BILATERAL MACULAR HOLE AFTER ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN A PATIENT WITH EXUDATIVE AGE-RELATED MACULAR DEGENERATION Caio V. Regatieri, MD, PhD, Jay S. Duker, MD
Purpose: To report a case of bilateral nonsequential macular holes that developed after intravitreal ranibizumab therapy for treatment of exudative age-related macular degeneration. Methods: A 76-year-old man presented with sudden vision loss in the right eye initially followed by the left eye 1 year later. Initial fundoscopic examination showed a subretinal hemorrhage in the right eye and dry macular degeneration in the left eye. Initial optical coherence tomography and fluorescein angiogram confirmed the diagnosis of subfoveal choroidal neovascularization in the right eye. There was no evidence of vitreofoveal traction. The patient was treated with intravitreal injections of ranibizumab (0.5 mg). One year later, choroidal neovascularization developed in his left eye as well. Results: After choroidal neovascularization regression, full-thickness macular holes were observed in both eyes. Pars plana vitrectomy with internal limiting membrane removal was performed in both eyes. Anatomic closure of the macular hole in the left eye without significant vision improvement occurred but the right macular hole remained open despite the surgery. Conclusion: Exudative age-related macular degeneration can be a precursor to macular hole formation. RETINAL CASES & BRIEF REPORTS 6:125–128, 2012
inhibitors, such as ranibizumab, in the treatment of ocular neovascular disorders.2 Ranibizumab (Lucentis; Genentech, Inc, San Francisco, CA) is a humanized monoclonal antibody fragment designed to bind all isoforms of vascular endothelial growth factor and as a result block vessel permeability and angiogenesis.3 Ranibizumab is an effective and safe antiangiogenic and anti–vascular endothelial growth factor agent used to treat CNV associated with exudative AMD.2 However, intravitreal antiangiogenic therapy may induce adverse complications such as endophthalmitis, retinal detachment, and retinal pigment epithelial (RPE) tears.2 We report the case of a patient who developed bilateral nonsequential macular holes (MHs) after
From the New England Eye Center, Tufts Medical Center, Boston, Massachusetts.
E
xudative age-related macular degeneration (AMD) is the leading cause of central vision loss in developed countries.1 Vascular endothelial growth factor plays an essential role in the pathogenesis of the choroidal neovascularization (CNV) secondary to AMD. Controlled clinical trials prove beneficial effects of intravitreal injections of angiogenesis The authors have no financial interest or conflicts of interest. Supported by unrestricted RPB Grant, Mass Lions Grant. Reprint requests: Jay S. Duker, MD, New England Eye Center, Tufts Medical Center, 800 Washington Street, Boston, MA 02111; e-mail: [email protected]
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intravitreal injections of ranibizumab for exudative AMD treatment. Case Report A 76-year-old man presented with sudden decrease in vision his right eye for 2 days. His medical history was significant for diabetes, which was well controlled. The best-corrected visual acuity was 20/200 in the right eye and 20/60 in the left eye. Fundoscopic examination showed a subretinal hemorrhage and soft drusen in the macular area of the right eye (Figure 1A). In the left eye, there were soft drusen in the macular area. Fluorescein angiography showed hypofluorescence because of the subretinal hemorrhage in the right eye (Figure 1B). Optical coherence tomography (OCT) of the right eye revealed thickened RPE with intraretinal cysts and subretinal fluid consistent with the diagnosis of CNV (Figure 1C), and in the left eye, the OCT showed RPE irregularity (Figure 1D). The patient was treated with 0.5 mg of ranibizumab, followed by a second injection 4 weeks later. Three weeks after the second intravitreal treatment, OCT confirmed regression of the CNV but a full-thickness MH was observed, without vitreous traction. The best-corrected visual acuity was 20/ 400 in the right eye and 20/60 in the left eye. A pars plana vitrectomy was performed with indocyanine green–assisted peeling of the internal limiting membrane (ILM) and an air–fluid exchange using 30% sulfur hexafluoride gas tamponade. One month after surgery, the MH remained open. At follow-up 6 months later, the patient reported an improvement in the vision of the right eye, but in the left eye, the vision had deteriorated. The best-corrected visual acuity was 20/200 in both eyes. Fundoscopic and OCT examinations of the right eye revealed an open MH. In the left eye, OCT images depicted thickened RPE raised by a nonuniform, slightly hyperreflective formation and intraretinal cysts, which confirmed the presence of a CNV (Figure 2A). The patient was treated with 3 intravitreal injections of ranibizumab
