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Repeated Intravitreal High-Dosage Injections of Triamcinolone Acetonide for Diffuse Diabetic Macular Edema
Repeated Intravitreal High-Dosage Injections of Triamcinolone Acetonide for Diffuse Diabetic Macular Edema Jost B. Jonas, MD, Ulrich H. Spandau, MD, Bernd A. Kamppeter, MD, Urs Vossmerbaeumer, MD, Björn Harder, MD, Gangolf Sauder, MD Objective: To report the results of repeated intravitreal injections of triamcinolone acetonide for treatment of diffuse diabetic macular edema. Design: Retrospective interventional comparative study. Participants: The investigation included a study group (the responders) of 19 patients (22 eyes) with diffuse diabetic macular edema, who showed an improvement in visual acuity after an intravitreal injection of approximately 20 mg triamcinolone acetonide, and who received a second intravitreal injection 10.0⫾3.8 months after the first injection. A control group consisted of 31 patients with diffuse diabetic macular edema without treatment during follow-up. Methods: Intravitreal injection of approximately 20 mg triamcinolone acetonide. Main Outcome Measures: Visual acuity and intraocular pressure. Results: Follow-up after the second injection was 9.1⫾4.9 months. Four patients received a third injection at 9.7⫾3.7 months after the second injection, with a follow-up after the third injection that was at 7.9⫾11.5 months. After the second and third injections, visual acuity increased significantly (P ⫽ 0.002 and P ⫽ 0.068, respectively) by 1.8⫾2.1 and 4.0⫾2.6 Snellen lines, respectively. Eleven eyes (50%) showed an improvement in visual acuity by at least 2 Snellen lines after the second injection, and 3 patients (75%) experienced a gain in visual acuity by at least 2 Snellen lines after the third injection. Intraocular pressure increased significantly (P⬍0.01) after each injection, and returned to baseline values before each reinjection. Visual acuity improvement (P⬎0.05) and intraocular pressure rise did not differ significantly (P⬎0.55) between the various injections. Improvement in visual acuity and rise of intraocular pressure lasted approximately 6 to 8 months after each injection. Conclusions: Intravitreal injection of approximately 20 mg triamcinolone acetonide may repeatedly lead to an improvement in visual acuity and a rise of intraocular pressure in patients with diffuse diabetic macular edema. The duration of the effect after each injection is approximately 6 to 8 months. Tachyphylaxis in visual acuity or intraocular pressure outcomes were not observed. Ophthalmology 2006;113:800 – 804 © 2006 by the American Academy of Ophthalmology.
Intravitreal triamcinolone acetonide has increasingly been used for the treatment of intraocular edematous and neovascular diseases, such as retinal vein occlusions,1– 4 neovascular glaucoma,5,6 chronic pre-phthisical ocular hypotony,7 chronic uveitis,8 –11 exudative neovascular age-related macular degeneration in combination with photodynamic therapy,12,13 and diffuse diabetic macular edema.14 –21 In most clinical descriptions, the effect of intravitreal triamcinolone acetonide was temporary, lasting approximately 2 to 4 months for a dosage of 4 mg triamcinolone acetonide, and lasting Originally received: June 3, 2005. Accepted: January 3, 2006. Manuscript no. 2005-482. From Department of Ophthalmology, Faculty of Clinical Medicine Mannheim of the University Heidelberg, Mannheim, Germany. The authors have no proprietary interest in any aspect of the article. Correspondence to Dr Jost B. Jonas, Universitäts-Augenklinik, TheodorKutzer-Ufer 1-3, Mannheim 68167, Germany. E-mail: Jost.Jonas@ma. augen.uni-heidelberg.de.
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© 2006 by the American Academy of Ophthalmology Published by Elsevier Inc.
approximately 6 to 8 months if a dosage of approximately 20 mg was applied.22–25 If the first injection was associated with an improvement in visual acuity, some patients received a second intravitreal injection, as described in previous studies on exudative age-related macular degeneration.22,23 It was the purpose of the present investigation to evaluate the effects and side-effects of repeated intravitreal injections of triamcinolone acetonide for treatment of diffuse diabetic macular edema.
