Seminars in Ophthalmology, 2015; 30(4): 276–280 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.847110
ORIGINAL ARTICLE
The Variable Efficacy of Intravitreal Bevacizumab and Triamcinolone Acetonide for Cystoid Macular Edema Due to Radiation Retinopathy Sophie J. Bakri and Theresa A. Larson Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
ABSTRACT Background: Both intravitreal bevacizumab and triamcinolone have been shown to be effective in treating macular edema secondary to VEGF-mediated disease. The purpose of this study is to describe the variable effects of intravitreal bevacizumab (IVB) and triamcinolone acetonide (IVTA) in the treatment of macular edema secondary to radiation retinopathy. Methods: Retrospective, nonrandomized, interventional case series. Charts of five patients with macular edema due to radiation retinopathy who received IVB with subsequent IVTA were reviewed. Clinical examination, Snellen visual acuity (VA), and central macular thickness (CMT) on optical coherence tomography (OCT) were examined. Main outcome measures included VA and CMT. Results: Of the five patients reviewed, patient 1 demonstrated complete resolution of macular edema both clinically and by OCT with IVB after the first two injections with a decrease in CMT to 243 and 284 mm from a baseline CMT of 340 mm. However, response diminished following successive injections and the patient was switched to IVTA with a complete response. Mean CMT was 249 mm following four injections of IVTA and vision improved 3 lines. Patients 2 and 3 demonstrated a partial response to IVB with a mean CMT of 362 and 451 mm from 436 and 596 mm, respectively. They similarly had a partial response to IVTA with a mean CMT of 363 and 433 mm from 460 and 429 mm. There was no improvement in vision. Patient 2 was then switched to a combination of IVB and IVTA with complete resolution of macular edema with a CMT of 299 and 289 mm following two treatments. Patients 4 and 5 failed to respond to IVB with a mean increase in CMT of 64.5 and 6 mm. Both responded well to IVTA with complete resolution of macular edema. Mean decrease in CMT was 146 and 183 mm with a mean CMT of 254 and 281 mm. Final vision was stable in patient 4 and improved 3 lines from 20/100 to 20/50 in patient 5. Conclusion: IVB and IVTA have variable effects on the reduction of macular edema due to radiation retinopathy. IVB appears to have an initial effect in reducing macular edema in some patients but after multiple injections there can be resistance to its effects. IVTA was effective in three of five patients with complete resolution of macular edema. The combination of IVB and IVTA completely resolved macular edema in one patient resistant to IVB or IVTA alone. The reason for this may be due to their different therapeutic mechanisms of action and consideration should therefore be given to their use in combination. Keywords: Avastin, bevacizumab, eye, macular edema, radiation retinopathy, steroid, triamcinolone acetonide, VEGF
neovascularization, and macular edema.1 Macular edema secondary to radiation retinopathy is common, occurring in one study in 87% of eyes treated with proton beam irradiation for choroidal melanoma after three years.2 It remains a challenging entity to treat with multiple off-label treatments, including focal laser, photodynamic therapy,
INTRODUCTION Radiation retinopathy can cause severe loss vision loss following local or external beam radiation to the eye or adjacent structures. Manifestations are similar to diabetic retinopathy demonstrating microvascular changes including capillary non-perfusion,
Received 29 April 2013; revised 1 September 2013; accepted 17 September 2013; published online 6 November 2013 Correspondence: Sophie J. Bakri, MD, Department of Ophthalmology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. E-mail: [email protected]
276
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intravitreal triamcinolone, and bevacizumab, which have demonstrated varying success.3,4,5,6,7 Intravitreal triamcinolone was shown to be effective at stabilizing or improving vision in 91% of patients at one month and 45% at six months.6 Recently, intravitreal bevacizumab has also shown promise with modest improvement in visual acuity in short-term studies.7 The purpose of this study is to describe the variable effects of intravitreal bevacizumab (IVB) and triamcinolone acetonide (IVTA) in the treatment of macular edema secondary to radiation retinopathy.