in the left eye with 4 weeks interval. Four weeks after of the third injection, a full-thickness MH developed in the left eye (Figure 2B). The patient underwent the same procedure as described above. Two months after the surgery, fundoscopic and OCT images of the left eye revealed an elevation of the RPE and subretinal fluid (Figure 2C), consistent with active CNV. The patient was treated with 3 intravitreal injections of ranibizumab with 4 weeks interval, with complete regression of the subretinal fluid. At follow-up 1 year later, the patient had best-corrected visual acuity of 20/200 in the right eye and 20/300 in the left eye. An open MH in the right eye with intraretinal cysts at the borders and drusen were observed on OCT (Figure 3A). In the left eye, no more treatment was required, the OCT showed anatomic closure of the MH, an elevation of RPE layer, and a disruption of inner–outer segment junction (Figure 3B).
Discussion This is a case of bilateral MH formation after intravitreal injection of ranibizumab for exudative AMD treatment in eyes without earlier abnormal vitreofoveolar traction. We are unaware of any previous report of bilateral MH formation after antiangiogenic treatment for exudative AMD. Previous reports describe MH formation after intravitreal treatment for myopic CNV; however, these eyes presented with preretinal vitreomacular traction as the causative factor.4 In this case, the first images were taken with a time-domain OCT and no evidence of vitreomacular traction was seen. A high-resolution spectral-domain OCT would allow a better evaluation of the vitreoretinal interface. It is important to note the
Fig. 1. Findings in the right and left eye before intravitreal administration of ranibizumab. A. Color fundus photograph showing the subretinal hemorrhage. B. Late-phase fluorescein angiogram showing hypofluorescent image. C. B-scan OCT image of the right eye showing thickened RPE, intraretinal cysts, and subretinal fluid. D. B-scan OCT image of the left eye showing RPE irregularity.
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Fig. 3. B–scan OCT images at 1–year follow–up. A. Right eye: open MH with intraretinal cysts in the borders, mild epiretinal membrane, and drusen. B. Left eye: anatomic closure of the MH and disruption of inner–outer segment junction.
Fig. 2. B-scan OCT image of the left eye showing (A) thickened RPE raised by a nonuniform, slightly hyperreflective formation and intraretinal cysts; (B) regression of CNV and MH formation 4 weeks after the third intravitreal ranibizumab injection; and (C) RPE detachment and subretinal fluid, consistent with active CNV.
absence of vitreomacular traction in this case as there is a higher incidence of tractional configuration of the attached posterior hyaloid in eyes with exudative AMD, which may predispose to MH formation.5 In the left eye, which did not present with subretinal hemorrhage, residual vitreomacular traction not identified by the time-domain OCT may have contributed to the MH formation. In this patient, we speculate that CNV regression lead to an upregulation in the expression of molecules related to fibrosis.6 This imbalance could induce preretinal fibrosis and a tangential contraction, resulting in MH formation. Additionally, the subretinal hemorrhage in the right eye (Figure 1) may have increased tangential pressure in the subretinal space, promoting dehiscence of the fovea.7 Other possibility is that the blood can stimulate the retinal pigment epithelium or establish a milieu in which fibrosis could develop, allowing for MH formation.7,8 In the right eye, despite the ILM peeling having been performed, the MH remained open. It can be
explained by the retinal damage from the subretinal hemorrhage, which may contribute to a low primary MH closure rate when compared with idiopathic MH.8 In the left eye, although an anatomic closure of the MH occurred, the best-corrected visual acuity did not improve significantly. The previous damage of the photoreceptor layer caused by the CNV may explain the low visual acuity. Moreover, this damage can be evidenced by the disruption of the inner–outer segment junction in the OCT (Figure 3B).9,10 In conclusion, while intravitreal ranibizumab is an effective treatment for exudative AMD, the possibility of infrequent complications or associated macular pathology should be considered.
