- Email: [email protected]
Intravitreal Triamcinolone Acetonide for the Treatment of Immune Recovery Uveitis Macular Edema
Intravitreal Triamcinolone Acetonide for the Treatment of Immune Recovery Uveitis Macular Edema Victoria L. Morrison, MD,1 Igor Kozak, MD,1 Laurie D. LaBree, MS,2 Stanley P. Azen, PhD,2 Ozcan O. Kayicioglu, MD,1 William R. Freeman, MD1 Purpose: To evaluate the use of intravitreal triamcinolone (IVTA) for the treatment of macular edema secondary to immune recovery uveitis (IRU) in patients with AIDS. Design: Prospective, consecutive, interventional case series. Participants: Eight eyes of 7 patients receiving 13 injections. Methods: Prospective, consecutive, interventional case series of 13 injections involving 8 eyes in 7 patients who underwent an intravitreal injection of 20 mg decanted triamcinolone acetate for fluorescein angiographically proven IRU-related macular edema. Main Outcome Measures: The primary outcome measure was vision (using the Early Treatment Diabetic Retinopathy Study chart). Other outcome measures included fluorescein angiography and optical coherence tomography. Results: Visual acuity improved at all time points and was statistically significant at the 1-month and 3-month follow-up examinations. The average visual improvement was 3 lines at 3 months. Retinal volume and thickness improvement were statistically significant at all time points. All patients had a minimum follow-up of 9 months, and there were no cases of cytomegalovirus reactivation. Conclusions: Previous studies showed that treatment with sub-Tenon repository steroids for the treatment of macular edema of IRU was only marginally effective. However, the current study shows that IVTA can be an effective short-term treatment for macular edema secondary to IRU in patients with AIDS. Longer follow-up is needed to assess the durability of the effect and to monitor for longer-term complications and outcomes. Ophthalmology 2007;114:334 –339 © 2007 by the American Academy of Ophthalmology.
Patients with AIDS and CD4 levels less than 50 cells/mm3 are at risk of experiencing cytomegalovirus (CMV) retinitis.1 Eventually, many of these patients exhibit immune reconstitution (specifically when their CD4 T-lymphocyte levels rise)2,3 as they are treated with highly active antiretroviral therapy (HAART), including protease inhibitors.4 This improvement in their CD4 T-lymphocyte levels can manifest clinically as an increased inflammatory response in the eye. Our group initially described this ocular inflammatory syndrome, known as immune recovery uveitis (IRU),5– 8 which occurs as the immune system improves in patients with healed CMV retinitis. Immune recovery uveitis Originally received: November 4, 2005. Accepted: July 13, 2006. Manuscript no. 2005-1064. 1 Jacobs Retina Center, Department of Ophthalmology, University of California, San Diego, La Jolla, California. 2 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. Supported by the National Institutes of Health, Bethesda, Maryland (grant no.: EY07366 [WRF]). None of the authors have any financial interest related to the article. Correspondence to William R. Freeman, MD, Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center 0946, 9415 Campus Point Drive, La Jolla, CA 92093. E-mail: [email protected].
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© 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
is an important cause of visual morbidity in patients with CMV retinitis. Symptoms include a decrease in vision and floaters secondary to posterior segment inflammation. Clinical examination may show vitreitis, papillitis, and macular changes (including epiretinal membrane and macular edema).7–11 Immune recovery uveitis is fairly common in patients with CMV retinitis; specifically, Jabs et al12 reported the prevalence of IRU to be 15.5% of patients in their prospective cohort study. We hypothesize that the use of intravitreal triamcinolone acetonide (IVTA) is an effective treatment in patients with IRU and macular edema. In this article, we address the results of using IVTA (Kenalog; Bristol-Myers Squibb Co., Princeton, NJ) for the treatment of macular edema in IRU patients.
Patients and Methods The current study was a prospective, interventional consecutive case series of AIDS patients with IRU and macular edema who sought treatment at the San Diego AIDS Ocular Research Unit. The study included 7 patients, 8 eyes, and 13 injections. Informed consent was obtained from all patients. Institutional review board/ ethics committee approval was obtained for this prospective study. Two patients were female and 5 patients were male. The average ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2006.07.013
Morrison et al 䡠 Intravitreal Triamcinolone Acetonide for Macular Edema Table 1. Baseline Characteristics of the Patient Cohort Duration of Immune Recovery Uveitis before Intravitreal Study Age Triamcinolone Acetonide Eye (yrs) Gender Treatment (mos) 1
63
M
84
2 3 4
46 46 50
M M F
26 25 51
5 6
57 54
F M
96 12
7 8
45 36
M M
72 3
Previous Surgery/Indication
Cytomegalovirus CD4 Count at Time of Retinitis Intravitreal Triamcinolone Medications Acetonide Treatment
TPPV, ERM removal for visually significant ERM TPPV, SB, and laser for retinal detachment None TPPV, IVTA, ERM removal for visually significant ERM TPPV for macular edema SB for retinal detachment; ganciclovir implant for active CMV retinitis None None
None
600
None None None
535 535, 503 745
Valcyte None
998, 768 430
None None*
358 77
CMV ⫽ cytomegalovirus; ERM ⫽ epiretinal membrane; F ⫽ female; IVTA ⫽ intravitreal triamcinolone acetonide; M ⫽ male; SB ⫽ scleral buckle; TPPV ⫽ trans pars plana vitrectomy. *Started on valganciclovir (Valcyte) at time of injection because of low CD4 count.