MATERIALS AND METHODS Charts of five patients with macular edema secondary to radiation retinopathy who received IVB with subsequent IVTA were reviewed. Institutional review board approval was obtained for the study. Patient 1 had an Iodine-125 plaque for a choroidal melanoma in the right eye in 2002. Patient 2 had an Iodine-125 plaque for a choroidal melanoma in the right eye in 1998. Patient 3 had radiation therapy for a grade 4 undifferentiated sinus carcinoma from 2000 to 2002. Patient 4 had radiation to the head and chest for small cell lung cancer in 1992. Patient 5 had an Iodine-125 plaque for a choroidal melanoma in the left eye in 2004. All patients were treated with IVB and subsequent IVTA from 2005 to 2008 and followed up at approximately four- to eight-week intervals by clinical exam and optical coherence tomography (OCT) to measure macular edema. Injections were performed in the same manner in all patients. After anesthetizing with cotton tip applicators soaked in 4% lidocaine applied to the inferotemporal limbus, the periocular area was prepped with 10% povidone-iodine, and 5% povidone-iodine was applied into the conjunctival fornix. An eyelid speculum was used. Using a 30-gauge needle through the pars plana, bevacizumab 1.25 mg (in 0.05 ml) or triamcinolone acetonide (4 mg in 0.1 mL) was injected. When IVB and IVTA were given together, two separate injections of 1.25 mg of bevacizumab (in 0.05 ml) and 2 mg of IVTA (in 0.05 ml) were given. Outcomes of treatment were measured by Snellen visual acuity, clinical examination, and central macular thickness (CMT) on OCT approximately four to eight weeks after injection. In patients with macular edema that did not respond or worsened with IVB, IVTA was given and, in one patient, a combination of IVB and IVTA was given.
RESULTS Patient 1 initially responded to IVB. The first injection of IVB was given after a baseline initial VA of 20/100 and CMT of 340 mm. One month later, VA was stable !
2015 Informa Healthcare USA, Inc.
FIGURE 1. (a) This shows the OCT of patient 2 before receiving intravitreal bevacizumab. Central macular thickness is 369 microns. 139 61 mm (150 150 DPI). (b) This shows the OCT of patient 2 one month after receiving intravitreal bevacizumab. Central macular thickness is 375 microns. 168 87 mm (150 150 DPI).
at 20/100 with complete resolution of edema with a CMT of 252 mm. The patient subsequently underwent cataract extraction followed by five additional injections of IVB. With each injection, response to IVB diminished with CMT declining 45 um and 21 um after the fifth and sixth injection. Mean change in CMT was 34.8 mm. The patient was switched to IVTA with CMT improving from 291 to 228 mm. The patient has received four IVTA injections to date with a reduction in CME from 291 mm to 260 mm after the IVTA was initiated. Partial responses to IVB were demonstrated in patients 2 and 3. Patient 2 had minimal response to IVB with a decrease in CMT of 70 and 12 mm following the first two injections from a baseline of 436 mm. However, the patient failed to respond after the third treatment and CMT increased 9 mm (Figure 1). VA was stable. The patient was switched to IVTA and demonstrated a partial response with a decline in CMT of 100, 26, and an increase of 60 mm, respectively, after each of the injections (Figure 2). During this period vision worsened to 20/400 from 20/40 secondary to a cataract. After phacoemulsification, VA improved to 20/40 but macular edema remained at eight weeks follow-up after the third IVTA injection with a mean CMT of 394 mm. A combination of IVB and IVTA were then used with complete resolution of macular edema. Mean CMT was 299 mm five weeks post-injection with VA improving one line (Figure 3). The patient has received a total of two combination therapies of IVB and IVTA to date. Similar to patient 2, patient 3 had minimal decrease in CMT with IVB. At a baseline CMT of 596 mm,
278 S. J. Bakri and T. A. Larson
FIGURE 2. (a) This shows the OCT of patient 2 before receiving intravitreal triamcinolone. Central macular thickness is 460 microns. 169 85 mm (150 150 DPI). (b) This shows the OCT of patient 2 six weeks after receiving intravitreal triamcinolone. Central macular thickness is 360 microns. 166 86 mm (150 150 DPI).