Key words: age-related macular degeneration, intravitreal ranibizumab, macular hole. References 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1992;99:933–943. 2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 3. Rodrigues EB, Farah ME, Maia M, et al. Therapeutic monoclonal antibodies in ophthalmology. Prog Retin Eye Res 2009;28:117–144.
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4. Miura M, Iwasaki T, Goto H. Macular hole formation after intravitreal bevacizumab administration in a patient with myopic choroidal neovascularization. Retin Cases Brief Rep 2011. 5. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results. Am J Ophthalmol 2008;146:218–227. 6. Regatieri CV, Dreyfuss JL, Melo GB, et al. Quantitative evaluation of experimental choroidal neovascularization by confocal scanning laser ophthalmoscopy: fluorescein angiogram parallels heparan sulfate proteoglycan expression. Braz J Med Biol Res 2010;43:627–633.
7. Wan MJ, Sheidow TG. Macular hole secondary to a subretinal hemorrhage. Retin Cases Brief Rep 2009;3:86–88. 8. Tashimo A, Mitamura Y, Ohtsuka K, et al. Macular hole formation following ruptured retinal arterial macroaneurysm. Am J Ophthalmol 2003;135:487–492. 9. Ko TH, Witkin AJ, Fujimoto JG, et al. Ultrahigh-resolution optical coherence tomography of surgically closed macular holes. Arch Ophthalmol 2006;124:827–836. 10. Oh J, Smiddy WE, Flynn HW Jr, et al. Photoreceptor inner/ outer segment defect imaging by spectral domain OCT and visual prognosis after macular hole surgery. Invest Ophthalmol Vis Sci 2010;51:1651–1658.
Purpose: To report a case of bilateral nonsequential macular holes that developed after intravitreal ranibizumab therapy for treatment of exudative age-related macular degeneration. Methods: A 76-year-old man presented with sudden vision loss in the right eye initially followed by the left eye 1 year later. Initial fundoscopic examination showed a subretinal hemorrhage in the right eye and dry macular degeneration in the left eye. Initial optical coherence tomography and fluorescein angiogram confirmed the diagnosis of subfoveal choroidal neovascularization in the right eye. There was no evidence of vitreofoveal traction. The patient was treated with intravitreal injections of ranibizumab (0.5 mg). One year later, choroidal neovascularization developed in his left eye as well. Results: After choroidal neovascularization regression, full-thickness macular holes were observed in both eyes. Pars plana vitrectomy with internal limiting membrane removal was performed in both eyes. Anatomic closure of the macular hole in the left eye without significant vision improvement occurred but the right macular hole remained open despite the surgery. Conclusion: Exudative age-related macular degeneration can be a precursor to macular hole formation. RETINAL CASES & BRIEF REPORTS 6:125–128, 2012
inhibitors, such as ranibizumab, in the treatment of ocular neovascular disorders.2 Ranibizumab (Lucentis; Genentech, Inc, San Francisco, CA) is a humanized monoclonal antibody fragment designed to bind all isoforms of vascular endothelial growth factor and as a result block vessel permeability and angiogenesis.3 Ranibizumab is an effective and safe antiangiogenic and anti–vascular endothelial growth factor agent used to treat CNV associated with exudative AMD.2 However, intravitreal antiangiogenic therapy may induce adverse complications such as endophthalmitis, retinal detachment, and retinal pigment epithelial (RPE) tears.2 We report the case of a patient who developed bilateral nonsequential macular holes (MHs) after
From the New England Eye Center, Tufts Medical Center, Boston, Massachusetts.
