TREATMENT OF RECALCITRANT RADIATION MACULOPATHY USING INTRAVITREAL DEXAMETHASONE (OZURDEX) IMPLANT Kelly M. Bui, MD, Clement C. Chow, MD, William F. Mieler, MD
Purpose: Radiation maculopathy is the most common cause of severe vision loss after radiotherapy of uveal melanoma. To date, no effective therapy exists. The authors report a novel approach to the treatment of radiation maculopathy using dexamethasone (Ozurdex, Allergan Inc) intravitreal implant. Methods: This is a retrospective case series of two patients who developed radiation maculopathy after radiotherapy for uveal melanoma and was treated with Ozurdex. Clinical outcomes included visual acuity, central foveal thickness by optical coherence tomography, intraocular pressure, and cataract formation. Results: Both patients were of Caucasian descent. Patient 1 received charged-particle radiation, whereas Patient 2 received iodine-125 brachytherapy for medium-sized uveal melanoma located in the midperipheral retina. Radiation maculopathy developed 47 months and 18 months after radiation exposure in Patient 1 and 2, respectively. Both patients initially received bevacizumab monotherapy followed by alternating therapy with bevacizumab and intravitreal triamcinolone. Secondary to a limited response, the patients were treated with Ozurdex implants. One patient had visual improvement, and both patients experienced a prolonged time frame of anatomical stability. Adverse effects included a rise in the intraocular pressure, which was controlled by topical hypotensive agents and posterior subcapsular cataract formation in Patient 1. Conclusion: Ozurdex intravitreal implant provides a prolonged period of anatomical stabilization in recalcitrant cases of radiation maculopathy in patients who have failed multiple intravitreal bevacizumab injections and had only a partial response to intravitreal triamcinolone. Larger prospective studies are required to determine the extent of visual beneﬁt. RETINAL CASES & BRIEF REPORTS 8:167–170, 2014
albeit short-term. We report a novel approach to the treatment of RM using intravitreal dexamethasone (Ozurdex; Allergan Inc, Irvine, CA) implant, which seems to prolong the treatment efﬁcacy.
From the Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Inﬁrmary, University of Illinois at Chicago, Chicago, Illinois.
adiation maculopathy (RM) is the most common cause of severe vision loss after radiotherapy of uveal melanoma.1,2 Different treatment modalities have been tried, including argon photocoagulation,3,4 anti–vascular endothelial growth factor (VEGF),5,6 and intravitreal triamcinolone (IVTA)7 with variable results. In recalcitrant cases of RM, alternating therapy with anti-VEGF and IVTA was used at our institution, which showed a rapid reduction in previously persistent macular edema with the addition of IVTA,
Case Reports Case 1 A 48-year-old white man presented for the treatment of RM. He had received charged-particle radiation 4 years ago at an outside hospital for a uveal melanoma in the left eye. The precise characteristics of the tumor before treatment were unknown. On examination, the best-corrected visual acuity was 20/30 in the right eye and 20/200 in the left eye. Intraocular pressures (IOP) were 19 in
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the right eye and 17 in the left eye. Examination of the right eye was within normal limits. In the left eye, anterior segment examination was notable for trace nuclear sclerosis cataract. Fundus examination revealed a regressed uveal melanoma in the superotemporal midperiphery, along with photocoagulation scars within an area of nonperfusion in the temporal macula extending out to the ora serrata. There was a network of vessels in the macula, juxtafoveal and nasal to the area of the nonperfusion consistent with collateral vessels with extensive microaneurysms, venous beading and loops, and intraretinal microvascular abnormality. There was juxtafoveal exudation with edema. Fluorescein angiography revealed late leakage along the extent of these vessels and in the fovea. The foveal avascular zone appeared normal in size. Optical coherence tomography showed cystoid macular edema (CME) with a central foveal thickness (CFT) of 257 mm. After a short period of observation, the CME worsened with a corresponding CFT of 489 mm, which prompted treatment with intravitreal bevacizumab. The patient was brieﬂy lost to followup, although he received 2 additional bevacizumab elsewhere. Ten months later, he returned with stable visual acuity of 20/200, CFT of 560, and IOP of 20. Given persistent CME despite bevacizumab, he was given a trial of IVTA 4 mg. One month later, his best-corrected visual acuity improved