FIGURE 3. (a) This shows the OCT of patient 2 before receiving intravitreal bevacizumab and triamcinolone in combination. Central macular thickness is 394 microns. 181 83 mm (143 150 DPI). (b) This shows the OCT of patient 2 five weeks after receiving intravitreal bevacizumab and triamcinolone in combination. Central macular thickness is 299 microns. 180 83 mm (144 150 DPI).
patient 3 had a decrease in CMT of 84, 82, and 57 mm following three injections of IVB. Following the four injection, the patient did not respond and CMT increased 56 mm. Vision improved from 20/400 to 20/150 by the third injection. The patient was then switched to IVTA and had minimal overall response
with decreases in CMT of 38, an increase of 79, and a decrease of 33 mm. VA worsened to 20/400 with the patient subsequently undergoing cataract extraction with a final visual acuity of 20/400. Both patients 4 and 5 worsened with IVB treatment but responded well to IVTA. Patient 4 received two IVB injections with increases in CMT of 119 and 10 mm from a baseline of 381 mm. Subsequently, the patient was treated with a total of 7 IVTA injections with a gradual decline in CMT from 519 mm to 226 mm. VA decreased to 20/150 from 20/40 during treatment. After undergoing cataract extraction, VA was 20/40 at final follow-up. Patient 5 also received two IVB injections. Initially, the patient had a partial response with a decrease in CMT of 42 mm from 525; however, following the second injection, CMT increased 54 mm. The patient received two injections of IVTA. Following the first, there was complete resolution of macular edema with a decrease in the CMT of 247 mm from 537 mm. At two months following the second injection of IVTA, CMT was 271. VA improved from a baseline of 20/100 to 20/50.
DISCUSSION Macular edema secondary to radiation retinopathy is a common vision-threatening complication. Preservation of vision is difficult and in one longterm follow-up study of 1,106 patients treated with plaque radiotherapy for uveal melanoma, visual acuity was 20/200 or worse in 68% of patients at 10 years.8 In another study of 135 patients with uveal melanoma treated with plaque radiotherapy, 51% of patients developed moderate visual loss over a two-year study period.9 There is currently limited success at treating macular edema secondary to radiation retinopathy. This study includes both patients treated locally with plaque radiotherapy and with external beam radiation. Time to onset of macular edema was greater than two years and average follow-up was 1.9 years. Only one patient responded to IVB with complete resolution of macular edema. This effect, however, was, short-lasting, and the response became diminished with each subsequent injection. Patients 2 and 3 had very minimal response and patients 4 and 5 worsened with IVB. Mason et al.7 reported 10 patients with macular edema secondary to radiation retinopathy were treated with one injection of IVB and all had reduction in macular edema with five of 10 having complete resolution. By 4 months postinjection, macular edema had returned. Patients in this study were excluded if there was 41 disk area of foveal nonperfusion shown on fluorescein angiogram.7 In this series, fluorescein angiography was not performed before the initial IVB in every patient and so patients with foveal nonperfusion were Seminars in Ophthalmology
Bevacizumab and triamcinolone for radiation macular edema likely included, thus potentially impacting the efficacy of any treatment. IVTA following IVB was effective in three of five patients with a decrease in macular edema one to two months post-injection. However, cataract was a common complication that limited VA following multiple injections that necessitated phacoemulsification in four of five patients. When comparing pre-treatment and final post-treatment vision, two of five patients had a 3-line VA improvement. Studies using IVTA have shown similar good results. Shields et al. report using IVTA in 31 patients with improvement in visual acuity of 2 lines at one month and foveal edema present in only 46%.6 In our series, of the patients with a poor response to IVTA, patient 2 required a combination of IVB and IVTA while patient 3 had minimal response to IVTA, which is likely secondary to the poor VA and severity of the macular edema present at baseline, as well as the presence of an intraretinal hemorrhage in the fovea. As this case series demonstrates, neither IVB nor IVTA alone definitively treats macular edema secondary to radiation retinopathy. Treatments, if they have an effect, are short-lasting, approximately one month with IVB and three months with IVTA, require multiple injections, and are complicated by cataract and glaucoma. Two of five patients had intraocular pressure rises greater than 21 mm Hg that required treatment medically. Why only one patient responded well to IVB and then grew resistant to its effects is unknown. One case series10 has reported rebound macular edema after IVB for macular edema due to CRVO. In another report,11 a patient with macular edema due to central retinal vein occlusion initially responded but then became resistant to IVB and then IVTA, and then responded to a combination of both. It is hypothesized that upregulation of VEGF receptors may occur after anti-VEGF agents. Radiation retinopathy is similar in manifestations to diabetic retinopathy; however, it is generally more severe with capillary nonperfusion as a dominant feature. A recent report comparing treatments of IVB to IVTA for diabetic macular edema in a series of 28 eyes showed better results with IVTA than IVB in reducing macular edema and improving vision.12 This may be secondary to the mechanism of action of IVB and IVTA. Bevacizumab is a full-length humanized monoclonal that binds all subtypes of vascular endothelial growth factor (VEGF). VEGF has been shown to be an endothelial cell mitogen and angiogenic inducer as well as increasing retinal vessel permeability.13 Corticosteroids are hypothesized to reduce the retinal capillary permeability by increasing the activity/ density of tight junctions and inhibiting the expression of VEGF and metabolic activity of VEGF.14 !
