal triamcinolone sion and is associated with is also a potential therapy for choroidal numerous coexisting con- neovascularization associated with age- ditions.C1-4 Initial treatment depends on the related , as it de- underlying cause and includes topical or creases capillary permeability and reduces periocular corticosteroids and nonsteroi- subretinal fluid exudation.19-22 dal anti-inflammatory medications.5 In cases As with any therapeutic modality, the associated with diabetic macular edema benefits must be weighed against the risks. and vascular occlusions, focal laser treat- The most common risks associated with ment is often indicated.6,7 In cases of an as- intraocular corticosteroid therapy are el- sociated macular pucker or vitreomacular evation of intraocular pressure and pro- traction, vitrectomy with membrane peel- gression of .23 The risk of endoph- ing is necessary.8 thalmitis exists with any intraocular From the Retina Vitreous However, despite using the pre- injection or penetration. We describe 7 pa- Center, Department of viously mentioned therapeutic modali- tients who developed a clinical picture , University of ties, many patients have persistent CME. simulating endophthalmitis after intravit- Medicine and Dentistry of New Corticosteroids inhibit prostaglandin real triamcinolone injection that we be- Jersey (Drs Roth, Spirn, Green, and leukotriene synthesis, thereby induc- lieve represents a toxic reaction to the ma- and Yarian and Ms Chieh), ing an anti-inflammatory effect.9 Further- terial injected. New Brunswick; and New England Retina Associates more, corticosteroids reverse capillary per- (Dr Chaudhry), New London, meability, stabilizing blood vessels and 10-12 METHODS Conn. The authors have no the blood-retinal barrier. Intravitreal relevant financial interest in has recently Intravitreal triamcinolone acetonide (Kena- this article. been shown to be nontoxic to the human log; Bristol-Myers Squibb, Princeton, NJ) in-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Patient Demographics

Dose of Previous Intraocular Patient No. Age, y Diagnosis Status Triamcinolone Injected, mg Previous PPV Triamcinolone Injection 1 37 DME/CME Phakic 1 Yes Yes (60 d earlier) 2 73 DME/CME Phakic 1 Yes No 3 84 Pseudophakic CME ACIOL 1 No No 4 72 CME with ERM PCIOL 1 Yes Yes (84 d earlier) 5 60 CME with BRVO PCIOL 4 Yes Yes (32 d earlier) 6 75 CNVM PCIOL 4 No Yes (23 d earlier) 7 68 DME/CME PCIOL 4 Yes No

Abbreviations: BRVO, branch retinal vein occlusion; CNVM, choroidal neovascular membrane; DME, diabetic macular edema; CME, cystoid macular edema; ERM, ; ACIOL, anterior chamber ; PCIOL, posterior chamber intraocular lens; PPV, pars plana vitrectomy.