to 20/50 with a corresponding reduction in CFT to 305 and IOP of 20. He received the second IVTA a month later, which kept his CFT and visual acuity stable. Two months later, his visual acuity declined to 20/80 with a corresponding increase in CFT to 515. However, given a rise of IOP to 25, he was switched back to bevacizumab. He subsequently received 13 additional bevacizumab injections and 2 additional IVTA injections over the course of 19 months. The average reduction in CFT with bevacizumab was 79 mm and 81 mm with IVTA. It was noted that the effect of IVTA did not last longer than 1 month (Figure 1A). Ozurdex was subsequently tried, after informed consent was obtained for off-label usage of the drug. This resulted in complete resolution of CME lasting 3 months with a total CFT reduction of 218 mm and visual acuity of 20/60 (Figure 1B). Seven months later, his CME recurred with decreased visual acuity to 20/200 (Figure 1C). He received a second Ozurdex injection, which again resolved the CME completely and improved the visual acuity to 20/60 lasting 4 months (Figure 1D). He did have a rise in IOP to 28 after the ﬁrst Ozurdex injection, which was controlled on topical hypotensive agents (dorzolamide–timolol). He developed a posterior subcapsular cataract and subsequently underwent uncomplicated phacoemulsiﬁcation with intraocular lens implant and a third injection of Ozurdex prior to surgery. His visual acuity improved to 20/30 two months later, and complete resolution of macular edema persisted for 4 months to date.
Case 2 A 69-year-old white woman was referred for retinal evaluation after seeing ﬂoaters for 3 months. On examination, she had a moderate nuclear sclerosis cataract, normal IOP, and a uveal melanoma in the left eye located in the temporal equatorial region with a basal diameter of 12.4 mm and a height of 9.9 mm. She subsequently received iodine-125 brachytherapy with an apex dose of 88 Gy. Her prebrachytherapy vision was 20/50. Postoperatively, she developed a transient exudative retinal detachment, which resolved at Month 7 after treatment with a corresponding vision of 20/200. Two months later, she presented with IOP to the 40s and None of the authors have any ﬁnancial/conﬂicting interests to disclose. Reprint requests: William F. Mieler, MD, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois; e-mail: [email protected]
Fig. 1. Spectral domain optical coherence tomography (SD-OCT) images of Patient 1 who developed radiation maculopathy 47 months after charge-particle radiation for uveal melanoma. A. After multiple intravitreal bevacizumab and triamcinolone injections, CME persisted. Central foveal thickness was 456 mm, and visual acuity was 20/60. B. Three months after intravitreal dexamethasone 0.7-mg (Ozurdex, Allergan Inc) implant, CME completely resolved, and CFT improved to 238 mm with stable visual acuity at 20/60. C. Seven months after Ozurdex injection, CME recurred with an increase in CFT to 434 mm, and a drop in the visual acuity to 20/200. A second Ozurdex implant was injected at this visit. D. Four months after the second Ozurdex injection, SD-OCT demonstrates good foveal contour and minimal CME temporally. Central foveal thickness improved to 277 mm, and the visual acuity improved to 20/60 despite moderate posterior subcapsular cataract.
was found to have neovascularization of the iris and angle. Her visual acuity at this time was 8/200. She was subsequently treated with 2 bevacizumab injections and panretinal photocoagulation for proliferative radiation retinopathy and neovascular glaucoma. She subsequently underwent cataract extraction in the left eye, and her vision stabilized at 20/400 postsurgery. At 18 months after brachytherapy, she was noted to have mild nonfoveal CME with CFT of 364 and microaneurysms in the macula consistent with early RM. Fluorescein angiography revealed mild expansion of the foveal avascular zone consistent with macular ischemia. During this period, her visual acuity ﬂuctuated between 20/200 and 20/400. At 2 years after brachytherapy, she had marked CME with a CFT of 684 mm. The IOP was 18 on 3 topical hypotensive drops. She was
OZURDEX FOR RADIATION MACULOPATHY
treated with 5 bevacizumab injections and 1 IVTA over the course of 12 months, which led to a corresponding mean reduction of 52 mm and 17 mm, respectively (Figure 2A). Her vision remained stable at 20/400. Given persistent CME and stabilization of neovascular glaucoma, she was given an Ozurdex trial, which led to a dramatic improvement of CME and a CFT reduction of 282 mm (Figure 2B) lasting 2 months, although there was no improvement in the visual acuity. The IOP was controlled by topical hypotensive agents.
