OCCLUSIVE VASCULITIS DUE TO HYPERACUTE STREPTOCOCCUS MITIS ENDOPHTHALMITIS AFTER INTRAVITREAL RANIBIZUMAB Kevin R. Baxter, DO,* Joshua E. Robinson, MD,† Alan J. Ruby, MD†
Purpose: To report a case of hyperacute Streptococcus mitis endophthalmitis after intravitreal ranibizumab resulting in occlusive vasculitis. Methods: Retrospective case report with ultra-wide-ﬁeld color fundoscopic and ﬂuorescein angiographic imaging. Results: An 83-year-old woman received an intravitreal injection of ranibizumab to her right eye and was evaluated the next day (less than 24 hours from the injection) because of acute loss of vision. Her vision had decreased from 20/50 to hand motions in the right eye at the time of reevaluation. Wide-ﬁeld fundus photography demonstrated pallid optic nerve head edema, generalized vascular attenuation, diffuse vascular sheathing, and scattered large postequatorial intraretinal hemorrhages. Ultra-wide-ﬁeld ﬂuorescein angiography revealed a severely delayed AV transit time associated with extensive areas of retinal nonperfusion and late retinal vascular leakage consistent with occlusive vasculitis. She underwent immediate pars plana vitrectomy with extensive irrigation of the vitreous cavity and intravitreal injection of antibiotics. In light of a worsening clinical course, she was taken for repeat vitrectomy 1 week later with panretinal endolaser photocoagulation, instillation of silicone oil, and sub-Tenon triamcinolone acetonide. At postoperative month 1, she maintained 20/200 vision with improved retinal perfusion on ﬂuorescein angiography. Conclusion: We describe a hyperacute case of S. mitis endophthalmitis after intravitreal injection with ranibizumab, associated with severe occlusive vasculitis on ultra-wide-ﬁeld ﬂuorescein angiography. Aggressive early surgical intervention may be associated with better outcomes than previously reported. RETINAL CASES & BRIEF REPORTS 9:201–204, 2015
From the *St John Providence Health System, Joseph H. Wyatt Ophthalmology Residency, Patrick Murray Eye Center, Detroit, Michigan; and †Associated Retinal consultants, William Beaumont Hospital, Royal Oak, Michigan.
Although rare, endophthalmitis after intravitreal injections has been associated with devastating visual outcomes and is estimated to occur once every 2,000 to 5,000 injections.2 This report describes the unique presenting features, including wide-ﬁeld angiography and aggressive surgical management of a case of hyperacute endophthalmitis with occlusive vasculitis caused by Streptococcus mitis after an intravitreal injection with ranibizumab.
he use of intravitreal vascular endothelial growth factor inhibitors has rapidly become the ﬁrst-line standard of care therapy for many retinal diseases. They are currently approved by the Food and Drug administration for use in neovascular age-related macular degeneration, macular edema from retinal vein occlusion, and diabetic macular edema. The most common adverse effect is transient elevation in intraocular pressure, and the most devastating is endophthalmitis.1,2
Case Report An 83-year-old woman received an intravitreal injection of ranibizumab to her right eye for persistent cystoid macular edema secondary to a macular branch retinal vein occlusion (see preinjection color photographs and ﬂuorescein angiogram in Figure 1, A and B).
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Fig. 1. A. Fundus photograph demonstrating macular branch retinal vein occlusion before injection resulting in endophthalmitis. B. Fluorescein angiogram demonstrating cystoid macular edema secondary to branch retinal vein occlusion before endophthalmitis.
