VITREOMACULAR TRACTION AFTER DEXAMETHASONE INTRAVITREAL IMPLANT (OZURDEX) INJECTION: THE EFFECT OF ANOMALOUS POSTERIOR VITREOUS DETACHMENT Ronakorn Panjaphongse, MD,*† Jay M. Stewart, MD*
Purpose: To describe an unusual macular complication after dexamethasone intravitreal implant (Ozurdex) injection. Methods: Case history and macular optical coherence tomography findings are described. The report describes a patient with proliferative diabetic retinopathy and vitreoschisis who received Ozurdex treatment for diabetic macular edema. Results: After Ozurdex injection, visual acuity worsened because of newly formed vitreomacular traction that was demonstrated on optical coherence tomography imaging. A mechanism is proposed by which the medication might have contributed to this outcome. Conclusion: In this patient with vitreoschisis, a thickened posterior hyaloid membrane and traction developed after Ozurdex injection. The authors recommend careful evaluation of the macula before injection, particularly in diabetic patients with vitreoschisis. RETINAL CASES & BRIEF REPORTS 10:55–57, 2016
From the *Department of Ophthalmology, University of California, San Francisco, San Francisco, California; and †Department of Ophthalmology, Bhumibol Adulyadej Hospital, Royal Thai Air Force, Bangkok, Thailand.
Case Report A 69-year-old man presented with proliferative diabetic retinopathy and diabetic macular edema in the left eye. Optical coherence tomography examination revealed multiple, large intraretinal cystoid fluid collections (Figure 1, A and B) with splitting of the premacular posterior cortical vitreous inferiorly (Figure 1B). After treatment with laser and posterior sub-Tenon’s triamcinolone injection, central macular edema still persisted. Optical coherence tomography examination revealed mild epimacular membrane (EMM) formation with a premacular posterior cortical vitreous membrane (Figure 2A). He elected to undergo off-label Ozurdex injection. Four weeks after injection, visual acuity decreased from 20/100 to 20/200. Fundus examination revealed an increase in diabetic macular edema with a preretinal membrane in the macula. Optical coherence tomography showed that this was due to thickening and adhesion between the previously formed EMM and the premacular membrane (Figure 2B). After 2 months without improvement, vitrectomy with membrane peeling was performed to release the traction. One month later, visual acuity was 20/60 and optical coherence tomography showed improvement of the retinal contour (Figure 2C).
C
ommon ocular adverse events after intravitreal injection of Ozurdex (dexamethasone delivery device; Allergan, Irvine, CA) include cataract and ocular hypertension.1 We describe an unusual development of vitreomacular traction after Ozurdex injection.
Supported by That Man May See, Inc and Research to Prevent Blindness. None of the authors have any conflicting interests to disclose. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Reprint requests: Jay M. Stewart, MD, Department of Ophthalmology, University of California, San Francisco, 10 Koret Way, K301, San Francisco, CA 94143-0730; e-mail: Jay.Stewart@ ucsf.edu
Discussion Abnormality of vitreomacular interface and status of posterior vitreous cortex are well documented in many 55
56
Fig. 1. Optical coherence tomography of the macula before any treatment shows significant macular edema with multiple, large intraretinal cystoid fluid collections. Note the splitting of the premacular, posterior cortical vitreous at the inferior part of the macula (arrows).
Fig. 2. Optical coherence tomography (OCT) of the macula. A. before Ozurdex injection, OCT shows macular edema with multiple intraretinal cystoid spaces and mild EMM formation. Note the hyperreflective preretinal membrane at the posterior vitreous cavity (arrows). B. One month after Ozurdex injection, OCT shows improvement in macular edema temporally with new vitreomacular traction on the nasal macula. Note the attachment of two membranous layers that form the Y-shaped sign suggestive of vitreoschisis7 (*). C. After vitrectomy with membrane peeling, OCT shows resolution of macular edema and resolution of vitreomacular traction.
