This article offers a brief overview of selected points in the history of intravitreal corticosteroid monotherapy for retinal disease.

PRECLINICAL WORK
The first reported intravitreal injection of a corticosteroid was performed by Graham and Peyman in 1974, when they injected dexamethasone for an experimentally induced case of endophthalmitis.¹² Subsequently, Peyman et al^13-15 published further cases where this agent was used in combination with gentamycin to treat bacterial endophthalmitis. In 1977, Floman and Zor¹⁶ elucidated that the mechanism of corticosteroid action against inflammation as involving the inhibition of prostaglandins. Later that decade, Machemer and Tano^17,18 showed that a single injection of dexamethasone in rabbit models inhibited fibroblast growth and significantly reduced the incidence of retinal detachment. They repeated the study using intravitreal triamcinolone (IVTA) with similar results.¹⁹ They also saw a reduction in retinal vascularization caused by fibrous strands coming into contact with the vascularized retina with IVTA to a greater extent than when they had used dexamethasone in the earlier studies.

Ishibashi et al^{20 investigated the effects of corticosteroids on a primate model of lase}r-induced lesions and found that eyes infused with either dexamethasone or dexamethasone combined with triamcinolone less frequently developed subretinal neovascularization when compared with controls, suggesting an antiangiogenic effect. In a later study using a rabbit model for preretinal neovascularization, a significantly fewer number of eyes developed new blood vessels after being treated with triamcinolone and then injected with dermal fibroblasts compared with controls.²¹

INTRAVITREAL STEROIDS FOR AMD
In 1995, Penfold et al²³ performed a pilot study using IVTA in patients to treat age-related macular degeneration (AMD). In this 30-eye study (n=28), IVTA was shown to decrease exudation and improved vision in patients with wet AMD and subfoveal and juxtafoveal choroidal neovascularization. With 18-month follow-up, there were no serious side effects and visual acuity was reported as significantly better than the data showed for untreated lesions.

In a study that was published in Retina in 2000, a single injection of 4-mg IVTA was administered to patients with wet AMD (n=27) and compared for 6-months follow-up against untreated patients. The patients in the treated group had significantly better visual acuity at 3 and 6 months (P<.005) and although an intraocular pressure (IOP) rise was seen in 25% of treated patients, this was managed with topical pressure-lowering medications.²⁴

Gillies et al²⁷ reported a biologic effect with one injection 4-mg IVTA for AMD at 3 months in their study in 2003, and in 1-year follow-up, found that one injection of IVTA did not increase the risk of visual loss in their 151 eye, randomized study.

Jonas et al25 performed a study evaluating high-dose 25-mg IVTA for wet AMD. Their study included 71 eyes of 67 patients and sought to find the duration of effect and side effects of the treatment over the course of an average of approximately 7-months follow-up. They found a significant increase in mean visual acuity (P<.001); however, they also saw a significant mean increase in IOP (P<.001). In another high-dose IVTA study with 1-year follow-up (39 eyes), however, no beneficial effect was found in the treated group vs the control group, who were treated with intravitreal dexamethasone. 26 Further, all eyes in the treated group developed marked cataract progression.

INTRAVITREAL STEROIDS FOR UVEITIS

Steroids have been used for uveitis for many years, and their intravitreal use was one of the obvious indications once this route of drug delivery became commonly employed. A key development for chronic intravitreal administration of steroids was the advent of extended delivery.

Pilot and clinical trials for the 0.59-mg fluocinolone acetonide sustained-delivery device (Retisert, Bausch & Lomb) for the treatment of chronic posterior uveitis proved that it was beneficial in controlling inflammation over a prolonged period of time.^28,29 Patients in the clinical trial (n=168) were followed for 3 years and, although the side effects of IOP and cataract progression were significant, they did not outweigh the damaging effects of the disease.^30,31 The US Food and Drug Administration (FDA) approved the device in 2005.

INTRAVITREAL STEROIDS FOR DIABETIC MACULAR EDEMA
Virtually all types of recalcitrant macular edema, diabetic macular edema (DME) being the most prevalent, have been reported to respond at least transiently to the use of intravitreal steroid therapy. An evidence-based paradigm for intravitreal steroid use, however, particularly in complex, multifactorial and chronic disease states such as DME, remains elusive. Multiple case series and small trials have investigated the use of intravitreal steroids for DME. For example, Gillies et al³² recently reported a small series of eyes (n=41) who were treated with IVTA for DME refractory to laser. Patients were randomized to IVTA or placebo. A greater percentage of patients achieved visual acuity improvement in the IVTA group (42%) than placebo (32%), and in 5-year follow-up, patients who responded to IVTA maintained their visual acuity gains.

The largest clinical trial to date on the efficacy and safety of IVTA for DME was from the Diabetic Retinopathy Clinical Research Network. The study compared focal/grid laser photocoagulation (n=330) to 1-mg IVTA (n=256), and 4-mg IVTA (n=254). Although IVTA 4 mg showed a benefit over laser at 4 months, by year 1, no differences in visual acuity were seen between the three groups. At 16 months and 2 years, patients in the laser group had significantly better visual acuity that the 1-mg IVTA group (P=.02) and the 4-mg IVTA group (P=.002).³³ The 3-year results were similar and supported laser as the best treatment option of those specific protocols tested for patients with DME similar to those recruited in the study.34Whether other protocols could show a benefit to intravitreal steroids in DME or other types of eyes respond better remains to be investigated in a large-scale fashion.35-38

The use of intravitreal steroids for macular edema due to retinal venous occlusive disease was first described in a series of case reports by Ip and Greenberg.39 Recently, steroids have been in the spotlight for central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) because of the report of results of two groups of clinical trials.

The 6-month results of identical multicenter, doublemasked, randomized, parallel phase 3 trials comparing the sustained-delivery intravitreal 0.7-mg dexamethasone implant (n=427) to sham (n=426) demonstrated a significant benefit with the dexamethasone implant (P<.001) for patients with CRVO and BRVO.40 The FDA gave approval to the dexamethasone implant (Ozurdex, Allergan, Inc.) for CRVO and BRVO earlier this year.

The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study group also recently released their results on steroids vs laser for CRVO and steroids vs laser for BRVO. SCORE-BRVO enrolled 411 patients and randomized them to treatment with laser, 1-mg IVTA, and 4-mg IVTA.41 No significant difference was seen in the 12-month visual acuity outcomes between the three groups. The rate of adverse events (IOP increase and cataract) was similar between the 1-mg IVTA and laser groups and highest in the 4-mg IVTA groups. The conclusion was that laser should remain the standard of care for patients with BRVO. SCORE-CRVO enrolled 271 patients and randomized them to either observation, treatment with 1-mg IVTA, or treatment with 4-mg IVTA.42 The patients treated with both 1-mg and 4-mg IVTA achieved an equally significantly better visual outcome than patients in the observation group (P=.001). The rate of complications was higher in the 4-mg group than in the 1-mg group. The authors concluded that 1-mg IVTA should be considered for patients with CRVO.

SUMMARY
Intravitreal injection of pharmacological agents was a radical concept when first introduced by Blumenkranz et al.43 Unique drug delivery issues in the posterior segment and the increasingly available and effective therapies for posterior segment disease processes have resulted in intravitreal administration becoming a routine line of therapy. Steroids are a class of drug that has been available for many years, and used via different routes for a variety of ocular conditions. As evidence of the inflammatory pathobiology underlying many prevalent retinal disorders continues to emerge, further support for the potential of steroids to impact on these disease processes has evolved. Careful prospective evaluation of these pharmacological options as monotherapy or in combination with other drugs and procedures holds significant promise for an expanding population of patients with blinding eye disorders.

Julia A. Haller, MD, is Professor and Chair of Ophthalmology at Thomas Jefferson University and Thomas Jefferson University Hospital. She is also Ophthalmologist in Chief at Wills Eye Institute. Dr. Haller can be reached at +1 215 928 3000.