age was 50 years (Table 1). Three eyes had more than 1 IVTA injection. Recurrent injections were performed at the time of symptomatic decrease in vision and clinical return of macular edema. Inclusion criteria included prior healed CMV retinitis not involving the fovea or optic nerve, current highly active antiretroviral therapy, immune recovery with CD4 counts of more than 50 cells/mm3 for at least 3 consecutive months, no history of steroid use within the past year, and IRU with symptomatic vision loss from macular edema in the involved eye. Patients with a history of glaucoma, steroid-response intraocular pressure rise, or family history of glaucoma were excluded. Baseline visual acuity was 20/100 (range, 20/32–2=/200) using the Early Treatment Diabetic Retinopathy Study chart. The 2=/200 patient had massive macular edema. Four of the eyes were previously vitrectomized. Five of the 8 eyes had a distant history (of at least 1 year prior) of steroid treatment (including sub-Tenon methylprednisolone acetate [Depo-Medrol, Pharmacia & Upjohn Co., Kalamazoo, MI] injection in the clinic or IVTA at the time of a prior vitrectomy). The only prior use of IVTA was at the time of vitrectomy (at least 1 year prior); IVTA was used to assist in the resolution of macular edema, removal of a possible epiretinal membrane associated with IRU at the time of surgery, or both. The eyes that had previous treatment with steroid for IRU continued to have persistent IRU despite these prior treatments. We gave these eyes at least a 1-year washout period before IVTA injection. All of our patients had active IRU at the time of IVTA injection. The average duration of IRU before IVTA injection was 51 months (range, 3–96 months). Two eyes had cataract surgery performed during this study. Three patients were phakic at the onset of the study, and only 1 was phakic at the conclusion of the study. The 2 patients that had cataract surgery had IVTA injections 1 month before their cataract surgery and already had visually significant cataracts before their IVTA injection. We note that their follow-up concluded before the cataract surgery; thus, cataract surgery was not a factor in vision improvement. There was 1 patient who had a CD4 count of less than 100 cells/mm3 (CD4 ⫽ 77 cells/mm3), and we treated him with valganciclovir 450 mg twice daily to help protect against the risk of reactivation. Patients received 20 mg decanted IVTA (total volume, 0.1 ml). Care was taken to perform a sterile procedure that consisted of a povidone–iodine preparation and use of a lid speculum. Follow-up visits were carried out at 1 week, 1 month, and 3 months. Best-corrected Early Treatment Diabetic Retinopathy Study vision, slit-lamp examination, and dilated fundus examination were
performed. Optical coherence tomography (OCT) and digital fluorescein angiography (FA) also were performed. Angiograms were obtained using a Heidelberg confocal scanning laser ophthalmoscope (Carl Zeiss, Dublin, CA), and OCT scans were performed using a high-resolution Stratus 3000 OCT model (Carl Zeiss) with software version 4.0 to measure retinal thickness and macular volume. All patients were dilated and consented to examination. We recorded from each examined eye 6-mm line scans in a radial spoke pattern intersecting at the macula (slow macular program). Each tomogram consisted of 512 A-scans in length and 2 mm in depth. All examinations were performed by one operator (IK). Retinal thickness was defined as the distance between internal retinal border (inner nerve fiber layer border) and external retinal border (retinal pigment epithelium/outer segment photoreceptor hyperreflective layer). To exclude the possibility of artifact by automatic delineation by OCT software, this was performed manually by the masked operator. The value was compared with the value on the retinal thickness map. The same map provided macular volume value that was used for statistical calculation. Changes from baseline visual acuity (Table 2), OCT volume and thickness (Table 3), and FA results were compared at each visit. Angiograms and OCT scans were compared for improvement or exacerbation (Figs 1, 2).
Statistical Methods Some patients had multiple injections; therefore, a repeated-measures analysis of variance was used to adjust for the correlation between repeated measures within eyes. Least square means and standard errors were obtained for volume, thickness, and logarithm of the minimum ⬎angle of resolution visual acuity measures before injection and at 1 week, 1 month, and 3 months after injection. Repeatedmeasures analysis of variance P values were calculated, and where statistically significant (P⬍0.05), multiple comparison t test P values were obtained to compare preinjection means with postinjection means. SAS software (SAS Institute, Cary, NC) was used for all analyses. Accepted level of significance for all tests was ␣ ⫽ 0.05.