Injection preparation included a sterile lid speculum, gloves, 10% betadine swabbing of the eyelids and eyelashes, and 10% betadine irrigation of the ocular surface. A face mask was not worn by the patient or the physician; however, as per routine, the physician and patient did not speak while the needle was exposed. She had received an intravitreal injection of ranibizumab into the same eye 1 month earlier, which was well tolerated and resulted in improvement in visual acuity to 20/50. She awoke that evening (approximately 16 hours after the injection) with painless severe loss of vision. She was evaluated in the ofﬁce later that morning (less than 24 hours after the injection) and was found to have a visual acuity of hand motions and an intraocular pressure of 11. Initial slit-lamp examination revealed mild conjunctival injection, 1+ anterior chamber cell without hypopyon or ﬁbrin deposition, a well-positioned PCIOL, and trace anterior vitreous cell. Dilated fundus examination revealed diffuse creamy tan-colored vitreous opacities with a relatively clear view of the retina that demonstrated pallid optic nerve head edema, generalized vascular attenuation, diffuse vascular sheathing, and scattered large postequatorial intraretinal hemorrhages (Figure 2A). Wide-ﬁeld ﬂuorescein angiography (Figure 2, B and C) obtained on the Optos 200Tx (Optos plc, Dunfermline, Scotland) revealed a severely delayed AV transit time associated with extensive areas of retinal
None of the authors have any ﬁnancial/conﬂicting interests to disclose. Reprint requests: Kevin R. Baxter, DO, Patrick Murray Eye Center, 4777 E. Outer Drive, Detroit, Michigan 48234; e-mail: [email protected]
nonperfusion and late retinal vascular leakage consistent with occlusive vasculitis. Given the explosive presentation associated with rapid vision loss and an apparent severe toxin-induced vasculopathy, early vitrectomy with intravitreal antibiotics was recommended. The patient underwent uncomplicated complete 25-gauge pars plana vitrectomy, extensive irrigation of the vitreous cavity with exchange of approximately 300 mL of sterile balanced salt solution, and injection of vancomycin (1 mg/0.1 mL) and ceftazidime (2.25 mg/0.1 mL). The eye was left under ﬂuid as no retinal break was suspected, and a homogenous concentration of antibiotic throughout the eye was desired. Examination on the ﬁrst postoperative day revealed a visual acuity of light perception, a 2-mm hypopyon, and an extensive ﬁbrinoid reaction in the anterior chamber that precluded a view to the posterior segment. B-scan ultrasound demonstrated dense vitreous debris and an attached retina. On the second postoperative day, when cultures demonstrated S. mitis sensitive to vancomycin, she was given a second intravitreal injection of vancomycin (1 mg/0.1 mL), started on 60 mg oral prednisone daily and continued on hourly topical prednisolone. With continuing clinical deterioration over the ensuing days, including persistent light perception vision, worsening hypopyon, and worsening ocular pain despite aggressive medical therapy including increasing oral prednisone to 80 mg daily, she was taken back to the operating room on the seventh postoperative day for repeat vitrectomy, panretinal endolaser photocoagulation, instillation of silicone oil, and posterior sub-Tenon injection of 40 mg of triamcinolone acetonide. The decision for panretinal endolaser photocoagulation and silicone oil instillation were driven by previous reports of S. mitis endophthalmitis that highlight neovascularization, neovascular glaucoma, and proliferative vitreoretinopathy–related recurrent retinal detachments as common sequelae.1–3 At follow-up examination (1 month after the second vitrectomy), she was found to have a visual acuity of 20/200 with mild optic nerve pallor, an attached retina under silicone oil, and improved retinal perfusion on ﬂuorescein angiography (Figure 3A). Optical coherence tomography demonstrates retinal thinning temporally consistent with a previous vasoocclusive event but preserved retinal architecture nasal to the fovea. Two months after vitrectomy and oil instillation, the patient then underwent repeat vitrectomy with inferior retinectomy and repeat silicone oil infusion. At 6-month follow-up, the retina remains attached with a vision of counting ﬁngers.
Discussion Infectious endophthalmitis after intravitreal injection can be a catastrophic event, resulting in a poor visual acuity or loss of the eye even when standard preinjection antiseptic precautions are appropriately undertaken. In the current case, these included the use of a sterile lid speculum, gloves, 10% betadine swabbing of the eyelids and eyelashes, and 10% betadine irrigation of the ocular surface. Neither preinjection nor postinjection antibiotics were administered. Recently, Moshfeghi et al4 estimated the risk of endophthalmitis after intravitreal injection of antivascular endothelial growth factor agents at approximately once every 2,000 to 5,000 injections. In this large retrospective review, a total of 60,322 eyes were injected with 12 cases of postinjection endophthalmitis, yielding a rate of 0.00114% to 0.0348%, which is
Fig. 2. A. Fundus photograph demonstrating pallid optic nerve head edema, generalized vascular attenuation, diffuse vascular sheathing, and scattered large postequatorial intraretinal hemorrhages at initial presentation after intravitreal injection. B. Wide-ﬁeld ﬂuorescein angiography at 0:26 demonstrating severely delayed AV transit time associated with extensive areas of retinal nonperfusion. C. Wide-ﬁeld ﬂuorescein angiography at 1:20 demonstrating severely delayed AV transit time associated with extensive areas of retinal nonperfusion and late retinal vascular leakage consistent with occlusive vasculitis.
