Supplement to

November/December 2009 Intravitreal : A Review of Therapeutic and Surgical Applications Articles and discussion featuring course director Timothy G. Murray, MD; and faculty members Julia A. Haller, MD; Allen C. Ho, MD; and Seenu M. Hariprasad, MD. A History of Intravitreal Corticosteroids as Monotherapy in Retinal Disease A brief overview of the intravitreal application of and clinical results. BY JULIA A. HALLER, MD

nflammatory processes are increasingly recognized to play of .12 Subsequently, Peyman et al13-15 pub- a significant role in many diseases of the . As a result, lished further cases where this agent was used in combina- Ithere has been burgeoning research interest in the extent tion with gentamycin to treat bacterial endophthalmitis. In to which is a factor in highly prevalent retinal 1977, Floman and Zor16 elucidated that the mechanism of disorders such as age-related (AMD), action against inflammation as involving the , and venous occlusive disease, and into inhibition of prostaglandins. Later that decade, Machemer expanding molecular targeting to encompass inflammation- and Tano17,18 showed that a single injection of dexametha- related mediators other than just vascular endothelial growth sone in rabbit models inhibited fibroblast growth and signifi- factor to improve clinical outcomes in these diseases. cantly reduced the incidence of . They Corticosteroids are a class of drugs that has been used via a repeated the study using intravitreal triamcinolone (IVTA) variety of routes for many years for ocular indications, and with similar results.19 They also saw a reduction in retinal vas- more recently in the posterior segment, as a primary therapy cularization caused by fibrous strands coming into contact and to improve the response to surgical intervention or to with the vascularized retina with IVTA to a greater extent than enhance therapeutic agents as an adjunctive measure.1-11 when they had used in the earlier studies. This article offers a brief overview of selected points in the Ishibashi et al20 investigated the effects of corticosteroids on history of intravitreal corticosteroid monotherapy for retinal a primate model of laser-induced lesions and found that eyes disease. infused with either dexamethasone or dexamethasone com- bined with triamcinolone less frequently developed subretinal PRECLINICAL WORK neovascularization when compared with controls, suggesting The first reported intravitreal injection of a corticosteroid an antiangiogenic effect. In a later study using a rabbit model was performed by Graham and Peyman in 1974, when they for preretinal neovascularization, a significantly fewer number injected dexamethasone for an experimentally induced case of eyes developed new blood vessels after being treated with Jointly sponsored by the Dulaney Foundation and Retina Today

NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 1 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

Jointly sponsored by the Dulaney Foundation and Retina Today. Release date: December 2009. Expiration date: December 2010. This continuing medical education activity is supported by an unrestricted educational grant from Alcon Laboratories, Inc. TARGET AUDIENCE turers of any commercial products/devices, or providers of commercial services; This activity is designed for retina specialists and other ophthalmologists. and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved. LEARNING OBJECTIVES Dr. Haller states that she is a consultant to Allergan, Inc., Genentech, Inc., Upon completion of this activity, the participant should be able to: Macusight, Novartis, and Optimedica. She is an equity owner in Macusight, • Discuss the history of intravitreal corticosteroid use in monotherapy and Opko Health, and Optimedica. combination therapy for retinal disease Dr. Hariprasad states that he is a paid consultant to OD-OS, Alcon • Analyze the advantages and limitations of the available corticosteroids and Laboratories, Inc., Ocular Therapeutix, and Pfizer, Inc., and on the speakers explain how to incorporate these agents into clinical practice immediately bureau for Genentech, Inc., Allergan, Inc., and Alcon Laboratories, Inc. • Outline the side effects, toxicities, and related issues with regard to corticos- Dr. Ho states that he is consultant to Alcon Laboratories, Inc., Allergan, Inc., teroids, both in the therapeutic and surgical setting (vs dyes for visualization), Eyetech, Genentech, Inc., Neovista, Ophthotech, Ophtherion, QLT, and and show how the right agents can improve outcomes Regeneron. He is on the speakers bureau for Alcon Laboratories, Inc., Allergan, • Describe the current use of corticosteroids to control postoperative inflam- Inc., Genentech, Inc., LifeGuard, Macusight, Neovista, QLT, and Regeneron. He mation and retinal edema associated with retina surgery receives lecture fees from Alcon Laboratories, Inc., Genentech, Inc., and Iridex. • Understand FDA status of agents and reimbursement Dr. Murray states that he is a consultant to Alcon Laboratories, Inc. All of those involved in the planning, editing, and peer review of this educa- METHOD OF INSTRUCTION tional activity have indicated that they have no financial relationships to disclose. Participants should read the continuing medical education (CME) activity in its entirety. After reviewing the material, please complete the self-assessment STATEMENT OF NEED test, which consists of a series of multiple-choice questions, and the course eval- A growing number of retina specialists have adopted the use of surgical adju- uation. To answer these questions online and receive real-time results, please vants to help with tissue visualization during vitrectomy surgery. The purpose of visit http://www.dulaneyfoundation.org and click “Online Courses.” Upon com- these surgical adjuvants is to improve patient outcomes and to facilitate teach- pleting the activity and achieving a passing score of over 70% on the self-assess- ing of vitrectomy surgery. Traditional vital dyes, such as indocyanine green (ICG) ment test, you may print out a CME credit letter awarding 1.5 AMA PRA and Trypan blue, are used for tissue visualization. Corticosteroids, such as triam- Category 1 Credits.™ The estimated time to complete this activity is 1.5 hours. cinolone acetonide, may offer visualization capabilities and have the potential to yield additional pharmacologic benefits in vitreoretinal surgery such as a reduc- ACCREDITATION AND DESIGNATION tion of postoperative inflammation and retinal edema. This activity has been planned and implemented in accordance with the Data elucidating the advantages and shortcomings of the four available Essential Areas and policies of the Accreditation Council for Continuing Medical agents in this area have been presented at meetings throughout the year includ- Education (ACCME) through the joint sponsorship of the Dulaney Foundation ing the Association for Research and Vision in (ARVO).1,2 In and Retina Today. The Dulaney Foundation is accredited by the ACCME to pro- addition to recent data presented at major scientific meetings, there are newly vide continuing education for physicians. The Dulaney Foundation designates FDA-approved agents available and a growing number of publications in the lit- this educational activity for a maximum of 1.5 AMA PRA Category 1 Credits.™ erature addressing surgical adjuvants.3 This large pool of information points to a Physicians should only claim credit commensurate with the extent of their par- clear need for a CME activity that highlights all these data, offers expert analysis, ticipation in the activity. and organizes it into a convenient resource for retina surgeons. Additionally, there are some data, presented within this supplement, suggest- CONTENT VALIDATION ing that utilizing corticosteroids in surgery may have a therapeutic effect against In compliance with ACCME standards for commercial support and the after vitrectomy and phacoemulsification. To fully understand Dulaney Foundation’s policy and procedure for resolving conflicts of interest, this the mechanism of action of corticosteroids, one must have knowledge of the CME activity was peer reviewed for clinical content validity to ensure the activity’s clinical studies on corticosteroids for therapeutic application, both in monother- materials are fair, balanced, and free of bias; the activity materials represent a stan- apy and combination therapy. dard of practice within the medical profession; and any studies cited in the mate- This educational activity will familiarize retina surgeons with the latest clinical rials upon which recommendations are based are scientifically objective and con- data on this topic and allow for a discussion of the use of corticosteroids and form to research principles generally accepted by the scientific community. vital dyes for perioperative use during vitreoretinal surgery. As demand for vitrectomy increases with an aging society, vitreoretinal spe- FACULTY CREDENTIALS cialists must arm themselves with the most current knowledge in order to per- Julia A. Haller, MD, is Professor and Chair of Ophthalmology at Thomas form safe and successful surgery. Health care authorities increasingly call for oph- Jefferson University and Thomas Jefferson University Hospital. She is also thalmologists and other physicians to follow evidence-based recommendations Ophthalmologist in Chief at Wills Eye Institute. to maximize efficiency, increase effectiveness of care, and ensure optimal patient Seenu M. Hariprasad, MD, is Associate Professor and Director of Clinical outcomes.4 Research at the University of Chicago Department of Surgery Section of Like other medical professionals, ophthalmologists routinely turn to expert Ophthalmology and Visual Science. He serves as Chief of the Vitreoretinal colleagues for knowledge that will help them to develop the most effective ther- Service and Director of the Surgical Retina Fellowship Program. apeutic strategies. This proposed CME activity will provide evidence-based Allen C. Ho, MD, is a Professor of Ophthalmology at Thomas Jefferson knowledge from experts addressing the use of surgical adjuvants in vitreoretinal University Retina Service and Wills Eye Hospital in Philadelphia. surgery. The activity will also provide perspectives to help clinicians plan for near- Timothy G. Murray, MD, MBA, FACS, is Professor of Ophthalmology and term developments in this area. Radiation Oncology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. 1. Genovesi-Ebert F, Rizzo S, Vento A, et al. Ultrahigh-speed 5000 cut rate 25-gauge vitrectomy system ver- sus standard 25-ga and 20-ga in the treatment of macular epiretinal membrane. #4201/A560. Presented at: the 2009 Association of Research in Vision and Ophthalmology meeting; May 6, 2009; Fort Lauderdale, FL. DISCLOSURE 2. Comparison of sedimentation rates of Kenalog and Triesence. #6238/D644. Presented at: the 2009 In accordance with the disclosure policies of the Dulaney Foundation and to Association of Research in Vision and Ophthalmology meeting; May 7, 2009; Fort Lauderdale, FL. conform with ACCME and FDA guidelines, anyone in a position to affect the 3. Rodrigues EB, Maia M, Meyer CH, et al. Vital dyes for chromovitrectomy. Curr Opin Ophthalmol. 2007;18:179–187. content of a CME activity is required to disclose to the activity participants: (1) 4. Lieb S. Principles of Adult Learning. 1991. honolulu.hawaii.edu/intranet/committees/FacDevCom/ the existence of any financial interest or other relationships with the manufac- guidebk/teachtip/adults-2.htm. Accessed June 22, 2009.