Results Baseline Early Treatment Diabetic Retinopathy Study visual acuity was 20/100 (range, 20/32–2=/200). Visual acuity results were
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Ophthalmology Volume 114, Number 2, February 2007 Table 2. Visual Acuity before Injection with Intravitreal Triamcinolone Acetonide versus after Injection with Intravitreal Triamcinolone Acetonide Visual Acuity Least Square Mean (Standard Error)* Visual acuity Before injection 1 wk after injection (n ⫽ 8) 1 mo after injection (n ⫽ 9) 3 mos after injection (n ⫽ 11)
P Value (Repeated Measures Analysis of Variance)
Compared with Preinjection P Value†
0.03 0.76 (0.07) 0.62 (0.09) 0.49 (0.09) 0.46 (0.08)
0.22 0.0208 0.008
*In logarithm of the minimum angle of resolution units using Early Treatment Diabetic Retinopathy Study charts. † Multiple comparison t test P value.
expressed in logarithm of the minimum angle of resolution units. Preinjection vision was 0.76 (standard error [SE], ⫾0.07). Postinjection vision at 1 week was 0.62 (SE, ⫾0.09), at 1 month was 0.49 (SE, ⫾0.09), and at 3 months was 0.46 (SE, ⫾0.08). The P values were 0.22, 0.0208, and 0.008, respectively. Average preinjection volume of macular edema as measured with OCT was 8.55 mm3 (SE, ⫾0.29). Average macular volume at 1 week after injection was 7.36 mm3 (SE, ⫾0.33), at 1 month was 7.32 mm3 (SE, ⫾0.34), and at 3 months was 7.60 mm3 (SE, ⫾0.36). The P value was statistically significant at each time point, with P values of 0.0092, 0.009, and 0.0487, respectively. The repeated-measures analysis of variance volume P value was 0.02. Average preinjection thickness of macular edema as measured with OCT was 341 m (SE, ⫾28 m). Average macular thickness at 1 week after injection was 227 m (SE, ⫾32 m), at 1 month was 246 m (SE, ⫾33 m), and at 3 months was 213 m (SE, ⫾35 m). The P value was statistically significant at each time point with P values of 0.01, 0.0338, and 0.009, respectively. The repeatedmeasures analysis of variance thickness P value was 0.02. The average CD4 count ranged from 77 to 998 cells/mm3. Hematologic and CD4 count data remained essentially stable throughout the patient follow-up. Of the 3 eyes that had repeat injections, the average duration between injections was 17.6 weeks (range, 10 –26 weeks). All eyes that required reinjection were eyes that had been previously vitrectomized. One patient had a slight rise in intraocular pressure of 26 mmHg that resolved quickly with institution of topical glaucoma medication. There was no case of endophthalmitis or significant
cataract formation noted. All patients had a minimum follow-up of 9 months, and there were no cases of CMV reactivation.
Discussion Spontaneous recovery of IRU can occur; however, longterm complications of untreated IRU have been reported, including severe proliferative vitreoretinopathy and spontaneous vitreous hemorrhage secondary to avulsion of a blood vessel from contraction of the inflamed vitreous.7 Several treatment options for patients with IRU and macular edema have been proposed. Physicians previously suggested the use of oral corticosteroids.13,14 We reported the use of repository sub-Tenon steroid injections for the treatment of patients with macular complications of immune recovery uveitis and found only a modest treatment effect.15,16 We also previously showed that valganciclovir treatment may benefit visual acuity in patients with macular edema resulting from IRU.17 This was a noncontrolled study of 5 patients, and there was a modest improvement in vision. We believe the dramatic clinical effects shown in the present study were likely the result of the IVTA treatment. Orbital floor injections of methylprednisolone acetate 40 mg or triamcinolone 20 mg were shown to improve vision
Table 3. Optical Coherence Tomography Measurements of Macular Volume and Thickness before Injection with Intravitreal Triamcinolone Acetonide versus after Injection with Intravitreal Triamcinolone Acetonide Least Squares Mean (Standard Error) Volume Before injection 1 wk after injection (n ⫽ 9) 1 mo after injection (n ⫽ 8) 3 mos after injection (n ⫽ 7) Thickness Before injection 1 wk after injection (n ⫽ 9) 1 mo after injection (n ⫽ 8) 3 mos after injection (n ⫽ 7) *Multiple comparison t test P value.
336
P Value (Repeated Measures Analysis of Variance)
Compared with Preinjection P Value*
0.02 8.55 (0.29) 7.36 (0.33) 7.32 (0.34) 7.60 (0.36)
0.0092 0.009 0.0487 0.02
341 (28) 227 (32) 246 (33) 213 (35)
0.01 0.0338 0.009
Morrison et al 䡠 Intravitreal Triamcinolone Acetonide for Macular Edema
Figure 1. Optical coherence tomograms from a patient with macular edema secondary to immune-recovery uveitis obtained (A) before injection and (B) after injection of intravitreal triamcinolone acetonide.