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2. Jonas JB, Kreissig I, Degenring RF. Intravitreal triamcinolone acetonide as treatment of macular edema in central retinal vein occlusion. Graefe's Arch Clin Exp Ophthalmol. 2002;240:782–783.
3. Sivaprasad S, McCluskey P, Lightman S. Intravitreal steroids in the management of macular oedema. Acta Ophthalmol Scand. 2006;84(6):722–733.
4. Jonas JB, Kreissig I, Kamppeter B, Degenring RF. [Intravitreal triamcinolone acetonide for the treatment of intraocular edematous and neovascular diseases. Article in German.] Ophthalmologe. 2004;101(2):113–120.
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6. Spaide RF. Combination therapies for choroidal neovascularization. In: Holz FG, Spaide RF, eds. Medical Retina (Essentials in Ophthalmology). Heidelberg: Springer; 2007:90–104.
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8. Vinores SA, Xiao WH, Aslam S, et al. Implication of the hypoxia response element of the VEGF promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development. J Cell Physiol. 2006;206(3):749–758.
9. Apte RS, Richter J, Herndon J, Ferguson TA. Macrophages inhibit choroidal neovascularization in age-related macular degeneration. PLoS Med. 2006;3:1371–1381.
10. Kelly J, Khan AA, Yin J, Ferguson TA, Apte RS. Senescence regulates macrophage polarization and angiogenic fate at sites of tissue injury. J Clin Invest. 2007;117:3421–3426.
11. Dace D, Khan AA, Kelly J, Apte RS. Interleukin-10 promotes pathologic developmental angiogenesis by regulating macrophage responsiveness to hypoxia. PLoS One. 2008;3:3381.
12. Graham RO, Peyman GA. Intravitreal injection of dexamethasone. Treatment of experimentally induced endophthalmitis. Arch Ophthalmol. 1974;92(2):149–154.
13. Peyman GA, Rose M, Sanders D. Intravitreal antibiotic injection and vitrectomy in acute bacterial endophthalmitis. Can J Ophthalmol. 1976;11(2):188–190.
14. Peyman GA, Vastine DW, Meisels HI. The experimental and clinical use of intravitreal antibiotics to 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 Herellea endophthalmitis after incomplete phacoemulsification. Am J Ophthalmol. 1975;80(4):764–765.
16. Floman N, Zor U. Mechanism of steroid action in ocular inflammation: Inhibition of prostaglandin production. Invest Ophthalmol Vis Sci. 1977;16(1):69–73.
17. Tano Y, Sugita G, Abrams G, Machemer R. Inhibition of intraocular proliferations with intravitreal corticosteroids. Am J Ophthalmol. 1980;89(1):131–136.
18. Machemer R, Sugita G, Tano Y. Treatment of intraocular proliferations with intravitreal steroids. Trans Am Ophthalmol Soc. 1979;77:171–180.
19. Tano Y, Chandler D, Machemer R. Treatment of intraocular proliferation with intravitreal injection of triamcinolone acetonide. Am J Ophthalmol. 1980;90(6):810–816.
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. 1985;103(5):708–711.
21. Antoszyk AN, Gottlieb JL, Machemer R, Hatchell DL. The effects of intravitreal triamcinolone acetonide on experimental pre-retinal neovascularization. Graefes Arch Clin Exp Ophthalmol. 1993;231(1):34–40.
22. Cheng CK, Berger AS, Pearson PA, Ashton P, Jaffe GJ. Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis. Invest Ophthalmol Vis Sci. 1995;36(2):442–453.
23. Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative macular degeneration and intravitreal triamcinolone. A pilot study. Aust N Z J Ophthalmol. 1995;23(4):29–38.
24. Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in exudative agerelated macular degeneration. Retina. 2000;20(3):244–250.
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.
26. Lee J, Freeman WR, Azen SP, Chung EJ, Koh HJ. Prospective, randomized clinical trial of intravitreal triamcinolone treatment of neovascular age-related macular degeneration: one-year results. Retina. 2007;27(9):1205–1213.
27. Gillies MC, Simpson JM, Luo W, et al. A randomized clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results. Arch Ophthalmol. 2003;121(5):667–673.
28. Jaffe GJ, McCallum RM, Branchaud B, Skalak C, Butuner Z, Ashton P. Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology. 2005;112(7):1192–1198.
29. Jaffe GJ, Martin D, Callanan D, Pearson PA, Levy B, Comstock T; Fluocinolone Acetonide Uveitis Study Group.Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-fourweek results of a multicenter randomized clinical study. Ophthalmology. 2006;113(6):1020–1027. Epub 2006 May 9.
30. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191–201.
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.
32. Gillies MC, Simpson JM, Gaston C, Hunt G, Ali H, Zhu M, Sutter F. Five-year results of a randomized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmology. 2009;116(11):2182–2187. Epub 2009 Oct 1.
33. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 Sep;115(9):1447–9, 1449.e1–10.
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 triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245–251.
35. Jonas J, Rensch F. Diabetic macular edema. Ophthalmology. 2009;116(3):594–5; author reply 596–597.
36. Blanco-Garavito R, Rodriguez-Valdes PJ. DRCR Study: outcomes in focal vs diffuse edema? Ophthalmology. 2009;116(3):595–596; author reply 596–597.
37. Gillies M. Diabetic macular edema. Ophthalmology. 2009;116(3):595; author reply 596–597.
38. Narula R, Agarwal M, Chaudhary SP, Shroff C. Diabetic macular edema. Ophthalmology. 2009;116(9):1833–1834; author reply 1834.
39. Ip MS, Kumar KS. Intravitreous triamcinolone acetonide as treatment for macular edema from central retinal vein occlusion. Arch Ophthalmol. 2002;120(9):1217–1219.
40. Haller JA. 6-month randomized controlled clinical trial of an intravitreal dexamethasone implant in macular edema associated with retinal vein occlusion. Paper presented at: Retina Congress 2009; October 4, 2009; New York, NY.
41. Scott IU, Ip MS, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115–1128.
42. Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5.Arch Ophthalmol. 2009;127(9):1101–1114.
43. Blumenkranz MS, Ophir A, Claflin AJ, Hajek A. Fluorouracil for the treatment of massive periretinal proliferation. Am J Ophthalmol. 1982;94(4):458–467.

My next step was an internship at Highland General Hospital in Oakland, CA, because I wanted to put all the things I learned in medical school together before focusing on a single specialty. There I experienced everything from delivering newborns to tending to patients with gunshot wounds—it was an exciting year.

When I entered into my ophthalmology residency at Pacific Medical Center, I met and worked with three individuals who had significant impacts on my future: medical retina specialist John Cavendar, MD, and retina surgeons Wayne E. Fung, MD, and George Hilton, MD. These three gentlemen lit my retina fire, so to speak.

2. Since your involvement in the pneumatic retinopexy trial early in your career as a retina specialist, you have been at the forefront of many surgical and medical developments. What do you consider most exciting?
I think the biggest breakthrough in my career has been the ability to treat macular holes, although to this day I don't understand why patients are forced to be positioned face down. Next, our surgical instruments and techniques have evolved significantly in terms of refinement and reliability. In the early days of vitrectomy surgery, you never knew if your instruments were going to last for an entire case. Our vitrectomy cutters were reusable (and very expensive) and had to sent to Switzerland to be sharpened—there was far more OR hassle then. Recently developed surgical tools, such as the wideangle binocular indirect microscope, perfluorocarbon liquids, triamcinolone acetonide and other dyes for staining and visualization, have made surgery much easier and have improved our outcomes. Of course, spectral domain optical coherence tomography and digital photography have changed our approach to many surgical and medical diseases.

On the medical side of retina, we are moving quickly toward the pharmacologic manipulation of disease, which is revolutionizing how we treat patients.

3. How would you describe your approach to treating your patients and medicine in general?

When I completed medical school, I remember my father, who also was a physician, offering the following advice: Always do what's best for the patient, and everything else will follow. For every patient I treat, I ask myself what decision I would make if the person were my father, my mother, or my child. With this approach, surgical decision-making is simple.

Regarding the direction of medicine in general, I am very concerned. Many of my colleagues, including myself, are not encouraging their children to go into medicine, which says a lot about how doctors feel about the course medicine is taking. It will always be a rewarding and satisfying profession, but it takes 14 years after high school to become a retina specialist, and a lot of personal sacrifice. At the end of that long road is a system that takes for granted the wonderful skills we have acquired. I knew we were in trouble when we began to be called (and accepted) the title of “provider” instead of “doctor.”

4. How have the roles of specialty groups such as the American Society of Retina Specialists (ASRS) evolved with the subspecialty? When the ASRS (formerly the Vitreous Society) was formed, the goal was to have an open society permitting anyone trained in retina to share his or her ideas in a relaxed collegial environment. We felt all our members had something to contribute. The pluralistic nature of the society and the exponential growth of our membership have, in my opinion, resulted in the ASRS being considered the political voice of retina. Unfortunately, our growth has forced us to trade a “one-on-one meeting” philosophy for a large “subspecialty day” type meeting. As an alternative, I have tried to fashion the International Masters of Retina meeting along the lines of the old Vitreous Society.

Looking ahead, the ASRS will be required to apply this leadership position to some of the pressing issues in retina, which in my opinion are accreditation (of programs) and certification (of fellows). First, we need to work with government officials to redefine what a retina fellowship is, so that teaching programs are compensated fairly for training high-quality retina specialists. Once the training programs are accredited, their graduates can be certified (boarded). As things stand today, any ophthalmologist can profess to be a retina specialist and can even train fellows! It really is a public health issue.

5. Where might one find you when you are not in clinic or teaching students?
When I was an undergraduate, I wanted to play professional golf. I played on the golf team at Colgate, but when we traveled to the South for golf matches, I realized that most of these guys from Sunbelt states were far above my level of play. I still enjoy the game, so I suppose if I am not working you can find me at the country club practicing. Usually I don't have the time to play entire rounds, but I like to practice every chance I get. It clears my mind.

Our understanding of nonexudative (dry) AMD, however, is limited, and we currently have no way of treating our patients with dry AMD or understanding how or why they convert to wet AMD.