2 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2009 triamcinolone and then injected with dermal fibroblasts progression were significant, they did not outweigh compared with controls.21 the damaging effects of the disease.30,31 The US Food and In 1995, Jaffe et al22 first applied an intravitreal sustained- Drug Administration (FDA) approved the device in 2005. release dexamethasone device to rabbit eyes that had been induced with antigen to simulate . The clinical and INTRAVITREAL STEROIDS FOR DIABETIC histopathological data collected showed the intraocular MACULAR EDEMA inflammation to be less (P<.05 in clinical exam) in the treated Virtually all types of recalcitrant macular edema, diabetic eyes than in the untreated eyes. macular edema (DME) being the most prevalent, have been reported to respond at least transiently to the use of intrav- INTRAVITREAL STEROIDS FOR AMD itreal therapy. An evidence-based paradigm for In 1995, Penfold et al23 performed a pilot study using IVTA intravitreal steroid use, however, particularly in complex, in patients to treat age-related macular degeneration (AMD). multifactorial and chronic disease states such as DME, In this 30-eye study (n=28), IVTA was shown to decrease exu- remains elusive. Multiple case series and small trials have dation and improved vision in patients with wet AMD and investigated the use of intravitreal steroids for DME. For subfoveal and juxtafoveal choroidal neovascularization. With example, Gillies et al32 recently reported a small series of eyes 18-month follow-up, there were no serious side effects and (n=41) who were treated with IVTA for DME refractory to visual acuity was reported as significantly better than the data laser. Patients were randomized to IVTA or placebo. A showed for untreated lesions. greater percentage of patients achieved visual acuity In a study that was published in Retina in 2000, a single improvement in the IVTA group (42%) than placebo (32%), injection of 4-mg IVTA was administered to patients with and in 5-year follow-up, patients who responded to IVTA wet AMD (n=27) and compared for 6-months follow-up maintained their visual acuity gains. against untreated patients. The patients in the treated The largest clinical trial to date on the efficacy and safety of group had significantly better visual acuity at 3 and IVTA for DME was from the Diabetic Retinopathy Clinical 6 months (P<.005) and although an intraocular pressure Research Network. The study compared focal/grid laser pho- (IOP) rise was seen in 25% of treated patients, this was tocoagulation (n=330) to 1-mg IVTA (n=256), and managed with topical pressure-lowering medications.24 4-mg IVTA (n=254). Although IVTA 4 mg showed a benefit Gillies et al27 reported a biologic effect with one injec- over laser at 4 months, by year 1, no differences in visual acu- tion 4-mg IVTA for AMD at 3 months in their study in ity were seen between the three groups. At 16 months and 2 2003, and in 1-year follow-up, found that one injection of years, patients in the laser group had significantly better visual IVTA did not increase the risk of visual loss in their 151 eye, acuity that the 1-mg IVTA group (P=.02) and the 4-mg IVTA randomized study. group (P=.002).33 The 3-year results were similar and support- Jonas et al25 performed a study evaluating high-dose 25-mg ed laser as the best treatment option of those specific proto- IVTA for wet AMD. Their study included 71 eyes of 67 cols tested for patients with DME similar to those recruited in patients and sought to find the duration of effect and side the study.34 Whether other protocols could show a benefit to effects of the treatment over the course of an average of intravitreal steroids in DME or other types of eyes respond approximately 7-months follow-up. They found a significant better remains to be investigated in a large-scale fashion.35-38 increase in mean visual acuity (P<.001); however, they also saw a significant mean increase in IOP (P<.001). In another INTRAVITREAL STEROIDS FOR VEIN OCCLUSION high-dose IVTA study with 1-year follow-up (39 eyes), howev- The use of intravitreal steroids for macular edema due to er, no beneficial effect was found in the treated group vs the retinal venous occlusive disease was first described in a series control group, who were treated with intravitreal dexametha- of case reports by Ip and Greenberg.39 Recently, steroids have sone.26 Further, all eyes in the treated group developed been in the spotlight for central retinal vein occlusion (CRVO) marked cataract progression. and branch retinal vein occlusion (BRVO) because of the report of results of two groups of clinical trials. INTRAVITREAL STEROIDS FOR UVEITIS The 6-month results of identical multicenter, double- Steroids have been used for uveitis for many years, and masked, randomized, parallel phase 3 trials comparing the their intravitreal use was one of the obvious indications once sustained-delivery intravitreal 0.7-mg dexamethasone implant this route of drug delivery became commonly employed. A (n=427) to sham (n=426) demonstrated a significant benefit key development for chronic intravitreal administration of with the dexamethasone implant (P<.001) for patients with steroids was the advent of extended delivery. CRVO and BRVO.40 The FDA gave approval to the dexam- Pilot and clinical trials for the 0.59-mg fluocinolone ace- ethasone implant (Ozurdex, Allergan, Inc.) for CRVO and tonide sustained-delivery device (Retisert, Bausch & Lomb) BRVO earlier this year. for the treatment of chronic posterior uveitis proved that it The Standard Care vs Corticosteroid for Retinal Vein was beneficial in controlling inflammation over a prolonged Occlusion (SCORE) study group also recently released their period of time.28,29 Patients in the clinical trial (n=168) were results on steroids vs laser for CRVO and steroids vs laser for followed for 3 years and, although the side effects of IOP and BRVO. SCORE-BRVO enrolled 411 patients and randomized

NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 3 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

them to treatment with laser, 1-mg IVTA, and 4-mg IVTA.41 12. Graham RO, Peyman GA. Intravitreal injection of dexamethasone. Treatment of experimentally induced endophthalmitis. Arch Ophthalmol. 1974;92(2):149–154. No significant difference was seen in the 12-month visual acu- 13. Peyman GA, Rose M, Sanders D. Intravitreal injection and vitrectomy in acute bacterial ity outcomes between the three groups. The rate of adverse endophthalmitis. Can J Ophthalmol. 1976;11(2):188–190. 14. Peyman GA, Vastine DW, Meisels HI. The experimental and clinical use of intravitreal to events (IOP increase and cataract) was similar between the treat bacterial and fungal endophthalmitis. Doc Ophthalmol. 1975;39(1):183–201. 15. Peyman GA, Vastine DW, Diamond JG. Vitrectomy and intraocular gentamycin management of 1-mg IVTA and laser groups and highest in the 4-mg IVTA Herellea endophthalmitis after incomplete phacoemulsification. Am J Ophthalmol. groups. The conclusion was that laser should remain the stan- 1975;80(4):764–765. 16. Floman N, Zor U. Mechanism of steroid action in ocular inflammation: Inhibition of prostaglandin dard of care for patients with BRVO. SCORE-CRVO enrolled production. Invest Ophthalmol Vis Sci. 1977;16(1):69–73. 271 patients and randomized them to either observation, 17. Tano Y, Sugita G, Abrams G, Machemer R. Inhibition of intraocular proliferations with intravitreal 42 corticosteroids. Am J Ophthalmol. 1980;89(1):131–136. treatment with 1-mg IVTA, or treatment with 4-mg IVTA. 18. Machemer R, Sugita G, Tano Y. Treatment of intraocular proliferations with intravitreal steroids. The patients treated with both 1-mg and 4-mg IVTA achiev- Trans Am Ophthalmol Soc. 1979;77:171–180. 19. Tano Y, Chandler D, Machemer R. Treatment of intraocular proliferation with intravitreal injection of ed an equally significantly better visual outcome than patients . Am J Ophthalmol. 1980;90(6):810–816. in the observation group (P=.001). The rate of complications 20. Ishibashi T, Miki K, Sorgente N, Patterson R, Ryan SJ. Effects of intravitreal administration of steroids on experimental subretinal neovascularization in the subhuman primate. Arch Ophthalmol. was higher in the 4-mg group than in the 1-mg group. The 1985;103(5):708–711. authors concluded that 1-mg IVTA should be considered for 21. Antoszyk AN, Gottlieb JL, Machemer R, Hatchell DL. The effects of intravitreal triamcinolone ace- tonide on experimental pre-retinal neovascularization. Graefes Arch Clin Exp Ophthalmol. patients with CRVO. 1993;231(1):34–40. 22. Cheng CK, Berger AS, Pearson PA, Ashton P, Jaffe GJ. Intravitreal sustained-release dexametha- sone device in the treatment of experimental uveitis. Invest Ophthalmol Vis Sci. 1995;36(2):442–453. SUMMARY 23. Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative macular degeneration and intravitreal tri- Intravitreal injection of pharmacological agents was a radi- amcinolone. A pilot study. Aust N Z J Ophthalmol. 1995;23(4):29–38. 43 24. Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in exudative age- cal concept when first introduced by Blumenkranz et al. related macular degeneration. Retina. 2000;20(3):244–250. Unique drug delivery issues in the posterior segment and the 25. Jonas JB, Kreissig I, Hugger P, Sauder G, Panda-Jonas S, Degenring R. Intravitreal triamcinolone acetonide for exudative age related macular degeneration. Br J Ophthalmol. 2003;87(4):462–468. increasingly available and effective therapies for posterior seg- 26. Lee J, Freeman WR, Azen SP, Chung EJ, Koh HJ. Prospective, randomized clinical trial of intravit- ment disease processes have resulted in intravitreal adminis- real triamcinolone treatment of neovascular age-related macular degeneration: one-year results. Retina. 2007;27(9):1205–1213. tration becoming a routine line of therapy. Steroids are a class 27. Gillies MC, Simpson JM, Luo W, et al. A randomized clinical trial of a single dose of intravitreal tri- of drug that has been available for many years, and used via amcinolone acetonide for neovascular age-related macular degeneration: one-year results. Arch Ophthalmol. 2003;121(5):667–673. different routes for a variety of ocular conditions. As evidence 28. Jaffe GJ, McCallum RM, Branchaud B, Skalak C, Butuner Z, Ashton P. Long-term follow-up results of the inflammatory pathobiology underlying many prevalent of a pilot trial of a implant to treat posterior uveitis. Ophthalmology. retinal disorders continues to emerge, further support for the 2005;112(7):1192–1198. 29. Jaffe GJ, Martin D, Callanan D, Pearson PA, Levy B, Comstock T; Fluocinolone Acetonide Uveitis potential of steroids to impact on these disease processes has Study Group.Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four- evolved. Careful prospective evaluation of these pharmaco- week results of a multicenter randomized clinical study. Ophthalmology. 2006;113(6):1020–1027. Epub 2006 May 9. logical options as monotherapy or in combination with other 30. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a drugs and procedures holds significant promise for an ex- fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191–201. panding population of patients with blinding eye disorders. 31. Nguyen QD, Callanan D, Dugel P, Godfrey DG, Goldstein DA, Wilensky JT. Treating chronic noninfectious posterior segment uveitis: the impact of cumulative damage. Proceedings of an expert panel roundtable discussion. Retina. 2006;Suppl:1–16. Julia A. Haller, MD, is Professor and Chair of 32. Gillies MC, Simpson JM, Gaston C, Hunt G, Ali H, Zhu M, Sutter F. Five-year results of a random- Ophthalmology at Thomas Jefferson University ized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmology. 2009;116(11):2182–2187. Epub 2009 Oct 1. and Thomas Jefferson University Hospital. 33. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamci- nolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 She is also Ophthalmologist in Chief at Wills Sep;115(9):1447–9, 1449.e1–10. Eye Institute. Dr. Haller can be reached at 34. Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triam- +1 215 928 3000. cinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245–251. 1. Lee HB, Pulido JS, McCannel CA, Buettner H. Role of inflammation in retinal vein occlusion. Can J 35. Jonas J, Rensch F. Diabetic macular edema. Ophthalmology. 2009;116(3):594–5; author reply Ophthalmol. 2007;42:131–133. 596–597. 2. Jonas JB, Kreissig I, Degenring RF. Intravitreal triamcinolone acetonide as treatment of macular 36. Blanco-Garavito R, Rodriguez-Valdes PJ. DRCR Study: outcomes in focal vs diffuse edema? edema in central retinal vein occlusion. Graefe’s Arch Clin Exp Ophthalmol. 2002;240:782–783. Ophthalmology. 2009;116(3):595–596; author reply 596–597. 3. Sivaprasad S, McCluskey P, Lightman S. Intravitreal steroids in the management of macular oedema. 37. Gillies M. Diabetic macular edema. Ophthalmology. 2009;116(3):595; author reply 596–597. Acta Ophthalmol Scand. 2006;84(6):722–733. 38. Narula R, Agarwal M, Chaudhary SP, Shroff C. Diabetic macular edema. Ophthalmology. 4. Jonas JB, Kreissig I, Kamppeter B, Degenring RF. [Intravitreal triamcinolone acetonide for the treat- 2009;116(9):1833–1834; author reply 1834. ment of intraocular edematous and neovascular diseases. Article in German.] Ophthalmologe. 39. Ip MS, Kumar KS. Intravitreous triamcinolone acetonide as treatment for macular edema from 2004;101(2):113–120. central retinal vein occlusion. Arch Ophthalmol. 2002;120(9):1217–1219. 5. Spaide RF. Rationale for combination therapies for choroidal neovascularization. Am J Ophthalmol. 40. Haller JA. 6-month randomized controlled clinical trial of an intravitreal dexametha- 2006;141:149–156. sone implant in macular edema associated with retinal vein occlusion. Paper presented 6. Spaide RF. Combination therapies for choroidal neovascularization. In: Holz FG, Spaide RF, eds. at: Retina Congress 2009; October 4, 2009; New York, NY. Medical Retina (Essentials in Ophthalmology). Heidelberg: Springer; 2007:90–104. 41. Scott IU, Ip MS, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial com- 7. Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids: new mechanisms for old drugs. paring the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associ- N Engl J Med. 2005;353:1711–1723. ated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs 8. Vinores SA, Xiao WH, Aslam S, et al. Implication of the hypoxia response element of the VEGF pro- Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. moter in mouse models of retinal and choroidal neovascularization, but not retinal vascular develop- Arch Ophthalmol. 2009;127(9):1115–1128. ment. J Cell Physiol. 2006;206(3):749–758. 42. Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. 9. Apte RS, Richter J, Herndon J, Ferguson TA. Macrophages inhibit choroidal neovascularization in A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to age-related macular degeneration. PLoS Med. 2006;3:1371–1381. treat vision loss associated with macular edema secondary to central retinal vein occlusion: the 10. Kelly J, Khan AA, Yin J, Ferguson TA, Apte RS. Senescence regulates macrophage polarization and Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. angiogenic fate at sites of tissue injury. J Clin Invest. 2007;117:3421–3426. 2009;127(9):1101–1114. 11. Dace D, Khan AA, Kelly J, Apte RS. Interleukin-10 promotes pathologic developmental angiogene- 43. Blumenkranz MS, Ophir A, Claflin AJ, Hajek A. Fluorouracil for the treatment of massive periretinal sis by regulating macrophage responsiveness to hypoxia. PLoS One. 2008;3:3381. proliferation. Am J Ophthalmol. 1982;94(4):458–467.