E
xudative age-related macular degeneration (AMD) is the leading cause of central vision loss in developed countries.1 Vascular endothelial growth factor plays an essential role in the pathogenesis of the choroidal neovascularization (CNV) secondary to AMD. Controlled clinical trials prove beneficial effects of intravitreal injections of angiogenesis The authors have no financial interest or conflicts of interest. Supported by unrestricted RPB Grant, Mass Lions Grant. Reprint requests: Jay S. Duker, MD, New England Eye Center, Tufts Medical Center, 800 Washington Street, Boston, MA 02111; e-mail: [email protected]
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intravitreal injections of ranibizumab for exudative AMD treatment. Case Report A 76-year-old man presented with sudden decrease in vision his right eye for 2 days. His medical history was significant for diabetes, which was well controlled. The best-corrected visual acuity was 20/200 in the right eye and 20/60 in the left eye. Fundoscopic examination showed a subretinal hemorrhage and soft drusen in the macular area of the right eye (Figure 1A). In the left eye, there were soft drusen in the macular area. Fluorescein angiography showed hypofluorescence because of the subretinal hemorrhage in the right eye (Figure 1B). Optical coherence tomography (OCT) of the right eye revealed thickened RPE with intraretinal cysts and subretinal fluid consistent with the diagnosis of CNV (Figure 1C), and in the left eye, the OCT showed RPE irregularity (Figure 1D). The patient was treated with 0.5 mg of ranibizumab, followed by a second injection 4 weeks later. Three weeks after the second intravitreal treatment, OCT confirmed regression of the CNV but a full-thickness MH was observed, without vitreous traction. The best-corrected visual acuity was 20/ 400 in the right eye and 20/60 in the left eye. A pars plana vitrectomy was performed with indocyanine green–assisted peeling of the internal limiting membrane (ILM) and an air–fluid exchange using 30% sulfur hexafluoride gas tamponade. One month after surgery, the MH remained open. At follow-up 6 months later, the patient reported an improvement in the vision of the right eye, but in the left eye, the vision had deteriorated. The best-corrected visual acuity was 20/200 in both eyes. Fundoscopic and OCT examinations of the right eye revealed an open MH. In the left eye, OCT images depicted thickened RPE raised by a nonuniform, slightly hyperreflective formation and intraretinal cysts, which confirmed the presence of a CNV (Figure 2A). The patient was treated with 3 intravitreal injections of ranibizumab
in the left eye with 4 weeks interval. Four weeks after of the third injection, a full-thickness MH developed in the left eye (Figure 2B). The patient underwent the same procedure as described above. Two months after the surgery, fundoscopic and OCT images of the left eye revealed an elevation of the RPE and subretinal fluid (Figure 2C), consistent with active CNV. The patient was treated with 3 intravitreal injections of ranibizumab with 4 weeks interval, with complete regression of the subretinal fluid. At follow-up 1 year later, the patient had best-corrected visual acuity of 20/200 in the right eye and 20/300 in the left eye. An open MH in the right eye with intraretinal cysts at the borders and drusen were observed on OCT (Figure 3A). In the left eye, no more treatment was required, the OCT showed anatomic closure of the MH, an elevation of RPE layer, and a disruption of inner–outer segment junction (Figure 3B).
Discussion This is a case of bilateral MH formation after intravitreal injection of ranibizumab for exudative AMD treatment in eyes without earlier abnormal vitreofoveolar traction. We are unaware of any previous report of bilateral MH formation after antiangiogenic treatment for exudative AMD. Previous reports describe MH formation after intravitreal treatment for myopic CNV; however, these eyes presented with preretinal vitreomacular traction as the causative factor.4 In this case, the first images were taken with a time-domain OCT and no evidence of vitreomacular traction was seen. A high-resolution spectral-domain OCT would allow a better evaluation of the vitreoretinal interface. It is important to note the
Fig. 1. Findings in the right and left eye before intravitreal administration of ranibizumab. A. Color fundus photograph showing the subretinal hemorrhage. B. Late-phase fluorescein angiogram showing hypofluorescent image. C. B-scan OCT image of the right eye showing thickened RPE, intraretinal cysts, and subretinal fluid. D. B-scan OCT image of the left eye showing RPE irregularity.
