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focal photocoagulation for clinically significant diabetic macular edema
Taiwan Journal of Ophthalmology 2 (2012) 131e135
Contents lists available at SciVerse ScienceDirect
Taiwan Journal of Ophthalmology journal homepage: www.e-tjo.com
Original article
Sequential posterior subtenon injection of triamcinolone acetonide with macular grid/focal photocoagulation for clinically significant diabetic macular edema Yu-Shu Liu a, c, Wun-Dun Shen b, c, Chung-May Yang c, * a
Department of Ophthalmology, En Chu Kong Hospital, Taipei, Taiwan Department of Ophthalmology, Taipei Medical University, Shuang Ho Hospital, Taipei, Taiwan c Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 May 2012 Received in revised form 26 July 2012 Accepted 16 August 2012 Available online 26 November 2012
Purpose: To evaluate the efficacy of sequential posterior subtenon triamcinolone acetonide (PSTA) injection with macular grid/focal laser photocoagulation for clinically significant diabetic macular edema (CSME). Methods: Prospective, interventional clinical trial. Between July 2007 and March 2008, 41 eyes of 32 patients (17 males and 15 females) with Type II diabetes mellitus and diffuse clinically significant macular edema according to the Early Treatment Diabetic Retinopathy Study criteria were recruited. PSTA was used as the first line of treatment, followed by macular focal/grid photocoagulation 2 weeks later. In patients with persistent macular edema, a second dose of PSTA followed by additional focal laser treatment was administered 8e10 weeks later. Results: Best-corrected visual acuity (BCVA) calculated as logarithm of the minimum angle of resolution (logMAR) unit showed significant improvement both after 3 weeks (0.79 0.27, p ¼ 0.001) and after 6 months (0.77 0.29, p ¼ 0.001) in comparison with the baseline values 0.92 0.24. Central macular thickness (CMT) was significantly reduced both after 3 weeks (336.2 125.8 mm, p ¼ 0.001) and after 6 months (342.2 127.2 mm, p ¼ 0.001) in comparison with the baseline values 437.1 186.5 mm. Total macular volume (TMV) was also significantly reduced both after 3 weeks (10.2 1.8 mm3, p < 0.05) and after 6 months (10.3 2.0 mm3, p < 0.05) in comparison with the baseline values 11.9 2.1 mm3. There were no significant differences in BCVA, CMT, and TMV between 3 weeks and 6 months posttreatment. Conclusion: One or two sessions of sequential PSTA injection and macular grid/focal photocoagulation may improve or stabilize visual acuity, CMT, and TMV for at least 6 months in patients with CSME. Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: clinically significant macular edema photocoagulation subtenon triamcinolone acetonide
1. Introduction Macular edema is the main cause of decreased visual acuity in patients with diabetes.1 The Early Treatment Diabetic Retinopathy Study (ETDRS) and other studies have shown that macular photocoagulation is effective for clinically significant diabetic macular edema (CSME).2,3 However, laser photocoagulation for macular edema prevents further moderate visual loss by approximately 50% and does not usually restore vision loss that occurred prior to treatment.2,4 Because of the limited efficacy of macular photocoagulation for diabetic macular edema, other treatment modalities have been taken into consideration in recent years. Intravitreal * Corresponding author. Department of Ophthalmology, National Taiwan University Hospital, Number 7, Chung Shan South Road, Taipei, Taiwan. E-mail address: [email protected] (C.-M. Yang).
triamcinolone acetonide (IVTA) has been shown to be highly effective for the treatment of diffuse diabetic macular edema, refractory to traditional laser photocoagulation.5 Despite prompt response from treatment with intravitreal steroid injections, this modality is associated with many severe vision-threatening ocular complications such as endophthalmitis and glaucoma.6,7 Triamcinolone acetonide delivered via the posterior subtenon route was later developed and has proved effective in treating posterior inflammation and macular edema associated with uveitis.8 Recently, some studies have reported that posterior subtenon triamcinolone acetonide (PSTA) injection combined with laser photocoagulation for diabetic macular edema improves visual outcome when compared with laser treatment alone.9,10 However, the optical coherence tomography (OCT) change and the response to repeated treatment in recurrent cases were not studied. Therefore, we planned a prospective interventional study to determine the effectiveness of
2211-5056/$ e see front matter Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.tjo.2012.10.003
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sequential PSTA combined with macular grid/focal photocoagulation as a primary treatment for CSME. 2. Patients and methods From July 2007 to March 2008, 41 eyes of 32 patients with Type II diabetes mellitus with diffuse clinical significant macular edema according to the ETDRS criteria were recruited in this prospective, interventional clinical study. Patients were included if they had central macular thickness (CMT) greater than 280 mm on OCT and best-corrected visual acuity (BCVA) between 0.2 and 1.3 logarithm of the minimum angle of resolution (logMAR). Exclusion criteria included prior history of focal/grid laser photocoagulation in the macula, prior steroid injection treatment for diabetic macular edema (such as intravitreal/peribulbar injection), major ocular surgery (including scleral buckle, glaucoma filtering surgery, and cornea transplant), panretinal scatter photocoagulation within the past 4 months, diabetic papillopathy, ischemic maculopathy with capillary nonperfusion, and any other ocular diseases such as glaucoma, retinal vessel occlusion, uveitis, or other ocular inflammatory/neovascular diseases. Furthermore, an eye was considered ineligible if OCT suggested that vitreoretinal interface disease (e.g., vitreoretinal traction, epiretinal