in one study.18 Canzano et al8 reported 2 cases of IRU with macular edema that were persistent and resistant to treatment. The authors attributed the edema to the presence of vitreomacular traction syndrome in these 2 patients, which was confirmed by ultrasonography. Over the past few years, IVTA has become popular for the treatment of macular edema resulting from various causes.19 –27 Intravitreal triamcinolone has the risk of the formation of cataracts, glaucoma, and endophthalmitis. The effect of trans pars plana vitrectomy in 4 of our patients likely accounted for an increased drug clearance, and we are cognizant that these patients tend to need more frequent reinjection schedules. We have shown that IVTA lasts 113 days in the vitrectomized eye.28 We have managed our patients successfully with planned repeat injections at their respective required symptomatic intervals without complications. We remain very cognizant of the long-term complications of repeat steroid injection; however, we have not experienced any significant complication from IVTA in IRU patients in our limited study population. We believe the use of absolute sterile technique (lid speculum, povidone iodine preparation) helps limit the devastating risk of endophthalmitis. None of our patients had a significant increase in eye pressure that required more than a temporary use of a topical drop. We believe this is because of the lower intraocular pressure associated with uveitis patients and
AIDS patients.29 Although we had a few patients with cataracts, it is also known that cataract formation is almost inevitable in an IRU patient. In this study, we used high dose of IVTA (20 mg) because we believe it lasts longer and has a stronger effect. Further, we concur with similar results of Jonas et al,30 who reported that typically they use a dose of 25 mg and noted that in more than 300 patients, they have not yet seen adverse effects that may be attributed to that high dose. We previously showed that the toxic concentration is very close to the actual concentration injected into the eye31; thus, we suggest that intravitreal triamcinolone acetonide be cleared of most of the vehicle before injection. Various methods can be considered, with some having been reported anecdotally. Possibilities include pharmacologic washing,22,27 decantation,32,33 and filtering. Decanting procedures may yield highly variable doses. Rodriguez-Coleman et al34 found that filtering techniques actually concentrated the benzyl alcohol; however, Jonas et al35 noted, using that technique, that no episodes of toxicity or pseudoendophthalmitis occurred in more than 500 injections administered. Garcia-Arumi et al36 showed that filter techniques, sedimentation, and centrifugation all effectively reduce the benzyl alcohol concentration in triamcinolone acetonide. We found that with simple decantation, we were able to remove a significant portion of the preservative (as verified with high-performance
337
Ophthalmology Volume 114, Number 2, February 2007 cover our patients with maintenance valganciclovir if their CD4 count was less than 100 cells/mm3 as an added protection against the possibility of recurrence. The optimal timing of IVTA treatment was not specifically examined in this study. Care should be taken regarding the use of IVTA in patients recently treated with HAART with improving CD4 counts. We believe cotreatment with valganciclovir is important in patients with recently improving low CD4 counts before any intravitreal steroid injection so as to prevent any possible reactivation of CMV retinitis. This study, however, did not specifically examine whether cotreatment with specific anti-CMV medications was necessary. We have now followed up our patients for at least 9 months, with many being monitored for more than 1 year, and no episode of reactivation has occurred in any of our patients. We show in this paper that IVTA improves vision, OCT volume and thickness, as well as FA results in patients with IRU. Intravitreal triamcinolone acetonide also allows the doctor to avoid the side effects of systemic oral corticosteroid treatment.
References
Figure 2. Fluorescein angiograms from the same patient as in Figure 1 obtained (A) before injection and (B) after injection of intravitreal triamcinolone acetonide.
liquid chromatography).31 This technique of decantation is a relatively simple step to perform in the office or operating room. We believe that this will help decrease the risk of retinal toxicity. Reactivation is a theoretical concern given the immune status of these patients and the use of an immunosuppressant treatment. Dalessandro and Bottaro37 reported a case of reactivation of CMV retinitis after treatment with subTenon corticosteroids for IRU. Of note, care was taken to
338
1. Song MK, Karavellas MP, MacDonald JC, et al. Characterization of reactivation of cytomegalovirus retinitis in patients healed after treatment with highly active antiretroviral therapy. Retina 2000;20:151–5. 2. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4 T cell homeostasis and function in advanced HIV disease. Science 1997;277:112– 6. 3. Lederman MM, Connick E. Landay A, et al. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 1998;178:70 –9. 4. Markowitz M, Saag M, Powderly WG, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. New Engl J Med 1995;333:1534 –9. 5. Karavellas MP, Lowder CY, Macdonald JC, et al. Immune recovery vitreitis associated with inactive cytomegalovirus retinitis. Arch Ophthalmol 1998;116:169 –75. 6. Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitreitis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 1999;179:697–700. 7. Karavellas MP, Song M, Macdonald JC, Freeman WR. Longterm posterior and anterior segment complications of immune recovery uveitis associated with cytomegalovirus retinitis. Am J Ophthalmol 2000;130:57– 64. 8. Canzano JC, Reed JB, Morse LS, et al. Vitreomacular traction syndrome following highly active antiretroviral therapy in AIDS patients with cytomegalovirus retinitis. Retina 1998;18: 443–7. 9. Whitcup SM. Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. JAMA 2000;283:653–7. 10. Robinson MR, Reed G, Csaky KG. Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy. Am J Ophthalmol 2000;130:49 –56. 11. Nguyen QD, Kempen JH, Bolton SG, et al. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129:634 –9.