At the annual meeting of the American Academy of Ophthalmology (AAO) this year, I presented a series of patients (n=128) for whom we reviewed ultra widefield angiograms, spectral domain optical coherence tomography (SD-OCT) scans, and fundus autofluorescence (FAF) images to assess the presence or absence of peripheral perfusion and/or ischemia and the correlation to wet AMD stage and rate of progression.¹ Our conclusion was that peripheral perfusion or lack thereof may be a key marker for the relative AMD disease state. Further, measuring peripheral angiographic perfusion and understanding this potential source of VEGF might be important in developing new AMD therapy and/or adjusting regimens with current therapies.

We hope to be able to apply this knowledge to dry AMD to better understand the factors that determine when and why patients convert.

ULTRA WIDEFIELD (PERIPHERAL) FA
Figure 1 shows case examples of differences seen in luminescence intensity when grading standard peripheral angiography between stage 1, 2, 3, and 4 wet AMD. Figure 2 is an ultra widefield image that shows a good deal of leakage and hyperfluorescence in the periphery. This might cause us to question whether there is something more to macular disease than leakage in the center to midperipheral field and whether some sort of peripheral end-artery ischemia is causing problems. The following case is presented to discuss the correlation between leakage seen out in the periphery and the reasons why the patient with dry AMD converted to wet AMD.

CASE EXAMPLE
Our patient was a 72-year-old man, with an exsmoker, had a history of alcohol use, hypertension, previous angina, and a myocardial infarction several years prior. He was taking medications for blood pressure and hypertension. His visual acuity was fluctuating wildly from visit to visit, and his OCT scans demonstrated variable neurosensory retinal edema; there was no evidence of choroidal neovascularization on fluorescein angiography (FA) or indocyanine green imaging. It was not until we took images using the ultra widefield Optos P200A (Optos, Fife, Scotland) and reviewed his FA Optomap (Optos) image that we saw zones of peripheral late vascular leakage. Out in the far periphery of Figure 2, it is clear that the blood vessels at approximately 2:00 to 3:00 are leaking profusely.

The patient recently converted to wet AMD, and treatment with anti-VEGF medications has been started.

Had the chronic small vessel disease, alcohol and tobacco use, hypertension, high blood pressure, and heart disease led to a relative hypoxia or ischemia that drove the patient's conversion to wet AMD?

DISCUSSION
We looked at a large series of wet AMD patients in the study presented at the AAO.1 After looking at the peripheral angiograms of 123 patients, we noted that 80% of them showed some evidence of hyperfluorescence and leakage in the periphery.

To attempt to answer the question posed above, we have gone further and normalized the gamma on each of the angiograms and measured the pixel luminence using a computer software program that we are currently developing. With this program, we are able to assign a numeric value (relative intensity and area) to a region of interest on the image, allowing us to quantify and numerically follow suspicious angiographic activity over time.

Figure 3 shows how we mapped the macula with the computer program. We then chose the brightest pixel luminence within the normal vascular channel. Based on the pixel intensity, values were assigned and graded between 1 and 100 in luminance value. In normal vasculature, the dye should go out to the periphery, stay relatively dark, and then re-circulate. Any areas that are brighter than what appears in the normal first-order vessels indicates clinical leakage. In Figure 3 we measured all the pixels in the main arcades, and the brightest pixel was assigned a luminance value of 55.7. After isolating the zone of brightness out in the periphery that was demonstrating relative hyperfluorescence, we calculated and summated each pixel within the entire grid. One of the brightest areas measured that was particularly hot measured a luminance value of 76.5, and another area that appeared rather bright was measured at a luminance value of 60.0, which is brighter than anything that we saw within the normal blood value columns (Figure 4). Figures 5 and 6 shows how a calculation of a percentage of how much illuminance actually existed, similar to an OCT—with yellow at the lower end of the spectrum of leakage, red being more intense, and white exceeding all anticipated values.

SUMMARY
Could it be that events in the peripheral vasculature are capable of catalyzing the conversion of AMD from dry to wet? The factors that have been implicated in the pathophysiology of AMD thus far—VEGF, inflammation, genetics and chromosomal linkages, and HF1 and HF2—may be only some of the factors that will help predict how AMD progresses. Our study found that peripheral vasculature may provide an indication that a patient is at risk for converting to wet AMD. In our opinion, further research is warranted in a larger group of patients to answer this question.

Third party image analysis on the Optos ultra widefield images were performed by W. Kent Demaine of Retina Metrics, LLC.

Michael D. Bennett, MD, is a vitreoretinal surgeon at the Retina Institute of Hawaii in Honolulu and an Associate Professor in the Department of Surgery at the University of Hawaii, John A. Burns School of Medicine. He states that he is an unpaid consultant for Optos. Dr. Bennett is a Retina Today Editorial Board member. He can be reached at +1 808 955 0255.

Eugene Ng, MD, MBA, is a vitreoretinal surgeon at the Retina Institute of Hawaii in Honolulu

1. Bennett MD. wide field angiography and documentation of peripheral perfusion and/or ischemia in patients with wet AMD. Presented at: the Annual Meeting of the American Academy of Ophthalmology. October 25, 2009; San Francisco.

In this installment, the clinical features of choroidal nevus are discussed, and the authors describe a rare variant of nevus, the giant choroidal nevus (over 10 mm in diameter). This is often mistaken for melanoma and can pose a diagnostic dilemma. The authors mention the classic features of choroidal nevi and then explain the features of giant choroidal nevi with a focus on the ultimate long-term outcomes of these tumors.

We extend an invitation to readers to submit informative cases, thoughts, short reviews, or new techniques to Retina Today. Please send submission for consideration to Rachel Renshaw at rrenshaw@bmctoday.com. We look forward to this exciting new column, and we guarantee that it will be filled with color.

-Carol L. Shields, MD; and Sara Lally, MD
The Ocular Oncology Service, Wills Eye Institute

A46-year-old white male was found on routine examination to have a large pigmented lesion in the fundus of his right eye. The patient had no personal or family history of ocular trauma, disease, or cancer.

On examination, visual acuity was 20/20 in the right eye and 20/15 in the left eye. Slit-lamp examination and intraocular pressures were normal in each eye. Fundus examination of the left eye was normal. Fundus examination of the right eye disclosed a pigmented lesion occupying the nasal region and measuring 15 x 12 mm in basal dimensions and 2.2 mm in thickness. The lesion was 1 mm nasal to the disc. Trace chronic subretinal fluid, retinal pigment epithelial (RPE) atrophy and hyperplasia, and numerous drusen were found overlying the lesion with areas of fibrous metaplasia of the RPE. The patient was diagnosed with giant choroidal nevus vs dormant choroidal melanoma.

Observation twice yearly with photographic documentation was provided. Twenty-two years later the giant choroidal nevus remained stable with no signs of growth, progressive subretinal fluid, or orange pigmentation. Over time, the picture evolved slightly, with change in drusen appearance and increased overlying RPE atrophy (Figure 1). Currently, the tumor thickness remains stable with features of acoustic solidity and no subretinal fluid (Figure 2). The patient continues to be followed with a stable giant choroidal nevus.

DISCUSSION
Choroidal nevus is a benign melanocytic lesion, appearing pigmented or non-pigmented, and classically less than 2 mm in thickness.¹ Although uncommon, malignant transformation of choroidal nevi into melanoma is possible. ^1,2 It has been estimated that one in 8,845 choroidal nevi transform into melanoma in the white population.³ The Blue Mountains Eye Study surveyed a large population- based sample in Australia and found that nevi were present in 6.5% of the general population over age 49, with a slight decrease in prevalence with increasing age.⁴ Shields and associates reported that factors predictive of growth into melanoma include tumor thickness greater than 2 mm, subretinal fluid, symptoms, orange pigment, tumor margin within 3 mm of the optic disc, ultrasonographic hollowness, and halo absence.⁵

Nevi are generally small, with a mean nevus diameter of 1.25 mm according to the population-based Blue Mountains Eye Study, but a clinic-based study from Wills Eye Institute Oncology Service found mean diameter of choroidal nevus to be larger at 5.1 mm.⁵ This discrepancy is likely related to referral bias of more suspicious nevi to an oncology service. Choroidal nevi rarely affect visual acuity unless they are located in a subfoveal site.⁶ According to the Blue Mountain Eye Study,⁴ there are no significant associations between choroidal nevus and iris or skin color or sun-induced skin damage.

Large choroidal nevi over 10 mm in diameter are extremely rare and are classified as giant choroidal nevi. Li and associates studied 322 patients with giant nevi (diameter greater than 10 mm) and found that these lesions commonly simulate melanoma.² However, there are features that suggest a benign lesion, such as the presence of drusen (81%), RPE atrophy (20%), RPE hyperplasia (15%), and fibrous metaplasia (15%).² Additionally, giant nevi tend to lack acoustic hollowness on ultrasound, orange pigmentation, and serous retinal detachment. 2 In that series, 13% grew into melanoma by 5 years and 24% by 15 years.²Most proved to be low-grade melanoma with extremely slow growth and minimal subretinal fluid. Features predictive of growth included acoustic hollowness and close proximity to the foveola (Table).²

In summary, most choroidal nevi are relatively small lesions of 5 mm diameter. Occasionally choroidal nevi, however, are giant and measure over 10 mm diameter. Long-term follow-up of these patients is crucial to monitor for transformation into melanoma. Our patient showed no change over 22 years.