Patients and Methods The study group (called the responders) of the nonrandomized, comparative clinical, interventional investigation included all patients (19 subjects: 17 women, 2 men; 22 eyes: 12 right eyes, 10 left eyes) who consecutively attended the hospital with a loss of vision due to diffuse diabetic macular edema; who received an intravitreal injection of approximately 20 mg of triamcinolone acetonide; who eventually received at least one repeated intravitISSN 0161-6420/06/$–see front matter doi:10.1016/j.ophtha.2006.01.002
Jonas et al 䡠 Treatment of Diffuse Diabetic Macular Edema real injection of triamcinolone acetonide; and who had a follow-up of at least 3 months after the second injection. The reason for the repeated intravitreal injection was that the patients experienced an improvement in visual acuity after the first injection, and some months later, a re-decline in visual acuity. In a parallel manner, cystoid macular edema resolved almost completely in the first months after the first injection, and returned some months later. The decision for a re-injection was solely based on visual acuity. Although optical coherence tomographic images and fluorescein angiograms were available, the results of these examinations were generally not taken into account for the decision on a re-injection. The re-injection took place 10.0⫾3.8 months (median, 9.7 months; range, 4.1–19.7 months) after the first intravitreal injection. Mean age of the patients was 66.1⫾11.5 years (range, 28.6 – 80.5 years; median, 68.2 years). Refractive error ranged between ⫺1.13 diopters (D) and ⫹4.25 D (mean ⫾ standard deviation, 0.55⫾1.27 D). Mean intraocular pressure prior to the first injection was 16.7⫾3.5 mmHg (median, 16 mmHg). All patients were fully informed about the experimental character of the therapy. All patients signed an informed consent. The ethics committee of the university approved the study. The study followed the tenets of the Declaration of Helsinki. Mean visual acuity at baseline of the study measured 0.14⫾0.11 (Snellen charts) (range, 0.03– 0.50; Table 1). After the first injection, visual acuity significantly (P⬍0.001) increased from 0.14⫾0.11 to a maximum of 0.28⫾0.21 (Table 1). Fifteen (73%) eyes increased in visual acuity by ⱖ2 Snellen lines. Mean improvement was 3.2⫾2.4 Snellen lines. The improvement in visual acuity was statistically significant for the measurements taken at 1 month (P ⫽ 0.002), 3 months (P ⫽ 0.005), and 5 months (P ⫽ 0.05) after the injection. Approximately 6 to 8 months after the injection, visual acuity decreased again, so that visual acuity did not vary significantly (P ⫽ 0.23) prior to the first injection or at the end of the follow-up prior to the second injection. Comparing the last examination at the end of the follow-up with the baseline examination, an improvement in visual acuity was found in 11 eyes (50%), and a decrease in visual acuity was observed in 7 eyes (32%). The control group of the study included 31 patients (31 eyes) (24 women, 7 men; 15 right eyes, 16 left eyes) with diffuse diabetic macular edema, who did not receive an intravitreal injection of triamcinolone nor any other treatment for their macular
disease during follow-up. Reason for assigning the patients to the control group was that the patients of the control group did not want to get an intravitreal injection, although it was offered to them in a similar way as it was to the patients of the study group. Mean refractive error was 0.75⫾1.06 D (range, ⫺2.00 D to ⫹2.50 D) and mean age was 67.6⫾8.4 years (49.5– 85.4 years; median, 65.4 years). Mean visual acuity at baseline of the study measured 0.15⫾0.06 (Snellen charts) (range, 0.05⫺0.25). For all patients, diffuse diabetic macular edema was substantiated by fluorescein angiography and by optical coherence tomography. For the patients of the study group and for the patients of the control group, focal laser treatment and macular grid laser treatment was performed in a similar manner. The last laser treatment was carried out at least 3 months prior to inclusion into the study. Due to the distribution of patients into the study group (the responders) and the control group, both groups did not vary significantly in preoperative visual acuity (P ⫽ 0.07), preoperative intraocular pressure (P ⫽ 0.21), age (P ⫽ 0.75), refractive error (P ⫽ 0.83), gender (P ⫽ 0.42), right or left eye (P ⫽ 0.78), and length of follow-up (P ⫽ 0.93). All patients of the study group (the responders) received the intravitreal injections of about 20 mg triamcinolone acetonide as previously described in detail.26,27 After the injections, the patients of the study group were reexamined on the first day after the injection, approximately 1 week after the injection, and in roughly 2-months intervals after that. The patients of the control group were reexamined in roughly 2-months intervals. Visual acuity (by Snellen chart) was determined in a standardized fashion by an observer performing best-corrected refractometry. Statistical analyses were performed using a commercially available statistical software package (SPSS for Windows, version 11.5; SPSS, Chicago, IL). To test the statistical significance of the differences between measurements at baseline and measurements obtained during follow-up, the nonparametric Wilcoxon test was applied. To test the statistical significance of differences between the study group and the control group, the Mann–Whitney U test was used. The level of significance was 0.05 (2 sided) in all statistical testing.
Table 1. Visual Acuity before and after Repeated Intravitreal Injections of Triamcinolone Acetonide (approximately 20 mg) for Diffuse Diabetic Macular Edema
Baseline Median Range Maximum after first injection Median Range Baseline prior to second injection Median Range Maximum after second injection Median Range Baseline prior to third injection Median Range Maximum after third injection Median Range
n (Eyes)
Visual Acuity (Snellen Acuity)
Visual Acuity logMAR
22
0.98⫾0.31
22
0.14⫾0.11 0.10 0.03–0.50 0.28⫾0.21 0.28 0.06–1.0 0.11⫾0.09
1.09⫾0.43
22
0.09 Hand movements–0.40 0.18⫾0.14
0.90⫾0.37
4
0.14 0.03–0.50 0.10⫾0.04
1.05⫾0.19
22
4
0.10 0.05–0.12 0.25⫾0.12 0.25 0.10–0.40
0.67⫾0.33
0.65⫾0.25
logMAR ⫽ logarithm of the minimum angle of resolution.
