STERILE ENDOPHTHALMITIS AFTER INTRAVITREAL OCRIPLASMIN INJECTION: REPORT OF A SINGLE CASE Ian C. Han, MD, Adrienne W. Scott, MD
Purpose: To report a case of presumed sterile endophthalmitis after intravitreal ocriplasmin injection. Methods: Observational case report. Review of clinical examination, ocular imaging, and published literature. Results: A 67-year-old woman with early cataracts presented with decreased vision in the left eye related to vitreomacular adhesion. She was treated with intravitreal ocriplasmin injection and developed a severe anterior chamber inflammatory reaction in less than 24 hours after the injection. Inflammation responded completely to topical steroids alone, without topical or intravitreal antibiotics. Conclusion: Patients treated with intravitreal ocriplasmin may develop an acute inflammatory reaction, which can be severe. RETINAL CASES & BRIEF REPORTS 9:242–244, 2015
visible intraocular inflammation or other change in anterior segment or fundus examination. Initial cautious observation was recommended. By 24 hours after injection, visual acuity had declined to counting fingers, with persistent pain and photophobia, and clinical examination revealed conjunctival hyperemia, fine keratic precipitates, and a static 4+ fibrinous anterior chamber reaction with 3-mm layered pseudohypopyon. Posterior synechiae formation and 2+ vitreous haze were also noted. The fundus appearance was otherwise unchanged and showed no retinal hemorrhages or vascular abnormalities. Although vitreous/aqueous tap with injection of intravitreal antibiotics was considered, the timing of symptoms and clinical appearance were believed most consistent with sterile rather than infectious endophthalmitis. The patient was started on intensive topical steroid therapy with hourly prednisolone acetate 1% and given atropine 1% for cycloplegia. At 48 hours after injection (24 hours after initiation of topical steroids), visual acuity improved to 20/200, with decreased anterior chamber inflammation with 1 mm pseudohypopyon. By 1 week after injection, visual acuity was 20/80, with complete resolution of anterior chamber inflammation and 1+ persistent vitreous haze, for which topical steroids were tapered. Repeat spectral domain optical coherence tomography showed persistent vitreomacular adhesion (Figure 1B), which released by 2 weeks after injection (Figure 1C). By 2 months, visual acuity improved to 20/30, with few residual vitreous opacities, mild epiretinal membrane, and lamellar hole configuration on spectral domain optical coherence tomography (Figure 1D), and these findings were stable on follow-up at 6 months (Figure 1E).
From the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
Case Report A 67-year-old woman with hypertension and early nuclear sclerosis cataracts presented with decreased vision in her left eye. On her initial visit, best-corrected visual acuity measured 20/40, and examination revealed mild nuclear sclerosis cataracts but otherwise normal anterior segment bilaterally, with no anterior chamber or vitreous cell or posterior synechiae. Fundus examination in the left eye revealed a blunt foveal reflex, and spectral domain optical coherence tomography confirmed foveal vitreomacular adhesion (Figure 1A). Options including observation, intravitreal ocriplasmin, and pars plana vitrectomy were discussed. After initial observation with no improvement, the patient elected to proceed with intravitreal ocriplasmin (0.125 mg/0.1 mL JETREA; ThromboGenics Inc, Iselin, NJ) injection, which was reconstituted per the manufacturer’s instructions and administered without complication. Within 2 hours after injection, the patient reported decreased vision, pain, and photophobia. She was seen in urgent follow-up by 4 hours after injection. Visual acuity measured 20/60, and there was no None of the authors have any financial/conflicting interests to disclose. Reprint requests: Adrienne W. Scott, MD, Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 N. Wolfe Street, Maumenee Room 719, Baltimore, MD 21287; e-mail: ascott28@ jhmi.edu
Discussion To the best of our knowledge, this is the first report of endophthalmitis, either infectious or sterile, after 242
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243
Fig. 1. Registered spectral domain optical coherence tomography line scans, left macula. A. Before treatment with intravitreal ocriplasmin, showing focal vitreomacular adhesion (VMA) at the fovea. B. One week after injection, with persistent VMA and mild disruption of the ellipsoid zone. Note that this image was obtained by a macular cube scan protocol, as a high-resolution scan was unable to be obtained because low signal from media opacity, as seen on the fundus infrared reference image. C. Two weeks after treatment, with release of VMA. There is improved image quality but persistent vertical linear shadowing from vitreous opacities as part of the postinjection inflammatory response. D. Two months after treatment, showing lamellar hole configuration with mild cystoid changes and mild persistent disruption of the ellipsoid zone. E. Six months after treatment, showing restored but slightly irregular foveal contour with mild cystoid abnormalities and restoration of the ellipsoid zone.
intravitreal ocriplasmin injection. The patient had no history of uveitis or any evidence of intraocular inflammation on her initial examination before treatment. Distinguishing between sterile and infectious endophthalmitis can present a diagnostic and treatment challenge, as the management and prognosis differ greatly. In our case, the rapid onset of symptoms and inflammation in less than 24 hours coupled with resolution of inflammation with topical steroids alone suggested sterile rather than infectious endophthalmitis.