Support provided by the Retina Research Foundation of the Retina Society in Capetown, South Africa (CLS); and the Eye Tumor Research Foundation, Philadelphia, PA (CLS).

Carol L. Shields, MD, is the Co-Director of the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University. Dr. Shields is a member of the Retina Today Editorial Board. She may be reached at carol.shields@shieldsoncology. com; phone: +1 215 928 3105; fax: +1 215 928 1140.

Sara E. Lally, MD, is with the Ocular Oncology Service and is a Clinical Instructor at Thomas Jefferson University

The authors have no financial interest in the devices or medications mentioned in this document.

1. Shields CL, Furuta M, Mashayekhi A, et al. Clinical spectrum of choroidal nevi based on age at presentation in 3422 consecutive eyes. Ophthalmology. 2008;115(3):546–552.
2. Li HK, Shields CL, Mashayekhi A, et al. Giant choroidal nevus. Clinical features and natural course in 322 cases. Ophthalmology. In Press.
3. Singh AD, Kalyani P, Topham A. Estimating the risk of malignant transformation of a choroidal nevus. Ophthalmology. 2005;112:1784–1789.
4. Sumich P, Mitchell P, Wang JJ. Choroidal nevi in a white population: the Blue Mountains Eye Study. Arch Ophthalmol. 1998;116(5):645–650.
5. Shields CL, Furuta M, Berman EL, et al. Choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases. Arch Ophthamol. 2009;127(8):981–987.
6. Shields CL, Furuta M, Mashayekhi A, et al. Visual acuity in 3422 consecutive eyes with choroidal nevus. Arch Ophthalmol. 2007;125:1501–1507.

NEW COLUMN IN RETINA TODAY
Beginning with this issue of Retina Today, the VBS will participate in a regular column featuring articles authored by VBS members to highlight topics of interest to the membership.Many of these articles will be cross-referenced to surgical videos on EYETUBE.NET , the ophthalmic video resource produced by Bryn Mawr Communications, publishers of Retina Today.

-Rohit Ross Lakhanpal, MD; and Thomas Albini, MD

Small-gauge vitrectomy system (25-gauge and 23-gauge) use has increased rapidly since 2002 due to its advantages of decreased surgical time, reduced postoperative inflammation, and faster visual recovery compared with 20-gauge vitrectomy.^1-5 The 2009 Preferences and Trends (PAT) Survey from the American Society of Retina Specialists reported that nearly 80% of respondents commonly employ smallgauge systems. Recently, however, concerns have arisen that use of small-gauge systems may increase the risk of endophthalmitis.^6-9 Proper preoperative sterilization techniques along with improved methods in entry, exit and surgical technique should decrease these risks. This article highlights some of these methods.

POTENTIAL RISKS OF
SMALL-GAUGE SYSTEMS
The risk of endophthalmitis in 20-gauge systems has been previously reported to be 0.03% to 0.05%.^10-13 Retrospective reviews of 25-gauge endophthalmitis data have reported conflicting information: As compared with 20-gauge studies, Kunimoto et al⁷ reported a 12-fold increased risk, Scott et al⁸ reported a 28-fold increased risk, but Hu et al14 reported no statistically significant difference (a 0.07% [1/1424] rate for the 25-gauge cases).

Several hypotheses have been proposed to explain why 25-gauge vitrectomy may lead to a higher rate of postoperative endophthalmitis: Complete wound closure may not be achieved;¹⁵ unsutured wounds may lead to early postoperative hypotony, allowing an intraocular influx of extraocular fluid and microorganisms;^1-4,10,16,17 lower infusion rates with reduced influx and efflux of fluid may allow a greater bacterial inoculum to remain in the eye;^1-3 residual vitreous skirt may facilitate bacterial adherence and sequester bacteria from normal immunologic factors and extraocular antibiotics;¹⁸ vitreous wick prolapse through the sclerotomy site may create a potentially open conduit through the conjunctival and scleral wound that may facilitate entry of bacteria into the eye.¹⁹

IMPROVEMENTS IN ENTRY TECHNIQUE
Successful outcomes in small-gauge vitrectomy are highly dependent upon preoperative preparation and entry technique. Preoperatively, the use of povidoneiodine along the lid margin and/or perioperative area significantly reduces bacterial flora, thus decreasing the risk of endophthalmitis. Furthermore, placing povidoneiodine for a few seconds near entry sites may further lower the risk, as direct application has been demonstrated in well-controlled studies to decrease the microbiologic flora before intraocular surgery.^20,21

Modifications in entry technique have also decreased complication risk. Original 25-gauge surgical systems employed a direct perpendicular entry through intact conjunctiva without displacement.^1-3 This allowed a direct opening to the vitreous cavity, thus increasing the risks of endophthalmitis, hypotony, and choroidal detachment in early studies. Lakhanpal et al³ reported no cases of endophthalmitis, but did report incidence of 4% of hypotony and persistent choroidal detachments associated with small blebs. Gupta et al²² reported hypotony within the first 24-hour period in numerous eyes as well.

Such complications necessitated the following improvements in entry technique (Figure 1): First, the conjunctiva and sclera should be flattened in order to allow entry more parallel to the limbus; next, the conjunctiva should be displaced laterally in order to prevent communication between this incision and the scleral incision; third, rather than a perpendicular incision, a two-step incision should be used, in which an oblique, beveled incision parallel to the limbus through the conjunctiva and sclera is followed by a perpendicular tunnel entry, thus creating a self-sealing wound.²³ In one study, angled incisions were associated with significantly lower risk for external communication as opposed to straight incisions (Figure 2).²⁴

Flattening and displacing the conjunctiva in order to create a self-sealing incision was an important development. This may be performed with a variety of instruments, such as a cotton-tip applicator, 0.3 forceps, or plug-pulling forceps. Another option is the Dugel End Plate (Peregrine Surgical, New Britain, PA): This instrument simultaneously flattens and displaces the conjunctiva, then designates the angle of entry, and finally aids in trocar removal (Figures 3 and 4).

IMPROVEMENTS IN SURGICAL PROCEDURE AND CANNULA REMOVAL
A variety of techniques may be employed during smallgauge vitrectomy in order to decrease the risks of hypotony and endophthalmitis. Previous studies have postulated that insufficient vitreous removal during 25-gauge vitrectomy may provide an area for bacterial adherence.²⁵ Thus, performing a more complete vitrectomy, particularly with triamcinolone staining near the sclerotomy sites, is a simple way to correct this problem. Another potential issue is that prolapse of a vitreous wick through the sclerotomy site may create a potentially open conduit through the conjunctival and scleral wound that may facilitate entry of bacteria into the eye.¹⁹ Once again, more complete vitrectomy at or near the sclerotomy sites decreases this risk. Also, the use of air tamponade at the conclusion of surgery may act as both a barrier to bacterial inoculation and a way to prevent hypotony.

Improvements in cannula removal and appropriate use of subconjunctival antibiotics near the sclerotomy sites may reduce potential complication risks. Vitreous wick prolapse may be prevented¹⁹ during closure by simply placing the light pipe through the microcannula during removal (Figure 5). This prevents the suction-like effect that can occur during cannula removal. This mechanism of cannula removal with air tamponade may allow air rather than vitreous to seal the sclerotomy site wound. Finally, injection of subconjunctival antibiotics adjacent to the sclerotomy sites may decrease bacterial entry through sclerotomy sites. Some authors have recently proposed that there is a correlation between relative hypotony at the conclusion of surgery and the influx of bacteria through sclerotomy sites, increasing the risk of endophthalmitis.^{26, 27} Air tamponade and relatively higher intraocular pressure may be a deterrent to bacterial influx.²⁷ Extra insufflation of air may also be necessary if the intraocular pressure is deemed to be too low. Many of these recommendations for small-gauge surgery improvements have been proposed by the Microsurgical Safety Task Force at the most recent meeting of the American Society of Retina Specialists.²⁸

CONCLUSIONS
Small-gauge vitrectomy systems have been in widespread use since 2002. For experienced surgeons, there has been a steep learning curve in terms of entry techniques, surgical technique and instrumentation, and microcannula removal. These improvements have decreased the relative risk of endophthalmitis, but longer-term study must be done. Hu et al¹⁴ determined that there is no statistically significant difference in endophthalmitis rates between 20— gauge and 25-gauge systems, directly contradicting two previous studies.^7,8

Currently, the prevailing evidence emphasizes the importance of the following measures to reduce endophthalmitis risk: Infection prevention measures, including lid scrubbing and direct povidone-iodine application; conjunctival displacement and angled/beveled incision; more complete vitreous removal adjacent to the sclerotomies; air tamponade; repositing potential extraconjunctival vitreous wick with light-pipe assisted cannula removal and subconjunctival antibiotic injection; and extra insufflation of air/gas, if necessary, to stabilize intraocular pressure.