membrane) was the primary cause of the macular edema. Informed consent was obtained from all patients after a thorough explanation of the study’s purpose and possible risk factors. This study was approved by the clinical research committee of the National Taiwan University Hospital. We recorded the following information: medical history, patient age, sex, and duration of systemic diabetic mellitus diagnosed. All patients received a comprehensive eye examination, including BCVA determined with the Snellen chart (which was then converted to logMAR), intraocular pressure (IOP) measured with a pneumotonometer, slit-lamp biomicroscopy, anterior segment examination, indirect ophthalmoscopy, fluorescein angiography, and an OCT examination at baseline and at both 3 weeks and 6 months after treatment. The clinical evaluation of the macular edema was performed with stereoscopic slit-lamp fundus examination using a noncontact (78 diopters) lens. Color fundus photographs and fluorescein angiography were both evaluated by an experienced retinal specialist. Retinal thickness measurements were obtained with an OCT scanner (Stratus, Carl Zeiss Meditec Inc, Dublin, CA, USA) using the Fast Macular Thickness Map protocol and the values were automatically generated by the OCT machine using the Retinal Map Analysis function. Central macular thickness (CMT) was the mean thickness at the point of intersection of 6 radial scans. Total macular volume (TMV) was defined as total volume of the macular map area. All baseline and follow-up examinations as well as OCT were evaluated by the same specialist (Yang). 2.1. Treatment intervention The interventional treatment protocol was designed as follows: PSTA was first administered, followed by macular grid/focal photocoagulation 2 weeks later. In patients with persistent macular edema with CMT > 300 mm or BCVA 0.4 logMAR, a second dose of PSTA was followed by additional focal laser treatment 8 to 10 weeks later. Patients were eligible for a repeat posterior subtenon injection if they did not have a significant IOP elevation (S10 mmHg) after the first injection. The procedure for the sequential PSTA injection was identical to that of the first injection. The macular laser photocoagulation was performed in the following way: an argon green laser was used at settings of 100 mm in spot size, 0.1 second in duration, and a power sufficient to cause
a Grade I burn in grid treatment and whitening of a microaneurysm in focal treatment. Leaking microaneurysms were treated with a focal laser; additional grid treatment to the diffusely thickened retina was performed only in the first session. Retinal areas within 500 mm from the foveal center and from the outer margin of the optic disc were avoided. For the PSTA injection, the patient was placed in the supine position. After 0.5% proparacaine topical anesthetic drops were used, 1.0 mL of a 40 mg/mL dosage of triamcinolone acetonide was injected in the inferotemporal quadrant using a 27-gauge needle on a 1-mL syringe.
2.2. Statistical analysis Statistical analysis was performed using the SPSS statistical program (SPSS Inc., Chicago, IL, USA). Serial comparison of pretreatment and posttreatment main outcome measures was evaluated using the paired Student t test. A p value less than 0.05 was considered statistically significant.
3. Results A total of 41 eyes of 32 patients (17 males and 15 females) ranging in age from 49 to 79 years were recruited. The duration of diabetic mellitus diagnosed ranged from 4 to 30 years. Baseline characteristics before treatment are summarized in Table 1. All the patients participated fully in both the treatment and the 6-month follow-up evaluations. The results of the main measure outcomes are listed in Table 2. BCVA calculated as LogMAR units showed significant improvement both after 3 weeks (0.79 0.27, p ¼ 0.001) and after 6 months (0.77 0.29, p ¼ 0.001) in comparison with the baseline values 0.92 0.24. There was no significant difference in visual acuity between 3 weeks and 6 months posttreatment. The CMT was significantly reduced both after 3 weeks (336.2 125.8 mm, p ¼ 0.001) and after 6 months (342.2 127.2 mm, p ¼ 0.001) in comparison with the baseline values 437.1 186.5 mm. There was no significant difference in CMT between 3 weeks and 6 months posttreatment. The TMV was also significantly reduced both after 3 weeks (10.2 1.8 mm3, p < 0.05) and after 6 months (10.3 2.0 mm3, p < 0.05) in comparison with the baseline values 11.9 2.1 mm3. There was no significant difference in TMV between 3 weeks and 6 months posttreatment. Most of the eyes (35 of 41, 85.4%) in our study received the second PSTA injection with an average interval of 5.2 2.1 weeks from the first injection. Fig. 1 shows the OCT findings of the right eye of a 74-year-old man with diabetic macular edema who received PSTA injection and macular grid photocoagulation followed by a PSTA injection 8 weeks later.
Table 1 Patients’ characteristics before treatment. Baseline characteristics
n ¼ 41
Age (mean SD), y Diabetic duration (mean SD), y Insulin treatment, n (%) Phakic, n (%) HbA1C (mean SD) Visual acuity (mean SD), logMAR Intraocular pressure (mean SD), mmHg
59.7 7.8 11.5 7.6 11 (26.8%) 30 (73.2%) 7.6 1.8 0.92 0.24 14.7 1.9
HbA1C ¼ glycosylated hemoglobin; logMAR ¼ logarithm of the minimum angle of resolution; SD ¼ standard deviation.
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 131e135 Table 2 Results of sequential macular grid/focal photocoagulation and posterior subtenon triamcinolone acetonide injection for diabetic macular edema. n ¼ 41
VA (logMAR) CMT (mm) TMV (mm3) IOP (mmHg)
Pretreatment
0.92 0.24 437.1 186.5 11.9 2.1 14.7 1.9
Posttreatment 3 wk
6 mo
0.79 0.27 336.2 125.8 10.2 1.8 15.9 2.1
0.77 0.29 342.2 127.2 10.3 2.0 15.3 2.2
p
0.001a 0.001a 0.032a 0.063
CMT ¼ central macular thickness; IOP ¼ intraocular pressure; logMAR ¼ logarithm of the minimum angle of resolution; TMV ¼ total macular volume; VA ¼ visual acuity. a p < 0.05 is statistically significant.