Morrison et al 䡠 Intravitreal Triamcinolone Acetonide for Macular Edema 12. Jabs DA, Van Natta ML, Kempen JH. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2002;133: 48 – 61. 13. Dunn JP. Immune recovery uveitis. Hopkins HIV Report 2001;9 –10. 14. Holland GN. Immune recovery uveitis. Ocul Immunol Inflamm 1999;7:215–21. 15. El-Bradey MH, Cheng L, Song MY, et al. Long-term results of treatment of macular complications in eyes with immune recovery uveitis using a graded treatment approach. Retina 2004;24:376 – 82. 16. Karavellas MP, Azen SP, MacDonald JC. Immune recovery vitritis and uveitis in AIDS. Clinical predictors, sequelae, and treatment. Retina 2001;21:1–9. 17. Kosobucki BR, Goldberg DE, Bessho K, et al. Valganciclovir therapy for immune recovery uveitis complicated by macular edema. Am J Ophthalmol 2004;137:636 – 8. 18. Henderson HW, Mitchell SM. Treatment of immune recovery vitreitis with local steroids. Br J Ophthalmol 1999;83:540 –5. 19. Jonas JB, Kreissig I, Söfker A, Degenring RF. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol 2003;121:57– 61. 20. Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol 2001;132:425–7. 21. Benhamou N, Massin P, Haouchine B, et al. Intravitreal triamcinolone for refractory pseudophakic macular edema. Am J Ophthalmol 2003;135:246 –9. 22. Jonas JB, Kreissig I, Degenring RF. Intravitreal triamcinolone acetonide for pseudophakic cystoid macular edema. Am J Ophthalmol 2003;136:384 – 6. 23. Antcliff RJ, Spalton DJ, Stanford MR, et al. Intravitreal triamcinolone for uveitis cystoid macular edema: an optical coherence tomography study. Ophthalmology 2001;108: 765–72. 24. Degenring RF, Jonas JB. Intravitreal injection of triamcinolone acetonide as treatment for chronic uveitis. Br J Ophthalmol 2003;87:361. 25. Park CH, Jaffe GJ, Fekrat S. Intravitreal triamcinolone acetonide in eyes with cystoid macular edema associated with central retinal vein occlusion. Am J Ophthalmol 2003;136: 419 –25.
26. 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. 27. Scott IU, Flynn HW, Rosenfeld PJ. Intravitreal triamcinolone acetonide for idiopathic cystoid macular edema. Am J Ophthalmol 2003;136:737–9. 28. Kosobucki BR, Freeman WR, Cheng L. Photographic estimation of the duration of high dose intravitreal triamcinolone in the vitrectomized eye. Br J Ophthalmol 2006;90:705– 8. 29. Arevalo JF, Munguia D, Faber D, et al. Correlation between intraocular pressure and CD4⫹ T-lymphocyte counts in patients with human immunodeficiency virus with and without cytomegalovirus retinitis. Am J Ophthalmol 1996;122:91– 6. 30. Jonas JB, Kreissig I, Söfker A, et al. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol 2003;121:57– 61. 31. Morrison VL, Koh HJ, Cheng L, et al. Intravitreal toxicity of the Kenalog vehicle (benzyl alcohol) in rabbits. Retina 2006; 26:339 – 44. 32. Jonas JB, Kreissig I, Degenring R. Repeated intravitreal injections of triamcinolone acetonide as treatment of progressive exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2002;240:873– 4. 33. Jonas JB, Hayler JK, Söfker A, Panda-Jonas S. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2001; 131:468 – 471. 34. Rodriguez-Coleman H, Yuan P, Kim H, et al. Intravitreal injection of triamcinolone for diffuse macular edema. Arch Ophthalmol 2004;122:1085– 6. 35. Jonas JB, Degenring RF, Kreissig I. Intravitreal injection of triamcinolone for diffuse macular edema. Authors Reply. Arch Ophthalmol 2004;122:1086 – 8. 36. Garcia-Arumi J, Boixadera A, Giralt J, et al. Comparison of different techniques for purification of triamcinolone acetonide suspension for intravitreal use. Br J Ophthalmol 2005; 89:1112– 4. 37. Dalessandro L, Bottaro E. Reactivation of CMV retinitis after treatment with subtenon corticosteroids for immune recovery uveitis in a patient with AIDS. Scand J Infect Dis 2002;34: 780 –2.
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Patients with AIDS and CD4 levels less than 50 cells/mm3 are at risk of experiencing cytomegalovirus (CMV) retinitis.1 Eventually, many of these patients exhibit immune reconstitution (specifically when their CD4 T-lymphocyte levels rise)2,3 as they are treated with highly active antiretroviral therapy (HAART), including protease inhibitors.4 This improvement in their CD4 T-lymphocyte levels can manifest clinically as an increased inflammatory response in the eye. Our group initially described this ocular inflammatory syndrome, known as immune recovery uveitis (IRU),5– 8 which occurs as the immune system improves in patients with healed CMV retinitis. Immune recovery uveitis Originally received: November 4, 2005. Accepted: July 13, 2006. Manuscript no. 2005-1064. 1 Jacobs Retina Center, Department of Ophthalmology, University of California, San Diego, La Jolla, California. 2 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. Supported by the National Institutes of Health, Bethesda, Maryland (grant no.: EY07366 [WRF]). None of the authors have any financial interest related to the article. Correspondence to William R. Freeman, MD, Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center 0946, 9415 Campus Point Drive, La Jolla, CA 92093. E-mail: [email protected].