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Therefore, bevacizumab may help by binding VEGF and triamcinolone by closing tight junctions, thus reducing leakage. Treatment of macular edema secondary to radiation retinopathy remains challenging and requires the use of multiple modalities. This case series, although limited in number of patients, demonstrates that IVB and or IVTA have the potential to improve vision and reduce macular edema. However, patients must be followed carefully, as rebound macular edema may occur and patients may become resistant to their effects. Additional longer-term and larger studies are needed that compare both treatments and their use in combination.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Amoaku WMK, Archer DB. Fluorescein angiographic features, natural course and treatment of radiation retinopathy. Eye 1990;4:657–667. 2. Guyer DR, Mukai S, Seddon JM, et al. Radiation maculopathy after proton beam irradiation for choroidal melanoma. Ophthalmology 1992;99:1278–1285. 3. Kinyoun JL, Zamber RW, Lawrence BS, et al. Photocoagulation treatment for clinically significant radiation macular edema. Br J Ophthalmol 1995;79:144–149. 4. Hykin PG, Shields CL, Shields JA, Arevalo JF. The efficacy of focal laser therapy in the management of radiation induced macular edema. Ophthalmology 1998;105: 470–478. 5. Bakri SJ, Beer PM. Photodynamic therapy for maculopathy due to radiation retinopathy. Eye 2005;19:470–478. 6. 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. 7. Mason JO, Albert MA, Persaud TO, Vail RS. Intravitreal bevacizumab treatment for radiation macular edema after plaque radiotherapy for choroidal melanoma. Retina 2007; 27:903–907. 8. Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for uveal melanoma: long-term visual outcome in 1106 consecutive patients. Arch Ophthalmol 2000;118: 1219–1228. 9. Horgan N, Shields CL, Mashayekhi A, et al. Early macular morphological changes following plaque radiotherapy for uveal melanoma. Retina 2008;28(2):263–273. 10. Bakri SJ, Ekdawi NS. Intravitreal triamcinolone and bevacizumab combination therapy for refractory choroidal neovascularization with retinal angiomatous proliferation. Eye 2008;22(7):978–980. 11. Matsumoto Y, Freund KB, Peiretti E, et al. Rebound macular edema following bevacizumab (Avastin) therapy for retinal venous occlusive disease. Retina 2007; 27(4):426–431.
280 S. J. Bakri and T. A. Larson 12. Shimura M, Nakazaw T, Yasuda K, et al. Comparative therapy evaluation of intravitreal bevacizumab and triamcinolone acetonide on persistent diffuse diabetic macular edema. Am J Ophthalmol 2008; 145:854–861.
13. Ferrar N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581–611. 14. Sivaprasad S, McCluskey P, Lightman S. Intravitreal steroids in the management of macular oedema. Acta Ophthalmol Scand 2006;84:722–733.