4. Adverse effects There were some unspecific complications noted such as mild ptosis as well as mild conjunctival necrosis. In two cases there was an increase in IOP 1 month after treatment, which was then controlled with ocular hypotensive drops. The highest IOP attained in any eye was 31 mmHg at 1 month in a patient who had an initial IOP of 16 mmHg. The IOP before treatment was 14.7 1.9 mmHg, and the posttreatment IOP was 15.9 2.1 mmHg at 3 weeks and 15.3 2.2 mmHg at 6 months (p > 0.05). 5. Discussion Macular edema is one of the main causes of visual loss in patients with diabetes.11 The pathogenesis of diabetic macular edema may include focal leakage from microaneurysms, which is often associated with intraretinal lipid deposition in a circinate pattern, and diffuse leakage from clusters of microaneurysms, capillaries, or small vascular segments in the macular area.12 In the ETDRS, focal laser photocoagulation was applied for leakage from
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the microaneurysms, and grid laser photocoagulation was applied for areas of diffuse capillary leakage.2,13 The ETDRS study reported that focal macular photocoagulation was beneficial in preventing moderate visual loss in 50% of patients. However, only 17% of patients had any improvement in vision, and only 3% had more than three lines of improvement in vision. The extent of the restoration of hematoretinal barrier function following laser treatment is debatable because many studies indicate an increase in edema following laser photocoagulation that is most likely due to the release of proinflammatory molecules.14,15 Thus, other treatment modalities for diffuse diabetic macular edema were evaluated. Several studies have shown that intravitreal injections of triamcinolone acetonide have a positive effect on those forms of diabetic macular edema that are refractory to retinal laser treatment.16,17 The use of corticosteroids for the treatment of retinal edema is linked to their capacity to inhibit the prostaglandin synthesis, to attenuate the tearing of the hematoretinal barrier, and to inhibit the mitogen-dependent transcription of vascular endothelial growth factor (VEGF).18e20 However, the beneficial effects on vision and macular thickness are only short term. Massin et al5 reported that IVTA reduced macular thickening and improved vision for 3 months; however, a recurrence of symptoms was noted after 6 months. Although recurrence of macular edema can be treated with repeat IVTA, Chan et al21 reported that a repeat injection might not be as effective as the initial one. Furthermore, use of IVTA was associated with complications such as endophthalmitis, intraocular hemorrhage, retinal detachment, and possible increases in IOP in a percentage of cases ranging from 20% to 80%.6,7,22 Considering the complications related to IVTA, PSTA is an alternative method to treat diabetic macular edema. Subtenon triamcinolone acetonide has already been used to treat macular edema associated with intermediate uveitis8 and to treat diabetic
Fig. 1. Optical coherence tomography (OCT) findings of the right eye of a 74-year-old man with diabetic macular edema. The patient received posterior subtenon triamcinolone acetonide (PSTA) injection and macular grid photocoagulation followed by a second PSTA injection 8 weeks later. (A) Pretreatment, visual acuity (VA): 20/160. (B) Three weeks after treatment, VA: 20/100. (C) Six months after treatment, VA: 20/63.
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macular edema.23 Choi et al24 reported that PSTA for diabetic macular edema has an effect comparable to that of IVTA with a significant decrease in central macular thickness at 1 month and 3 months postinjection, and PSTA is associated with a lower risk of elevated IOP. Although the subtenon approach is not free of potential complications such as elevation of IOP, retinal and choroidal vascular occlusion, blepharoptosis, and periocular abscess,25e27 it is clearly less invasive than the intravitreal approach. After a PSTA treatment, the decreased foveal thickness and restoration of retinal transparency facilitates adequate laser application to the outer retinal and retinal pigment epithelium. Verma et al9 and Tunc et al10 reported that PSTA combined with focal photocoagulation on the same day for treatment of diabetic macular edema improved visual outcome compared with macular photocoagulation alone. However, the OCT change and the response to repeated treatment in severe cases were not studied. Perhaps if PSTA had been given earlier in the course of the disease, prior to permanent retinal damage, there might have been an even greater improvement in visual acuity. In our study, we designed an interventional treatment protocol for diabetic macular edema with PSTA injection followed by macular/grid photocoagulation 2 weeks later and a sequential PSTA injection. The main outcome measures of our study were BCVA, CMT, and TMV measured by OCT. Our results showed that, when compared with baseline BCVA, the eyes had significant improvement in visual acuity 3 weeks after treatment that was maintained until 6 months after treatment (p < 0.05). CMT and TMV also were significantly reduced 3 weeks after treatment, which was maintained until at least 6 months after the treatment (p < 0.05). In our study, there were no significant complications with the exception of two cases with an increase in IOP 1 month after treatment, which was then treated with ocular hypotensive drops. We did not observe any complications due to infection in our study. Shimura et al28,29 also reported similar results, that PSTA prior to macular photocoagulation allows for treatment with less laser power and has maintained the improvement in macular thickness and visual acuity for up to 24 weeks without recurrence of macular edema. Compared with other research, most of the studies on IVTA or PSTA treatment for diabetic macular edema mainly focus on vision improvement and CMT reduction; however, our study found that TMV also showed significant reduction that was sustained for at least 6 months after the treatment. We conclude that TMV is also a good parameter to use when assessing changes of macular area and to estimate the degree of diabetic macular edema in the eyes of patients with diabetes. Recently, intravitreal injection of anti-VEGF agents has become a new therapeutic approach for patients with diffuse and refractory diabetic macular edema. In diabetic retinopathy, VEGF