4 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2009 Combination Therapy for Retinal Disease A review of the studies that have been performed using corticosteroids. BY ALLEN C. HO, MD

n recent years, a number of medical options have Further study has shown an adjunctive effect with IVTA become available for treating retinal disease. As under- plus PDT.7-9 Istanding of the disease processes in the retina has Piermarocchi et al,10 despite finding an early positive increased, it has become clear that many of the conditions response with PDT plus IVTA in an 84-patient study com- for which we treat our patients are multifactorial in nature. paring patients randomized to PDT (n=41) or IVTA fol- For example, there are data showing that choroidal neovas- lowed by PDT (n=43), did not find functional benefits over cularization (CNV), although an important factor in age- the long-term follow-up. Additionally, a study by the NAPP related macular degeneration (AMD), is not the only com- (Neovascular Age-Related Macular Degeneration, Periocular ponent to this disease and that the inflammatory response Corticosteroids, and Photodynamic Therapy) Trial Research and cellular proliferation in AMD should also be considered Group did not find a reduction in leakage upon fluorescein as potential therapeutic targets.1,2 Similarly, combination angiography after a single treatment with IVTA and PDT therapy has been explored for the treatment of diabetic compared with PDT alone.11 macular edema (DME). Thus, some diseases may respond better to combination therapy rather than to a single thera- ANTI-VEGF + STEROIDS FOR DME peutic agent. Because corticosteroids target the inflamma- There are fewer published studies investigating the effect tory cells and also decrease the production of inflammatory of combined anti-VEGF agents with corticosteroids, but ,3 they may be useful adjuncts for some cases. This many studies are currently underway. Soheilian et al12 hypothesis has been tested in several published studies. This reported 12-week results for 103 eyes of 97 patients enrolled article provides an overview summary. in a study to evaluate the effects of intravitreal (IVB; Avastin, Genentech, Inc.) with or without IVTA vs laser PDT + STEROIDS FOR AMD photocoagulation for the primary treatment of DME. The One of the earliest combination therapies investigated was 12-week results demonstrated significantly better visual verteporfin photodynamic therapy (PDT; Visudyne, acuity results for patients treated with IVB or IVB/IVTA at Novartis) with intravitreal triamcinolone acetonide (IVTA). In 6 weeks (P<.0001) than those treated with laser photocoag- 2005, Spaide et al4 published 12-month results with this ulation, but did not find an adjunctive effect with IVTA; fur- combination for CNV secondary to AMD. Twenty-six eyes of ther, the significant improvement in visual acuity was only 26 patients were included in this noncomparative case series. seen in the IVB-alone group at 12 weeks (P=.024). Half of the patients in the study were treatment naïve and In a more recent report by Soheilian et al,13 150 eyes of the other half had visual loss during prior PDT treatment. All 129 patients were randomized in a similar fashion to IVB patients were treated with PDT and then immediately given injections, IVB/IVTA injections, and focal or modified grid intravitreal injections of 4-mg IVTA (Kenalog, Bristol-Myers laser. The visual acuity data showed a significant visual acu- Squibb). The retreatment criteria were based on leakage seen ity improvement at 6 and 12 weeks for both the IVB and with fluorescein angiography. IVB/IVTA groups (P<.001 and P=.012, respectively) and for At 12 months, the newly treated group had an average of all follow-up time points for the IVB group. An anatomical 2.5 lines of visual acuity improvement (P=.011). The previ- effect of central macular thickness (CMT) reduction, al- ously treated patients had an average of 0.44 lines improve- though significant at 6 weeks for all groups, was not seen in ment in visual acuity (P=.53). Ten patients in the study any of the groups at 12 and 24 weeks. required (IOP)-lowering medication. Another study by the same group evaluated the effect of Augustin and Schmidt-Erfurth5,6 demonstrated similar three injections of IVB on both CMT and visual acuity in results with PDT and IVTA for CNV secondary to AMD. In patients with refractory DME. The first injections of IVB their investigations, a method of applying PDT and then were combined with IVTA or sham.14 At 24 weeks, the CMT injecting 25-mg IVTA 16 hours after the PDT procedure was for both treatment groups was significantly reduced com- used. Additionally, both studies reported lower-than-expect- pared with the sham group (IVB: P=.012; IVB/IVTA: P=.01). ed retreatment rates. One case series included 184 patients At 24 weeks the visual acuity differences between the IVB and the second case series included 41 patients. The mean and sham groups were significant (P=.01) as were those visual acuity improvement in the first case series was signifi- between the IVB/IVTA and sham groups (P=.006). The dif- cant at 1.22 lines (P<.01). ference in visual acuity between the IVB and IVB/IVTA

NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 5 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

groups was not significant; however, visual acuity improve- In Lam et al,19 111 eyes of 111 patients were randomized ment was initiated earlier (at 6 weeks) in the IVB/IVTA to laser, 4 mg IVTA, or IVTA followed by laser approximately group than in the IVB only group (12 weeks). IOP rise was 1 month later. The reduction in central foveal thickness in seen in 8% of the IVB/IVTA group. Investigators concluded the IVTA and the IVTA/laser was significant initially (P<.01) that, although combined IVB and IVTA appeared to result but the difference was not significant between groups by in an earlier improvement in visual acuity, the long-term month 6. Macular thickening seemed to be delayed in the results did not support an adjunctive effect. combined group, suggesting that the laser prolonged the effect of TA. LASER + STEROIDS FOR DME There was no significant difference in best-corrected visu- The recent DRCR Study Group report15 comparing pre- al acuity among the treatment groups. The study authors servative free triamcinolone acetonide 4 mg intravitreal concluded that there were no differences in the IVTA group injection with macular laser treatment showed superiority and combination group, but that TA yielded better effects of laser treatment over 2 years of follow-up. Over the first than laser when injected alone or in conjunction with laser. several months, however, triamcinolone acetonide therapy demonstrated an improvement in vision not observed with TRIPLE THERAPY FOR AMD macular laser treatment; this study did not address combi- Since 2006, there have been several reports of clinical nation treatment for DME and it is possible that combina- research into triple therapy for AMD. Liggett et al20 first tion therapy may afford improved efficacy. Prospective reported the 6-month results of high-dose IVTA (10 mg), studies are in progress. PDT, and sodium (Macugen, Eyetech). The The results of studies evaluating IVTA and sub-Tenon’s study reviewed the records of 16 patients and 22 eyes; 13 injection of triamcinolone acetonide are variable. Shimura eyes had previous IVTA and PDT treatment, and nine eyes et al16 showed a protective effect with a posterior sub- had been newly diagnosed with CNV. Mean visual acuity Tenon’s injection of TA prior to grid laser photocoagulation improvement for both groups was 2.2 lines, which was sig- for diffuse DME by allowing for lower intensity laser spots nificant in the newly treated group (P=.013); however, and decrease in central visual field sensitivity. Using similar improvement in the previously treated group was not con- methods, Chung et al17 also found that visual outcomes in sidered significant, suggesting that triple therapy may be diffuse DME were better when triamcinolone TA was more beneficial for treatment-naïve patients. administered via sub-Tenon’s injection prior to laser. Unoki Augustin et al21 performed a prospective, noncompara- et al,18 in an 82-eye study, found that posterior sub-Tenon’s tive case series in 104 patients to evaluate triple therapy injection of TA prior to laser resulted in a significant with reduced light-dose PDT, IVB, and intravitreal dexam- improvement in vision at 6 months compared with laser ethasone (IVD) for CNV in AMD. The mean increase in visu- alone (P=.04). The investigators determined that the al acuity among patients at 40 weeks was 1.8 lines (P<.01) improved vision in this study was directly linked to TA’s and the mean decrease in CRT was 182 µm (P<.01). Further, effect of reducing macular thickening, which was also sig- many of the patients in the study had visual acuity improve- nificant in this study (P=.03). ment after a single cycle of treatment. DISCUSSION Dr. Murray: Do you believe that intravitreal steroids have a greater impact on intraretinal edema than current anti-VEGF agents? In light of this response, do you see a role in targeting VEGF and inflammatory mediators with combined or alter- nating regimens of IVTA and anti-VEGF agents? Dr. Ho: Intravitreal steroids can have a greater impact on intraretinal edema than anti-VEGF agents in certain patients. In my experience, this is observed in patients with DME more frequently than in those with retinal vein occlusion or exudative AMD. Many of these patients respond better to anti-VEGF agents, so there are no hard rules here. Combining or alternating regimens of IVTA and anti-VEGF agents may make sense, particularly for recalcitrant macular edema. Dr. Murray: In regard to your discussion of the use of intravitreal steroids and focal laser photocoagulation: Do you believe that different preparations of intravitreal steroids and/or different treatment schedules have an effect on the modulation of intraretinal edema? Dr. Ho: At this time, there is very little scientific evidence comparing different preparations of intravitreal steroids, so any response would be based on clinical impression and not scientific evidence. We know that different corticosteroids have different potencies for different characteristics (for example, antiinflammation, vascular permeability) so it could stand to reason that different agents could have differential effects on intraretinal edema. We do have some evidence that differ- ent treatment schedules can modulate efficacy. One recent trial for example, for the intravitreal sustained-delivery dex- amethasone device, likely underdosed intravitreal steroids in the treatment of retinal venous occlusive macular edema.

6 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2009 Bakri et al,22 also used reduced-fluence PDT, IVD, and offering the safest, least burdensome treatments for our IVB for a study on same-day triple therapy for wet AMD in patients while achieving efficacious outcomes. ■ 31 patients, 18 of whom had received previous treatment and 13 of whom were treatment naïve. The follow-up in Allen C. Ho, MD, is a Professor of this study was an average of 13.7 months. Treatment-naïve Ophthalmology at Thomas Jefferson University patients had a mean baseline visual acuity of 20/60, which Retina Service and Wills Eye Hospital in improved to 20/40 at final follow-up (P=.31). Previously Philadelphia. Dr. Ho is the Chief Medical Editor treated patients had a baseline visual acuity of 20/100, of Retina Today. Dr. Ho can be reached at which remained at final follow-up. Baseline and final CMT [email protected]. for treatment-naïve patients was 249 µm and 218 µm, 1. Spaide RF. Rationale for combination therapies for choroidal neovascularization. Am J respectively (P=.34). Baseline and final CMT for previously Ophthalmol. 2006;141:149–156. treated patients was 325 µm and 265 µm, respectively 2. Spaide RF. Combination therapies for choroidal neovascularization. In: Holz FG, Spaide RF, eds. Medical Retina (Essentials in Ophthalmology). Heidelberg: Springer; 2007:90–104. (P=.10). For all patients the baseline CMTs and CMTs at 3. Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids: new mechanisms for old final follow-up were 293 µm and 245 µm, respectively drugs. N Engl J Med. 2005;353:1711–1723. 4. Spaide RF, Sorenson J, Maranan L. Photodynamic therapy with verteporfin combined with (P=.053). The treatment-naïve patients required fewer anti- intravitreal injection of triamcinolone acetonide for choroidal neovascularization. Ophthalmology. VEGF injections than those who had received prior treat- 2005;112:301–304. 5. Augustin AJ, Schmidt- Erfurth U. Verteporfin therapy combined with intravitreal triamcinolone ment. The study authors concluded that triple therapy in all types of choroidal neovascularization due to age-related macular degeneration. may reduce the frequency of injections for some patients Ophthalmology. 2006;113:14–22. 6. Augustin AJ, Schmidt- Erfurth U. Verteporfin and intravitreal triamcinolone acetonide combina- and stabilize vision in patients who are unresponsive to tion therapy for occult choroidal neovascularization in age-related macular degeneration. Am J anti-VEGF therapy alone. Ophthalmol. 2006;141:638–645. 7. Frimpong-Boateng A, Bunse A, Rüfer F, Roider J. Photodynamic therapy with intravitreal appli- 23 Another study by Yip et al used a single session of cation of triamcinolone acetonide in age-related macular degeneration: functional results in 54 PDT, IVB, and IVTA for 36 eyes. At 6 months, 61.6% patients. Acta Ophthalmol. 2009;87(2):183–187. Epub 2008 Jun 11. 8. Rouvas AA, Papakostas TD, Vavvas D, et al. Intravitreal , intravitreal ranibizumab had either stable or improving vision and 27.8% gained with PDT, and intravitreal triamcinolone with PDT for the treatment of retinal angiomatous prolifer- ation: a prospective study. Retina. 2009;29(4):536–544. three or more lines. CNV resolved after the single triple- 9. Chaudhary V, Mao A, Hooper PL, Sheidow TG. Triamcinolone acetonide as adjunctive treatment therapy session in 77.8% of eyes. The authors concluded to verteporfin in neovascular age-related macular degeneration: a prospective randomized trial. Ophthalmology. 2007;114(12):2183–2189. that triple therapy may be a good treatment option for 10. Piermarocchi S, Sartore M, Lo Giudice G, Maritan V, Midena E, Segato T. Combination of CNV in AMD, but that the complications associated photodynamic therapy and intraocular triamcinolone for exudative age-related macular degenera- tion and long-term chorioretinal macular atrophy. Arch Ophthalmol. 2008;126(10):1367–1374. with IVTA, such as cataract and increased pressure, 11. Neovascular Age-Related Macular Degeneration, Periocular Corticosteroids, and should be considered. Photodynamic Therapy (NAPP) Trial Research Group; Gilson MM, Bressler NM, Jabs DA, 24 Solomon SD, Thorne JE, Wilson DJ. Periocular triamcinolone and photodynamic therapy for sub- Finally, a recent paper by Koss et al, investigated the effi- foveal choroidal neovascularization in age-related macular degeneration. Ophthalmology. cacy and safety of vitrectomy, IVB, and IVTA over the course 2007;114(9):1713–1721. 12. Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (avastin) injection of 6 months. The prospective case series included 106 alone or combined with triamcinolone versus macular photocoagulation as primary treatment of patients with CNV. The gain in best-corrected visual acuity diabetic macular edema. Retina. 2007;27(9):1187–1195. 13. Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or compared with baseline at 2, 4, and 6 months were signifi- combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116(6):1142–1150. Epub 2009 Apr 19. cant; visual acuity declined in 20 of 96 patients at month 6, 14. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamci- remained stable in 38 patients, and improved in 31 patients. nolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2008;246(4):483–489. Epub 2007 Oct 5. Pressure rises in 11 of the patients were managed with topi- 15. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal tri- cal medications. The authors reported a sustained visual amcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 Sep;115(9):1447–9, 1449.e1–10 acuity improvement after the procedure over 6 months, 16.Shimura M, Nakazawa T, Yasuda K, Shiono T, Nishida K. Pretreatment of posterior subtenon and that in 45% of treated patients, anti-VEGF injections injection of triamcinolone acetonide has beneficial effects for grid pattern photocoagulation against diffuse diabetic macular oedema. Br J Ophthalmol. 2007;91(4):449–454. were discontinued. 17. Chung EJ, Freeman WR, Azen SP, Lee H, Koh HJ. Comparison of combination posterior sub- tenon triamcinolone and modified grid laser treatment with intravitreal triamcinolone treatment in patients with diffuse diabetic macular edema. Yonsei Med J. 2008 Dec 31;49(6):955–964. SUMMARY 18. Unoki N, Nishijima K, Kita M, et al. Randomized controlled trial of posterior sub-Tenon triam- cinolone as adjunct to panretinal photocoagulation for treatment of diabetic retinopathy. Br J It is clear that there will be no magic bullet for our Ophthalmol. 2009;93(6):765–770. Epub 2009 Feb 12. patients who require intervention for these complex 19. Lam DS, Chan CK, Mohamed S, et al. Intravitreal triamcinolone plus sequential grid laser ver- sus triamcinolone or laser alone for treating diabetic macular edema: six-month outcomes. disease states. The promise of combination therapy Ophthalmology. 2007;114(12):2162–2167. with corticosteroids for AMD and DME and other reti- 20. Liggett PE, Colina J, Chaudhry NA, Tom D, Haffner G. Triple therapy of intravitreal triamci- nolone, photodynamic therapy, and pegaptanib sodium for choroidal neovascularization. Am J nal vascular disease remains largely unrealized at this Ophthalmol. 2006;142(6):1072–1074. time with respect to level one clinical trial evidence 21. Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age- related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina. although some series report on potential efficacy. In 2007;27:133–140. light of the number of patients who still do not respond 22. Bakri SJ, Couch SM, McCannel CA, Edwards AO. Same-day triple therapy with photodynamic therapy, intravitreal dexamethasone, and bevacizumab in wet age-related macular degeneration. to current therapies for exudative AMD and DME, it is Retina. 2009;29(5):573–578. 23. Yip PP, Woo CF, Tang HH, Ho CK. Triple therapy for neovascular age-related macular degener- reasonable to pursue randomized clinical trials employ- ation using single-session photodynamic therapy combined with intravitreal bevacizumab and tri- ing corticosteroid therapy. Further study is required to amcinolone. Br J Ophthalmol. 2009;93(6):754–758. Epub 2009 Mar 8. 24. Koss MJ, Scholtz S, Haeussler-Sinangin Y, Singh P, Koch FH. Combined Intravitreal determine how medical, laser, and surgical interventions Pharmacosurgery in Patients with Occult Choroidal Neovascularization Secondary to Wet Age- complement one another and to ensure that we are Related Macular Degeneration. Ophthalmologica. 2009 Aug 26;224(2):72-78. [Epub ahead of print]

NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 7 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications Intravitreal Corticosteroids for Therapeutic and Surgical Use The available agents for treatment and visualization in surgery are reviewed. BY SEENU M. HARIPRASAD, MD

rior to 2007, the only corticosteroid that was available which I practice. Additionally, when the situation is such for intraocular use was off-label preserved intravitreal that the patient will be paying for the injection out of Ptriamcinolone acetonide (IVTA; Kenalog, Bristol-Myers pocket, the off-label preserved IVTA is more cost effec- Squibb). Since the US Food and Drug Administration (FDA) tive at $14 per injection. Regarding cost, the dexametha- approval of and availability of preservative-free triamci- sone sustained-delivery device is only FDA-approved for nolone (Triesence, Alcon Laboratories, Inc.) and the dexam- the treatment of macular edema secondary to branch ethasone sustained-delivery device (Ozurdex, Allergan, Inc.), retinal vein occlusion (BRVO) or central retinal vein we have more options for patients when considering utiliz- occlusion (CRVO), and outside of these indications, the ing steroids as therapeutic agents. use of the implant is prohibitively expensive. The FDA- Additionally, steroids may also be applied as visualization approved IVTA represents a good balance of an on-label agents in surgery, and the therapeutic effect against postoper- steroid specifically formulated for intraocular use that is ative inflammation can be an added benefit. Compared with available for a reasonable cost. indocyanine green (ICG; IC-Green, Akorn, Lake Forest, IL), and Trypan blue (Vision Blue, Dutch Ophthalmic Research Center, VISUALIZATION AGENTS FOR SURGERY Zuidland, The Netherlands), steroids have low toxicity, require Currently, the available agents for visualization in vitreo- less preparation time, and are typically less expensive. retinal surgery include ICG, Trypan blue, preserved IVTA, The question is: How does one decide between these and preservative-free IVTA. There are benefits and short- three steroids for treating retinal disease and between comings to each visualization agent. For example, the pre- steroids and dyes for visualization? It is important to consid- served and preservative-free IVTA agents are more advan- er three factors: safety, efficacy, and cost. This article weighs tageous when considering visualization of the cortical vit- the evidence for all three in both therapeutic application reous, vitreous base, epiretinal membrane, and internal and surgery. limiting membrane (ILM). In terms of ease of preparation, Trypan blue and preservative-free IVTA have a slight THERAPEUTIC APPLICATION OF advantage over the preserved preparation of IVTA, and a CORTICOSTEROIDS distinct advantage over ICG. The costs of vital dyes such as When considering safety of the available corticos- ICG and Trypan blue are typically more expensive than teroids, there are factors beyond pressure increases and steroids. With ICG and Trypan Blue, there is a higher risk of risk of cataract. In the therapeutic arena, there have toxicity than with the other agents,15-27 and so this must been published case series and retrospective reports be taken into careful consideration when choosing an concerning sterile endophthalmitis after intravitreal agent for visualization. Furthermore, ICG should not be injection with preserved triamcinolone acetonide1-14 used in patients who have an iodine allergy. The off-label and it has been suggested that this complication is in preserved IVTA must be compounded for use in the eye part caused by the preservative agent, benzyl alco- so, as with therapeutic use, it does not come in a sterilized hol.2,3,12 Because both the dexamethasone sustained- pack, as does preservative-free IVTA, ICG, and Trypan blue. delivery device and the on-label IVTA do not contain Finally, only Trypan blue and preservative-free IVTA are preservatives, they may have a distinct advantage over FDA-approved for staining in vitreoretinal surgery. the former in regard to this complication. Additionally, although preserved IVTA has been used for CORTICOSTEROID-ASSISTED VITRECTOMY some time by ophthalmologists with good results, its use In my experience, corticosteroids offer an advantage in remains off label and the agent often must be compounded vitrectomy for the visualization of vitreous in the anterior before use in the eye. Alternatively, both the FDA-approved chamber, such as in retained lens fragment cases where preservative-free IVTA and the dexamethasone sustained- corneal haze may limit the view. There are three techniques delivery device come in sterile packs, which reduces the risk for using steroids for this purpose: of contamination with these agents. 1. inject diluted steroid just anterior to the limbus using a I will use the off-label preserved IVTA in situations such 27-gauge needle; as when I do not have the preservative-free IVTA avail- 2. create a paracentesis site and inject using a cannula; able, which I do not in one of the satellite offices in 3. or inject through the sclerotomy up into the ante-

8 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2009 behind on the retinal surface after a “complete” hyaloid sep- aration. Enaida et al29 also showed the benefits to IVTA- assisted pars plana vitrectomy in both an interventional, nonrandomized study and case reports of surgeries for pro- liferative diabetic retinopathy, diabetic macular edema, rhegmatogenous retinal detachment, and branch retinal vein occlusion. The studies also showed that the use of IVTA when removing cortical vitreous resulted in lower rates of reoperation and postoperative epiretinal membrane forma- tion. They found no serious complications associated with the use of IVTA and no significant differences in postopera- tive intraocular pressure (IOP). Furino et al30 found similar results with cortical vitreous removal in PVR. Figure 2 shows the use of IVTA in posterior cortical vitreous removal.

MEMBRANE PEELING AND VITREOUS BASE DISSECTION Figure 1. Intraoperative steroid as an aid in teaching Membrane peeling is often used as an adjunct in macular vitrectomy. surgery for macular hole, epiretinal membrane (ERM)/mac- ular pucker, and macular edema. ICG dye has facilitated rior chamber. visualization and removal of the ILM, but both preserved Corticosteroids are also useful for visualization of the core IVTA and preservative-free IVTA are able to highlight both vitreous, which is important for training fellows and resi- the ILM and the ERM. Additionally, as earlier stated, con- dents (Figure 1) and having an FDA-approved agent for this cerns exist as to the toxicity of ICG dye.15-27 IVTA has the purpose is a plus. advantage of being able to be reapplied after ERM removal and even ILM removal; whereas with ICG, one must be cau- POSTERIOR HYALOID ELEVATION/CORTICAL tious of reapplying this agent to the bare retina. VITREOUS REMOVAL For certain surgical situations, good vitreous base dissec- Additionally, corticosteroids offer an advantage in posteri- tion may be necessary and IVTA can be used as an aid to or hyaloid elevation and cortical vitreous removal. The use highlight the vitreous base. I recommend injecting steroid of IVTA for posterior hyaloid removal was first described by into the posterior segment using a cannula. Next, the vitrec- Peyman et al28 in 2000. IVTA-assisted posterior hyaloid ele- tor can be applied to spread the steroid throughout the vation allows the surgeon to identify or create a break in the posterior segment. Dilution is essential for this technique. posterior hyaloid. Once the break or Weiss ring is created, the posterior hyaloid can be easily separated from the retina CORTICOSTEROIDS VS ICG using low suction pressure. This technique is most useful When comparing the benefits of IVTA to those of ICG when performing microincisional vitrectomy surgery, partic- dye for use in vitreoretinal surgical procedures, IVTA ularly 25-gauge vitrectomy. requires minimal preparation and can be reapplied once In patients who are diabetic, vitreoschesis is frequent, and ILM peeling has begun. IVTA is not a photosensitizer, as is residual cortical vitreous may cause persistent tangential ICG and is not contraindicated for patients with iodine aller- traction, serving as a scaffold for neovascular proliferation or gy. Additionally, IVTA may have a beneficial postoperative proliferative vitreoretinopathy (PVR). So, when performing inflammatory affect, and may stabilize the blood-ocular bar- cortical vitreous removal, I use preservative-free IVTA to rier, benefitting eyes with DME or cystoid macular edema. visualize islands of thin cortical vitreous that may be left Finally, IVTA is inexpensive.31 (Figure 2 appears courtesy of Gaurav Shah, MD.)

Figure 2. Posterior cortical vitreous removal.

NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 9 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