RETINAL CASES & BRIEF REPORTS´ 2016 VOLUME 10 NUMBER 1
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VITREOMACULAR TRACTION AFTER OZURDEX INJECTION
diseases such as diabetes2 and retinal vein occlusion.3 In this case, we present an unusual clinical scenario after Ozurdex injection in which a previously formed EMM became thickened and fused with a premacular posterior cortical vitreous membrane, resulting in a visually significant change because of an abnormal vitreoretinal interface. This process may be explained by considering the concept of anomalous posterior vitreous detachment,4 which occurs from variability in the rates of vitreous liquefaction and vitreoretinal interface detachment, causing the collapse of the vitreous body with an abnormal vitreoretinal interface. According to this concept, EMM occurs from splitting of the posterior cortical vitreous somewhere anterior to the location of the hyalocytes,5,6 leaving a thick, hypercellular, and contractile membrane attached to the retina. In this case, the presence of vitreoschisis is suggested by the appearance of a Y-shaped membranous layer on optical coherence tomography7 before Ozurdex administration (Figure 2A). Because Ozurdex is injected into the eye using a special mechanical applicator, the injected Ozurdex pellet has been reported as having significant muzzle velocity, and it has been hypothesized that although this velocity does not reach the reported damage levels of the retina,8 it could possibly cause a drag force on the entire vitreous gel.9 We propose that Ozurdex injection can physically induce a shock wave on the entire vitreous causing posterior movement of a premacular membrane, leading to accidental attachment of this membrane to an EMM and resulting in clinically significant vitreomacular traction with a worsening of a patient’s macular edema. This physical effect from injection may not be specific to Ozurdex as opposed to other types of intravitreal injections, as the Vitrase study10 demonstrated that even an intravitreal saline injection can induce changes in the vitreous. It is also possible that a chemical stimulus, resulting in cytokine up-regulation and cellular proliferation at the retinal surface and/or posterior hyaloid face, may contribute to this event. We previously reported that an Ozurdex-shaped epiretinal membrane formed at the site of contact after being retained in a silicone oil– filled eye for several weeks.11 In support of this hypothesis, a foreign body cellular response and EMM formation have been observed in vivo after intravitreal implantation of a biodegradable copolymer of lactic acid and glycolic acid,12 the drug vehicle in the Ozurdex implant. In this case, such an effect was
likely compounded by the preexisting EMM on the retinal surface, serving as a scaffold for the proliferating cells at the posterior pole.5 Their production of extracellular matrix may form a suitable condition for attachment of a premacular membrane, eventually causing increased traction. In conclusion, Ozurdex injection in a patient with vitreoschisis and EMM may be a risk factor for vitreomacular traction. We recommend careful evaluation of the macula with attention to premacular membranes and the vitreoretinal interface before administering this treatment. Key words: dexamethasone intravitreal implant, diabetic retinopathy, Ozurdex, vitreomacular traction, vitreoschisis. References 1. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453–2460. 2. Sebag J. Diabetic vitreopathy. Ophthalmology 1996;103:205–206. 3. Bertelmann T, Kicová N, Messerschmidt-Roth A, et al. The vitreomacular interface in retinal vein occlusion. Acta Ophthalmol 2011;89:e327–e331. 4. Sebag J. Anomalous posterior vitreous detachment: a unifying concept in vitreo-retinal disease. Graefes Arch Clin Exp Ophthalmol 2004;242:690–698. 5. Sakamoto T, Ishibashi T. Hyalocytes: Essential cells of the vitreous cavity in vitreoretinal pathophysiology? Retina 2011;31:222–228. 6. Sebag J. Vitreoschisis. Graefes Arch Clin Exp Ophthalmol 2008;246:329–332. 7. Gupta P, Yee KM, Garcia P, et al. Vitreoschisis in macular diseases. Br J Ophthalmol 2011;95:376–380. 8. Meyer CH, Klein A, Alten F, et al. Release and velocity of micronized dexamethasone implants with an intravitreal drug delivery system: kinematic analysis with a high-speed camera. Retina 2012;32:2133–2140. 9. Clemens CR, Bertelmann T, Meyer CH. Vitreous traction after Ozurdex injection. J Ocul Pharmacol Ther 2013;29:3–4. 10. Kuppermann BD, Thomas EL, de Smet MD, et al. Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 2005;140:573–584. 11. Afshar AR, Loh AR, Pongsachareonnont P, et al. Dexamethasone intravitreal implant trapped at the macula in a silicone oil-filled eye. Ophthalmology 2013;120:2748–2749. 12. Giordano GG, Chevez-Barrios P, Refojo MF, Garcia CA. Biodegradation and tissue reaction to intravitreous biodegradable poly(D,L-lactic-co-glycolic)acid microspheres. Curr Eye Res 1995;14:761–768.