stimulates new vessel growth during the proliferative stage of the disease. VEGF has been linked to leakage of retinal vessels and hence the formation of retinal edema.30 Some studies demonstrated that intravitreal anti-VEGF injection, agents including ranibizumab and bevacizumab, seem to reduce macular thickness and provide stability or improvement in both BCVA and OCT.31e33 However, it is still an elective treatment, not covered by insurance, and most of the time it would need to be repeated monthly or several times for severe diabetic macular edema. Combined PSTA and photocoagulation treatment offers another choice for patients with diabetic macular edema who are unable to afford expensive anti-VEGF therapy. In summary, our study shows stabilization and improved vision in patients who received sequential PSTA combined with macular grid/focal photocoagulation for diabetic macular edema. The posterior subtenon injections appeared effective and safe. The limitations of our study include the small sample size and
the absence of a control group. Further prospective studies with an adequate control group are needed to fully evaluate the effect of PSTA in diabetic macular edema and to determine whether this treatment should be considered a promising treatment option for this visually debilitating disease. 6. Conclusion Our study with 6-month follow-up evaluations suggests that one or two sessions of sequential PSTA injection combined with macular grid/focal photocoagulation may improve or stabilize vision loss in patients with diabetic macular edema. References 1. Moss SE, Klein R, Klein BE. The incidence of visual loss in diabetic population. Ophthalmology 1988;95:1340e8. 2. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796e806. 3. Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136: 122e35. 4. Akduman L, Olk RJ. Laser photocoagulation of diabetic macular edema. Ophthalmic Surg Lasers 1997;28:387e408. 5. Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 2004;111: 218e24. 6. Moshfeghi DM, Kaiser PK, Scott IU. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2003;136:791e6. 7. Jonas JB, Kreissig I, Degenring R. Secondary chronic open-angle glaucoma after intravitreal triamcinolone acetonide. Arch Ophthalmol 2003;121:729e30. 8. Helm CJ, Holland GN. The effects of posterior subtenon injection of triamcinolone acetonide in patients with intermediate uveitis. Am J Ophthalmol 1995;120:55e64. 9. Verma LK, Vivek MB, Kumar A, Tewari HK, Venkatesh P. A prospective controlled trial to evaluate the adjunctive role of posterior subtenon triamcinolone in the treatment of diffuse diabetic macular edema. J Ocul Pharmacol Ther 2004;20:277e84. 10. Tunc M, Onder HI, Kaya M. Posterior sub-Tenon’s capsule triamcinolone injection combined with focal laser photocoagulation for diabetic macular edema. Ophthalmology 2005;112:1086e91. 11. Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 1998;105:998e1003. 12. Pelzek C, Lim JI. Diabetic macular edema: review and update. Ophthalmol Clin North Am 2002;15:555e63. 13. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1987;94:761e74. 14. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1995;113:1144e55. 15. Nonaka A, Kiryu J, Tsujikawa A, Yamashiro K, Nishijima K, Kamizuru H, et al. Inflammatory response after scatter laser photocoagulation in nonphotocoagulated retina. Invest Ophthalmol Vis Sci 2002;43:1204e9. 16. Jonas JB, Kreissig I, Sofker A, Degenring RF. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol 2003;121:57e61. 17. Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002;109:920e7. 18. Jonas JB, Sofker A. Intraocular injection of crystalline cortisone as adjunctive treatment for diabetic macular edema. Arch Ophthalmol 2001;132:425e7. 19. Wilson CA, Berkowitz BA, Sato Y. Treatment with intravitreal steroid reduces blood-retinal barrier breakdown due to retinal photocoagulation. Arch Ophthalmol 1992;110:1155e9. 20. Nauck M, Karakiulakis G, Andre PP, Papakonstantinou E, Poth M. Corticosteroids inhibit expression of the vascular endothelial growth factor in human vascular smooth muscle cells. Eur J Pharmacol 1998;34:309e15. 21. Chan CK, Mohamed S, Shanmugam MP, Tsang CW, Lai TY, Lam DS. Decreasing efficacy of repeated intravitreal triamcinolone injections in diabetic macular oedema. Br J Ophthalmol 2006;90:1137e41. 22. Smithen LM, Ober MD, Maranan L, Spaide RF. Intravitreal triamcinolone acetonide and intraocular pressure. Am J Ophthalmol 2004;138:740e3. 23. Bakri SJ, Kaiser PK. Posterior subtenon triamcinolone acetonide for refractory diabetic macular edema. Am J Ophthalmol 2005;139:290e4. 24. Choi YJ, Oh IK, Oh JR, Huh K. Intravitreal versus posterior subtenon injection of triamcinolone acetonide for diabetic macular edema. Korean J Ophthalmol 2006;20:205e9.
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 131e135 25. Mueller AJ, Jian G, Banker AS, Rahhal FM, Capparelli E, Freeman WR. The effect of deep posterior subtenon injection of corticosteroids on intraocular pressure. Am J Ophthalmol 1998;125:158e63. 26. Moshfeghi DM, Lowder CY, Roth DB, Kaiser PK. Retinal and choroidal vascular occlusion after posterior sub-tenon triamcinolone injection. Am J Ophthalmol 2002;134:132e4. 27. Oh IK, Baek S, Huh K, Oh J. Periocular abscess caused by Pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide. Grafes Arch Clin Exp Ophthalmol 2007;245:164e6. 28. Shimura M, Yasuda K, Shiono T. Posterior sub-Tenon’s capsule injection of triamcinolone acetonide prevents panretinal photocoagulation-induced visual dysfunction in patients with severe diabetic retinopathy and good vision. Ophthalmology 2006;113:381e7. 29. Shimura M, Nakazawa T, Yasuda K, Shiono T, Nishida K. Pretreatment of posterior subtenon injection of triamcinolone acetonide has beneficial effects
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for grid pattern photocoagulation against diffuse diabetic macular oedema. Br J Ophthalmol 2007;91:449e54. Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 2006;142:961e9. Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Do DV, et al. READ-2 Study Group. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 2010;117:2146e51. Haritoglou C, Kook D, Neubauer A, Wolf A, Priglinger S, Strauss R, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 2006;26:999e1005. Arevalo JF, Sanchez JG, Wu L, Maia M, Alezzandrini AA, Brito M, et al. PanAmerican Collaborative Retina Study Group. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology 2009;116:1488e97.