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Results Mean follow-up after the second injection was 9.1⫾4.9 months (median, 8.1 months; range, 3.0 –21.0 months). A third injection was given to 4 patients 5.8 to 13.7 months (9.7⫾3.7 months) after the second injection. Follow-up after the third injection was 7.9⫾11.5 months. After the second injection, visual acuity increased significantly (P ⫽ 0.002) from 0.11⫾0.09 to a mean maximal visual acuity of 0.18⫾0.14 (Table 1). Expressed in Snellen lines, 11 eyes (50%) increased in visual acuity by ⱖ2 Snellen lines. Mean improvement was 1.8⫾2.1 Snellen lines. Approximately 6 to 8 months after the second injection, visual acuity re-decreased again, so that visual acuity prior to the injection and visual acuity at the end of the follow-up prior to the third injection did not vary significantly (P ⫽ 0.23). Comparing the last examination at the end of the follow-up with the baseline examination, an improvement in visual acuity was found in 9 eyes (41%), and a decrease in visual acuity was observed in 7 eyes (32%). The follow-up for the patients who did not receive a third intravitreal injection was 8.1⫾6.9 months. Among those patients was one patient with a follow-up longer than 1 year. At 18 months after the second injection, this patient still experienced a gain in visual acuity by 2 Snellen lines compared with the baseline prior to the second injection. After the third injection, visual acuity increased by a significant margin (P ⫽ 0.068; n ⫽ 4 patients) from 0.10⫾0.04 to a mean maximal visual acuity of 0.25⫾0.12 (Table 1). Expressed in Snellen lines, 3 eyes (75%) increased in visual acuity by ⱖ2 Snellen lines. Comparing the last examination at the end of follow-up with the baseline examination, an improvement in visual acuity was found in all 4 eyes (100%). Mean improvement was 4.0⫾2.6 Snellen lines. In the control group, visual acuity at baseline of the study (0.15⫾0.06; range, 0.05– 0.25; median, 0.16) and at any time during follow-up did not vary significantly (P⬎0.10). Comparing the last examination at the end of follow-up with the baseline examination, an improvement in visual acuity was found in 10 patients (32%), and a decrease in visual acuity was observed in 12 eyes (39%). Mean visual acuity at the end of follow-up (0.14⫾0.10), and visual acuity at baseline of the study (0.15⫾0.06) did not vary significantly (P ⫽ 0.67). The change in visual acuity after the first injection did not vary significantly from the change in visual acuity after the second injection (P ⫽ 0.078), and from the change in visual acuity after the third injection (P ⫽ 0.39). The differences in change in best visual acuity between the control group and the responders (study group) were significant for the measurements obtained after the first injection (P ⫽ 0.001) and after the third injection (P ⫽ 0.027). After the first injection, intraocular pressure increased significantly (P ⫽ 0.002) from 16.7⫾3.5 mmHg at baseline of the study to a maximum of 20.7⫾4.2 mmHg (range, 12–28 mmHg; median, 21 mmHg) during the follow-up. Nine eyes (41%) developed maximal intraocular pressure measurements of greater than 21 mmHg. Toward the end of follow-up after the first injection, intraocular pressure re-decreased significantly (P ⫽ 0.001) so that the intraocular pressure at the end of follow-up and the at baseline did not vary significantly (P ⫽ 0.27). After the second injection, intraocular pressure increased significantly (P ⫽ 0.001) from 16.0⫾3.8 mmHg prior to the second injection to a maximum of 21.9⫾5.8 mmHg (range, 10 –36 mmHg; median, 22 mmHg) during the follow-up. Twelve eyes (54%) developed maximal intraocular pressure measurements of greater than 21 mmHg. Toward the end of follow-up after the first injection, intraocular pressure re-decreased significantly (P ⫽ 0.005) so that the intraocular pressure at the end of follow-up and at baseline did not vary
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significantly (P ⫽ 0.20). Of the 9 eyes that showed an elevated intraocular pressure after the first injection, 7 (78%) also had at least one intraocular pressure measurement greater than 21 mmHg after the second injection. Of the 12 eyes that showed an elevated intraocular pressure after the second injection, 6 eyes (50%) had at least an intraocular pressure measurement greater than 21 mmHg after the first injection. After the third injection, intraocular pressure increased from 18.0⫾0.0 mmHg prior to the third injection to a maximum of 26.3⫾8.4 mmHg (range, 21–36 mmHg; median, 22 mmHg) during follow-up. Two eyes (50%) developed maximal intraocular pressure measurements greater than 21 mmHg. The mean increase in intraocular pressure after the first injection (4.0⫾4.0 mmHg), after the second injection (5.7⫾5.9 mmHg), and after the third injection (3.5⫾0.7 mmHg) did not vary significantly between these various injections (P⬎0.55). In the control group, intraocular pressure did not vary significantly (P⬎0.10) between the baseline value, the maximal value during follow-up, and the value at the end of follow-up.