Numerous case series have characterized inflammation after intravitreal anti-vascular endothelial growth factor injections. Although published reports vary, rates of postinjection inflammation are generally less than 1% in larger case series involving bevacizumab, ranibizumab, or aflibercept.1–3 By contrast, the literature describing postinjection inflammation with intravitreal ocriplasmin is limited. In Phase 3 clinical trials, 7.1% of patients treated with intravitreal ocriplasmin were found to have postinjection inflammation compared with 3.7% of those
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injected with vehicle alone.4 Although inflammation was typically mild, severe inflammation was noted in one patient with known ocriplasmin overdose where the medication was improperly diluted.4 Our patient’s presenting symptoms of pain, photophobia, and decreased vision are relatively common adverse events, with rates of 13.1, 8.4, and 3.7%, respectively, in the Phase 3 trials.4 The relative frequency of these symptoms highlights the clinical challenge in distinguishing between an expected postinjection response versus endophthalmitis based on symptoms alone. Ocriplasmin contains the active moiety of plasmin, which has multiple known systemic proinflammatory properties.5 Although the inflammatory effects of ocriplasmin in the human vitreous are not well described, a higher rate of inflammation after injection of ocriplasmin compared with anti-vascular endothelial growth factor may be expected. As a proteolytic enzyme, ocriplasmin needs to be stored frozen, thawed, and reconstituted in sterile balanced saline solution before use. It is unclear what effect these preparatory steps may have on any potential inflammatory properties. Recent reports have raised additional safety concerns regarding ocriplasmin, noting a focal disruption of the ellipsoid zone under the fovea in some cases, with an apparent global dysfunction as evidence by reduced photopic and scotopic function on electroretinography.6–8 These reports suggest that the activity of ocriplasmin is not isolated to the vitreomacular interface and that ocriplasmin may have more diffuse enzymatic effects within the neurosensory retina. Interestingly, our patient also had mild disruption of the ellipsoid zone noted on spectral domain optical coherence tomography (Figure 1, C and D). Although the patient’s initial decrease in vision can be attributed to the media opacity from sterile endophthalmitis, visual acuity did not return to baseline until 2 months after injection, and the disruption at the level of the photoreceptors may account for this delayed improvement.
Physicians should be aware that patients injected with intravitreal ocriplasmin may develop an acute inflammatory reaction, which can be severe. Distinguishing between infectious and sterile endophthalmitis in this context can be challenging, and physicians should use caution in determining the best course of management. The informed consent process should include a discussion of complications, including mild or severe inflammation and transient vision loss, and the physician should carefully weigh these additional potential risks when considering treatment. Key words: endophthalmitis, intravitreal injection, macular hole, ocriplasmin, uveitis, vitreomacular adhesion. References 1. Chong DY, Anand R, Williams PD, et al. Characterization of sterile intraocular inflammatory responses after intravitreal bevacizumab injection. Retina 2010;30:1432–1440. 2. Hahn P, Kim JE, Stinnett S, et al. Aflibercept-related sterile inflammation. Ophthalmology 2013;120:1100–1101.e1-5. 3. Shah CP, Garg SJ, Vander JF, et al. Outcomes and risk factors associated with endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmology 2011;118:2028–2034. 4. Dermatologic and Ophthalmic Drugs Advisory Committee. Ocriplasmin (Jetrea) briefing document. 2012. Available at: http://www.fda.gov/downloads/advisorycommittees/committees meetingmaterials/drugs/dermatologicandophthalmicdrugs advis orycommittee/ucm313091.pdf. Accessed March 23, 2014. 5. Syrovets T, Lunov O, Simmet T. Plasmin as a proinflammatory cell activator. J Leukoc Biol 2012;92:509–519. 6. Tibbetts MD, Reichel E, Witkins AJ. Vision loss after intravitreal ocriplasmin: correlation of spectral-domain optical coherence tomography and electroretinography. JAMA Ophthalmol 2014;132:487–490. 7. Fahim AT, Khan NW, Johnson MW. Acute panretinal structural and functional abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol 2014;132:484–486. 8. Freund KB, Shah SA, Shah VP. Correlation of transient vision loss with outer retinal disruption following intravitreal ocriplasmin. Eye (Lond) 2013;27:773–774.