consistent with previously published data. Typically, patients presented within 3 days after injection. Although endophthalmitis is a rare complication associated with intravitreal injections, the most commonly isolated organisms are staphylococcus and streptococcus species. Our patient demonstrated culture-proven S. mitis endophthalmitis, which is an a-hemolytic gram-positive bacterium that is found to normally colonize the human oral cavity and is a wellknown frequent cause of infectious endocarditis. Historically, S. mitis was considered to have low virulence and pathogenicity, although recent reports have demonstrated a more aggressive nature and increasing resistance to treatment. Recently, Goldberg et al1,2 described a series of endophthalmitis resulting from S. mitis in 12 patients after intravitreal injection of contaminated compounded bevacizumab. The eyes in this series were associated with poor outcomes, with 7 of 12 eyes requiring
Fig. 3. Wide-ﬁeld ﬂuorescein angiography after multiple vitrectomy and silicone oil placement demonstrating an attached retina and improved retinal perfusion.
enucleation or evisceration and only 1 eye regaining preinjection acuity despite aggressive management.1,2 Subsequently reported histopathologic evaluation revealed complete retinal detachment in all ﬁve enucleated eyes in addition to moderate-to-marked retinal necrosis in six of seven examined specimens, and extensive neovascularization in all eyes.3 In 2009, Chen et al5 described a case of S. mitis endophthalmitis presenting as frosted branch angiitis after intravitreal injection with pegaptanib sodium. Early ﬂuorescein angiography demonstrated diffuse vasculitis and petalloid macular edema. Although retinal vasculitis and intraretinal hemorrhage have been previously described in cases of infectious endophthalmitis, to the best of our knowledge, this case represents the ﬁrst of a severe occlusive vasculitis with a paucity of inﬂammatory signs and symptoms presenting within hours after an intravitreal injection. We believe the unique clinical presentation of this case to be at least in part due to the effect of bacterial toxins on retinal vasculature. Streptolysin O is a toxin released by S. mitis that may induce a reduction in blood ﬂow through formation of intravascular aggregates in arterioles and venules.6 In addition, streptolysin O has been shown to promote adherence between platelets and neutrophils forming complexes that can further decrease perfusion to retinal tissue.6,7 We believe the early aggressive surgical interventions to have played a pivotal role in yielding visual and structural outcomes that may be better than those would be expected for this destructive pathogen. At the time of the ﬁrst vitrectomy, the eye was copiously irrigated with at least 300 mL of BSS in an effort to lavage out as much toxin as possible. Instillation of silicone oil and addition of panretinal endolaser photocoagulation during the second surgery were efforts to help prevent the development of neovascular glaucoma and proliferative vitreoretinopathy, which
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have been reported to be common long-term sequelae after S. mitis endophthalmitis.3 In conclusion, we describe a very unusual and explosive presentation of infectious endophthalmitis caused by S. mitis after intravitreal injection with ranibizumab. Aggressive early surgical intervention as described above may be associated with better outcomes than previously reported. Key words: endophthalmitis, hyperacute, vasculitis, ranibizumab, wide-ﬁeld photography and angiography, anti-VEGF, vitrectomy.
References 1. Goldberg RA, Flynn HW Jr, Isom RF, et al. An outbreak of Streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol 2012;153:204–208. 2. Goldberg RA, Flynn HW Jr, Miller D, et al. Streptococcus endopthalmitis outbreak after intravitreal injection of bevacizumab:
one year outcomes and investigative results. Ophthalmology 2013;120:1448–1453. Mathews JL, Dubovy SR, Goldberg RA, et al. Histopathology of streptococcus mitis/oralis endophthalmitis after intravitreal injection with bevacizumab: a report of 7 patients. Ophthalmology 2014;121:702–708. Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr, et al. Endophthalmitis after intravitreal anti-vascular endothelial growth factor antagonists: a six year experience at a university referral center. Retina 2011;31:662–668. Chen E, Ho AC, Garg SJ, et al. Streptococcus mitis endophthalmitis presenting as frosted branch angiitis after intravitreal pegaptanib sodium injection. Ophthalmic Surg Lasers Imaging 2009;40:192–194. Bryant AE, Bayer CR, Chen RY, et al. Vascular dysfunction and ischemic destruction of tissue in streptococcus pyrogenes infection: the role of streptolyson O-induced platelet/neutrophil complexes. J Infect Dis 2005;192:1014–1022. Kuriyan AE, Weiss KD, Flynn HW, et al. Endophthalmitis caused by streptococcal species: clinical settings, microbiology, management, and outcomes. Am J Ophthalmol 2014;157:774–780.