Discussion In the present study, patients with diffuse diabetic macular edema were retreated with an intravitreal injection of approximately 20 mg of triamcinolone acetonide if the first intravitreal injection was associated with an improvement in vision followed by an eventual re-deterioration in visual acuity. The reinjection led to a significant (P ⫽ 0.002) reimprovement in visual acuity, with 11 eyes (50%) showing an improvement in visual acuity by at least 2 Snellen lines during the follow-up after the second injection. Confirming previous studies on the use of intravitreal triamcinolone acetonide for exudative age-related macular degeneration and small case series reports on patients with diffuse diabetic macular edema,22,23,28 one may infer that eyes that showed a functional improvement after an intravitreal triamcinolone acetonide injection may safely and effectively receive a reinjection if visual acuity deteriorates again. The increases in visual acuity, noted after the first injection and after the second injection, lasted approximately 6 to 8 months with no marked difference between the first injection and the reinjections. It suggests that a reinjection of triamcinolone acetonide may be performed at approximately 6 to 8 months or later after an initial injection if the first injection was associated with an improvement in visual acuity. Correspondingly, the reinjections performed in the present study were carried out 10.0⫾3.8 months after the first injection, and 9.7⫾3.7 months after the second injection. The duration of the effect of 20 mg of intravitreal triamcinolone acetonide (6 to 8 months) is considerably longer than the duration for a dosage of 4 mg intravitreal triamcinolone acetonide (approximately 2 to 4 months) as reported in other studies.1,3,8,9,15,17,20 As long as other studies have not shown an increased risk profile of the high dosage, one may consider the advantages of the high dosage (i.e., longer duration of the effect combined with a lower frequency of reinjections, which may lead to a lower risk of injection-associated infectious endophthalmitis, lower cost, and less burden for the patients). Similarly, as the improvement in visual acuity occurred, the elevation of intraocular pressure lasted approximately 6
Jonas et al 䡠 Treatment of Diffuse Diabetic Macular Edema to 8 months after the injections. This indicates that patients should be followed-up for several months after an intravitreal injection of approximately 20 mg triamcinolone acetonide to detect a steroid-induced increase in intraocular pressure. There are limitations to the present study. The number of patients treated in the study is relatively small. The study, including all patients with an intravitreal reinjection for diabetic macular edema, however, showed that despite the relatively small number of patients, the postinjection visual acuity measurements were statistically and significantly higher than the baseline values. The small number of patients may thus serve to support the conclusions of the study. Another important limitation of the study is its design as a nonrandomized comparative investigation. However, because the first intravitreal injection of triamcinolone acetonide was associated with an improvement in visual acuity, it might have been difficult to convince patients to take part in a randomized trial in which some patients would not have received the treatment. Furthermore, comparing the patients of the study group (the responders) with the patients of the control group showed statistically significant differences in the change in visual acuity during the follow-up. This suggests that the repeated improvement in visual acuity after the second injection of triamcinolone acetonide was caused by the treatment, and that it might not have occurred coincidentally due to the natural course of the disease. In addition, a recent prospective, randomized, doublemasked, placebo-controlled clinical trial by Sutter et al20 have shown that intravitreal triamcinolone acetonide increases visual acuity in patients with diabetic macular edema. Another limitation of the present study is the method to measure visual acuity. Instead of using charts that were also taken for the Early Treatment of Diabetic Retinopathy Study, visual acuity was determined using Snellen charts in a standardized fashion by an observer performing bestcorrected refractometry. However, the same method for assessment of visual acuity was applied for the study group as well as for the control group, so that this flaw in the methodology of the study might have been compensated for partially. Although intravitreal triamcinolone may have increased cataracts, another limitation may be that cataract surgery was not performed in combination with or after the intravitreal injections. However, the vision-reducing effect of progressive cataract may have hidden parts of a visionimproving effect of triamcinolone so that this limitation of the study may serve to support the conclusion of the investigation again. The main side-effect of intravitreal triamcinolone acetonide observed in the present study was an elevation of intraocular pressure. Interestingly, the rise in intraocular pressure did not vary between the various injections. One may infer that the high-dosage reinjections neither had an accumulating effect in the sense that the rise in intraocular pressure was more pronounced after the reinjections than after the first injection, nor that the reinjections damaged the eye in the sense of a decreased production of aqueous humor leading to lower intraocular pressure after repeated injections. This is in agreement with another recent study on the change in intraocular pressure after intravitreal injec-
tions of triamcinolone acetonide.24 Correspondingly, eyes with an elevation of intraocular pressure after the first injection had a relatively high chance (78%) of having a repeated improvement in intraocular pressure after the second injection. In conclusion, the data of the present pilot study may suggest that the repeated intravitreal injection of approximately 20 mg of triamcinolone acetonide as treatment of diffuse diabetic macular edema can be associated with a repeated improvement in visual acuity in patients (who as triamcinolone responders) have shown an improvement in visual acuity after a preceding intravitreal injection. The duration of the effect and of the rise in intraocular pressure as side-effect lasted approximately 6 to 8 months after each injection, without signs of marked tachyphylaxis.