Contents lists available at SciVerse ScienceDirect
Taiwan Journal of Ophthalmology journal homepage: www.e-tjo.com
Original article
Sequential posterior subtenon injection of triamcinolone acetonide with macular grid/focal photocoagulation for clinically significant diabetic macular edema Yu-Shu Liu a, c, Wun-Dun Shen b, c, Chung-May Yang c, * a
Department of Ophthalmology, En Chu Kong Hospital, Taipei, Taiwan Department of Ophthalmology, Taipei Medical University, Shuang Ho Hospital, Taipei, Taiwan c Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 May 2012 Received in revised form 26 July 2012 Accepted 16 August 2012 Available online 26 November 2012
Purpose: To evaluate the efficacy of sequential posterior subtenon triamcinolone acetonide (PSTA) injection with macular grid/focal laser photocoagulation for clinically significant diabetic macular edema (CSME). Methods: Prospective, interventional clinical trial. Between July 2007 and March 2008, 41 eyes of 32 patients (17 males and 15 females) with Type II diabetes mellitus and diffuse clinically significant macular edema according to the Early Treatment Diabetic Retinopathy Study criteria were recruited. PSTA was used as the first line of treatment, followed by macular focal/grid photocoagulation 2 weeks later. In patients with persistent macular edema, a second dose of PSTA followed by additional focal laser treatment was administered 8e10 weeks later. Results: Best-corrected visual acuity (BCVA) calculated as logarithm of the minimum angle of resolution (logMAR) unit showed significant improvement both after 3 weeks (0.79 0.27, p ¼ 0.001) and after 6 months (0.77 0.29, p ¼ 0.001) in comparison with the baseline values 0.92 0.24. Central macular thickness (CMT) was significantly reduced both after 3 weeks (336.2 125.8 mm, p ¼ 0.001) and after 6 months (342.2 127.2 mm, p ¼ 0.001) in comparison with the baseline values 437.1 186.5 mm. Total macular volume (TMV) was also significantly reduced both after 3 weeks (10.2 1.8 mm3, p < 0.05) and after 6 months (10.3 2.0 mm3, p < 0.05) in comparison with the baseline values 11.9 2.1 mm3. There were no significant differences in BCVA, CMT, and TMV between 3 weeks and 6 months posttreatment. Conclusion: One or two sessions of sequential PSTA injection and macular grid/focal photocoagulation may improve or stabilize visual acuity, CMT, and TMV for at least 6 months in patients with CSME. Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: clinically significant macular edema photocoagulation subtenon triamcinolone acetonide
1. Introduction Macular edema is the main cause of decreased visual acuity in patients with diabetes.1 The Early Treatment Diabetic Retinopathy Study (ETDRS) and other studies have shown that macular photocoagulation is effective for clinically significant diabetic macular edema (CSME).2,3 However, laser photocoagulation for macular edema prevents further moderate visual loss by approximately 50% and does not usually restore vision loss that occurred prior to treatment.2,4 Because of the limited efficacy of macular photocoagulation for diabetic macular edema, other treatment modalities have been taken into consideration in recent years. Intravitreal * Corresponding author. Department of Ophthalmology, National Taiwan University Hospital, Number 7, Chung Shan South Road, Taipei, Taiwan. E-mail address: [email protected] (C.-M. Yang).