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Fig. 3. B–scan OCT images at 1–year follow–up. A. Right eye: open MH with intraretinal cysts in the borders, mild epiretinal membrane, and drusen. B. Left eye: anatomic closure of the MH and disruption of inner–outer segment junction.
Fig. 2. B-scan OCT image of the left eye showing (A) thickened RPE raised by a nonuniform, slightly hyperreflective formation and intraretinal cysts; (B) regression of CNV and MH formation 4 weeks after the third intravitreal ranibizumab injection; and (C) RPE detachment and subretinal fluid, consistent with active CNV.
absence of vitreomacular traction in this case as there is a higher incidence of tractional configuration of the attached posterior hyaloid in eyes with exudative AMD, which may predispose to MH formation.5 In the left eye, which did not present with subretinal hemorrhage, residual vitreomacular traction not identified by the time-domain OCT may have contributed to the MH formation. In this patient, we speculate that CNV regression lead to an upregulation in the expression of molecules related to fibrosis.6 This imbalance could induce preretinal fibrosis and a tangential contraction, resulting in MH formation. Additionally, the subretinal hemorrhage in the right eye (Figure 1) may have increased tangential pressure in the subretinal space, promoting dehiscence of the fovea.7 Other possibility is that the blood can stimulate the retinal pigment epithelium or establish a milieu in which fibrosis could develop, allowing for MH formation.7,8 In the right eye, despite the ILM peeling having been performed, the MH remained open. It can be
explained by the retinal damage from the subretinal hemorrhage, which may contribute to a low primary MH closure rate when compared with idiopathic MH.8 In the left eye, although an anatomic closure of the MH occurred, the best-corrected visual acuity did not improve significantly. The previous damage of the photoreceptor layer caused by the CNV may explain the low visual acuity. Moreover, this damage can be evidenced by the disruption of the inner–outer segment junction in the OCT (Figure 3B).9,10 In conclusion, while intravitreal ranibizumab is an effective treatment for exudative AMD, the possibility of infrequent complications or associated macular pathology should be considered.
Key words: age-related macular degeneration, intravitreal ranibizumab, macular hole. References 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1992;99:933–943. 2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 3. Rodrigues EB, Farah ME, Maia M, et al. Therapeutic monoclonal antibodies in ophthalmology. Prog Retin Eye Res 2009;28:117–144.
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4. Miura M, Iwasaki T, Goto H. Macular hole formation after intravitreal bevacizumab administration in a patient with myopic choroidal neovascularization. Retin Cases Brief Rep 2011. 5. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results. Am J Ophthalmol 2008;146:218–227. 6. Regatieri CV, Dreyfuss JL, Melo GB, et al. Quantitative evaluation of experimental choroidal neovascularization by confocal scanning laser ophthalmoscopy: fluorescein angiogram parallels heparan sulfate proteoglycan expression. Braz J Med Biol Res 2010;43:627–633.
7. Wan MJ, Sheidow TG. Macular hole secondary to a subretinal hemorrhage. Retin Cases Brief Rep 2009;3:86–88. 8. Tashimo A, Mitamura Y, Ohtsuka K, et al. Macular hole formation following ruptured retinal arterial macroaneurysm. Am J Ophthalmol 2003;135:487–492. 9. Ko TH, Witkin AJ, Fujimoto JG, et al. Ultrahigh-resolution optical coherence tomography of surgically closed macular holes. Arch Ophthalmol 2006;124:827–836. 10. Oh J, Smiddy WE, Flynn HW Jr, et al. Photoreceptor inner/ outer segment defect imaging by spectral domain OCT and visual prognosis after macular hole surgery. Invest Ophthalmol Vis Sci 2010;51:1651–1658.