References 1. Greenberg PB, Martidis A, Rogers AH, et al. Intravitreal triamcinolone acetonide for macular oedema due to central retinal vein occlusion. Br J Ophthalmol 2002;86:247– 8. 2. Jonas JB, Kreissig I, Degenring RF. Intravitreal triamcinolone acetonide as treatment of macular edema in central retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2002;240:782–3. 3. Chen SD, Lochhead J, Patel CK, Frith P. Intravitreal triamcinolone acetonide for ischaemic macular oedema caused by branch retinal vein occlusion. Br J Ophthalmol 2004;88:154 –5. 4. Jonas JB, Akkoyun I, Kamppeter B, et al. Branch retinal vein occlusion treated by intravitreal triamcinolone acetonide. Eye 2005;19:65–71. 5. Jonas JB, Hayler JK, Söfker A, Panda-Jonas S. Regression of neovascular iris vessels by intravitreal injection of crystalline cortisone. J Glaucoma 2001;10:284 –7. 6. Jonas JB, Söfker A. Intravitreal triamcinolone acetonide for cataract surgery with iris neovascularisation. J Cataract Refr Surg 2002;28:2040 –1. 7. Jonas JB, Hayler JK, Panda-Jonas S. Intravitreal injection of crystalline cortisone as treatment of pre-phthisical ocular hypotony [letter]. Graefes Arch Clin Exp Ophthalmol 2001;239: 464 –5. 8. Benitez Del Castillo Sanchez JM, Garcia Sanchez J. Intravitreal injection of triamcinolone acetonide in non infectious uveitis [in Spanish]. Arch Soc Esp Oftalmol 2001;76:661– 4. 9. Martidis A, Duker JS, Puliafito CA. Intravitreal triamcinolone for refractory cystoid macular edema secondary to birdshot retinochoroidopathy. Arch Ophthalmol 2001;119:1380 –3. 10. Young S, Larkin G, Branley M, Lightman S. Safety and efficacy of intravitreal triamcinolone for cystoid macular oedema in uveitis. Clin Experiment Ophthalmol 2001;29:2– 6. 11. Antcliff RJ, Spalton DJ, Stanford MR, et al. Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study. Ophthalmology 2001;108:765–72. 12. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2003; 110:1517–25. 13. Rechtman E, Danis RP, Pratt LM, Harris A. Intravitreal triamcinolone with photodynamic therapy for subfoveal choroidal neovascularisation in age related macular degeneration. Br J Ophthalmol 2004;88:344 –7. 14. Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol 2001;132:425–7.
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Ophthalmology Volume 113, Number 5, May 2006 15. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002;109:920 –7. 16. Jonas JB, Kreissig I, Söfker A, Degenring RF. Intravitreal injection of triamcinolone acetonide for diabetic macular edema. Arch Ophthalmol 2003;121:57– 61. 17. Massin P, Audren F, Haouchine B, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 2004;111:218 –24. 18. Jonas JB, Degenring R, Kamppeter B, et al. Duration of the effect of intravitreal triamcinolone acetonide as treatment of diffuse diabetic macular edema. Am J Ophthalmol 2004;138:158 – 60. 19. Jonas JB, Harder B, Kamppeter B. Inter-eye difference in diabetic macular edema after unilateral intravitreal injection of triamcinolone acetonide. Am J Ophthalmol 2004;138:970 –7. 20. Sutter FK, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment: three-month efficacy and safety results of a prospective, randomized, double-masked, placebo-controlled clinical trial. Ophthalmology 2004;111:2044 –9. 21. Jonas JB, Martus P, Degenring RF, et al. Predictive factors for visual acuity after intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2005;123:1338 – 43.
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22. Jonas JB, Kreissig I, Degenring RF. Repeated intravitreal injections of triamcinolone acetonide as treatment of progressive exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2002;240:873– 4. 23. Jonas JB, Akkoyun I, Budde WM, et al. Intravitreal reinjection of triamcinolone for exudative age-related macular degeneration. Arch Ophthalmol 2004;122:218 –22. 24. Jonas JB, Degenring RF, Kreissig I, et al. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Ophthalmology 2005;112:593– 8. 25. Spandau UH, Derse M, Schmitz-Valckenberg P, et al. Dosagedependency of intravitreal triamcinolone acetonide as treatment for diabetic macular edema. Br J Ophthalmol 2005;89: 999 –1003. 26. Jonas JB, Kreissig I, Degenring RF. Endophthalmitis after intravitreal injection of triamcinolone acetonide [letter]. Arch Ophthalmol 2003;121:1663– 4. 27. Spandau UH, Derse M, Schmitz-Valckenberg P, et al. Triamcinolone acetonide concentration after filtration of the solvent agent. Am J Ophthalmol 2005;139:712–3. 28. Jonas JB, Kreissig I, Degenring RF, Kamppeter B. Repeated intravitreal injection of triamcinolone acetonide for diffuse diabetic macular oedema [letter]. Br J Ophthalmol 2005;89:122.
Intravitreal triamcinolone acetonide has increasingly been used for the treatment of intraocular edematous and neovascular diseases, such as retinal vein occlusions,1– 4 neovascular glaucoma,5,6 chronic pre-phthisical ocular hypotony,7 chronic uveitis,8 –11 exudative neovascular age-related macular degeneration in combination with photodynamic therapy,12,13 and diffuse diabetic macular edema.14 –21 In most clinical descriptions, the effect of intravitreal triamcinolone acetonide was temporary, lasting approximately 2 to 4 months for a dosage of 4 mg triamcinolone acetonide, and lasting Originally received: June 3, 2005. Accepted: January 3, 2006. Manuscript no. 2005-482. From Department of Ophthalmology, Faculty of Clinical Medicine Mannheim of the University Heidelberg, Mannheim, Germany. The authors have no proprietary interest in any aspect of the article. Correspondence to Dr Jost B. Jonas, Universitäts-Augenklinik, TheodorKutzer-Ufer 1-3, Mannheim 68167, Germany. E-mail: Jost.Jonas@ma. augen.uni-heidelberg.de.
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© 2006 by the American Academy of Ophthalmology Published by Elsevier Inc.
approximately 6 to 8 months if a dosage of approximately 20 mg was applied.22–25 If the first injection was associated with an improvement in visual acuity, some patients received a second intravitreal injection, as described in previous studies on exudative age-related macular degeneration.22,23 It was the purpose of the present investigation to evaluate the effects and side-effects of repeated intravitreal injections of triamcinolone acetonide for treatment of diffuse diabetic macular edema.