triamcinolone acetonide (IVTA) has been shown to be highly effective for the treatment of diffuse diabetic macular edema, refractory to traditional laser photocoagulation.5 Despite prompt response from treatment with intravitreal steroid injections, this modality is associated with many severe vision-threatening ocular complications such as endophthalmitis and glaucoma.6,7 Triamcinolone acetonide delivered via the posterior subtenon route was later developed and has proved effective in treating posterior inflammation and macular edema associated with uveitis.8 Recently, some studies have reported that posterior subtenon triamcinolone acetonide (PSTA) injection combined with laser photocoagulation for diabetic macular edema improves visual outcome when compared with laser treatment alone.9,10 However, the optical coherence tomography (OCT) change and the response to repeated treatment in recurrent cases were not studied. Therefore, we planned a prospective interventional study to determine the effectiveness of
2211-5056/$ e see front matter Copyright Ó 2012, The Ophthalmologic Society of Taiwan. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.tjo.2012.10.003
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sequential PSTA combined with macular grid/focal photocoagulation as a primary treatment for CSME. 2. Patients and methods From July 2007 to March 2008, 41 eyes of 32 patients with Type II diabetes mellitus with diffuse clinical significant macular edema according to the ETDRS criteria were recruited in this prospective, interventional clinical study. Patients were included if they had central macular thickness (CMT) greater than 280 mm on OCT and best-corrected visual acuity (BCVA) between 0.2 and 1.3 logarithm of the minimum angle of resolution (logMAR). Exclusion criteria included prior history of focal/grid laser photocoagulation in the macula, prior steroid injection treatment for diabetic macular edema (such as intravitreal/peribulbar injection), major ocular surgery (including scleral buckle, glaucoma filtering surgery, and cornea transplant), panretinal scatter photocoagulation within the past 4 months, diabetic papillopathy, ischemic maculopathy with capillary nonperfusion, and any other ocular diseases such as glaucoma, retinal vessel occlusion, uveitis, or other ocular inflammatory/neovascular diseases. Furthermore, an eye was considered ineligible if OCT suggested that vitreoretinal interface disease (e.g., vitreoretinal traction, epiretinal membrane) was the primary cause of the macular edema. Informed consent was obtained from all patients after a thorough explanation of the study’s purpose and possible risk factors. This study was approved by the clinical research committee of the National Taiwan University Hospital. We recorded the following information: medical history, patient age, sex, and duration of systemic diabetic mellitus diagnosed. All patients received a comprehensive eye examination, including BCVA determined with the Snellen chart (which was then converted to logMAR), intraocular pressure (IOP) measured with a pneumotonometer, slit-lamp biomicroscopy, anterior segment examination, indirect ophthalmoscopy, fluorescein angiography, and an OCT examination at baseline and at both 3 weeks and 6 months after treatment. The clinical evaluation of the macular edema was performed with stereoscopic slit-lamp fundus examination using a noncontact (78 diopters) lens. Color fundus photographs and fluorescein angiography were both evaluated by an experienced retinal specialist. Retinal thickness measurements were obtained with an OCT scanner (Stratus, Carl Zeiss Meditec Inc, Dublin, CA, USA) using the Fast Macular Thickness Map protocol and the values were automatically generated by the OCT machine using the Retinal Map Analysis function. Central macular thickness (CMT) was the mean thickness at the point of intersection of 6 radial scans. Total macular volume (TMV) was defined as total volume of the macular map area. All baseline and follow-up examinations as well as OCT were evaluated by the same specialist (Yang). 2.1. Treatment intervention The interventional treatment protocol was designed as follows: PSTA was first administered, followed by macular grid/focal photocoagulation 2 weeks later. In patients with persistent macular edema with CMT > 300 mm or BCVA 0.4 logMAR, a second dose of PSTA was followed by additional focal laser treatment 8 to 10 weeks later. Patients were eligible for a repeat posterior subtenon injection if they did not have a significant IOP elevation (S10 mmHg) after the first injection. The procedure for the sequential PSTA injection was identical to that of the first injection. The macular laser photocoagulation was performed in the following way: an argon green laser was used at settings of 100 mm in spot size, 0.1 second in duration, and a power sufficient to cause
a Grade I burn in grid treatment and whitening of a microaneurysm in focal treatment. Leaking microaneurysms were treated with a focal laser; additional grid treatment to the diffusely thickened retina was performed only in the first session. Retinal areas within 500 mm from the foveal center and from the outer margin of the optic disc were avoided. For the PSTA injection, the patient was placed in the supine position. After 0.5% proparacaine topical anesthetic drops were used, 1.0 mL of a 40 mg/mL dosage of triamcinolone acetonide was injected in the inferotemporal quadrant using a 27-gauge needle on a 1-mL syringe.
2.2. Statistical analysis Statistical analysis was performed using the SPSS statistical program (SPSS Inc., Chicago, IL, USA). Serial comparison of pretreatment and posttreatment main outcome measures was evaluated using the paired Student t test. A p value less than 0.05 was considered statistically significant.
3. Results A total of 41 eyes of 32 patients (17 males and 15 females) ranging in age from 49 to 79 years were recruited. The duration of diabetic mellitus diagnosed ranged from 4 to 30 years. Baseline characteristics before treatment are summarized in Table 1. All the patients participated fully in both the treatment and the 6-month follow-up evaluations. The results of the main measure outcomes are listed in Table 2. BCVA calculated as LogMAR units showed significant improvement both after 3 weeks (0.79 0.27, p ¼ 0.001) and after 6 months (0.77 0.29, p ¼ 0.001) in comparison with the baseline values 0.92 0.24. There was no significant difference in visual acuity between 3 weeks and 6 months posttreatment. The CMT was significantly reduced both after 3 weeks (336.2 125.8 mm, p ¼ 0.001) and after 6 months (342.2 127.2 mm, p ¼ 0.001) in comparison with the baseline values 437.1 186.5 mm. There was no significant difference in CMT between 3 weeks and 6 months posttreatment. The TMV was also significantly reduced both after 3 weeks (10.2 1.8 mm3, p < 0.05) and after 6 months (10.3 2.0 mm3, p < 0.05) in comparison with the baseline values 11.9 2.1 mm3. There was no significant difference in TMV between 3 weeks and 6 months posttreatment. Most of the eyes (35 of 41, 85.4%) in our study received the second PSTA injection with an average interval of 5.2 2.1 weeks from the first injection. Fig. 1 shows the OCT findings of the right eye of a 74-year-old man with diabetic macular edema who received PSTA injection and macular grid photocoagulation followed by a PSTA injection 8 weeks later.
Table 1 Patients’ characteristics before treatment. Baseline characteristics
n ¼ 41
Age (mean SD), y Diabetic duration (mean SD), y Insulin treatment, n (%) Phakic, n (%) HbA1C (mean SD) Visual acuity (mean SD), logMAR Intraocular pressure (mean SD), mmHg
59.7 7.8 11.5 7.6 11 (26.8%) 30 (73.2%) 7.6 1.8 0.92 0.24 14.7 1.9
HbA1C ¼ glycosylated hemoglobin; logMAR ¼ logarithm of the minimum angle of resolution; SD ¼ standard deviation.