Seminars in Ophthalmology
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ORIGINAL ARTICLE
The Variable Efficacy of Intravitreal Bevacizumab and Triamcinolone Acetonide for Cystoid Macular Edema Due to Radiation Retinopathy Sophie J. Bakri and Theresa A. Larson Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
ABSTRACT Background: Both intravitreal bevacizumab and triamcinolone have been shown to be effective in treating macular edema secondary to VEGF-mediated disease. The purpose of this study is to describe the variable effects of intravitreal bevacizumab (IVB) and triamcinolone acetonide (IVTA) in the treatment of macular edema secondary to radiation retinopathy. Methods: Retrospective, nonrandomized, interventional case series. Charts of five patients with macular edema due to radiation retinopathy who received IVB with subsequent IVTA were reviewed. Clinical examination, Snellen visual acuity (VA), and central macular thickness (CMT) on optical coherence tomography (OCT) were examined. Main outcome measures included VA and CMT. Results: Of the five patients reviewed, patient 1 demonstrated complete resolution of macular edema both clinically and by OCT with IVB after the first two injections with a decrease in CMT to 243 and 284 mm from a baseline CMT of 340 mm. However, response diminished following successive injections and the patient was switched to IVTA with a complete response. Mean CMT was 249 mm following four injections of IVTA and vision improved 3 lines. Patients 2 and 3 demonstrated a partial response to IVB with a mean CMT of 362 and 451 mm from 436 and 596 mm, respectively. They similarly had a partial response to IVTA with a mean CMT of 363 and 433 mm from 460 and 429 mm. There was no improvement in vision. Patient 2 was then switched to a combination of IVB and IVTA with complete resolution of macular edema with a CMT of 299 and 289 mm following two treatments. Patients 4 and 5 failed to respond to IVB with a mean increase in CMT of 64.5 and 6 mm. Both responded well to IVTA with complete resolution of macular edema. Mean decrease in CMT was 146 and 183 mm with a mean CMT of 254 and 281 mm. Final vision was stable in patient 4 and improved 3 lines from 20/100 to 20/50 in patient 5. Conclusion: IVB and IVTA have variable effects on the reduction of macular edema due to radiation retinopathy. IVB appears to have an initial effect in reducing macular edema in some patients but after multiple injections there can be resistance to its effects. IVTA was effective in three of five patients with complete resolution of macular edema. The combination of IVB and IVTA completely resolved macular edema in one patient resistant to IVB or IVTA alone. The reason for this may be due to their different therapeutic mechanisms of action and consideration should therefore be given to their use in combination. Keywords: Avastin, bevacizumab, eye, macular edema, radiation retinopathy, steroid, triamcinolone acetonide, VEGF
neovascularization, and macular edema.1 Macular edema secondary to radiation retinopathy is common, occurring in one study in 87% of eyes treated with proton beam irradiation for choroidal melanoma after three years.2 It remains a challenging entity to treat with multiple off-label treatments, including focal laser, photodynamic therapy,
INTRODUCTION Radiation retinopathy can cause severe loss vision loss following local or external beam radiation to the eye or adjacent structures. Manifestations are similar to diabetic retinopathy demonstrating microvascular changes including capillary non-perfusion,
Received 29 April 2013; revised 1 September 2013; accepted 17 September 2013; published online 6 November 2013 Correspondence: Sophie J. Bakri, MD, Department of Ophthalmology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. E-mail: [email protected]
276
Bevacizumab and triamcinolone for radiation macular edema
277
intravitreal triamcinolone, and bevacizumab, which have demonstrated varying success.3,4,5,6,7 Intravitreal triamcinolone was shown to be effective at stabilizing or improving vision in 91% of patients at one month and 45% at six months.6 Recently, intravitreal bevacizumab has also shown promise with modest improvement in visual acuity in short-term studies.7 The purpose of this study is to describe the variable effects of intravitreal bevacizumab (IVB) and triamcinolone acetonide (IVTA) in the treatment of macular edema secondary to radiation retinopathy.
MATERIALS AND METHODS Charts of five patients with macular edema secondary to radiation retinopathy who received IVB with subsequent IVTA were reviewed. Institutional review board approval was obtained for the study. Patient 1 had an Iodine-125 plaque for a choroidal melanoma in the right eye in 2002. Patient 2 had an Iodine-125 plaque for a choroidal melanoma in the right eye in 1998. Patient 3 had radiation therapy for a grade 4 undifferentiated sinus carcinoma from 2000 to 2002. Patient 4 had radiation to the head and chest for small cell lung cancer in 1992. Patient 5 had an Iodine-125 plaque for a choroidal melanoma in the left eye in 2004. All patients were treated with IVB and subsequent IVTA from 2005 to 2008 and followed up at approximately four- to eight-week intervals by clinical exam and optical coherence tomography (OCT) to measure macular edema. Injections were performed in the same manner in all patients. After anesthetizing with cotton tip applicators soaked in 4% lidocaine applied to the inferotemporal limbus, the periocular area was prepped with 10% povidone-iodine, and 5% povidone-iodine was applied into the conjunctival fornix. An eyelid speculum was used. Using a 30-gauge needle through the pars plana, bevacizumab 1.25 mg (in 0.05 ml) or triamcinolone acetonide (4 mg in 0.1 mL) was injected. When IVB and IVTA were given together, two separate injections of 1.25 mg of bevacizumab (in 0.05 ml) and 2 mg of IVTA (in 0.05 ml) were given. Outcomes of treatment were measured by Snellen visual acuity, clinical examination, and central macular thickness (CMT) on OCT approximately four to eight weeks after injection. In patients with macular edema that did not respond or worsened with IVB, IVTA was given and, in one patient, a combination of IVB and IVTA was given.