Patients and Methods The study group (called the responders) of the nonrandomized, comparative clinical, interventional investigation included all patients (19 subjects: 17 women, 2 men; 22 eyes: 12 right eyes, 10 left eyes) who consecutively attended the hospital with a loss of vision due to diffuse diabetic macular edema; who received an intravitreal injection of approximately 20 mg of triamcinolone acetonide; who eventually received at least one repeated intravitISSN 0161-6420/06/$–see front matter doi:10.1016/j.ophtha.2006.01.002
Jonas et al 䡠 Treatment of Diffuse Diabetic Macular Edema real injection of triamcinolone acetonide; and who had a follow-up of at least 3 months after the second injection. The reason for the repeated intravitreal injection was that the patients experienced an improvement in visual acuity after the first injection, and some months later, a re-decline in visual acuity. In a parallel manner, cystoid macular edema resolved almost completely in the first months after the first injection, and returned some months later. The decision for a re-injection was solely based on visual acuity. Although optical coherence tomographic images and fluorescein angiograms were available, the results of these examinations were generally not taken into account for the decision on a re-injection. The re-injection took place 10.0⫾3.8 months (median, 9.7 months; range, 4.1–19.7 months) after the first intravitreal injection. Mean age of the patients was 66.1⫾11.5 years (range, 28.6 – 80.5 years; median, 68.2 years). Refractive error ranged between ⫺1.13 diopters (D) and ⫹4.25 D (mean ⫾ standard deviation, 0.55⫾1.27 D). Mean intraocular pressure prior to the first injection was 16.7⫾3.5 mmHg (median, 16 mmHg). All patients were fully informed about the experimental character of the therapy. All patients signed an informed consent. The ethics committee of the university approved the study. The study followed the tenets of the Declaration of Helsinki. Mean visual acuity at baseline of the study measured 0.14⫾0.11 (Snellen charts) (range, 0.03– 0.50; Table 1). After the first injection, visual acuity significantly (P⬍0.001) increased from 0.14⫾0.11 to a maximum of 0.28⫾0.21 (Table 1). Fifteen (73%) eyes increased in visual acuity by ⱖ2 Snellen lines. Mean improvement was 3.2⫾2.4 Snellen lines. The improvement in visual acuity was statistically significant for the measurements taken at 1 month (P ⫽ 0.002), 3 months (P ⫽ 0.005), and 5 months (P ⫽ 0.05) after the injection. Approximately 6 to 8 months after the injection, visual acuity decreased again, so that visual acuity did not vary significantly (P ⫽ 0.23) prior to the first injection or at the end of the follow-up prior to the second injection. Comparing the last examination at the end of the follow-up with the baseline examination, an improvement in visual acuity was found in 11 eyes (50%), and a decrease in visual acuity was observed in 7 eyes (32%). The control group of the study included 31 patients (31 eyes) (24 women, 7 men; 15 right eyes, 16 left eyes) with diffuse diabetic macular edema, who did not receive an intravitreal injection of triamcinolone nor any other treatment for their macular
disease during follow-up. Reason for assigning the patients to the control group was that the patients of the control group did not want to get an intravitreal injection, although it was offered to them in a similar way as it was to the patients of the study group. Mean refractive error was 0.75⫾1.06 D (range, ⫺2.00 D to ⫹2.50 D) and mean age was 67.6⫾8.4 years (49.5– 85.4 years; median, 65.4 years). Mean visual acuity at baseline of the study measured 0.15⫾0.06 (Snellen charts) (range, 0.05⫺0.25). For all patients, diffuse diabetic macular edema was substantiated by fluorescein angiography and by optical coherence tomography. For the patients of the study group and for the patients of the control group, focal laser treatment and macular grid laser treatment was performed in a similar manner. The last laser treatment was carried out at least 3 months prior to inclusion into the study. Due to the distribution of patients into the study group (the responders) and the control group, both groups did not vary significantly in preoperative visual acuity (P ⫽ 0.07), preoperative intraocular pressure (P ⫽ 0.21), age (P ⫽ 0.75), refractive error (P ⫽ 0.83), gender (P ⫽ 0.42), right or left eye (P ⫽ 0.78), and length of follow-up (P ⫽ 0.93). All patients of the study group (the responders) received the intravitreal injections of about 20 mg triamcinolone acetonide as previously described in detail.26,27 After the injections, the patients of the study group were reexamined on the first day after the injection, approximately 1 week after the injection, and in roughly 2-months intervals after that. The patients of the control group were reexamined in roughly 2-months intervals. Visual acuity (by Snellen chart) was determined in a standardized fashion by an observer performing best-corrected refractometry. Statistical analyses were performed using a commercially available statistical software package (SPSS for Windows, version 11.5; SPSS, Chicago, IL). To test the statistical significance of the differences between measurements at baseline and measurements obtained during follow-up, the nonparametric Wilcoxon test was applied. To test the statistical significance of differences between the study group and the control group, the Mann–Whitney U test was used. The level of significance was 0.05 (2 sided) in all statistical testing.