334
© 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
is an important cause of visual morbidity in patients with CMV retinitis. Symptoms include a decrease in vision and floaters secondary to posterior segment inflammation. Clinical examination may show vitreitis, papillitis, and macular changes (including epiretinal membrane and macular edema).7–11 Immune recovery uveitis is fairly common in patients with CMV retinitis; specifically, Jabs et al12 reported the prevalence of IRU to be 15.5% of patients in their prospective cohort study. We hypothesize that the use of intravitreal triamcinolone acetonide (IVTA) is an effective treatment in patients with IRU and macular edema. In this article, we address the results of using IVTA (Kenalog; Bristol-Myers Squibb Co., Princeton, NJ) for the treatment of macular edema in IRU patients.
Patients and Methods The current study was a prospective, interventional consecutive case series of AIDS patients with IRU and macular edema who sought treatment at the San Diego AIDS Ocular Research Unit. The study included 7 patients, 8 eyes, and 13 injections. Informed consent was obtained from all patients. Institutional review board/ ethics committee approval was obtained for this prospective study. Two patients were female and 5 patients were male. The average ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2006.07.013
Morrison et al 䡠 Intravitreal Triamcinolone Acetonide for Macular Edema Table 1. Baseline Characteristics of the Patient Cohort Duration of Immune Recovery Uveitis before Intravitreal Study Age Triamcinolone Acetonide Eye (yrs) Gender Treatment (mos) 1
63
M
84
2 3 4
46 46 50
M M F
26 25 51
5 6
57 54
F M
96 12
7 8
45 36
M M
72 3
Previous Surgery/Indication
Cytomegalovirus CD4 Count at Time of Retinitis Intravitreal Triamcinolone Medications Acetonide Treatment
TPPV, ERM removal for visually significant ERM TPPV, SB, and laser for retinal detachment None TPPV, IVTA, ERM removal for visually significant ERM TPPV for macular edema SB for retinal detachment; ganciclovir implant for active CMV retinitis None None
None
600
None None None
535 535, 503 745
Valcyte None
998, 768 430
None None*
358 77
CMV ⫽ cytomegalovirus; ERM ⫽ epiretinal membrane; F ⫽ female; IVTA ⫽ intravitreal triamcinolone acetonide; M ⫽ male; SB ⫽ scleral buckle; TPPV ⫽ trans pars plana vitrectomy. *Started on valganciclovir (Valcyte) at time of injection because of low CD4 count.
age was 50 years (Table 1). Three eyes had more than 1 IVTA injection. Recurrent injections were performed at the time of symptomatic decrease in vision and clinical return of macular edema. Inclusion criteria included prior healed CMV retinitis not involving the fovea or optic nerve, current highly active antiretroviral therapy, immune recovery with CD4 counts of more than 50 cells/mm3 for at least 3 consecutive months, no history of steroid use within the past year, and IRU with symptomatic vision loss from macular edema in the involved eye. Patients with a history of glaucoma, steroid-response intraocular pressure rise, or family history of glaucoma were excluded. Baseline visual acuity was 20/100 (range, 20/32–2=/200) using the Early Treatment Diabetic Retinopathy Study chart. The 2=/200 patient had massive macular edema. Four of the eyes were previously vitrectomized. Five of the 8 eyes had a distant history (of at least 1 year prior) of steroid treatment (including sub-Tenon methylprednisolone acetate [Depo-Medrol, Pharmacia & Upjohn Co., Kalamazoo, MI] injection in the clinic or IVTA at the time of a prior vitrectomy). The only prior use of IVTA was at the time of vitrectomy (at least 1 year prior); IVTA was used to assist in the resolution of macular edema, removal of a possible epiretinal membrane associated with IRU at the time of surgery, or both. The eyes that had previous treatment with steroid for IRU continued to have persistent IRU despite these prior treatments. We gave these eyes at least a 1-year washout period before IVTA injection. All of our patients had active IRU at the time of IVTA injection. The average duration of IRU before IVTA injection was 51 months (range, 3–96 months). Two eyes had cataract surgery performed during this study. Three patients were phakic at the onset of the study, and only 1 was phakic at the conclusion of the study. The 2 patients that had cataract surgery had IVTA injections 1 month before their cataract surgery and already had visually significant cataracts before their IVTA injection. We note that their follow-up concluded before the cataract surgery; thus, cataract surgery was not a factor in vision improvement. There was 1 patient who had a CD4 count of less than 100 cells/mm3 (CD4 ⫽ 77 cells/mm3), and we treated him with valganciclovir 450 mg twice daily to help protect against the risk of reactivation. Patients received 20 mg decanted IVTA (total volume, 0.1 ml). Care was taken to perform a sterile procedure that consisted of a povidone–iodine preparation and use of a lid speculum. Follow-up visits were carried out at 1 week, 1 month, and 3 months. Best-corrected Early Treatment Diabetic Retinopathy Study vision, slit-lamp examination, and dilated fundus examination were
performed. Optical coherence tomography (OCT) and digital fluorescein angiography (FA) also were performed. Angiograms were obtained using a Heidelberg confocal scanning laser ophthalmoscope (Carl Zeiss, Dublin, CA), and OCT scans were performed using a high-resolution Stratus 3000 OCT model (Carl Zeiss) with software version 4.0 to measure retinal thickness and macular volume. All patients were dilated and consented to examination. We recorded from each examined eye 6-mm line scans in a radial spoke pattern intersecting at the macula (slow macular program). Each tomogram consisted of 512 A-scans in length and 2 mm in depth. All examinations were performed by one operator (IK). Retinal thickness was defined as the distance between internal retinal border (inner nerve fiber layer border) and external retinal border (retinal pigment epithelium/outer segment photoreceptor hyperreflective layer). To exclude the possibility of artifact by automatic delineation by OCT software, this was performed manually by the masked operator. The value was compared with the value on the retinal thickness map. The same map provided macular volume value that was used for statistical calculation. Changes from baseline visual acuity (Table 2), OCT volume and thickness (Table 3), and FA results were compared at each visit. Angiograms and OCT scans were compared for improvement or exacerbation (Figs 1, 2).