Having performed thousands of small gauge vitrectomies since 2002 without a case of endophthalmitis, I believe that the increased risk is largely techniquedependent. The documented risk modifications described above should decrease the endophthalmitis risk dramatically.

Rohit Ross Lakhanpal, MD is a Partner at Eye Consultants of Maryland and a Clinical Assistant Professor of Ophthalmology at The University of Maryland School of Medicine. He reports no financial or proprietary interest in any of the products or techniques mentioned in this article. He has been a Consultant in the past for both Bausch & Lomb and Alcon Surgical. He is currently the Vice-president of the Vit-Buckle Society (VBS). Dr. Lakhanpal is Section Co-Editor of the VBS page in Retina Today and on EYETUBE.NET. He can be reached at +1 410 581 2020 or via e-mail at retinaross@yahoo.com.

Thomas Albini, MD is Assistant Professor of Clinical Ophthalmology at the Bascom Palmer Eye Institute in Miami, FL. He specializes in vitreoretinal diseases and surgery and uveitis. He has served as a speaker for both Bausch & Lomb and Alcon Surgical, as well as consultant for Alcon Surgical. He is currently the Membership Chair of the Vit-Buckle Society (VBS). Dr. Albini is Section Co-Editor of the VBS page in Retina Today and on EYETUBE.NET. He can be reached at +1 305 482 5006; or via e-mail at talbini@med.miami.edu.

1. Fuji GY, de Juan E Jr, Humayun MS, et al. A new 25-gauge instrument system for transconjunctival sutureless vitrectomy surgery. Ophthalmology. 2002:109:1807–1812.
2. Fujii GY, de Juan E Jr, Humayun MS, et al. Initial experience using the transconjunctival sutureless vitrectomy system for vitreoretinal surgery. Ophthalmology. 2002;109:1814–1820.
3. Lakhanpal RR, Humayun MS, de Juan E, et al. Outcomes of 140 consecutive cases of 25- gauge transconjunctival surgery for posterior segment disease. Ophthalmology. 2005;112(5):817–824.
4. Ibarra MS, Hermel M, Prenner JL, Hassan TS.Longer-term outcomes of transconjunctival sutureless 25-gauge vitrectomy. Am J Ophthalmol. 2005;139(5):831–836.
5. Eckardt C. Transconjunctival sutureless 23-gauge vitrectomy. Retina. 2005;25:208–211.
6. Acar N, Unver YB, Altan T, Kapran Z. Acute endophthalmitis after 25-gauge sutureless vitrectomy. Int Ophthalmol. 2007;27:361–363.
7. Kunimoto DY, Kaiser RS, Willis Eye Retina Service. Incidence of endophthalmitis after 20- and 25-gauge vitrectomy. Ophthalmology. 2007;114:2133–2137.
8. Scott IU, Flynn HW Jr, Dev S, et al. Endophthalmitis after 25-gauge and 20-gauge pars plana vitrectomy: incidence and outcomes. Retina. 2008;28:138–142.
9. Taban M, Ufret-Vincenty RL, Sears JE. Endophthalmitis after 25-gauge transconjunctival sutureless vitrectomy. Retina. 2006;26:830–831.
10. Aaberg TM Jr, Flynn HW Jr, Schiffman J, Newton J. Nosocomial acute-onset postoperative endophthalmitis survey: a 10-year review of incidence and outcomes. Ophthalmology. 1998;105:1004–1010.
11. Eifrig CW, Flynn HW Jr, Scott IU, Newton J. Acute-onset postoperative endophthalmitis: review of incidence and visual outcomes (1995–2001). Ophthalmic Surg Lasers. 2002;33:373–378.
12. Eifrig CW, Scott IU, Flynn HW Jr, et al. Endophthalmitis after pars plana vitrectomy: incidence, causative organisms, and visual acuity outcomes. Am J Ophthalmol. 2004;138:799–802.
13. Sakamoto T, Enaida H, Kubota T, et al. Incidence of acute endophthalmitis after triamcinolone- assisted pars plana vitrectomy. Am J Ophthalmol. 2004;138:137– 8.
14. Hu AY, Bourges JL, Shah SP, et al. Endophthalmitis after pars plana vitrectomy a 20- and 25-gauge comparison. Ophthalmology. 2009;116(7):1360-5.
15. Keshavamurthy R, Venkatesh P, Garg S. Ultrasound biomicroscopy findings of 25 G transconjunctival sutureless (TSV) and conventional (20G) pars plana sclerotomy in the same patient. BMC Ophthalmol [serial online] 2006;6:7. Available at: http://www.biomedcentral.com/1471-2415/6/7. Accessed January 21, 2009.
16. Shimada H, Nakashizuka H, Mori R, Mizutani Y. Expanded indications for 25-gauge transconjunctival vitrectomy. Jpn J Ophthalmol. 2005;49:397– 401.
17. Yanyali A, Celik E, Horozoglu F, et al. 25-Gauge transconjunctival sutureless pars plana vitrectomy. Eur J Ophthalmol. 2006;16:141–147.
18. Meredith TA. Antimicrobial pharmacokinetics in endophthalmitis treatment: studies of ceftazidime. Trans Am Ophthalmol Soc. 1993;91:653–699.
19. Chen SD, Mohammed Q, Bowling B, Patel CK. Vitreous wick syndrome—a potential cause of endophthalmitis after intravitreal injection of triamcinolone through the pars plana [letter]. Am J Ophthalmol. 2004;137:1159–1160.
20. Apt L, Isenberg S, Yoshimori R, Paez JH. Chemical preparation of the eye in ophthalmic surgery. III. Effect of povidone-iodine on the conjunctiva. Arch Ophthalmol. 1984;102:728 –729.
21. Apt L, Isenberg SJ, Yoshimori R. Antimicrobial preparation of the eye for surgery. J Hosp Infect. 1985;6(suppl):163–72.
22. Gupta A et al Invest Ophthalmol Vis Sci.2003, v 44
23. Inoue M, Shinoda K, Shinoda H, et al. Two-step oblique incision during 25-gauge vitrectomy reduces incidence of postoperative hypotony. Clin Experiment Ophthalmol. 2007;35:693–696.
24. Singh RP, Bando H, Brasil OFM, et al. Evaluation of wound closure using different incision techniques with 23-gauge and 25-gauge microincision vitrectomy systems. Retina. 2008;828:242–248.
25. Meredith TA. Antimicrobial pharmacokinetics in endophthalmitis treatment: studies of ceftazidime. Trans Am Ophthalmol Soc. 1993;91:653–699.
26. Taban M, Sharma S, Ventura AA, Kaiser PK. Evaluation of wound closure in oblique 23- gauge sutureless sclerotomies with visante optical coherence tomography. Am J Ophthalmol. 2009;147(1):101–107.e1. Epub 2008 Oct 4
27. Lakhanpal RR. Air tamponade reduces complications in 23-gauge vitrectomy. Presented at: 2009 Retina Congress; September 30-October 4, 2009; New York.
28. Kaiser RK. Endophthalmitis in sutureless vitrectomy surgery and the findings of the micro-surgical safety task force. Presented at: 2009 Retina Congress; September 30-October 4, 2009; New York.

Transscleral suture fixation of a posterior chamber intraocular lens (TS-IOL) is a well-established technique to secure an IOL when there is loss of posterior capsular support. A number of postoperative complications have been described with transscleral suture fixation, including endophthalmitis, retinal detachments and breaks, vitreous and choroidal hemorrhage, and lens dislocation.^12-4 This is in contrast to the incidence of posterior chamber intraocular lens (PC-IOL) dislocation, which has been reported to range from 0.2% to 2%.⁵

In a case series by Kim et al,⁶ trauma and an underlying diagnosis of Marfan syndrome were associated with an increased incidence of lens dislocation with TS-IOL. Suture breakage may occur secondary to knot erosion, suture degradation, or iatrogenic severing of the suture by its contact with the lens haptic. Based on histopathology, Parekh et al⁷ reported that cutting of the suture by the sharp surface of the lens haptic was the most likely etiology for lens dislocation.

Over the past 2 decades, a number of techniques for scleral fixation of an IOL have been reported in the literature. Techniques for both primary insertion of a TSIOL, ^8-10 as well as subsequent scleral fixation of dislocated PC-IOLs, have been described.^11-15 These techniques often involve a combined approach of pars plana vitrectomy (PPV) with a scleral-based flap to suture the lens. In some recent cases, clear corneal incisions, sometimes with haptic externalization, have also been used to aid in visualization and securing of the suture around the haptic.^16,17 There are limited reports in the literature to describe techniques for refixation of a previously sutured TS-IOL that has subsequently dislocated.¹⁸

Recently, a patient presented with her second dislocation of a TS-IOL. In this article, we describe a novel approach using 23-gauge microincisional vitrectomy surgery (MIVS) to resuture a TS-IOL in a patient with two previous lens dislocations.

Click here to view the video on eyetube.net.