Y.-S. Liu et al. / Taiwan Journal of Ophthalmology 2 (2012) 131e135 Table 2 Results of sequential macular grid/focal photocoagulation and posterior subtenon triamcinolone acetonide injection for diabetic macular edema. n ¼ 41
VA (logMAR) CMT (mm) TMV (mm3) IOP (mmHg)
Pretreatment
0.92 0.24 437.1 186.5 11.9 2.1 14.7 1.9
Posttreatment 3 wk
6 mo
0.79 0.27 336.2 125.8 10.2 1.8 15.9 2.1
0.77 0.29 342.2 127.2 10.3 2.0 15.3 2.2
p
0.001a 0.001a 0.032a 0.063
CMT ¼ central macular thickness; IOP ¼ intraocular pressure; logMAR ¼ logarithm of the minimum angle of resolution; TMV ¼ total macular volume; VA ¼ visual acuity. a p < 0.05 is statistically significant.
4. Adverse effects There were some unspecific complications noted such as mild ptosis as well as mild conjunctival necrosis. In two cases there was an increase in IOP 1 month after treatment, which was then controlled with ocular hypotensive drops. The highest IOP attained in any eye was 31 mmHg at 1 month in a patient who had an initial IOP of 16 mmHg. The IOP before treatment was 14.7 1.9 mmHg, and the posttreatment IOP was 15.9 2.1 mmHg at 3 weeks and 15.3 2.2 mmHg at 6 months (p > 0.05). 5. Discussion Macular edema is one of the main causes of visual loss in patients with diabetes.11 The pathogenesis of diabetic macular edema may include focal leakage from microaneurysms, which is often associated with intraretinal lipid deposition in a circinate pattern, and diffuse leakage from clusters of microaneurysms, capillaries, or small vascular segments in the macular area.12 In the ETDRS, focal laser photocoagulation was applied for leakage from
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the microaneurysms, and grid laser photocoagulation was applied for areas of diffuse capillary leakage.2,13 The ETDRS study reported that focal macular photocoagulation was beneficial in preventing moderate visual loss in 50% of patients. However, only 17% of patients had any improvement in vision, and only 3% had more than three lines of improvement in vision. The extent of the restoration of hematoretinal barrier function following laser treatment is debatable because many studies indicate an increase in edema following laser photocoagulation that is most likely due to the release of proinflammatory molecules.14,15 Thus, other treatment modalities for diffuse diabetic macular edema were evaluated. Several studies have shown that intravitreal injections of triamcinolone acetonide have a positive effect on those forms of diabetic macular edema that are refractory to retinal laser treatment.16,17 The use of corticosteroids for the treatment of retinal edema is linked to their capacity to inhibit the prostaglandin synthesis, to attenuate the tearing of the hematoretinal barrier, and to inhibit the mitogen-dependent transcription of vascular endothelial growth factor (VEGF).18e20 However, the beneficial effects on vision and macular thickness are only short term. Massin et al5 reported that IVTA reduced macular thickening and improved vision for 3 months; however, a recurrence of symptoms was noted after 6 months. Although recurrence of macular edema can be treated with repeat IVTA, Chan et al21 reported that a repeat injection might not be as effective as the initial one. Furthermore, use of IVTA was associated with complications such as endophthalmitis, intraocular hemorrhage, retinal detachment, and possible increases in IOP in a percentage of cases ranging from 20% to 80%.6,7,22 Considering the complications related to IVTA, PSTA is an alternative method to treat diabetic macular edema. Subtenon triamcinolone acetonide has already been used to treat macular edema associated with intermediate uveitis8 and to treat diabetic
Fig. 1. Optical coherence tomography (OCT) findings of the right eye of a 74-year-old man with diabetic macular edema. The patient received posterior subtenon triamcinolone acetonide (PSTA) injection and macular grid photocoagulation followed by a second PSTA injection 8 weeks later. (A) Pretreatment, visual acuity (VA): 20/160. (B) Three weeks after treatment, VA: 20/100. (C) Six months after treatment, VA: 20/63.