ICG is advantageous for use in surgery because it is specif- Needle size. The needle size should be 27 gauge for pre- ic for Type 4 collagen, allowing the surgeon to distinguish served TA and 30 gauge for preservative-free TA. the ILM from cortical vitreous and ERM. ICG does not stick to forceps and forceps mechanism, as is possible with IVTA. SUMMARY Further, ICG will not accumulate in a macular hole and Having an option for a steroid to use in clinic and in sur- inhibit closure, which also has been known to occur with gery that is FDA approved, nontoxic, and cost effective is IVTA, although not in our experience. obviously an advantage. There is not one solution that fits every situation, therefore, the clinician needs to make a deci- PRESERVED VS PRESERVATIVE-FREE IVTA sion as to which agent makes most sense in a particular sce- When comparing preserved vs preservative-free IVTA, it is nario. For therapy, in particular, we are finding that a combi- important to consider that the preservative-free IVTA is nation of agents works for our patients, so having one more FDA-approved and also is available in a sterile pack. option is certainly beneficial. Regarding cost, the preserved IVTA is less expensive, but the The versatility of corticosteroids makes their use in thera- preservative-free agent is certainly affordable and reim- peutics and vitrectomy surgery appealing. These agents are bursable. Preservative-free IVTA contains no benzyl alcohol, inexpensive, easy to use, have no proven retinal/choroidal tox- and so in theory, the risk of sterile endophthalmitis is icity, and may potentially lead to superior visual outcomes. ■ lower.2,3,12 Finally, and not least important, the particles in preservative-free IVTA are finer than in the preserved agent, Seenu M. Hariprasad, MD, is an Associate and can potentially adhere more effectively to membranes. Professor and Director of Clinical Research at the University of Chicago Department of Surgery TIPS FOR INTRAOPERATIVE USE OF Section of Ophthalmology and Visual Science. He CORTICOSTEROIDS serves as Chief of the Vitreoretinal Service and When using preserved and preservative-free IVTA in sur- Director of the Surgical Retina Fellowship Program. gery, the following are some tips to ensure a successful out- Dr. Hariprasad can be reached by e-mail: come. [email protected]. Dilution. The ratio of preserved TA to BSS should be about 4:1. For preservative-free TA, the ratio is about 8:1. 1. Stepien KE, Eaton AM, Jaffe GJ, Davis JL, Raja J, Feuer W. Increased incidence of sterile endophthalmitis after intravitreal triamcinolone acetonide in spring 2006. Retina. Surgeons can dilute to personal preference. 2009;29(2):207–213. Mixing. After appropriate ratio of steroid:BSS is drawn 2. Jonisch J, Lai JC, Deramo VA, Flug AJ, Fastenberg DM. Increased incidence of sterile endophthalmitis following intravitreal preserved triamcinolone acetonide. Br J Ophthalmol. into the syringe, a 0.1 cc air bubble should be placed to aid 2008;92(8):1051–1054. in the mixing of particles as the syringe is turned upside 3. Lorenzo Carrero J, González Barcia M, Pérez Flores I. Sterile endophthalmitis after benzyl down several times. alcohol filtered triamcinolone acetonide injection. Arch Ophthalmol. 2008;126(1):142–143. 4. Roth DB, Realini T, Feuer WJ, et al. Short-term complications of intravitreal injection of tri- IOP. Lower the IOP when the particles are on the surface amcinolone acetonide. Retina. 2008;28(1):66–70. of the macula to reduce the likelihood of the infusion line 5. Taban M, Singh RP, Chung JY, Lowder CY, Perez VL, Kaiser PK. Sterile endophthalmitis after intravitreal triamcinolone: a possible association with uveitis. Am J Ophthalmol. blowing the crystals off the retinal surface. 2007;144(1):50–54. 6. Deckers V, Priem H, Verbraeken H. One year of intravitreal injections of steroids. Bull Soc Belge Ophtalmol. 2005;(297):69–77. 7. Chieh JJ, Roth DB, Liu M, Belmont J, Nelson M, Regillo C, Martidis A. Intravitreal triamci- DISCUSSION nolone acetonide for diabetic macular edema. Retina. 2005;25(7):828–834. 8. Tewari HK, Sony P, Chawla R, Garg SP, Venkatesh P. Prospective evaluation of intravitreal Dr. Murray: Do you currently employ intravitreal triamcinolone acetonide injection in macular edema associated with retinal vascular disor- steroids in the management of primary macular patholo- ders. Eur J Ophthalmol. 2005;15(5):619–626. 9. Wang LC, Yang CM. Sterile endophthalmitis following intravitreal injection of triamci- gy undergoing vitrectomy management or do you nolone acetonide. Ocul Immunol Inflamm. 2005;13(4):295–300. reserve this application for more complex vitreoretinal 10. Kreissig I, Degenring RF, Jonas JB. [Intravitreal triamcinolone acetonide. Complication of pathology? infectious and sterile endophthalmitis.] Ophthalmologe. 2006;103(1):30–34. 11. Moshfeghi DM, Kaiser PK, Bakri SJ, et al. Presumed sterile endophthalmitis following intrav- Dr. Hariprasad: I use IVTA during all cases where I have itreal triamcinolone acetonide injection. Ophthalmic Surg Lasers Imaging. 2005;36(1):24–29. 12. Chen SD, Lochhead J, Patel CK. Diffuse intraocular dispersion of triamcinolone particles as to peel membranes over the surface of the macula such a cause of sterile endophthalmitis. Arch Ophthalmol. 2004;122(11):1733; author reply 1733. as in ERM and ILM peeling. I also commonly use IVTA in 13. Jaissle GB, Szurman P, Bartz-Schmidt KU. [Ocular side effects and complications of intrav- itreal triamcinolone acetonide injection.] Ophthalmologe. 2004;101(2):121–128. diabetic cases to ensure that I have removed all remnants 14. Nelson ML, Tennant MT, Sivalingam A, Regillo CD, Belmont JB, Martidis A. Infectious of cortical vitreous. and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injec- tion. Retina. 2003;23(5):686–691. Dr. Murray: Do you have concerns related to increased 15. Engelbrecht NE, Freeman J, Sternberg P Jr, et al. Retinal pigment epithelial changes after risks of either endophthalmitis or elevated IOP associat- macular hole surgery with indocyanine green-assisted internal limiting membrane peeling. Am J Ophthalmol. 2002;133(1):89–94. ed with the use of IVTA for intraoperative surgical visu- 16. Enaida H, Sakamoto T, Hisatomi T, Goto Y, Ishibashi T. Morphological and functional alization? damage of the retina caused by intravitreous indocyanine green in rat eyes. Graefes Arch Clin Exp Ophthalmol. 2002;240(3):209–213. Dr. Hariprasad: I do not. 17. Stalmans P, Van Aken EH, Veckeneer M, Feron EJ, Stalmans I. Toxic effect of indocyanine green on retinal pigment epithelium related to osmotic effects of the solvent.

10 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2009 Am J Ophthalmol. 2002;134(2):282–285. 25. Maia M, Kellner L, de Juan E Jr, et al. Effects of indocyanine green injection on the retinal 18. Ho JD, Tsai RJ, Chen SN, Chen HC. Cytotoxicity of indocyanine green on retinal pigment surface and into the subretinal space in rabbits. Retina. 2004;24(1):80–91. epithelium: implications for macular hole surgery. Arch Ophthalmol. 2003;121(10):1423–1429. 26. Maia M, Margalit E, Lakhanpal R, et al. Effects of intravitreal indocyanine green injection 19. Lee JE, Yoon TJ, Oum BS, Lee JS, Choi HY. Toxicity of indocyanine green injected into in rabbits. Retina. 2004;24(1):69–79. the subretinal space: subretinal toxicity of indocyanine green. Retina. 2003;23(5):675–681. 27. Cheng SN, Yang TC, Ho JD, Hwang JF, Cheng CK. Ocular toxicity of intravitreal indocya- 20. Kawaji T, Hirata A, Inomata Y, Koga T, Tanihara H. Morphological damage in rabbit retina nine green. J Ocul Pharmacol Ther. 2005;21(1):85–93. caused by subretinal injection of indocyanine green. Graefes Arch Clin Exp Ophthalmol. 28. Peyman GA, Cheema R, Conway MD, Fang T. Triamcinolone acetonide as an aid to visu- 2004;242(2):158–164. alization of the vitreous and the posterior hyaloid during pars plana vitrectomy. Retina. 21. Haritoglou C, Gandorfer A, Gass CA, Kampik A. Histology of the vitreoretinal interface 2000;20(5):554–555. after staining of the internal limiting membrane using glucose 5% diluted indocyanine and 29. Enaida H, Hata Y, Ueno A, Nakamura T, et al. Possible benefits of triamcinolone-assisted infracyanine green. Am J Ophthalmol. 2004;137(2):345–348. pars plana vitrectomy for retinal diseases. Retina. 2003;23(6):764–770. 22. Iriyama A, Uchida S, Yanagi Y, et al. Effects of indocyanine green on retinal ganglion 30. Furino C, Micelli Ferrari T, Boscia F, Cardascia N, Recchimurzo N, Sborgia C. cells. Invest Ophthalmol Vis Sci. 2004;45(3):943–947. Triamcinolone-assisted pars plana vitrectomy for proliferative vitreoretinopathy. Retina. 23. Rezai KA, Farrokh-Siar L, Ernest JT, van Seventer GA. Indocyanine green induces apopto- 2003;23(6):771–776. sis in human retinal pigment epithelial cells. Am J Ophthalmol. 2004;137(5):931–933. 31. Sakamoto T, Miyazaki M, Hisatomi T, et al. Triamcinolone-assisted pars plana vitrectomy 24. Rodrigues EB, Meyer CH, Schmidt JC, Kroll P. Toxic effects of intravitreal indocyanine improves the surgical procedures and decreases the postoperative blood-ocular barrier green on neuroretinal cells. Arch Ophthalmol. 2004;122(4):663; author reply 664. breakdown. Graefes Arch Clin Exp Ophthalmol. 2002;240(6):423–429. The Use of Corticosteroids in Surgery IVTA as a pharmacosurgical adjunct in the management of macular edema associated with complex macular pathology. BY D. WILKIN PARKE III, MD; ROBERT A. SISK, MD; AND TIMOTHY G. MURRAY, MD, MBA

itreoretinal surgeons have evaluated the use of phar- increasingly utilized as means to facilitate intra- and postoper- macologic intraoperative adjuncts since intravitreal ative viewing to the posterior segment. Additionally, com- V steroid delivery for complex proliferative vitreo- bined procedures are performed to eliminate the risks and retinopathy (PVR) was pioneered by Dr. Robert Machemer costs inherent to a second phacoemulsification surgery in a and colleagues.1-3 Intravitreal surgical agents as diverse as recently vitrectomized eye.9-12 Several small series have shown 5-fluorouracil, heparin, and tissue plasminogen activator comparative improvement in postoperative visual acuity have been evaluated for intravitreal use in PVR. when vitrectomy was combined with phacoemulsification, Recent reports have focused on intraretinal edema, cyst, with no associated rise in complication frequency.13-17 and persistent subretinal fluid as limiting factors in visual Both vitrectomy and phacoemulsification, as well as the recovery in complex and common macular pathologies.4 combination of both surgeries, have been shown to induce Cataract surgeons have addressed issues related to postop- ME that can negatively affect visual recovery. There has been erative cystoid macular edema and its management for over considerable interest in surgical adjuvant medications to two decades. Recent data have suggested that inflammato- address this problem. The role of intravitreal agents, particu- ry mediators play a major role in postoperative CME but larly antiinflammatory agents such as triamcinolone ace- may be modulated by underlying unique patient factors or tonide, have garnered recent interest. intraoperative surgical events.5 This retrospective, consecutive case series from the Macular edema (ME) is a common cause of visual limita- Bascom Palmer Eye Institute presents pre- and postopera- tion in both post-vitrectomy eyes and those that have tive OCT analysis in eyes that underwent combined pha- undergone phacoemulsification for . coemulsification and vitrectomy with the use of intravitreal Although the incidence of ME after phacoemulsification has triamcinolone acetonide as an intraoperative pharmacolog- been well characterized, there are few data on CME after vit- ic adjunct targeted at decreasing postoperative ME. The pri- rectomy. Optical coherence tomography (OCT) has proven mary objective was to analyze the incidence and resolution particularly advantageous in the diagnosis and analysis of in ME after surgery. ME over time, as it offers a quantitative as well as qualitative interpretation and is highly reproducible. Prior to OCT, PATIENTS AND METHODS studies by Staudt et al6 and McDonald et al7 showed evi- The study was performed with the approval of the dence of leakage on postoperative angiography in 80% of University of Miami Institutional Review Board and in accor- macular hole surgeries and 70% of epiretinal membrane sur- dance with the US Health Insurance Portability and geries. Kim et7 al recently incorporated OCT into an investi- Accountability Act and the Declaration of Helsinki guidelines. gation of post-vitrectomy ME, and reported that 47% of A retrospective review was conducted of all patients who eyes undergoing vitrectomy for predominantly epiretinal underwent combined sutureless 23-gauge pars plana vitrecto- membrane, macular hole, or had my with phacoemulsification cataract extraction between evidence of edema on postoperative OCT. January 1, 2006 and March 1, 2009 at the Bascom Palmer Eye Combination of vitrectomy with phacoemulsification is Institute by a single vitreoretinal and ocular oncology surgeon

NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 11 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

TABLE 1. BASELINE CHARACTERISTICS TABLE 2. SURGICAL INDICATIONS OF THE STUDY EYES Primary Surgical Indication Number (%) Total eyes included 45 Cystoid macular edema 10 Mean age 58.6 Radiation retinopathy 13 Female (%) 20 (44) Epiretinal membrane 4 Mean preoperative logMAR acuity 0.93 Retinal detachment 4 Mean preoperative Snellen acuity 20/400 Vascular tumor 6 Previous vitrectomy (%) 2 (4) Coats Disease 2 Macular Schisis 2 Diabetic 3 (7) Coloboma 1 Preoperative ME 18 (40) Dislocated 1 (TGM) and his vitreoretinal surgical fellows. All patients with Uveal effusion syndrome 1 fewer than 6 months of follow-up were excluded. All patients underwent surgery with the Accurus 2500 surgical system cling band placement, and use of internal tamponade. (Alcon Laboratories, Inc., Fort Worth, TX) followed by utiliza- Intravitreal triamcinolone acetonide (IVTA; 4 mg/0.1 cc tion of the Constellation Vision System (Alcon Laboratories, Triesence, Alcon Laboratories., Inc.) was injected into any Inc.). All patients had clinically significant lens opacification at eye not receiving tamponade following removal of the last the time of combined surgery. Preoperative biometry for cannula. Subconjunctival gentamicin (20 mg) and dexam- intraocular lens (IOL) power was performed with the IOL ethasone (4 mg) were administered at the conclusion of the Master (Carl Zeiss Meditec, Dublin, CA). Postoperative clinic procedure in all eyes. evaluations were performed at 1 day, 1 week, 1 month, 3 Study characteristics recorded included age, gender, pres- months, 6 months, and 12 months. Refractions were per- ence of , primary surgical indication, past ocular his- formed at 1 or 3 months postoperatively. Patients received tory, lens status, previous intraocular surgery, laser, and topical antiinflammatory, antibiotic, and cycloplegic drops intravitreal injections. Pre- and postoperative visual acuity, postoperatively when indicated. intra- and postoperative complications, and postoperative interventions were recorded. SURGICAL PROCEDURE Preoperative and postoperative OCT was performed with After informed consent was obtained, patients received the Stratus OCT3 machine (CZM, Dublin, CA) and then pref- local or general anesthesia. After a betadine preparation and erentially, with the Spectralis HRA+OCT (Heidelberg sterile draping, the 23-gauge trochars were inserted 3.5 mm Engineering, Vista, CA) by a trained technician as member of posterior to the limbus in a shallow beveled fashion then a dedicated photography department. OCT images were directed perpendicularly toward the optic nerve. The supe- generated with standard manufacturer protocol. Centerpoint rior 23-gauge ports were temporarily occluded and the infu- thickness and central subfield thickness were measured in sion cannula was connected but kept off until the pha- microns, and total macular volume in millimeters cubed. coemulsification portion of the procedure was completed. Values were obtained from the macular thickness map and Clear corneal incisions were created and viscoelastic was data table, and the scans were evaluated retrospectively for used to replace the aqueous. A 5- to 6-mm continuous curvi- artifact. Macular edema was defined as a central subfield linear capsulorrhexis was initiated with a bent cystotome and thickness (CSF) equal to or greater than 272 µm, a value completed with forceps. After hydrodissection and rotation, reported by Chan et al19 as three standard deviations above the nucleus was removed using a bimanual divide-and-con- the mean thickness of 212 µm. This value was similarly quer technique. The cortex was removed with automated employed by Kim et al8 in their study to define ME on OCT. aspiration, and the capsular bag was inflated with viscoelastic. The 3-mm corneal wound was enlarged with a crescent STATISTICAL ANALYSIS blade to 4 mm. An acrylic foldable IOL (three-piece MA60AC Snellen visual acuities were converted to logMAR acuities or MA50BM, Acrysof [Alcon Laboratories, Inc.]) was prefer- for data analysis. Acuities too poor or otherwise unable to entially placed in the capsular bag, but the ciliary sulcus was be assessed with Snellen charts were converted using the used when inadequate zonular or capsular support was pres- following convention: count fingers (CF) = 20/2000; hand ent. Viscoelastic was left filling the anterior chamber. The motions (HM) = 20/20,000; and light perception (LP) = corneal wound was closed with a single nylon suture. 20/200,000. LogMAR acuities were compared with baseline Vitrectomy was performed using the AVI (Advanced values using the paired t-test and the nonparametric paired Visual Instruments, Inc., New York, NY) 130˚ widefield view- Wilcoxon test with SSPS 17 software. OCT values were ing system. In some patients, vitrectomy was combined compared using the paired t-test. Both eyes of two patients with other procedures, including membrane removal, encir- were included as if they were independent observations in

12 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2009 TABLE 3. POSTOPERATIVE OUTCOMES rior capsular opacification was performed in 10 eyes. Preop Postop Difference Mean visual acuity was the same at 1 week postoperatively (20/150-1, logMAR Macular Edema 18 eyes (40%) 18 eyes (40%) 0.92) compared with baseline (20/150-2, (CSF>272 um) logMAR 0.93), but improved through All included eyes (45) each subsequent measurement. Improvement was seen at 3 months CMT 258 µm 250 µm -8 µm (20/100-3, logMAR 0.85) and at 6 months CSF 277 µm 269 µm -8 µm (20/100-1, logMAR 0.78). At 3 months 19 (42%) gained two or more lines of vision, Mac Vol 7.53 mm3 7.46 mm3 -0.07 mm3 and seven (16%) lost two or more lines. With preop CME (18) OCT thickness decreased overall an average of 9 µm per CMT, 8 µm per CSF, CMT 352 µm 306 µm -46 µm and 0.1 mm3 per macular volume without reaching statistical significance. In the 18 CSF 361 µm 314 µm -47 µm patients with preoperative OCT evidence Mac Vol 8.35 mm3 7.86 mm3 -0.49 mm3 of ME, thickness decreased by 46 µm per CMT (P=.26), 47 µm per CSF (P=.22), and Without preop CME (27) 0.5 mm3 per macular volume (P=.30). In the 27 patients without preoperative ME, CMT 206 µm 198 µm -8 µm the respective decreases were 8 µm per CSF 232 µm 225 µm -7 µm CMT (P=.62), 7 µm per CSF (P=.56), and 0.2 mm3 per macular volume (P=.69). 3 3 3 Mac Vol 7.10 mm 6.88 mm -0.22 mm None of these changes proved statistically significant. this analysis; however, a second analysis including only one Seven patients in the series met inclusion criteria regard- eye per patient gave the same results. ing preoperative and postoperative OCT and underwent vitrectomy with phacoemulsification but without intraop- RESULTS erative IVTA. They were analyzed as a small comparison Baseline characteristics of the study cohort are listed in population to the larger group that received IVTA. Of these Table 1. A total of 114 eyes from 111 patients underwent seven, four had preoperative ME and experienced postoper- combined 23-gauge sutureless vitrectomy with phacoemul- ative OCT thickness increases of 95 µm per CSF, 81 µm per sification during the study period for various indications. Of CSF, and 2.2 mm3 per macular volume. Three lacked preop- those eyes, 62 were excluded for not having a preoperative erative ME and had similar increases of 150 µm, 160 µm, and OCT or a postoperative OCT within ninety days of surgery. 2.6 mm3. Thus this small group experienced worsening Of the remaining 52 eyes, 45 had received IVTA at time of edema after surgery. surgery, and were included in the primary analysis. Retinal detachment occurred in four patients after sur- Mean age at surgery was 58.6 years, and mean follow-up gery, two of which were recurrent detachments, and one of was 334 days. Two eyes had previously undergone vitrecto- which was an exudative detachment in a patient with a my. All eyes were phakic prior to surgery. Three eyes were of choroidal hemangioma. There were no cases of supra- diabetic patients. Primary indication for surgery was refracto- choroidal hemorrhage or endophthalmitis. Other intra- ry cystoid macular edema in 10, radiation retinopathy in 13, and postoperative complications included capsular tear in epiretinal membrane in four, vitreous hemorrhage in one, eight, zonular dehiscence in one, blepharoptosis in one, and coloboma in one, dislocated lens in one, macular schisis in hypotony in one eye requiring repeated postoperative two, retinal detachment in four, retinal and choroidal vascu- intravitreal triamcinolone injections. lar tumors in six, Coats disease in two, and uveal effusion Mean intraocular pressure (IOP) rose from a preopera- syndrome in one. Twelve eyes had optic nerve compromise tive baseline of 16.0 to 19.0 on postoperative day 1, but nor- from prior radiation optic neuropathy. Surgery included malized to 16.6 by postoperative month 1, and had de- membrane peeling in 30, endolaser in 15, fluid-air exchange creased to 14.8 by month 3 and 13.8 by month 6. Eleva-ted and gas tamponade in two, iris retractors in three, and sili- IOP (>25 mm Hg) was noted postoperatively in four eyes, cone oil removal in two. Thirty-one required additional two of which appeared steroid-related, and one of which intravitreal injections after surgery (13 for CME, four for wet required the Baerveldt implant (Abbott Medical Optics, AMD, eight for radiation retinopathy, two for diabetic macu- Inc., Irvine, CA). The other two eyes with elevated IOP post- lar edema, two for neovascular glaucoma, and two for operatively had neovascular glaucoma from radiation CNVM secondary to angioma). YAG capsulotomy for poste- retinopathy, and both eventually required enucleation.

NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 13 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

DISCUSSION his patients were quite different from those of a more typical Post-vitrectomy ME remains imperfectly characterized by retina practice. This study also introduced two variables— existing literature, but recent studies have begun to utilize combined surgery and intravitreal triamcinolone—that indi- OCT to further our understanding of this common problem. vidually have not been previously studied with the use of Even less is known about the incidence of ME that follows OCT to look for ME, complicating interpretation of the data. combined surgery involving vitrectomy and phacoemulsifi- Nonetheless, this study, along with those discussed in this cation, a technique that is gaining increasing interest and article, sets the stage to consider intraoperative pharma- applicability to a variety of clinical situations. This retrospec- cotherapy as a major advance in the surgical armamentari- tive series was organized to characterize the OCT findings um of the vitreoretinal surgeron. The lack of demonstrable associated with combined vitrectomy and phacoemulsifica- toxicity, the ease of delivery, and the ability to influence tion with an intravitreal antiinflammatory agent in the form postoperative factors that affect anatomic results and of TA. patient visual functional outcomes greatly extends the reach The recent study by Kim et al8 demonstrated a 47% inci- of the surgeon in the management of both basic and com- dence of ME on OCT after vitrectomy alone. The combina- plex macular pathologies. We owe a debt of gratitude to tion of vitrectomy and phacoemulsification would reason- Dr. Robert Machemer and colleagues for initiating the study ably seem to have no less of a tendency towards ME than of intraoperative surgical pharmacotherapy. ■ either procedure alone, and perhaps if anything, combined surgery would be more likely to cause postoperative edema. Timothy G. Murray, MD, MBA, FACS, is In this series of combined surgery the postoperative ME Professor of Ophthalmology and Radiation incidence was 40%, which was actually the same as the pre- Oncology at the Bascom Palmer Eye Institute, operative ME on OCT (40%). The mean retinal thickness by University of Miami Miller School of Medicine. Dr. each of three recorded parameters likewise decreased in this Murray is a consultant for Alcon Laboratories, Inc. study group, most dramatically when there was already pre- He can be reached at +1 305 326 6000, ext. 6166; fax: +1 305 operative edema. This relative improvement in retinal thick- 326 6147; or via e-mail at [email protected]. ness could be attributed to the adjuvant IVTA injection that these patients received at the time of surgery. The worsen- 1. Faulborn J, Conway BP, Machemer R. Surgical complications of pars plana vitreous sur- gery. Ophthalmology. 1978;85(2):116–125. ing thickness values on OCT for the seven patients who did 2. Spirn MJ. Comparison of 25, 23, and 20-gauge vitrectomy. Curr Opin Ophthalmol. not receive IVTA seems to support this possibility, but that 2009;20(3):195–199. 3. Misra A, Ho-Yen G, Burton RL. 23-gauge sutureless vitrectomy and 20-gauge vitrectomy: group was particularly small, and this retrospective study a case series comparison. Eye. 2008 [Epub ahead of print] carries risk of selection bias. 4. Chaudry NA, Cohen KA, Flynn HW Jr, Murray TG. Combined pars plana vitrectomy and lens management in complex vitreoretinal disease. Semin Ophthlamol. 2003;18(3):132–141. Another issue that this study presents is the appropriate- 5. Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory fac- ness of quantitative OCT measurements for the diagnosis tors with diabetic macular edema. Ophthalmology. 2009;116(1):73-79. 6. Staudt S, Miller DW, Unnebrink K, Holz FG. [Incidence and extent of postoperative macular and interpretation of ME. Other causes of intra- or subreti- edema following vitreoretinal surgery with and without combined cataract operation] nal fluid or thickening can complicate the retina thickness Ophthalmologe. 2003;100(9):702–707. 7. McDonald HR, Johnson RN, Schatz H. Surgical results in the vitreomacular traction syn- values. Several patients in this study had coexisting epiretinal drome. Ophthalmology. 1994;101(8):1397–1302; discussion 1403. membranes and macular edema, and determination of the 8. Kim SJ, Martin DF, Hubbard GB 3rd, et al. Incidence of postvitrectomy macular edema using optical coherence tomography. Ophthalmology. 2009;116(8):1531–1537. primary disease process in these patients relied on qualita- 9. Smiddy WE, Stark WJ, Michels RG, et al. Cataract extraction after vitrectomy. tive OCT interpretation. When the membrane appeared to Ophthalmology. 1987;94(5):483–487. be the direct cause of retinal thickening, and the membrane 10. Meyers SM et al. Unplanned extracapsular cataract extraction in postvitrectomy eyes. Am J Ophthalmol. 1978;86:624–626. peel seemed the reason for decreased thickness postopera- 11. Braunstein RE, Airlani S. Cataract surgery results after pars plana vitrectomy. Curr Opin tively, that eye was excluded from OCT thickness analysis. Ophthalmol. 2003;14(3):150–154. 12. McDermott ML, Puklin JE, Abrams GW. Phacoemulsification for cataract following pars However, other cases with coexistent ME and epiretinal plana vitrectomy. Ophthalmic Surg Lasers. 1997;28(7):558–569. membranes were more ambiguous, and the categorization 13. Blankenship GW, Flynn HW Jr, Kokame GT. Posterior chamber intraocular lens insertion 18 during pars plana lensectomy and vitrectomy for complications of proliferative diabetic and analysis of these eyes is problematic. retinopathy. Am J Ophthalmol. 1989;108(1):1–5 This study has several important limitations. It is retro- 14. Jun Z, Pavlovic S, Jacobi KW. Results of combined vitreoretinal surgery and phacoemul- sification with intraocular lens implantation. Clin Exp Ophthalmol. 2001;29:307–311. spective in nature, and while 114 consecutive cases were ana- 15. Lahey JM, Francis RR, Kearney JJ, Cheung M. Combining phacoemulsification and vit- lyzed, data was limited in a large subset due to inadequacies rectomy in patients with proliferative diabetic retinopathy. Curr Opin Ophthlamol. 2004;15(3):192–196. in postoperative OCT imaging. The time interval between 16. Androudi S, Ahmed M, Fiore T, Brazitikos P, Foster CS. Combined pars plana vitrectomy surgery and the pre- and postoperative OCTs varied, and the and phacoemulsification to restore visual acuity in patients with chronic uveitis. J Cataract Refract Surg. 2005;31(3):472–428. mean postoperative interval was 6 weeks, 2 weeks longer 17. Soheilian M, Mirdehqhan SA, Peyman GA. Sutureless combined 25-gauge vitrectomy, than that of the study by Kim et al.8 The additional 2 weeks phacoemulsification, and posterior chamber intraocular lens implantation for management of uveitic cataract associated with posterior segment disease. Retina. 2008;28(7):941–946. affords more time for macular edema to spontaneously 18. Browning DJ, Glassman AR, Aiello LP, et al; Diabetic Retinopathy Clinical Research resolve, which may have accounted for the lower incidence Network. Optical coherence tomography measurements and analysis methods in optical than in the Kim study. This patient series was that of a vitreo- coherence tomography studies of diabetic macular edema. Ophthalmology. 2008;115(8):1366–1371. retinal specialist whose practice has a large component of 19. de Bustros S, Thompson JT, Michels RG, et al. Nuclear sclerosis after vitrectomy for idio- ocular oncology. The diagnoses and indications for surgery in pathic epiretinal membranes. Am J Ophthalmol. 1988;105(2):160–164.

14 I SUPPLEMENT TO RETINA TODAY I NOVEMBER/DECEMBER 2009 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

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CME QUESTIONS 1. In preclinical studies, investigators found evidence of the 5. Koss et al reported a sustained effect in visual acuity following possible effects from intravitreal corticosteroids: improvement with vitrectomy combined with intravitreal a. prostaglandin inhibition injections of bevacizumab and triamcinolone acetonide over b. fibroblast growth inhibition 6 months. c. angiogenic inhibition a. true d. all of the above b. false e. A and C 6. The preservative agent in off-label intravitreal triamci- 2. High-dose (25 mg) intravitreal triamcinolone acetonide nolone acetonide (IVTA), benzyl alcohol, has been implicated (IVTA) monotherapy for wet age-related macular degenera- in: tion was found in two separate studies by Jonas et al to: a. cataract formation a. significantly increase visual acuity in 7-months follow-up b. sterile endophthalmitis b. significantly increase intraocular pressure in 7-months follow-up c. glaucoma c. significantly increase visual acuity in 1-year follow-up d. all of the above d. A and B e. All of the above 7. Data show that ______have a higher toxicity com- pared to other visualization agents for retina surgery. 3. The DRCR.net study authors concluded that: a. preserved IVTA and nonpreserved IVTA a. steroids are beneficial and should be used as an adjunct to b. nonpreserved IVTAand indocyanine green (ICG) lasers c. Trypan blue and preserved IVTA b. focal/grid laser photocoagulation should be the benchmark d. Trypan blue and ICG against other treatments for DME e. none of the above c. lasers and steroids are equivalent d. none of the above 8. Limiting factors in visual recovery in macular pathology include: 4. Concerns raised regarding the study design and protocol a. persistent subretinal fluid of the Diabetic Retinopathy Clinical Research Network trial b. cyst comparing focal/grid laser photocoagulation to IVTA c. intraretinal edema included: d. all of the above a. inclusion/exclusion criteria b. number of patients in each study group 9. The use of corticosteroids during surgery for complex mac- c. dosing regimens with IVTA ular pathology can potentially postoperatively improve: d. all of the above a. retinal thickness e. A and C b. macular edema c. intraocular pressure d. A and B e. B and C

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NOVEMBER/DECEMBER 2009 I SUPPLEMENT TO RETINA TODAY I 15 Intravitreal Corticosteroids: A Review of Therapeutic and Surgical Applications

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Sponsored by the Dulaney Foundation November/December 2009 supplement to Retina Today