PREOPERATIVE CONSIDERATIONS
A 45-year-old patient was referred to our retina practice by a local cornea specialist for management of a TS-IOL that had dislocated two times in 8 years. The patient's ocular history was significant for a complicated cataract extraction in 2001 with a posterior capsular tear and retained lens fragment. The patient was left aphakic and referred to a retina specialist. She underwent a partial PPV/pars plana lensectomy to remove the residual lens fragment and had a TS-IOL placed. In 2005, the patient required additional surgery because the TS-IOL had dislocated.

The patient had done well until approximately 3 months prior to presentation, when she began to notice “shifting images” in her right eye. She reported no history of recent trauma. Her visual acuity was 20/25 OD. On slit-lamp examination, her TS-IOL was displaced inferotemporally (Figure 1). The loose lens haptic was suspended over the macula. There was no evidence of retinal detachment or a retinal tear, although the view to the posterior pole was limited due to the displaced TS-IOL.

After weighing the risks and benefits of various surgical approaches, including lens removal and insertion of an anterior chamber intraocular lens, we decided to attempt refixation of the subluxed lens haptic.

Although the patient had undergone a previous vitrectomy, there was still significant vitreous present. In consultation with our cornea specialist, we elected to proceed with a combined 23-gauge MIVS and transscleral approach using a novel technique to refixate the subluxed lens haptic.

DESCRIPTION OF SURGICAL TECHNIQUE
In the OR, three cannulas were placed to perform 23-gauge MIVS. Because we planned to create our scleral flap nasally, we had to displace our superonasal port clockwise 2 clock hours relative to where it is typically placed. A 360º vitrectomy was performed using diluted triamcinolone acetonide (Triesence, Alcon Laboratories, Inc.) to enhance vitreous visualization during vitreous base shaving with skilled scleral depression from an assistant. Although our patient had undergone a previous vitrectomy, multiple adhesions between the vitreous and lens implant were noted. The dislocated TS-IOL was still secured temporally while the nasal haptic was suspended in the vitreous cavity over the macula. No retinal tears or breaks were noted on scleral depression under the binocular indirect ophthalmoscope.

Following the vitrectomy, a partial thickness limbalbased scleral flap was created using #66 and a #69 blades 1-mm posterior to the nasal limbus (Figure 2). One end of a double-armed STC6 needle (Ethicon, Inc,10-0 Prolene, 16.0 mm) was passed through the superotemporal 23-gauge cannula, through the eyelet of the free-floating nasal haptic of the CZ70 BD lens (Alcon Laboratories, Inc., Fort Worth, TX) with 23-gauge disposable forceps assistance through the nasal 23-gauge cannula. A hollow bore 27-gauge needle was then inserted through the nasal scleral flap into the posterior chamber. Both the STC6 needle and the tip of the 27-gauge needle could be directly visualized under the microscope. The STC6 needle was docked into the hollow bore of the 27-gauge needle (Figure 3). With the STC6 needle engaged by frictional forces, the 27-gauge needle was slowly removed with resultant externalization of the STC6 needle through the scleral flap. The other half of the double-armed STC6 needle was passed in a similar fashion temporally through the 23-gauge cannula. Instead of passing the second half of the STC6 needle through the eyelet, however, it was passed anterior to the haptic. The second half of the STC6 needle was docked within the bore of the 27-gauge needle and removed through the scleral flap in a manner similar to the first half. The two ends of the STC6 needle were pulled to the appropriate tension to re-suspend and center the TS-IOL and then tied. The scleral flap was then closed with 8-0 Vicryl suture. The entire case time less than local anesthesia/retrobulbar block was under 25 minutes.

POSTOPERATIVE RESULTS
Our patient has done well postoperatively. Her visual acuity remains 20/25, and her TS- IOL is well-centered without evidence of dislocation (Figure 4). She has remained stable for 6 months since surgery and will continue to be followed by the referring cornea specialist.

CONCLUSIONS
Although there have been several case reports of multiple episodes of suture breakage after insertion of a TS-IOL, the actual incidence of rebreakage remains unknown. In our patient, this was her second case of a dislocated TS-IOL, each episode occurring approximately 4 years after lens insertion or repair. A number of techniques have been described for initial insertion of a TS-IOL or scleral fixation of a PC-IOL following lens dislocation. There are limited data on surgical approaches for refixation of a recurrently dislocated TS-IOL.

Our surgical approach was based on the principles established for scleral suture fixation of a dislocated PC-IOL. We combined a three-port MIVS with a limbalbased partial thickness scleral flap to refixate the subluxed lens haptic. There are several unique aspects to our minimally invasive approach in comparison with those reported previously. First, to the best of our knowledge, this is the first time an STC6 needle has been used to refixate a dislocated TS-IOL. In addition, this is the only description in the literature of directing the STC6 needle through the vitrectomy port rather than through a scleral flap to secure a lens haptic. Second, although several previous authors have used a 25- or 27-gauge needle as a docking port, this is the first report of the use of a 23-gauge MIVS cannula; as previous cases reported the need for creation of an addition al scleral flap or a corneal incision. Finally, most of the techniques described previously involve suturing the haptic arm of a foldable IOL. We had to develop an approach for securing the suture through the eyelet of the CZ70 lens. The use of disposable 23-gauge MIVS forceps (disposable is preferred as the forceps tip may be damaged during this procedure) to hold the haptic while the STC6 needle was passed through the eyelet proved to be invaluable and easy to perform. By using a combined PPV/transscleral approach, we were able to have adequate visualization of the haptic eyelet without the need for haptic externalization.

In conclusion, this is the first reported case of performing a combined 23-gauge MIVS-transscleral approach to secure a dislocated TS-IOL. There are several advantages of our technique, including its minimally invasive approach; direct visualization of the haptic while it is being secured with the STC6 needle; passing the STC6 needle through the 23-gauge cannula to avoid the creation of a second scleral flap or a corneal incision; and using the 27 gauge needle to guide externalization of the STC6 needle.

Seenu M. Hariprasad, MD, is an Associate Professor and the Director of Clinical Research at the University of Chicago Department of Surgery, Section of Ophthalmology and Visual Science. He serves as Chief of the Vitreoretinal Service and Director of the Surgical Retina Fellowship Program. Dr. Hariprasad states that he is a paid consultant for OD-OS, Alcon Laboratories, Inc., Ocular Therapeutix, and Pfizer, Inc., and is on the speakers bureau for Genentech, Inc., Allergan, Inc., and Alcon Laboratories, Inc. He can be reached by e-mail: retina@uchicago.edu.

Megan. E. Collins MD, Veeral Sheth, MD, and Michael A. Saidel, MD, are all with the University of Chicago, Department of Surgery, Section of Ophthalmology and Visual Science in Chicago. Sunil Raichand, MD, is with DuPage Eye Associates in Downer's Grove, IL

Ingrid U. Scott, MD, MPH, is a Professor of Ophthalmology and Public Health Sciences, Penn State College of Medicine, and is a member of the Retina Today Editorial Board. She may be reached by phone: +1 717 531 4662; fax: +1 717 531 5475; or via e-mail at iscott@psu.edu.

Dean Eliott, MD, is a Professor of Ophthalmology and Director of Clinical Affairs, Doheny Eye Institute, Keck School of Medicine at University of Southern Carolina and is a member of the Retina Today Editorial Board. He may be reached by phone: +1 323 442 6582; fax: +1 323 442 6766; or via e-mail at deliott@doheny.org.

1. Bading G, Hillecamp J, Sachs HG, et al. Long-term safety and functional outcome of combined pars plana vitrectomy and sclera-fixated posterior chamber lens implantation. Am J Ophthalmol. 2007;144:371–377.
2. Vote BJ, Tranos P, Bunce C. Long-term outcome of combined pars plana vitrectomy and scleral fixated sutured posterior chamber intraocular lens implantation. Am J Ophthalmol. 2006;141: 308–312.
3. Johnston RL, Charteris DG. Pars plana vitrectomy and sutured posterior chamber lens implanation. Curr Opin Ophthalmol. 2001;12:216–221.
4. Filipovic T, Grzetic R, Merlak M, et al. Complications after primary and secondary transsclerally sutured posterior chamber intraocular lens implantation. Coll Anthropol. 2005;29:Supp 1:37–40.
5. Kim SS, Smiddy WE, Feuer W et al. Management of dislocated intraocular lenses. Ophthalmology. 2008;115:1699–1704.
6. Kim J, Kinyoun JL, Saperstein DA, et al. Subluxation of a transcleral sutured posterior chamber intraocular lens. Am J Ophthalmol. 2003;136:382–384.
7. Parekh P, P, Green WR, Stark WJ, et al. Subluxation of suture-fixated posterior chamber intraocular lenses: a clinicopathologic study. Ophthalmology. 2007;114:232-237.
8. Peden M, Adams S, Huffman B, et al. Alternative technique for implantation of a scleral-fixated intraocular lens. J Cataract Refract Surg. 2009;35:226–229.
9. Hannush SB. Sutured posterior chamber intraocular lenses: indications and procedure. Curr Opin Ophthalmol. 2000;11:233–240.
10. Berler DK, Friedberg MA. Scleral fixation of posterior chamber intraocular lens implants combined with vitrectomy. Tr Am Ophth Soc. 1991; 215–234.
11. Smiddy WE, Flynn HW. Needle-assisted scleral fixation suture technique for relocating posteriorly dislocated IOLs. Arch Ophthalmol. 1993;111:161–162.
12. Smiddy WE. Modification of scleral suture fixation technique for dislocated posterior chamber intraocular lens implants. Arch Ophthalmol. 1998;116:967.
13. Nikeghbali A, Falavarjani K. Modified transcleral fixation technique for refixation of dislocated intraocular lenses. J Cataract Refract Surg. 2008;34:743–748.
14. Han Q, Wang L, Hui Y et al. Transcleral suture technique for fixation of a dislocated posterior chamber intraocular lens. J Cataract Refract Surg. 2004;30:1396–1400.
15. Rahim M, Malyugin B. Two-string technique to manage dislocated posterior chamber plate-haptic intraocular lens. J Cataract Refract Surg. 2006;32:722–726.
16. Kokame GT, Yamamato I, Mandel H. Scleral fixation of dislocated posterior chamber intraocular lenses: temporary haptic externalization through a clear corneal incision. J Cataract Refract Surg. 2004;30:1049–1056.
17. Kokame GT, Atebara NH, Bennett MD. Modified technique of haptic externalization for scleral fixation of dislocated posterior chamber lens implants. Am J Ophthalmol. 2001;131:129–131.
18. Balta FN, FN. Surgical technique for repositioning subluxated previously scleral-fixated intraocular lenses. Am J Ophthalmol. 2004;138:676–677.