Discussion Radiation retinopathy is an ischemic vasculopathy characterized by destruction of endothelial cells and pericytes8 on histopathologic examination and clinical ﬁndings of cotton-wool spots, retinal hemorrhages and microaneurysms, retinal ischemia and neovascularization, and exudation.3 We deﬁned RM as the presence of the microangiopathy described above in the presence of macular edema. Risk factors for RM have been enumerated by previous studies and include tumor located posterior to the equator, tumor height .6 mm, radiation dose to the fovea $70 Gy in 1 case series9 and $90 Gy in another series,2 tumor located less than 4 mm from the foveola,10 and the presence of preoperative subretinal ﬂuid.1 Previous studies on focal photocoagulation have suggested modest beneﬁt in vision and short-term resolution of radiation-induced macular edema. Kinyoun et al3 looked at 12 eyes that had macular edema related to radiation retinopathy and were treated with focal and grid laser photocoagulation. Seven of the 12 eyes (58%) improved by 1 or more lines on Snellen visual acuity at initial postoperative follow-up (mean, 5 months), and 8 of the 12 eyes (67%) improved by 1 or more lines at ﬁnal postoperative follow-up (mean, 39 months). Fifty percent of the eyes had complete resolution of macular edema at ﬁnal follow-up. On average, these eyes received 1 retreatment for persistent or recurrent macular edema. In a retrospective study4 comparing patients who received focal and grid laser photocoagulation for radiationinduced macular edema (n = 19) and those who were observed (n = 23), results showed that at 6 months, 42% of treated eyes compared with 0% of the observed eyes had 1 or more lines of improvement on Snellen visual acuity. This effect waned by Month 24, where only 21% of the treated eyes maintained this level of improvement. Complete resolution of macular edema occurred in 26% of the treated patients compared with 4% of the observed patients at 6 months. The results of these two studies suggest that focal laser photocoagulation can be beneﬁcial in the treatment of RM.
Fig. 2. Spectral domain optical coherence tomography images of Patient 2 who developed radiation maculopathy 18 months after iodine125 brachytherapy for uveal melanoma. A. Diffuse large cystoid spaces were present in the macula despite multiple intravitreal bevacizumab and triamcinolone injections. Central foveal thickness was 618 mm, and visual acuity was 20/400. B. Two months after intravitreal dexamethasone 0.7-mg (Ozurdex; Allergan Inc) implant, CME improved dramatically with a CFT of 336 mm although the visual acuity remained stable at 20/400.
However, the authors noted that repeat treatment is often necessary for sustained efﬁcacy. Anti-VEGF therapy has been widely used for the treatment of macular edema in retinal vascular diseases such as diabetes and retinal vein occlusion, whereby ischemia is the underlying culprit. Regarding RM, however, the results have been less promising. In a case series of 21 patients who developed RM after brachytherapy with palladium103 and were treated with a mean of 4 bevacizumab injections over 8 months, 86% of these patients had stable to improved vision and 14% improved 2 or more lines on the Snellen eye chart.4 A subsequent trial of ranibizumab for RM, albeit a small sample size (n = 5), appeared to be more promising.6 Patients received a monthly injection of ranibizumab for 8 months. Of 5 patients, 4 patients (80%) gained on average 9.5 ETDRS letters with corresponding mean reduction in CFT of 146 mm. Shields et al7 described the use of IVTA in the treatment of RM in a series of 31 patients. One month after injection of 4 mg IVTA, 91% had stable or improved vision, though this effect waned by month 6, whereby only 45% of the patients had stable or improved vision. Our personal experience with IVTA has been similar with rapid dissipation of efﬁcacy, although it seems to work well in cases of recalcitrant RM, where initial trial of anti-VEGF therapy had failed. The mechanism behind the efﬁcacy of intravitreal corticosteroid in cases of recalcitrant RM remains unclear because RM has been traditionally thought to arise from ischemia and production of VEGF, but perhaps inﬂammatory mediators play a more