jection for the treatment of refractory CME or occult choroi- of CME, 1 mg was typically administered. For patients dal neovascularization has been used as a treatment modality with an incomplete response to a previous injection or by us since May 2001. The risks and benefits of the procedure recurrent macular edema after an excellent response to were discussed with and written informed consent was ob- a previous injection, 4 mg was injected. For patients with tained from each patient before injection. The eye was pre- choroidal neovascularization, 4 mg was administered. Pa- pared with povidone-iodine (Betadine; Purdue Frederick Co, Norwalk, Conn) (5% or 10%) solution and ciprofloxacin hy- tient 7 is an exception in that he received a 4-mg injec- drochloride (Ciloxan; Alcon Inc, Ft Worth, Tex) drops to ob- tion for diabetic CME without any previous intraocular tain sterile conditions. A sterile wire lid speculum was placed corticosteroid treatment. in the eye, and sterile topical or subconjunctival lidocaine hy- Preinjection visual acuity ranged from 20/50 to 20/ drochloride was used to anesthetize the inferotemporal quad- 400. All 7 eyes had acute, painless loss of vision on the first rant of the eye to be injected. visit after intravitreal injection. Visual acuity after injec- The triamcinolone was injected inferotemporally through tion ranged from 20/400 to hand movements. Three pa- the pars plana using a 30-gauge needle on a 1-mL syringe. In 4 tients were examined 1 day after injection, and the other 4 eyes, 1 mg of drug was injected from a new, sterile bottle of were seen 2 days after injection. An extensive inflamma- triamcinolone acetonide, 10 mg/mL, in a volume of 0.1 mL. In 3 eyes, 4 mg of drug was injected from a new, sterile bottle of tory response was observed in all 7 patients, with anterior triamcinolone acetonide, 40 mg/mL, in a volume of 0.1 mL. The chamber cell and flare and posterior segment vitritis suspension was shaken vigorously before drawing it into the (Table 2). The response was distinct from triamcinolone syringe to ensure the correct concentration. The supernatant suspension particles. In the 4 eyes with , the col- was not removed, and the drug was not resuspended in other lection in the angle was distinguished from triamcinolone diluent. Patients were instructed to instill ciprofloxacin drops suspension particles, even in pseudophakic eyes, by its ap- for 2 days after injection, and they returned for a follow-up ex- pearance and slightly yellow color. The vitritis obscured amination either 1 or 2 days after the procedure. the fundus details in all 7 eyes; however, in 4 eyes, the in- Between May 1, 2001, and June 30, 2002, we performed flammation was so extensive that B-scan ultrasonography 104 intravitreal injections to treat cystoid or diffuse diabetic was necessary to evaluate the retina, as only the red reflex macular edema that did not respond to focal laser photoco- agulation; CME associated with retinal vein occlusions, was visible. B-scan ultrasonography in these cases re- pseudophakia, or preretinal gliosis; and choroidal neovascu- vealed dense vitritis without . larization. We encountered 7 cases of atypical inflammation The first 6 patients were treated for presumed in- simulating endophthalmitis after triamcinolone injection, all fectious endophthalmitis; they underwent vitreous cul- occurring between January 16, 2002, and February 19, 2002. ture and injection of intraocular antibiotics. Each of these 6 eyes received 1 mg of vancomycin hydrochloride and RESULTS 2 mg of ceftazidime by intravitreal injection through the pars plana. Four of the vitreous samples were obtained Four women and 3 men were identified as having a clini- using a vitreous cutter and 2 were obtained via needle cal picture simulating endophthalmitis after intravitreal tri- aspiration. All vitreous cultures had adequate samples and amcinolone injection (mean age, 67 years; range, 37-84 were plated on blood, chocolate, and Sabouraud agar and years). All 7 eyes had previously undergone intraocular sur- on thioglycolate broth. Initial gram stains were not per- gery. Five eyes were pseudophakic, and 5 eyes had previ- formed routinely. None of the samples were positive for ously undergone vitrectomy (Table 1). Intravitreal tri- any organisms on these media, and all were thought to amcinolone injections were performed to treat cystoid or be sterile. Owing to a concern that the vials of triam- diffuse diabetic macular edema that did not respond to fo- cinolone carried infectious organisms, 3 of the bottles used cal laser photocoagulation in 3 eyes, CME associated with for injection were cultured. One culture was positive for a mild macular pucker or with a branch retinal vein oc- a presumed contaminant colony of Staphylococcus au- clusion in 1 eye each, pseudophakic CME after a second- reus on blood and chocolate agar, and the other 2 were ary anterior chamber intraocular lens in 1 eye, and exuda- negative. The lot numbers of the triamcinolone vials used tion associated with choroidal neovascularization in 1 eye. for intravitreal injection were recorded, and samples of The dose of triamcinolone injected was either 1 or each lot number were sent for routine culture; all were 4 mg. In patients with their first injection for treatment negative for any organisms.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 2. Clinical Findings

Visual Acuity Vitritis Examination AC Reaction (Range, Final Patient No. Before Injection After Injection After Injection, d (Range, 0-4) Hypopyon 0-4) Cultures Visual Acuity 1 20/300 20/400 2 1+ No 4+ Negative 20/200 2 20/400 1/200 2 1+ No 2+ Negative 20/200 3 20/200 2/200 1 3+ Yes 2+ Negative 20/200 4 20/400 HM 2 3+ Yes 3+ Negative 20/200 5 20/50 HM 1 4+ Yes 4+ Negative 20/30 6 20/200 HM 1 4+ Yes 3+ Negative 20/60 7 20/200 HM 2 3+ No 4+ Not performed 20/70

Abbreviations: AC, anterior chamber; HM, hand movements.