SHOW OFF A GOOD TEAM
A finely tuned office is like a great soccer team: everyone works together to move the ball forward until it finds the back of the net. Your patient's retina care experience and subsequent impression of you begins to form long before he or she reaches your examination chair. Impressions are formed from the scheduler on the other end of the telephone, the front desk person, the assistant checking their vision, and the technicians performing the optical coherence tomography and fluorescein angiogram. By the time you are face to face with a patient, he has already met your team and has a flavor of the captain. Choose good people and reward kindness. Further, be mindful of the atmosphere and culture you foster in the office.

CLEANLINESS
Despite your elegant ILM-peeling skills, the closest you will get to godliness, at least in the eyes of your patients, is determined by your cleanliness. Wash or sterilize your hands in front of the patient. Also, you or your assistant should clean the slit lamp in front of your patient. Obviously, keep every inch of your office clean, tidy, and professional.

CONNECTION
Connecting with the patient begins the moment you walk into the room. The best tips are the most obvious. Make eye contact. Despite the 40 patients waiting to see you, treat the patient in the room as if he or she is the only patient coming to see you today. Greet your patient with a handshake and “Mr.,” “Mrs.,” or “Ms.,” unless he or she is a child or you have permission to use his or her first name. Jot down interesting tidbits about your patient and bring them up during his or her next visit. In a busy practice, it is hard to remember personal details of every patient. Patients will appreciate you asking about their grandson's wedding or their recent trip to Florida. Introduce yourself to family members and thank them for accompanying your patient. After all, many of them took a day off of work to bring their parent to see you. Play with your patient's children or grandchildren. Most kids love peeking through the slit lamp, and parents or grandparents love the attention you give to their little one. Try your best to not turn your back to the patient during the encounter. For those who have a scribe, it may be easier to focus on the patient and not on the chart. For those without a scribe, consider putting the chart in your lap so you can face the patient. For those with an electronic medical record system, you may have no choice but to turn and face the computer screen. Some physicians input data into a tablet computer, allowing them to face the patient.

SECOND SET OF EARS
Involve the family in caring for your patient. Though there are exceptions, it is almost always better to have a second set of ears in the room when counseling patients. This is particularly true when delivering bad news or discussing the risks of surgery. Patients may shut down when learning they have a blinding condition or need surgery; family members can help reexplain things to the patients while providing a level of support that you cannot.

WORST DAY OF YOUR PATIENT'S LIFE
You will be meeting retinal detachment patients on the worst day of their lives. They go to sleep with normal lives and normal vision, not expecting to be blind the next day. Even we myopic ophthalmologists cannot fully understand the dramatic impact of a retinal detachment that reverberates into every aspect of one's personal and professional life. It is scary, and it happens to innocent people. Subconsciously, it may be tempting to rush through the emergency add-on patient so you can stay on schedule. Putting yourself in the patient's shoes is one the most important aspects of caring for a retinal detachment patient, eclipsed only by successfully fixing the detachment (with good postoperative vision and no proliferative vitreoretinopathy).

WHEN YOU ARE RUNNING BEHIND
You are running late, again. It happens, but patients and physicians alike prefer punctuality. In an effort to improve the patient's waiting experience, consider playing educational ophthalmic videos in the waiting room. This helps pass the time while answering some of your patients' questions. Also, keep your patients moving. They can move from the waiting area to the assistant taking the history, to a different waiting area, then to the technician performing the OCT and/or fluorescein, back to a waiting area, and then finally to you. Of course, patients would rather stay on schedule than run laps around your office. If you are behind consistently, scrutinize your schedule. Are you not allocating time for emergency visits? Are you kidding yourself by booking three patients every 15 minutes? By the end of the day, you will see all of your patients, but you can work to improve the flow. Further, have your staff apologize on your behalf, and offer coffee or a snack while the patients are waiting (especially your NPO diabetic patients).

Approaching an angry patient who has been waiting patiently—and then impatiently—for you takes time and composure. You are stressed, and the patient is heated. Always apologize for being late. Some would consider joking to the patient upon entering the room to lighten the mood: “I thought you would never get here.” If you are late because of an emergency, let the patient know. You can even relate it back to the patient, if he or she was once an emergency patient. For the most irate patients, schedule their follow-up visits at the start of the day so you do not have the opportunity to make them wait again.

USE HUMOR APPROPRIATELY Patients perceive you as an authority figure, a professional, and a doctor who is helping them maintain vision and quality of life. Know yourself, and be yourself. With this in mind, it is OK to use humor during appropriate situations. Of course, this decision is physician- and patient-dependent. For instance, after reviewing postoperative instructions with a male patient and his wife, his spirits may be lifted if you instruct him to refrain from housework for at least a year. Either that or his wife will smack you.

NEVER BLAME THE PATIENT
In your career, you may care for a handful of patients who remain scornful and even hateful despite your genuine efforts to earn their respect. In these situations, when all else fails, you may need to end your patientdoctor relationship. Despite any visceral inclinations that may be buried deep beneath your white coat, never blame the patient. Instead, blame yourself. say something like this: “The most important aspect of the physician's relationship with a patient is earning trust. I have failed you as a physician and was unable to garner your trust. Thus, I cannot provide you with the best care possible. I would like you to continue your care with one of these fine physicians, who I hope will do better than I in earning your trust.” Give them a list of retina specialists in the area from which to choose. These tips only begin to address on the intricate art and skill of establishing a solid rapport with every patient, a goal that must often be accomplished within just a few minutes. As always, know yourself, your stressors, and your biases as you continue to attempt to connect with your patients.

Darrell E. Baskin, MD; Jeremy D. Wolfe, MD; and Chirag P. Shah, MD, MPH, are second-year vitreoretinal fellows at Wills Eye Institute in Philadelphia, PA, and members of the Retina Today Editorial Board. Dr. Baskin may be reached at darrellbaskin@gmail.com; Dr. Wolfe may be reached at jeremydwolfe@gmail.com; and Dr. Shah may be reached at cshah@post.harvard.edu.

Most retinal surgery cases have historically been performed in the hospital setting; however, many surgeons and ambulatory surgery centers (ASCs) are now considering incorporating retina into their facilities. Over the past few years, there have been dramatic changes in retinal surgery, including the use of topical and sub-Tenon's anesthesia and improvements in surgical instruments, which have made surgeons more efficient, resulting in shorter case time. In addition, with the implementation of the new Medicare ASC payment methodology, there has been a significant increase in facility fee reimbursement for retina procedures. These factors have spurred many retinal surgeons to consider moving their cases to an ASC.

Prior to making a decision to bring retina into the ASC setting, there are several factors that must be considered, including the cost of equipment and supplies, incremental operating expenses, the types of cases to be performed, and the efficiency of the surgeon. The following case study illustrates a process that can be used to analyze necessary factors and make a sound business decision about bringing retina cases into the ASC.

CASE STUDY
Mid-Town Eye Surgery Center is owned by three anterior segment surgeons. The facility has been operational for 3 years and has two fully equipped ORs. The surgeons perform approximately 3,500 cases per year, including 2,400 cataract surgeries. Currently, the facility is open 3.5 days per week, and both ORs are being utilized on those days.

The center owners were recently approached by two community-based retina surgeons who expressed an interest in bringing their cases to the facility. In addition, they were hopeful there might be an opportunity for future ownership in the ASC.