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prominent role than previously realized. Animal studies suggest that Müller cell dysfunction plays a role in chronic macular edema, and intraocular steroid can help resolve macular edema by both inhibition of vascular leakage and stimulation of ﬂuid clearance by Müller cells.11 Intravitreal dexamethasone 0.7-mg implant (Ozurdex; Allergan Inc) is an FDA-approved treatment for macular edema after branch or central retinal vein occlusion and noninfectious uveitis. In the retinal vein occlusion studies, peak efﬁcacy took place at 60 days and waned thereafter.12 Repeat injection at 6 months was well tolerated and led to similar efﬁcacy at 12 months. Although cataract progression and IOP rise are well-known side effects of corticosteroid injection, the incidence of these adverse effects were much lower with the use of Ozurdex compared with IVTA 4 mg. To the best of our knowledge, there is one other study13 reporting the use of Ozurdex for the treatment of RM. This particular patient developed RM after Ru-106 plaque brachytherapy and failed one injection of intravitreal bevacizumab. Macular edema resolved with improvement in the visual acuity after 1 Ozurdex injection and lasted for 5 months. In summary, we present the off-label use of Ozurdex in treating two unique cases of recalcitrant RM after radiotherapy of uveal melanoma. There was a complete resolution of CME for 2 months to 4 months with visual improvement in 1 patient and limited visual beneﬁt in the second patient who had underlying neovascular glaucoma and macular ischemia. Intraocular pressure rise was controlled with topical medications alone. Although this study is limited by a small sample size, the results are promising in these recalcitrant RM cases. The complication proﬁle of the use of Ozurdex for the treatment of RM needs to be better determined, specifically the incidence of elevated IOP and cataract formation. Additionally, these patients often have compromised macular capillary function or photoreceptor damage from persistent CME, which may limit visual recovery. Future studies are warranted to investigate the use of the Ozurdex implant early in the course of RM.
Key words: dexamethasone, Ozurdex, macular edema, radiation maculopathy, radiation, retinopathy. References 1. Gunduz K, Shields CL, Shields JA, et al. Radiation complications and tumor control after plaque radiotherapy of choroidal melanoma with macular Involvement. Am J Ophthalmol 1999;127:579–589. 2. Stach R, Elder M, Abdelall A, et al. New Zealand experience of I-125 brachytherapy for choroidal melanoma. Clin Experiment Ophthalmol 2005;33:490–494. 3. Kinyoun JL, Zamber RW, Lawrence BS, et al. Photocoagulation treatment for clinically signiﬁcant radiation macular oedema. Br J Ophthalmol 1995;79:144–149. 4. Hykin PG, Shields CL, Shields JA, Arevalo F. The efﬁcacy of focal laser therapy in radiation-induced macular edema. Ophthalmology 1998;105:1425–1429. 5. Finger PT. Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin). Int J Radiat Oncol Biol Phys 2008;70:974–977. 6. Finger PT, Chin KJ. Intravitreous ranibizumab (Lucentis) for radiation maculopathy. Arch Ophthalmol 2010;128:249–252. 7. Shields CL, Demirci H, Dai V, et al. Intravitreal triamcinolone acetonide for radiation maculopathy after plaque radiotherapy for choroidal melanoma. Retina 2005;25:868–874. 8. Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy— clinical, histopathological, ultrastructural and experimental correlations. Eye (Lond) 1991;5:239–251. 9. Finger PT, Chin KJ, Yu GP. Risk factors for radiation maculopathy after ophthalmic plaque radiation for choroidal melanoma. Am J Ophthalmol 2010;149:608–615. 10. Gunduz K, Shields CL, Shields JA, et al. Radiation retinopathy following plaque radiotherapy for posterior uveal melanoma. Arch Ophthalmol 1999;117:609–614. 11. Reichenbach A, Wurm A, Pannicke T, et al. Müller cells as players in retinal degeneration and edema. Graefes Arch Clin Exp Ophthalmol 2007;245:627–636. 12. 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. 13. Russo A, Avitabile T, Uva M, et al. Radiation macular edema after Ru-106 plaque brachytherapy for choroidal melanoma resolved by an intravitreal dexamethasone 0.7-mg implant. Case Rep Ophthalmol 2012;3:71–76.