Table 1. Visual Acuity before and after Repeated Intravitreal Injections of Triamcinolone Acetonide (approximately 20 mg) for Diffuse Diabetic Macular Edema
Baseline Median Range Maximum after first injection Median Range Baseline prior to second injection Median Range Maximum after second injection Median Range Baseline prior to third injection Median Range Maximum after third injection Median Range
n (Eyes)
Visual Acuity (Snellen Acuity)
Visual Acuity logMAR
22
0.98⫾0.31
22
0.14⫾0.11 0.10 0.03–0.50 0.28⫾0.21 0.28 0.06–1.0 0.11⫾0.09
1.09⫾0.43
22
0.09 Hand movements–0.40 0.18⫾0.14
0.90⫾0.37
4
0.14 0.03–0.50 0.10⫾0.04
1.05⫾0.19
22
4
0.10 0.05–0.12 0.25⫾0.12 0.25 0.10–0.40
0.67⫾0.33
0.65⫾0.25
logMAR ⫽ logarithm of the minimum angle of resolution.
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Results Mean follow-up after the second injection was 9.1⫾4.9 months (median, 8.1 months; range, 3.0 –21.0 months). A third injection was given to 4 patients 5.8 to 13.7 months (9.7⫾3.7 months) after the second injection. Follow-up after the third injection was 7.9⫾11.5 months. After the second injection, visual acuity increased significantly (P ⫽ 0.002) from 0.11⫾0.09 to a mean maximal visual acuity of 0.18⫾0.14 (Table 1). Expressed in Snellen lines, 11 eyes (50%) increased in visual acuity by ⱖ2 Snellen lines. Mean improvement was 1.8⫾2.1 Snellen lines. Approximately 6 to 8 months after the second injection, visual acuity re-decreased again, so that visual acuity prior to the injection and visual acuity at the end of the follow-up prior to the third injection did not vary significantly (P ⫽ 0.23). Comparing the last examination at the end of the follow-up with the baseline examination, an improvement in visual acuity was found in 9 eyes (41%), and a decrease in visual acuity was observed in 7 eyes (32%). The follow-up for the patients who did not receive a third intravitreal injection was 8.1⫾6.9 months. Among those patients was one patient with a follow-up longer than 1 year. At 18 months after the second injection, this patient still experienced a gain in visual acuity by 2 Snellen lines compared with the baseline prior to the second injection. After the third injection, visual acuity increased by a significant margin (P ⫽ 0.068; n ⫽ 4 patients) from 0.10⫾0.04 to a mean maximal visual acuity of 0.25⫾0.12 (Table 1). Expressed in Snellen lines, 3 eyes (75%) increased in visual acuity by ⱖ2 Snellen lines. Comparing the last examination at the end of follow-up with the baseline examination, an improvement in visual acuity was found in all 4 eyes (100%). Mean improvement was 4.0⫾2.6 Snellen lines. In the control group, visual acuity at baseline of the study (0.15⫾0.06; range, 0.05– 0.25; median, 0.16) and at any time during follow-up did not vary significantly (P⬎0.10). Comparing the last examination at the end of follow-up with the baseline examination, an improvement in visual acuity was found in 10 patients (32%), and a decrease in visual acuity was observed in 12 eyes (39%). Mean visual acuity at the end of follow-up (0.14⫾0.10), and visual acuity at baseline of the study (0.15⫾0.06) did not vary significantly (P ⫽ 0.67). The change in visual acuity after the first injection did not vary significantly from the change in visual acuity after the second injection (P ⫽ 0.078), and from the change in visual acuity after the third injection (P ⫽ 0.39). The differences in change in best visual acuity between the control group and the responders (study group) were significant for the measurements obtained after the first injection (P ⫽ 0.001) and after the third injection (P ⫽ 0.027). After the first injection, intraocular pressure increased significantly (P ⫽ 0.002) from 16.7⫾3.5 mmHg at baseline of the study to a maximum of 20.7⫾4.2 mmHg (range, 12–28 mmHg; median, 21 mmHg) during the follow-up. Nine eyes (41%) developed maximal intraocular pressure measurements of greater than 21 mmHg. Toward the end of follow-up after the first injection, intraocular pressure re-decreased significantly (P ⫽ 0.001) so that the intraocular pressure at the end of follow-up and the at baseline did not vary significantly (P ⫽ 0.27). After the second injection, intraocular pressure increased significantly (P ⫽ 0.001) from 16.0⫾3.8 mmHg prior to the second injection to a maximum of 21.9⫾5.8 mmHg (range, 10 –36 mmHg; median, 22 mmHg) during the follow-up. Twelve eyes (54%) developed maximal intraocular pressure measurements of greater than 21 mmHg. Toward the end of follow-up after the first injection, intraocular pressure re-decreased significantly (P ⫽ 0.005) so that the intraocular pressure at the end of follow-up and at baseline did not vary
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significantly (P ⫽ 0.20). Of the 9 eyes that showed an elevated intraocular pressure after the first injection, 7 (78%) also had at least one intraocular pressure measurement greater than 21 mmHg after the second injection. Of the 12 eyes that showed an elevated intraocular pressure after the second injection, 6 eyes (50%) had at least an intraocular pressure measurement greater than 21 mmHg after the first injection. After the third injection, intraocular pressure increased from 18.0⫾0.0 mmHg prior to the third injection to a maximum of 26.3⫾8.4 mmHg (range, 21–36 mmHg; median, 22 mmHg) during follow-up. Two eyes (50%) developed maximal intraocular pressure measurements greater than 21 mmHg. The mean increase in intraocular pressure after the first injection (4.0⫾4.0 mmHg), after the second injection (5.7⫾5.9 mmHg), and after the third injection (3.5⫾0.7 mmHg) did not vary significantly between these various injections (P⬎0.55). In the control group, intraocular pressure did not vary significantly (P⬎0.10) between the baseline value, the maximal value during follow-up, and the value at the end of follow-up.