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macular edema.23 Choi et al24 reported that PSTA for diabetic macular edema has an effect comparable to that of IVTA with a significant decrease in central macular thickness at 1 month and 3 months postinjection, and PSTA is associated with a lower risk of elevated IOP. Although the subtenon approach is not free of potential complications such as elevation of IOP, retinal and choroidal vascular occlusion, blepharoptosis, and periocular abscess,25e27 it is clearly less invasive than the intravitreal approach. After a PSTA treatment, the decreased foveal thickness and restoration of retinal transparency facilitates adequate laser application to the outer retinal and retinal pigment epithelium. Verma et al9 and Tunc et al10 reported that PSTA combined with focal photocoagulation on the same day for treatment of diabetic macular edema improved visual outcome compared with macular photocoagulation alone. However, the OCT change and the response to repeated treatment in severe cases were not studied. Perhaps if PSTA had been given earlier in the course of the disease, prior to permanent retinal damage, there might have been an even greater improvement in visual acuity. In our study, we designed an interventional treatment protocol for diabetic macular edema with PSTA injection followed by macular/grid photocoagulation 2 weeks later and a sequential PSTA injection. The main outcome measures of our study were BCVA, CMT, and TMV measured by OCT. Our results showed that, when compared with baseline BCVA, the eyes had significant improvement in visual acuity 3 weeks after treatment that was maintained until 6 months after treatment (p < 0.05). CMT and TMV also were significantly reduced 3 weeks after treatment, which was maintained until at least 6 months after the treatment (p < 0.05). In our study, there were no significant complications with the exception of two cases with an increase in IOP 1 month after treatment, which was then treated with ocular hypotensive drops. We did not observe any complications due to infection in our study. Shimura et al28,29 also reported similar results, that PSTA prior to macular photocoagulation allows for treatment with less laser power and has maintained the improvement in macular thickness and visual acuity for up to 24 weeks without recurrence of macular edema. Compared with other research, most of the studies on IVTA or PSTA treatment for diabetic macular edema mainly focus on vision improvement and CMT reduction; however, our study found that TMV also showed significant reduction that was sustained for at least 6 months after the treatment. We conclude that TMV is also a good parameter to use when assessing changes of macular area and to estimate the degree of diabetic macular edema in the eyes of patients with diabetes. Recently, intravitreal injection of anti-VEGF agents has become a new therapeutic approach for patients with diffuse and refractory diabetic macular edema. In diabetic retinopathy, VEGF stimulates new vessel growth during the proliferative stage of the disease. VEGF has been linked to leakage of retinal vessels and hence the formation of retinal edema.30 Some studies demonstrated that intravitreal anti-VEGF injection, agents including ranibizumab and bevacizumab, seem to reduce macular thickness and provide stability or improvement in both BCVA and OCT.31e33 However, it is still an elective treatment, not covered by insurance, and most of the time it would need to be repeated monthly or several times for severe diabetic macular edema. Combined PSTA and photocoagulation treatment offers another choice for patients with diabetic macular edema who are unable to afford expensive anti-VEGF therapy. In summary, our study shows stabilization and improved vision in patients who received sequential PSTA combined with macular grid/focal photocoagulation for diabetic macular edema. The posterior subtenon injections appeared effective and safe. The limitations of our study include the small sample size and
the absence of a control group. Further prospective studies with an adequate control group are needed to fully evaluate the effect of PSTA in diabetic macular edema and to determine whether this treatment should be considered a promising treatment option for this visually debilitating disease. 6. Conclusion Our study with 6-month follow-up evaluations suggests that one or two sessions of sequential PSTA injection combined with macular grid/focal photocoagulation may improve or stabilize vision loss in patients with diabetic macular edema. References 1. Moss SE, Klein R, Klein BE. The incidence of visual loss in diabetic population. Ophthalmology 1988;95:1340e8. 2. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796e806. 3. Aiello LM. Perspectives on diabetic retinopathy. Am J Ophthalmol 2003;136: 122e35. 4. Akduman L, Olk RJ. Laser photocoagulation of diabetic macular edema. Ophthalmic Surg Lasers 1997;28:387e408. 5. Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 2004;111: 218e24. 6. Moshfeghi DM, Kaiser PK, Scott IU. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2003;136:791e6. 7. Jonas JB, Kreissig I, Degenring R. Secondary chronic open-angle glaucoma after intravitreal triamcinolone acetonide. Arch Ophthalmol 2003;121:729e30. 8. Helm CJ, Holland GN. The effects of posterior subtenon injection of triamcinolone acetonide in patients with intermediate uveitis. Am J Ophthalmol 1995;120:55e64. 9. Verma LK, Vivek MB, Kumar A, Tewari HK, Venkatesh P. A prospective controlled trial to evaluate the adjunctive role of posterior subtenon triamcinolone in the treatment of diffuse diabetic macular edema. J Ocul Pharmacol Ther 2004;20:277e84. 10. Tunc M, Onder HI, Kaya M. Posterior sub-Tenon’s capsule triamcinolone injection combined with focal laser photocoagulation for diabetic macular edema. Ophthalmology 2005;112:1086e91. 11. Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 1998;105:998e1003. 12. Pelzek C, Lim JI. Diabetic macular edema: review and update. Ophthalmol Clin North Am 2002;15:555e63. 13. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1987;94:761e74. 14. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1995;113:1144e55. 15. Nonaka A, Kiryu J, Tsujikawa A, Yamashiro K, Nishijima K, Kamizuru H, et al. Inflammatory response after scatter laser photocoagulation in nonphotocoagulated retina. Invest Ophthalmol Vis Sci 2002;43:1204e9. 16. Jonas JB, Kreissig I, Sofker A, Degenring RF. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol 2003;121:57e61. 17. Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002;109:920e7. 18. Jonas JB, Sofker A. Intraocular injection of crystalline cortisone as adjunctive treatment for diabetic macular edema. Arch Ophthalmol 2001;132:425e7. 19. Wilson CA, Berkowitz BA, Sato Y. Treatment with intravitreal steroid reduces blood-retinal barrier breakdown due to retinal photocoagulation. Arch Ophthalmol 1992;110:1155e9. 20. Nauck M, Karakiulakis G, Andre PP, Papakonstantinou E, Poth M. Corticosteroids inhibit expression of the vascular endothelial growth factor in human vascular smooth muscle cells. Eur J Pharmacol 1998;34:309e15. 21. Chan CK, Mohamed S, Shanmugam MP, Tsang CW, Lai TY, Lam DS. Decreasing efficacy of repeated intravitreal triamcinolone injections in diabetic macular oedema. Br J Ophthalmol 2006;90:1137e41. 22. Smithen LM, Ober MD, Maranan L, Spaide RF. Intravitreal triamcinolone acetonide and intraocular pressure. Am J Ophthalmol 2004;138:740e3. 23. Bakri SJ, Kaiser PK. Posterior subtenon triamcinolone acetonide for refractory diabetic macular edema. Am J Ophthalmol 2005;139:290e4. 24. Choi YJ, Oh IK, Oh JR, Huh K. Intravitreal versus posterior subtenon injection of triamcinolone acetonide for diabetic macular edema. Korean J Ophthalmol 2006;20:205e9.
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