RESULTS Patient 1 initially responded to IVB. The first injection of IVB was given after a baseline initial VA of 20/100 and CMT of 340 mm. One month later, VA was stable !
2015 Informa Healthcare USA, Inc.
FIGURE 1. (a) This shows the OCT of patient 2 before receiving intravitreal bevacizumab. Central macular thickness is 369 microns. 139 61 mm (150 150 DPI). (b) This shows the OCT of patient 2 one month after receiving intravitreal bevacizumab. Central macular thickness is 375 microns. 168 87 mm (150 150 DPI).
at 20/100 with complete resolution of edema with a CMT of 252 mm. The patient subsequently underwent cataract extraction followed by five additional injections of IVB. With each injection, response to IVB diminished with CMT declining 45 um and 21 um after the fifth and sixth injection. Mean change in CMT was 34.8 mm. The patient was switched to IVTA with CMT improving from 291 to 228 mm. The patient has received four IVTA injections to date with a reduction in CME from 291 mm to 260 mm after the IVTA was initiated. Partial responses to IVB were demonstrated in patients 2 and 3. Patient 2 had minimal response to IVB with a decrease in CMT of 70 and 12 mm following the first two injections from a baseline of 436 mm. However, the patient failed to respond after the third treatment and CMT increased 9 mm (Figure 1). VA was stable. The patient was switched to IVTA and demonstrated a partial response with a decline in CMT of 100, 26, and an increase of 60 mm, respectively, after each of the injections (Figure 2). During this period vision worsened to 20/400 from 20/40 secondary to a cataract. After phacoemulsification, VA improved to 20/40 but macular edema remained at eight weeks follow-up after the third IVTA injection with a mean CMT of 394 mm. A combination of IVB and IVTA were then used with complete resolution of macular edema. Mean CMT was 299 mm five weeks post-injection with VA improving one line (Figure 3). The patient has received a total of two combination therapies of IVB and IVTA to date. Similar to patient 2, patient 3 had minimal decrease in CMT with IVB. At a baseline CMT of 596 mm,
278 S. J. Bakri and T. A. Larson
FIGURE 2. (a) This shows the OCT of patient 2 before receiving intravitreal triamcinolone. Central macular thickness is 460 microns. 169 85 mm (150 150 DPI). (b) This shows the OCT of patient 2 six weeks after receiving intravitreal triamcinolone. Central macular thickness is 360 microns. 166 86 mm (150 150 DPI).
FIGURE 3. (a) This shows the OCT of patient 2 before receiving intravitreal bevacizumab and triamcinolone in combination. Central macular thickness is 394 microns. 181 83 mm (143 150 DPI). (b) This shows the OCT of patient 2 five weeks after receiving intravitreal bevacizumab and triamcinolone in combination. Central macular thickness is 299 microns. 180 83 mm (144 150 DPI).
patient 3 had a decrease in CMT of 84, 82, and 57 mm following three injections of IVB. Following the four injection, the patient did not respond and CMT increased 56 mm. Vision improved from 20/400 to 20/150 by the third injection. The patient was then switched to IVTA and had minimal overall response
with decreases in CMT of 38, an increase of 79, and a decrease of 33 mm. VA worsened to 20/400 with the patient subsequently undergoing cataract extraction with a final visual acuity of 20/400. Both patients 4 and 5 worsened with IVB treatment but responded well to IVTA. Patient 4 received two IVB injections with increases in CMT of 119 and 10 mm from a baseline of 381 mm. Subsequently, the patient was treated with a total of 7 IVTA injections with a gradual decline in CMT from 519 mm to 226 mm. VA decreased to 20/150 from 20/40 during treatment. After undergoing cataract extraction, VA was 20/40 at final follow-up. Patient 5 also received two IVB injections. Initially, the patient had a partial response with a decrease in CMT of 42 mm from 525; however, following the second injection, CMT increased 54 mm. The patient received two injections of IVTA. Following the first, there was complete resolution of macular edema with a decrease in the CMT of 247 mm from 537 mm. At two months following the second injection of IVTA, CMT was 271. VA improved from a baseline of 20/100 to 20/50.