Purpose: To report a case of presumed sterile endophthalmitis after intravitreal ocriplasmin injection. Methods: Observational case report. Review of clinical examination, ocular imaging, and published literature. Results: A 67-year-old woman with early cataracts presented with decreased vision in the left eye related to vitreomacular adhesion. She was treated with intravitreal ocriplasmin injection and developed a severe anterior chamber inflammatory reaction in less than 24 hours after the injection. Inflammation responded completely to topical steroids alone, without topical or intravitreal antibiotics. Conclusion: Patients treated with intravitreal ocriplasmin may develop an acute inflammatory reaction, which can be severe. RETINAL CASES & BRIEF REPORTS 9:242–244, 2015
visible intraocular inflammation or other change in anterior segment or fundus examination. Initial cautious observation was recommended. By 24 hours after injection, visual acuity had declined to counting fingers, with persistent pain and photophobia, and clinical examination revealed conjunctival hyperemia, fine keratic precipitates, and a static 4+ fibrinous anterior chamber reaction with 3-mm layered pseudohypopyon. Posterior synechiae formation and 2+ vitreous haze were also noted. The fundus appearance was otherwise unchanged and showed no retinal hemorrhages or vascular abnormalities. Although vitreous/aqueous tap with injection of intravitreal antibiotics was considered, the timing of symptoms and clinical appearance were believed most consistent with sterile rather than infectious endophthalmitis. The patient was started on intensive topical steroid therapy with hourly prednisolone acetate 1% and given atropine 1% for cycloplegia. At 48 hours after injection (24 hours after initiation of topical steroids), visual acuity improved to 20/200, with decreased anterior chamber inflammation with 1 mm pseudohypopyon. By 1 week after injection, visual acuity was 20/80, with complete resolution of anterior chamber inflammation and 1+ persistent vitreous haze, for which topical steroids were tapered. Repeat spectral domain optical coherence tomography showed persistent vitreomacular adhesion (Figure 1B), which released by 2 weeks after injection (Figure 1C). By 2 months, visual acuity improved to 20/30, with few residual vitreous opacities, mild epiretinal membrane, and lamellar hole configuration on spectral domain optical coherence tomography (Figure 1D), and these findings were stable on follow-up at 6 months (Figure 1E).
From the Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
Case Report A 67-year-old woman with hypertension and early nuclear sclerosis cataracts presented with decreased vision in her left eye. On her initial visit, best-corrected visual acuity measured 20/40, and examination revealed mild nuclear sclerosis cataracts but otherwise normal anterior segment bilaterally, with no anterior chamber or vitreous cell or posterior synechiae. Fundus examination in the left eye revealed a blunt foveal reflex, and spectral domain optical coherence tomography confirmed foveal vitreomacular adhesion (Figure 1A). Options including observation, intravitreal ocriplasmin, and pars plana vitrectomy were discussed. After initial observation with no improvement, the patient elected to proceed with intravitreal ocriplasmin (0.125 mg/0.1 mL JETREA; ThromboGenics Inc, Iselin, NJ) injection, which was reconstituted per the manufacturer’s instructions and administered without complication. Within 2 hours after injection, the patient reported decreased vision, pain, and photophobia. She was seen in urgent follow-up by 4 hours after injection. Visual acuity measured 20/60, and there was no None of the authors have any financial/conflicting interests to disclose. Reprint requests: Adrienne W. Scott, MD, Wilmer Eye Institute, Johns Hopkins School of Medicine, 600 N. Wolfe Street, Maumenee Room 719, Baltimore, MD 21287; e-mail: ascott28@ jhmi.edu
Discussion To the best of our knowledge, this is the first report of endophthalmitis, either infectious or sterile, after 242
OCRIPLASMIN-ASSOCIATED ENDOPHTHALMITIS
243
Fig. 1. Registered spectral domain optical coherence tomography line scans, left macula. A. Before treatment with intravitreal ocriplasmin, showing focal vitreomacular adhesion (VMA) at the fovea. B. One week after injection, with persistent VMA and mild disruption of the ellipsoid zone. Note that this image was obtained by a macular cube scan protocol, as a high-resolution scan was unable to be obtained because low signal from media opacity, as seen on the fundus infrared reference image. C. Two weeks after treatment, with release of VMA. There is improved image quality but persistent vertical linear shadowing from vitreous opacities as part of the postinjection inflammatory response. D. Two months after treatment, showing lamellar hole configuration with mild cystoid changes and mild persistent disruption of the ellipsoid zone. E. Six months after treatment, showing restored but slightly irregular foveal contour with mild cystoid abnormalities and restoration of the ellipsoid zone.
intravitreal ocriplasmin injection. The patient had no history of uveitis or any evidence of intraocular inflammation on her initial examination before treatment. Distinguishing between sterile and infectious endophthalmitis can present a diagnostic and treatment challenge, as the management and prognosis differ greatly. In our case, the rapid onset of symptoms and inflammation in less than 24 hours coupled with resolution of inflammation with topical steroids alone suggested sterile rather than infectious endophthalmitis.