Purpose: To describe an unusual macular complication after dexamethasone intravitreal implant (Ozurdex) injection. Methods: Case history and macular optical coherence tomography findings are described. The report describes a patient with proliferative diabetic retinopathy and vitreoschisis who received Ozurdex treatment for diabetic macular edema. Results: After Ozurdex injection, visual acuity worsened because of newly formed vitreomacular traction that was demonstrated on optical coherence tomography imaging. A mechanism is proposed by which the medication might have contributed to this outcome. Conclusion: In this patient with vitreoschisis, a thickened posterior hyaloid membrane and traction developed after Ozurdex injection. The authors recommend careful evaluation of the macula before injection, particularly in diabetic patients with vitreoschisis. RETINAL CASES & BRIEF REPORTS 10:55–57, 2016
From the *Department of Ophthalmology, University of California, San Francisco, San Francisco, California; and †Department of Ophthalmology, Bhumibol Adulyadej Hospital, Royal Thai Air Force, Bangkok, Thailand.
Case Report A 69-year-old man presented with proliferative diabetic retinopathy and diabetic macular edema in the left eye. Optical coherence tomography examination revealed multiple, large intraretinal cystoid fluid collections (Figure 1, A and B) with splitting of the premacular posterior cortical vitreous inferiorly (Figure 1B). After treatment with laser and posterior sub-Tenon’s triamcinolone injection, central macular edema still persisted. Optical coherence tomography examination revealed mild epimacular membrane (EMM) formation with a premacular posterior cortical vitreous membrane (Figure 2A). He elected to undergo off-label Ozurdex injection. Four weeks after injection, visual acuity decreased from 20/100 to 20/200. Fundus examination revealed an increase in diabetic macular edema with a preretinal membrane in the macula. Optical coherence tomography showed that this was due to thickening and adhesion between the previously formed EMM and the premacular membrane (Figure 2B). After 2 months without improvement, vitrectomy with membrane peeling was performed to release the traction. One month later, visual acuity was 20/60 and optical coherence tomography showed improvement of the retinal contour (Figure 2C).
C
ommon ocular adverse events after intravitreal injection of Ozurdex (dexamethasone delivery device; Allergan, Irvine, CA) include cataract and ocular hypertension.1 We describe an unusual development of vitreomacular traction after Ozurdex injection.
Supported by That Man May See, Inc and Research to Prevent Blindness. None of the authors have any conflicting interests to disclose. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Reprint requests: Jay M. Stewart, MD, Department of Ophthalmology, University of California, San Francisco, 10 Koret Way, K301, San Francisco, CA 94143-0730; e-mail: Jay.Stewart@ ucsf.edu
Discussion Abnormality of vitreomacular interface and status of posterior vitreous cortex are well documented in many 55
56
Fig. 1. Optical coherence tomography of the macula before any treatment shows significant macular edema with multiple, large intraretinal cystoid fluid collections. Note the splitting of the premacular, posterior cortical vitreous at the inferior part of the macula (arrows).
Fig. 2. Optical coherence tomography (OCT) of the macula. A. before Ozurdex injection, OCT shows macular edema with multiple intraretinal cystoid spaces and mild EMM formation. Note the hyperreflective preretinal membrane at the posterior vitreous cavity (arrows). B. One month after Ozurdex injection, OCT shows improvement in macular edema temporally with new vitreomacular traction on the nasal macula. Note the attachment of two membranous layers that form the Y-shaped sign suggestive of vitreoschisis7 (*). C. After vitrectomy with membrane peeling, OCT shows resolution of macular edema and resolution of vitreomacular traction.