DISCUSSION Macular edema secondary to radiation retinopathy is a common vision-threatening complication. Preservation of vision is difficult and in one longterm follow-up study of 1,106 patients treated with plaque radiotherapy for uveal melanoma, visual acuity was 20/200 or worse in 68% of patients at 10 years.8 In another study of 135 patients with uveal melanoma treated with plaque radiotherapy, 51% of patients developed moderate visual loss over a two-year study period.9 There is currently limited success at treating macular edema secondary to radiation retinopathy. This study includes both patients treated locally with plaque radiotherapy and with external beam radiation. Time to onset of macular edema was greater than two years and average follow-up was 1.9 years. Only one patient responded to IVB with complete resolution of macular edema. This effect, however, was, short-lasting, and the response became diminished with each subsequent injection. Patients 2 and 3 had very minimal response and patients 4 and 5 worsened with IVB. Mason et al.7 reported 10 patients with macular edema secondary to radiation retinopathy were treated with one injection of IVB and all had reduction in macular edema with five of 10 having complete resolution. By 4 months postinjection, macular edema had returned. Patients in this study were excluded if there was 41 disk area of foveal nonperfusion shown on fluorescein angiogram.7 In this series, fluorescein angiography was not performed before the initial IVB in every patient and so patients with foveal nonperfusion were Seminars in Ophthalmology
Bevacizumab and triamcinolone for radiation macular edema likely included, thus potentially impacting the efficacy of any treatment. IVTA following IVB was effective in three of five patients with a decrease in macular edema one to two months post-injection. However, cataract was a common complication that limited VA following multiple injections that necessitated phacoemulsification in four of five patients. When comparing pre-treatment and final post-treatment vision, two of five patients had a 3-line VA improvement. Studies using IVTA have shown similar good results. Shields et al. report using IVTA in 31 patients with improvement in visual acuity of 2 lines at one month and foveal edema present in only 46%.6 In our series, of the patients with a poor response to IVTA, patient 2 required a combination of IVB and IVTA while patient 3 had minimal response to IVTA, which is likely secondary to the poor VA and severity of the macular edema present at baseline, as well as the presence of an intraretinal hemorrhage in the fovea. As this case series demonstrates, neither IVB nor IVTA alone definitively treats macular edema secondary to radiation retinopathy. Treatments, if they have an effect, are short-lasting, approximately one month with IVB and three months with IVTA, require multiple injections, and are complicated by cataract and glaucoma. Two of five patients had intraocular pressure rises greater than 21 mm Hg that required treatment medically. Why only one patient responded well to IVB and then grew resistant to its effects is unknown. One case series10 has reported rebound macular edema after IVB for macular edema due to CRVO. In another report,11 a patient with macular edema due to central retinal vein occlusion initially responded but then became resistant to IVB and then IVTA, and then responded to a combination of both. It is hypothesized that upregulation of VEGF receptors may occur after anti-VEGF agents. Radiation retinopathy is similar in manifestations to diabetic retinopathy; however, it is generally more severe with capillary nonperfusion as a dominant feature. A recent report comparing treatments of IVB to IVTA for diabetic macular edema in a series of 28 eyes showed better results with IVTA than IVB in reducing macular edema and improving vision.12 This may be secondary to the mechanism of action of IVB and IVTA. Bevacizumab is a full-length humanized monoclonal that binds all subtypes of vascular endothelial growth factor (VEGF). VEGF has been shown to be an endothelial cell mitogen and angiogenic inducer as well as increasing retinal vessel permeability.13 Corticosteroids are hypothesized to reduce the retinal capillary permeability by increasing the activity/ density of tight junctions and inhibiting the expression of VEGF and metabolic activity of VEGF.14 !
2015 Informa Healthcare USA, Inc.
279
Therefore, bevacizumab may help by binding VEGF and triamcinolone by closing tight junctions, thus reducing leakage. Treatment of macular edema secondary to radiation retinopathy remains challenging and requires the use of multiple modalities. This case series, although limited in number of patients, demonstrates that IVB and or IVTA have the potential to improve vision and reduce macular edema. However, patients must be followed carefully, as rebound macular edema may occur and patients may become resistant to their effects. Additional longer-term and larger studies are needed that compare both treatments and their use in combination.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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