Numerous case series have characterized inflammation after intravitreal anti-vascular endothelial growth factor injections. Although published reports vary, rates of postinjection inflammation are generally less than 1% in larger case series involving bevacizumab, ranibizumab, or aflibercept.1–3 By contrast, the literature describing postinjection inflammation with intravitreal ocriplasmin is limited. In Phase 3 clinical trials, 7.1% of patients treated with intravitreal ocriplasmin were found to have postinjection inflammation compared with 3.7% of those
244
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injected with vehicle alone.4 Although inflammation was typically mild, severe inflammation was noted in one patient with known ocriplasmin overdose where the medication was improperly diluted.4 Our patient’s presenting symptoms of pain, photophobia, and decreased vision are relatively common adverse events, with rates of 13.1, 8.4, and 3.7%, respectively, in the Phase 3 trials.4 The relative frequency of these symptoms highlights the clinical challenge in distinguishing between an expected postinjection response versus endophthalmitis based on symptoms alone. Ocriplasmin contains the active moiety of plasmin, which has multiple known systemic proinflammatory properties.5 Although the inflammatory effects of ocriplasmin in the human vitreous are not well described, a higher rate of inflammation after injection of ocriplasmin compared with anti-vascular endothelial growth factor may be expected. As a proteolytic enzyme, ocriplasmin needs to be stored frozen, thawed, and reconstituted in sterile balanced saline solution before use. It is unclear what effect these preparatory steps may have on any potential inflammatory properties. Recent reports have raised additional safety concerns regarding ocriplasmin, noting a focal disruption of the ellipsoid zone under the fovea in some cases, with an apparent global dysfunction as evidence by reduced photopic and scotopic function on electroretinography.6–8 These reports suggest that the activity of ocriplasmin is not isolated to the vitreomacular interface and that ocriplasmin may have more diffuse enzymatic effects within the neurosensory retina. Interestingly, our patient also had mild disruption of the ellipsoid zone noted on spectral domain optical coherence tomography (Figure 1, C and D). Although the patient’s initial decrease in vision can be attributed to the media opacity from sterile endophthalmitis, visual acuity did not return to baseline until 2 months after injection, and the disruption at the level of the photoreceptors may account for this delayed improvement.
Physicians should be aware that patients injected with intravitreal ocriplasmin may develop an acute inflammatory reaction, which can be severe. Distinguishing between infectious and sterile endophthalmitis in this context can be challenging, and physicians should use caution in determining the best course of management. The informed consent process should include a discussion of complications, including mild or severe inflammation and transient vision loss, and the physician should carefully weigh these additional potential risks when considering treatment. Key words: endophthalmitis, intravitreal injection, macular hole, ocriplasmin, uveitis, vitreomacular adhesion. References 1. Chong DY, Anand R, Williams PD, et al. Characterization of sterile intraocular inflammatory responses after intravitreal bevacizumab injection. Retina 2010;30:1432–1440. 2. Hahn P, Kim JE, Stinnett S, et al. Aflibercept-related sterile inflammation. Ophthalmology 2013;120:1100–1101.e1-5. 3. Shah CP, Garg SJ, Vander JF, et al. Outcomes and risk factors associated with endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmology 2011;118:2028–2034. 4. Dermatologic and Ophthalmic Drugs Advisory Committee. Ocriplasmin (Jetrea) briefing document. 2012. Available at: http://www.fda.gov/downloads/advisorycommittees/committees meetingmaterials/drugs/dermatologicandophthalmicdrugs advis orycommittee/ucm313091.pdf. Accessed March 23, 2014. 5. Syrovets T, Lunov O, Simmet T. Plasmin as a proinflammatory cell activator. J Leukoc Biol 2012;92:509–519. 6. Tibbetts MD, Reichel E, Witkins AJ. Vision loss after intravitreal ocriplasmin: correlation of spectral-domain optical coherence tomography and electroretinography. JAMA Ophthalmol 2014;132:487–490. 7. Fahim AT, Khan NW, Johnson MW. Acute panretinal structural and functional abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol 2014;132:484–486. 8. Freund KB, Shah SA, Shah VP. Correlation of transient vision loss with outer retinal disruption following intravitreal ocriplasmin. Eye (Lond) 2013;27:773–774.