RETINAL CASES & BRIEF REPORTS´ 2016 VOLUME 10 NUMBER 1
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VITREOMACULAR TRACTION AFTER OZURDEX INJECTION
diseases such as diabetes2 and retinal vein occlusion.3 In this case, we present an unusual clinical scenario after Ozurdex injection in which a previously formed EMM became thickened and fused with a premacular posterior cortical vitreous membrane, resulting in a visually significant change because of an abnormal vitreoretinal interface. This process may be explained by considering the concept of anomalous posterior vitreous detachment,4 which occurs from variability in the rates of vitreous liquefaction and vitreoretinal interface detachment, causing the collapse of the vitreous body with an abnormal vitreoretinal interface. According to this concept, EMM occurs from splitting of the posterior cortical vitreous somewhere anterior to the location of the hyalocytes,5,6 leaving a thick, hypercellular, and contractile membrane attached to the retina. In this case, the presence of vitreoschisis is suggested by the appearance of a Y-shaped membranous layer on optical coherence tomography7 before Ozurdex administration (Figure 2A). Because Ozurdex is injected into the eye using a special mechanical applicator, the injected Ozurdex pellet has been reported as having significant muzzle velocity, and it has been hypothesized that although this velocity does not reach the reported damage levels of the retina,8 it could possibly cause a drag force on the entire vitreous gel.9 We propose that Ozurdex injection can physically induce a shock wave on the entire vitreous causing posterior movement of a premacular membrane, leading to accidental attachment of this membrane to an EMM and resulting in clinically significant vitreomacular traction with a worsening of a patient’s macular edema. This physical effect from injection may not be specific to Ozurdex as opposed to other types of intravitreal injections, as the Vitrase study10 demonstrated that even an intravitreal saline injection can induce changes in the vitreous. It is also possible that a chemical stimulus, resulting in cytokine up-regulation and cellular proliferation at the retinal surface and/or posterior hyaloid face, may contribute to this event. We previously reported that an Ozurdex-shaped epiretinal membrane formed at the site of contact after being retained in a silicone oil– filled eye for several weeks.11 In support of this hypothesis, a foreign body cellular response and EMM formation have been observed in vivo after intravitreal implantation of a biodegradable copolymer of lactic acid and glycolic acid,12 the drug vehicle in the Ozurdex implant. In this case, such an effect was
likely compounded by the preexisting EMM on the retinal surface, serving as a scaffold for the proliferating cells at the posterior pole.5 Their production of extracellular matrix may form a suitable condition for attachment of a premacular membrane, eventually causing increased traction. In conclusion, Ozurdex injection in a patient with vitreoschisis and EMM may be a risk factor for vitreomacular traction. We recommend careful evaluation of the macula with attention to premacular membranes and the vitreoretinal interface before administering this treatment. Key words: dexamethasone intravitreal implant, diabetic retinopathy, Ozurdex, vitreomacular traction, vitreoschisis. References 1. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453–2460. 2. Sebag J. Diabetic vitreopathy. Ophthalmology 1996;103:205–206. 3. Bertelmann T, Kicová N, Messerschmidt-Roth A, et al. The vitreomacular interface in retinal vein occlusion. Acta Ophthalmol 2011;89:e327–e331. 4. Sebag J. Anomalous posterior vitreous detachment: a unifying concept in vitreo-retinal disease. Graefes Arch Clin Exp Ophthalmol 2004;242:690–698. 5. Sakamoto T, Ishibashi T. Hyalocytes: Essential cells of the vitreous cavity in vitreoretinal pathophysiology? Retina 2011;31:222–228. 6. Sebag J. Vitreoschisis. Graefes Arch Clin Exp Ophthalmol 2008;246:329–332. 7. Gupta P, Yee KM, Garcia P, et al. Vitreoschisis in macular diseases. Br J Ophthalmol 2011;95:376–380. 8. Meyer CH, Klein A, Alten F, et al. Release and velocity of micronized dexamethasone implants with an intravitreal drug delivery system: kinematic analysis with a high-speed camera. Retina 2012;32:2133–2140. 9. Clemens CR, Bertelmann T, Meyer CH. Vitreous traction after Ozurdex injection. J Ocul Pharmacol Ther 2013;29:3–4. 10. Kuppermann BD, Thomas EL, de Smet MD, et al. Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 2005;140:573–584. 11. Afshar AR, Loh AR, Pongsachareonnont P, et al. Dexamethasone intravitreal implant trapped at the macula in a silicone oil-filled eye. Ophthalmology 2013;120:2748–2749. 12. Giordano GG, Chevez-Barrios P, Refojo MF, Garcia CA. Biodegradation and tissue reaction to intravitreous biodegradable poly(D,L-lactic-co-glycolic)acid microspheres. Curr Eye Res 1995;14:761–768.