Statistical Methods Some patients had multiple injections; therefore, a repeated-measures analysis of variance was used to adjust for the correlation between repeated measures within eyes. Least square means and standard errors were obtained for volume, thickness, and logarithm of the minimum ⬎angle of resolution visual acuity measures before injection and at 1 week, 1 month, and 3 months after injection. Repeatedmeasures analysis of variance P values were calculated, and where statistically significant (P⬍0.05), multiple comparison t test P values were obtained to compare preinjection means with postinjection means. SAS software (SAS Institute, Cary, NC) was used for all analyses. Accepted level of significance for all tests was ␣ ⫽ 0.05.
Results Baseline Early Treatment Diabetic Retinopathy Study visual acuity was 20/100 (range, 20/32–2=/200). Visual acuity results were
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Ophthalmology Volume 114, Number 2, February 2007 Table 2. Visual Acuity before Injection with Intravitreal Triamcinolone Acetonide versus after Injection with Intravitreal Triamcinolone Acetonide Visual Acuity Least Square Mean (Standard Error)* Visual acuity Before injection 1 wk after injection (n ⫽ 8) 1 mo after injection (n ⫽ 9) 3 mos after injection (n ⫽ 11)
P Value (Repeated Measures Analysis of Variance)
Compared with Preinjection P Value†
0.03 0.76 (0.07) 0.62 (0.09) 0.49 (0.09) 0.46 (0.08)
0.22 0.0208 0.008
*In logarithm of the minimum angle of resolution units using Early Treatment Diabetic Retinopathy Study charts. † Multiple comparison t test P value.
expressed in logarithm of the minimum angle of resolution units. Preinjection vision was 0.76 (standard error [SE], ⫾0.07). Postinjection vision at 1 week was 0.62 (SE, ⫾0.09), at 1 month was 0.49 (SE, ⫾0.09), and at 3 months was 0.46 (SE, ⫾0.08). The P values were 0.22, 0.0208, and 0.008, respectively. Average preinjection volume of macular edema as measured with OCT was 8.55 mm3 (SE, ⫾0.29). Average macular volume at 1 week after injection was 7.36 mm3 (SE, ⫾0.33), at 1 month was 7.32 mm3 (SE, ⫾0.34), and at 3 months was 7.60 mm3 (SE, ⫾0.36). The P value was statistically significant at each time point, with P values of 0.0092, 0.009, and 0.0487, respectively. The repeated-measures analysis of variance volume P value was 0.02. Average preinjection thickness of macular edema as measured with OCT was 341 m (SE, ⫾28 m). Average macular thickness at 1 week after injection was 227 m (SE, ⫾32 m), at 1 month was 246 m (SE, ⫾33 m), and at 3 months was 213 m (SE, ⫾35 m). The P value was statistically significant at each time point with P values of 0.01, 0.0338, and 0.009, respectively. The repeatedmeasures analysis of variance thickness P value was 0.02. The average CD4 count ranged from 77 to 998 cells/mm3. Hematologic and CD4 count data remained essentially stable throughout the patient follow-up. Of the 3 eyes that had repeat injections, the average duration between injections was 17.6 weeks (range, 10 –26 weeks). All eyes that required reinjection were eyes that had been previously vitrectomized. One patient had a slight rise in intraocular pressure of 26 mmHg that resolved quickly with institution of topical glaucoma medication. There was no case of endophthalmitis or significant
cataract formation noted. All patients had a minimum follow-up of 9 months, and there were no cases of CMV reactivation.
Discussion Spontaneous recovery of IRU can occur; however, longterm complications of untreated IRU have been reported, including severe proliferative vitreoretinopathy and spontaneous vitreous hemorrhage secondary to avulsion of a blood vessel from contraction of the inflamed vitreous.7 Several treatment options for patients with IRU and macular edema have been proposed. Physicians previously suggested the use of oral corticosteroids.13,14 We reported the use of repository sub-Tenon steroid injections for the treatment of patients with macular complications of immune recovery uveitis and found only a modest treatment effect.15,16 We also previously showed that valganciclovir treatment may benefit visual acuity in patients with macular edema resulting from IRU.17 This was a noncontrolled study of 5 patients, and there was a modest improvement in vision. We believe the dramatic clinical effects shown in the present study were likely the result of the IVTA treatment. Orbital floor injections of methylprednisolone acetate 40 mg or triamcinolone 20 mg were shown to improve vision
Table 3. Optical Coherence Tomography Measurements of Macular Volume and Thickness before Injection with Intravitreal Triamcinolone Acetonide versus after Injection with Intravitreal Triamcinolone Acetonide Least Squares Mean (Standard Error) Volume Before injection 1 wk after injection (n ⫽ 9) 1 mo after injection (n ⫽ 8) 3 mos after injection (n ⫽ 7) Thickness Before injection 1 wk after injection (n ⫽ 9) 1 mo after injection (n ⫽ 8) 3 mos after injection (n ⫽ 7) *Multiple comparison t test P value.