Discussion In the present study, patients with diffuse diabetic macular edema were retreated with an intravitreal injection of approximately 20 mg of triamcinolone acetonide if the first intravitreal injection was associated with an improvement in vision followed by an eventual re-deterioration in visual acuity. The reinjection led to a significant (P ⫽ 0.002) reimprovement in visual acuity, with 11 eyes (50%) showing an improvement in visual acuity by at least 2 Snellen lines during the follow-up after the second injection. Confirming previous studies on the use of intravitreal triamcinolone acetonide for exudative age-related macular degeneration and small case series reports on patients with diffuse diabetic macular edema,22,23,28 one may infer that eyes that showed a functional improvement after an intravitreal triamcinolone acetonide injection may safely and effectively receive a reinjection if visual acuity deteriorates again. The increases in visual acuity, noted after the first injection and after the second injection, lasted approximately 6 to 8 months with no marked difference between the first injection and the reinjections. It suggests that a reinjection of triamcinolone acetonide may be performed at approximately 6 to 8 months or later after an initial injection if the first injection was associated with an improvement in visual acuity. Correspondingly, the reinjections performed in the present study were carried out 10.0⫾3.8 months after the first injection, and 9.7⫾3.7 months after the second injection. The duration of the effect of 20 mg of intravitreal triamcinolone acetonide (6 to 8 months) is considerably longer than the duration for a dosage of 4 mg intravitreal triamcinolone acetonide (approximately 2 to 4 months) as reported in other studies.1,3,8,9,15,17,20 As long as other studies have not shown an increased risk profile of the high dosage, one may consider the advantages of the high dosage (i.e., longer duration of the effect combined with a lower frequency of reinjections, which may lead to a lower risk of injection-associated infectious endophthalmitis, lower cost, and less burden for the patients). Similarly, as the improvement in visual acuity occurred, the elevation of intraocular pressure lasted approximately 6
Jonas et al 䡠 Treatment of Diffuse Diabetic Macular Edema to 8 months after the injections. This indicates that patients should be followed-up for several months after an intravitreal injection of approximately 20 mg triamcinolone acetonide to detect a steroid-induced increase in intraocular pressure. There are limitations to the present study. The number of patients treated in the study is relatively small. The study, including all patients with an intravitreal reinjection for diabetic macular edema, however, showed that despite the relatively small number of patients, the postinjection visual acuity measurements were statistically and significantly higher than the baseline values. The small number of patients may thus serve to support the conclusions of the study. Another important limitation of the study is its design as a nonrandomized comparative investigation. However, because the first intravitreal injection of triamcinolone acetonide was associated with an improvement in visual acuity, it might have been difficult to convince patients to take part in a randomized trial in which some patients would not have received the treatment. Furthermore, comparing the patients of the study group (the responders) with the patients of the control group showed statistically significant differences in the change in visual acuity during the follow-up. This suggests that the repeated improvement in visual acuity after the second injection of triamcinolone acetonide was caused by the treatment, and that it might not have occurred coincidentally due to the natural course of the disease. In addition, a recent prospective, randomized, doublemasked, placebo-controlled clinical trial by Sutter et al20 have shown that intravitreal triamcinolone acetonide increases visual acuity in patients with diabetic macular edema. Another limitation of the present study is the method to measure visual acuity. Instead of using charts that were also taken for the Early Treatment of Diabetic Retinopathy Study, visual acuity was determined using Snellen charts in a standardized fashion by an observer performing bestcorrected refractometry. However, the same method for assessment of visual acuity was applied for the study group as well as for the control group, so that this flaw in the methodology of the study might have been compensated for partially. Although intravitreal triamcinolone may have increased cataracts, another limitation may be that cataract surgery was not performed in combination with or after the intravitreal injections. However, the vision-reducing effect of progressive cataract may have hidden parts of a visionimproving effect of triamcinolone so that this limitation of the study may serve to support the conclusion of the investigation again. The main side-effect of intravitreal triamcinolone acetonide observed in the present study was an elevation of intraocular pressure. Interestingly, the rise in intraocular pressure did not vary between the various injections. One may infer that the high-dosage reinjections neither had an accumulating effect in the sense that the rise in intraocular pressure was more pronounced after the reinjections than after the first injection, nor that the reinjections damaged the eye in the sense of a decreased production of aqueous humor leading to lower intraocular pressure after repeated injections. This is in agreement with another recent study on the change in intraocular pressure after intravitreal injec-
tions of triamcinolone acetonide.24 Correspondingly, eyes with an elevation of intraocular pressure after the first injection had a relatively high chance (78%) of having a repeated improvement in intraocular pressure after the second injection. In conclusion, the data of the present pilot study may suggest that the repeated intravitreal injection of approximately 20 mg of triamcinolone acetonide as treatment of diffuse diabetic macular edema can be associated with a repeated improvement in visual acuity in patients (who as triamcinolone responders) have shown an improvement in visual acuity after a preceding intravitreal injection. The duration of the effect and of the rise in intraocular pressure as side-effect lasted approximately 6 to 8 months after each injection, without signs of marked tachyphylaxis.
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