Patient 7 had a similar clinical picture of endoph- organisms, and the 1 eye that was observed resolved spon- thalmitis but was observed closely and was treated with taneously without antibiotic therapy. No cases of culture- topical prednisolone acetate without topical, intraocu- positive endophthalmitis have been seen since we be- lar, or systemic antibiotic therapy. The inflammation im- gan using this therapeutic modality. (2) All 7 cases proved in the initial 2 days and resolved completely dur- presented acutely without pain, whereas infectious en- ing the ensuing 3 weeks, with disappearance of all vitritis dophthalmitis typically manifests acutely or subacutely and absence of the preexisting macular edema. Visual acu- with pain. (3) All 7 patients rapidly recovered to their ity improved from 20/200 before triamcinolone injec- preinjection levels of visual acuity, typically within days tion to 20/70 afterward. of developing endophthalmitis, suggesting a toxic reac- In the other 5 eyes with macular edema (patients 1-5), tion to the dose of injected material. Most of the pa- the CME resolved completely in 3 and was reduced on fluo- tients even recovered to better visual acuity owing to reso- rescein angiography in the other 2, despite developing en- lution of the macular edema. dophthalmitis and undergoing further intervention. The All 7 patients experienced severe inflammation patient with choroidal neovascularization associated with within 2 days of intravitreal injection. If a patient devel- age-related macular degeneration was later enrolled in a ops new symptoms more than several days after injec- clinical trial that involved intravitreal injections of an in- tion, infectious endophthalmitis should be presumed and hibitor of vascular endothelial growth factor. She mounted immediate therapy should be initiated. a similar inflammatory response to this injection, but her Many patients in this series were pseudophakic or inflammation resolved without sequelae and her visual had previously undergone vitrectomy (n=5 [71%] for acuity improved from an initial baseline value of 20/200 both). It is possible that in eyes that have not undergone to 20/60, with a substantial decrease in subretinal fluid vitrectomy, the drug remains more sequestered in the vit- exudation. reous cavity, diffusing more slowly to the intraocular struc- tures. In eyes that have undergone vitrectomy, the drug COMMENT has direct access to the ocular coats, allowing any toxic agent to more readily induce a brisk immune response. Intravitreal triamcinolone injections have been associ- Similarly, in patients with pseudophakia, the relative uni- ated with reductions in capillary permeability and reso- cameral nature of the eye may allow for a more robust lution of macular edema in patients with CME with mul- immune response. tiple causes.15-18 Patients with choroidal neovascularization Furthermore, many patients developed endophthal- may benefit from intraocular corticosteroid therapy ow- mitis after receiving a second injection of triamcinolone ing to the reduction in subretinal fluid exudation and from (n=4 [57%]). It is possible that the eye is more likely to the bacteriostatic effect of triamcinolone.24-26 However, mount an immune response when receiving a second in- any invasive intervention has risks. The most common jection, especially if less than 6 weeks has elapsed since adverse effects of intravitreal triamcinolone injection are the previous injection. a transient elevation in intraocular pressure and poten- We did not pinpoint a specific lot number or type tial worsening of a cataract.23 Although endophthalmi- of triamcinolone packaging (10 mg/mL, 1-mL vials; 40 tis is an obvious potential adverse effect of intraocular mg/mL, 5-mL vials; or 40 mg/mL, 1-mL vials) that was injections, it is extremely rare when appropriate sterile more suspect because these endophthalmitis cases rep- technique is practiced. In our review of 104 cases of in- resent varied lot numbers and were administered from travitreal triamcinolone injection, we found 7 cases of all 3 types of newly opened triamcinolone vials. The clus- endophthalmitis clustered between January 16, 2002, and tering of cases in a 5-week period raises the suspicion February 19, 2002. We believe that these cases repre- that some toxin existed in the vial that prompted sus- sent noninfectious endophthalmitis—probably a toxic re- ceptible patients to mount an inflammatory reaction. No action to the drug, the vehicle in which it is suspended, modification of the intravitreal injection technique was or a contaminant in the vials involved in this series. noted during this period that could explain the inci- The basis of this assumption derives from multiple dence of severe inflammation or endophthalmitis. After facts. (1) All 6 cases that were cultured failed to reveal these cases were noted, we returned all our held stock

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