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P Value (Repeated Measures Analysis of Variance)
Compared with Preinjection P Value*
0.02 8.55 (0.29) 7.36 (0.33) 7.32 (0.34) 7.60 (0.36)
0.0092 0.009 0.0487 0.02
341 (28) 227 (32) 246 (33) 213 (35)
0.01 0.0338 0.009
Morrison et al 䡠 Intravitreal Triamcinolone Acetonide for Macular Edema
Figure 1. Optical coherence tomograms from a patient with macular edema secondary to immune-recovery uveitis obtained (A) before injection and (B) after injection of intravitreal triamcinolone acetonide.
in one study.18 Canzano et al8 reported 2 cases of IRU with macular edema that were persistent and resistant to treatment. The authors attributed the edema to the presence of vitreomacular traction syndrome in these 2 patients, which was confirmed by ultrasonography. Over the past few years, IVTA has become popular for the treatment of macular edema resulting from various causes.19 –27 Intravitreal triamcinolone has the risk of the formation of cataracts, glaucoma, and endophthalmitis. The effect of trans pars plana vitrectomy in 4 of our patients likely accounted for an increased drug clearance, and we are cognizant that these patients tend to need more frequent reinjection schedules. We have shown that IVTA lasts 113 days in the vitrectomized eye.28 We have managed our patients successfully with planned repeat injections at their respective required symptomatic intervals without complications. We remain very cognizant of the long-term complications of repeat steroid injection; however, we have not experienced any significant complication from IVTA in IRU patients in our limited study population. We believe the use of absolute sterile technique (lid speculum, povidone iodine preparation) helps limit the devastating risk of endophthalmitis. None of our patients had a significant increase in eye pressure that required more than a temporary use of a topical drop. We believe this is because of the lower intraocular pressure associated with uveitis patients and
AIDS patients.29 Although we had a few patients with cataracts, it is also known that cataract formation is almost inevitable in an IRU patient. In this study, we used high dose of IVTA (20 mg) because we believe it lasts longer and has a stronger effect. Further, we concur with similar results of Jonas et al,30 who reported that typically they use a dose of 25 mg and noted that in more than 300 patients, they have not yet seen adverse effects that may be attributed to that high dose. We previously showed that the toxic concentration is very close to the actual concentration injected into the eye31; thus, we suggest that intravitreal triamcinolone acetonide be cleared of most of the vehicle before injection. Various methods can be considered, with some having been reported anecdotally. Possibilities include pharmacologic washing,22,27 decantation,32,33 and filtering. Decanting procedures may yield highly variable doses. Rodriguez-Coleman et al34 found that filtering techniques actually concentrated the benzyl alcohol; however, Jonas et al35 noted, using that technique, that no episodes of toxicity or pseudoendophthalmitis occurred in more than 500 injections administered. Garcia-Arumi et al36 showed that filter techniques, sedimentation, and centrifugation all effectively reduce the benzyl alcohol concentration in triamcinolone acetonide. We found that with simple decantation, we were able to remove a significant portion of the preservative (as verified with high-performance
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Ophthalmology Volume 114, Number 2, February 2007 cover our patients with maintenance valganciclovir if their CD4 count was less than 100 cells/mm3 as an added protection against the possibility of recurrence. The optimal timing of IVTA treatment was not specifically examined in this study. Care should be taken regarding the use of IVTA in patients recently treated with HAART with improving CD4 counts. We believe cotreatment with valganciclovir is important in patients with recently improving low CD4 counts before any intravitreal steroid injection so as to prevent any possible reactivation of CMV retinitis. This study, however, did not specifically examine whether cotreatment with specific anti-CMV medications was necessary. We have now followed up our patients for at least 9 months, with many being monitored for more than 1 year, and no episode of reactivation has occurred in any of our patients. We show in this paper that IVTA improves vision, OCT volume and thickness, as well as FA results in patients with IRU. Intravitreal triamcinolone acetonide also allows the doctor to avoid the side effects of systemic oral corticosteroid treatment.
References
Figure 2. Fluorescein angiograms from the same patient as in Figure 1 obtained (A) before injection and (B) after injection of intravitreal triamcinolone acetonide.
liquid chromatography).31 This technique of decantation is a relatively simple step to perform in the office or operating room. We believe that this will help decrease the risk of retinal toxicity. Reactivation is a theoretical concern given the immune status of these patients and the use of an immunosuppressant treatment. Dalessandro and Bottaro37 reported a case of reactivation of CMV retinitis after treatment with subTenon corticosteroids for IRU. Of note, care was taken to
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