Based on their historical volume and types of cases being performed, the retina surgeons estimated approximately 400 cases could be done in the ASC. Additionally, there was potential to move their laser procedures (430 cases), and they also expressed an interest in doing intravitreal injections in the facility. The owners were interested in pursuing these discussions. They asked the ASC administrator to do some homework and complete a financial assessment in preparation for a follow-up meeting with the retina surgeons. The administrator gathered some preliminary information and contacted a consultant to assist her with the analysis.

CAPITAL REQUIREMENTS
The addition of retina would require the center to purchase new equipment and instruments. The administrator contacted several facilities that perform retina cases to identify assumptions for equipment and instruments. Once a list was established, the retina surgeons confirmed what equipment and instruments they felt were necessary, bids were obtained from vendors, and the total estimated capital requirements were determined (Table 1).

It should be pointed out that capital costs will vary depending on the existing facility equipment, whether laser procedures will be performed, and other surgeon requirements.

REVENUE FORECAST
The ASC owners were concerned about the ability to perform enough retina cases to cover the capital requirements, as well as other direct costs incurred for these cases. With the help of the retina surgeons, the group reviewed the current surgical procedure volume and the types of cases being performed. It was determined that the majority of cases could be done in the ASC, and the more difficult cases would still need to be performed in the hospital outpatient setting.

Using current-year Medicare facility rates and the expected surgery volume by CPT code, a 2-year revenue forecast was completed. It was assumed procedure volume would increase by 3% in year 2 and Medicare fees would be at a higher rate in the second year based on the new ASC payment methodology. It was understood that commercial rates will vary from Medicare; however, for purposes of the analysis, revenue was based solely on Medicare rates. The revenue forecast is shown below in Table 2.

EXPENSE FORECAST
In order to determine the estimated direct costs and incremental operating expenses, the following analysis was performed.

SUPPLY COSTS
This aspect of the assessment proved challenging because the retina surgeons did not have information on supply costs for cases they perform at the hospital. In order to estimate costs, the ASC administrator spoke with colleagues at other facilities performing retinal procedures. This data was compared with cost estimates provided by the consultant, and they determined an appropriate average cost per case. Detail regarding the estimated supply costs is provided in Table 3.

STAFFING COSTS
Staffing requirements and related costs were then analyzed. With the additional case volume and the estimated time required to perform these procedures, it was determined the center would be open one additional day per week. It was estimated that this would result in a total of 4,608 incremental staff hours. The annual total wages, payroll taxes and benefit costs for this added surgical day was $133,391. Table 4 illustrates the analysis that was completed to determine incremental staffing costs.

OTHER EXPENSES
Additional costs were factored into the assessment for other expenses including instrument repair, staff training, EMR, utilities, office supplies, laundry, and bank charges. These expense items were estimated at 5% of operating revenue based on historical operating expenses of the facility. Interest expense related to the anticipated capital expenditures was also included in the expense forecast. It was assumed 100% of the capital cost would be financed at an interest rate of 8% over a 5-year term.

FINANCIAL FEASIBILITY ASSESSMENT
Once the revenue and expense components were identified, the next step was to complete a feasibility assessment to determine if the estimated retina volume would be sufficient to cover related costs and generate incremental net income to the owners. As shown in Table 5, the projected incremental net income in was $53,527 year 1 and $96,213 in year 2. Operating cash flows were also identified for the owners to show the cash available when considering the impact of depreciation expense and repayment of the principal portion of the new debt. The good news was that once all costs were covered, the facility was expected to have incremental cash flow starting in the first year the retina surgeons moved their cases to the facility.

INTRAVITREAL INJECTIONS AND LASER PROCEDURES
The final step in this analysis was to determine the feasibility of performing intravitreal injections and laser procedures in the facility. The retina surgeons had a strong desire to do this because they felt it could enhance their efficiency and allow them to do these procedures between surgery cases. They also felt it would be a good revenue opportunity for the ASC.

On the surface, this seemed plausible; however, the ASC administrator expressed serious concerns about bringing these patients into the facility. First of all, the surgeons do a high number of injections (approximately 1,500), and she anticipated this would have a significant impact on patient flow. Although the surgeons would spend only a few minutes with the patients, the fact they would be seen in the facility would require them to be managed in the same manner as any surgical patient. Additional staffing time would be required for check-in and checkout, preoperative and postoperative, and chart documentation would be much more cumbersome than if these procedures were performed in the surgeon's office.

INJECTIONS
Despite the opportunity to capture a facility fee, the offsetting costs did not seem to justify performing injections in the facility. Also, the professional fee component for the retina surgeons would be reduced based on Medicare's site-of-service differential.

After completing an assessment of potential facility fee income vs the difference in professional fee reimbursement (Table 6), it was agreed that even though there would be a slight financial gain, it was not sufficient to justify making this change in operations.

LASERS
Regarding laser procedures, the same issues applied regarding the reduction in professional fee income when cases were performed in the ASC vs the clinic. The laser facility fees, however, presented a more favorable outcome for the group to consider. When weighing the difference in net facility fee income vs the variance in professional fees, the potential upside for the facility was approximately $48,000 in year 1 with the opportunity for growth in subsequent years. Further analysis was to be performed by the ASC administrator to determine if the center could accommodate these additional patients from a scheduling standpoint.

Given the results of this analysis, the owners were confident the decision to add retina would enhance the operating performance of the ASC. Longer term, the group expects to achieve greater profitability from these cases and realize a return on their investment through anticipated growth in procedure volume and expected increases in reimbursement.

The key lesson learned from this case study is the importance of performing the proper analysis before making strategic business decisions. Although there is a fair amount of time involved in performing this type of assessment, business owners can feel more confident in the decisions being made when armed with the appropriate information.

Bruce Maller is the President of BSM Consulting, a global health care services company with offices in Incline Village, NV, and Scottsdale, AZ.

Pravin U. Dugel, MD, is Managing Partner of Retinal Consultants of Arizona and Founding Member of the Spectra Eye Institute in Sun City, AZ. He is a Retina Today Editorial Board member. He can be reached at pdugel@gmail.com.

1. As a first-year fellow, what are some of the most important things you have learned from your attendings about intravitreal injection protocol?
Postinjection corneal abrasions are a pain for both you and the patient. We have all met a patient who had posttraumatic stress disorder induced by an abrasion sustained during a prior injection. The key here is patience and cooperation. It is always a good idea to let the patient know that you are about to place the speculum (or anything for that matter) onto their eye. This may mitigate blinking or moving against the speculum during insertion. Try to minimize the time the speculum is in place. Most abrasions seem to occur while retracting or removing the speculum from the upper lid. Therefore once the lower lid is stabilized, have the patient look down, manually retract the upper lid, and then disinsert the speculum. Some clinicians advocate rotating the speculum 90° to disengage the lids upon removal. Although as retina surgeons we sometimes perform corneal epitheliectomies to improve our view intraoperatively, this is one instance where we must respect the cornea.

There is little consensus and no evidence regarding postinjection antibiotics. The majority of us prescribe some sort of antibiotic drop, while others argue against any. While we know that povidone-iodine lowers endophthalmitis risk, it dries the cornea and can lead to significant patient discomfort as soon as the topical anesthesia wears off. Do not let that sway you from using the proper amount of povidone-iodine. Consider postinjection antibiotic ointment to lubricate the ocular surface while providing some antibiotic effect.

2. Flashes and floaters: You look in and see a phakic superior retinal detachment with a single, 1-clock-hour break—the perfect candidate for pneumatic retinopexy. What hurdles have you encountered in performing this procedure?
A common hurdle for first-year fellows learning pneumatic retinopexy is deciding which gas to inject. There are many considerations in choosing the appropriate gas. Assess the anterior chamber depth to determine how much fluid can be aspirated during the paracentesis. Also, it is important to remember that myopic eyes can be large with correspondingly large posterior cavities; the ultimate gas bubble should be big enough to cover the break with coverage to spare. Further, patients who may be able to position adequately but not perfectly may benefit from a larger C3F8 bubble. Remember that C3F8 requires a smaller injectable volume than SF6 and quadruples in size, helping to reduce postprocedure spikes in intraocular pressure. The longer duration of C3F8 (6 weeks vs 2 weeks), however, may be overkill for some patients.

Consider this scenario: You have chosen and injected a gas, and seconds later you see the retina covered with caviar. Fish eggs are a common problem for fellows still on the learning curve, but they can be readily avoided by keeping the needle vertical while trying to inject steadily within the gas bubble. A 30-gauge needle is approximately 12 mm in length. Find a location to inject that is away from the detached retina (if possible). When you first enter bevel up, aim toward the center of the globe and make sure that two-thirds of the needle is in the eye. At this point, the globe can be slightly rotated with the needle so that the needle is positioned at the uppermost portion of the eye (now it should be vertical in space and normal to the globe). Withdraw slightly to expose two-thirds of the needle, leaving one-third buried in the eye; inject at a moderately brisk speed. This maneuver minimizes the travel of the gas after leaving the tip of the needle. Having too much of the needle buried in the eye facilitates the development of fish eggs around the shaft of the needle. If, however, you see fish eggs, consider the following:

1. Position the patient to keep the fish eggs away from retinal breaks, thereby preventing migration of gas into the subretinal space.
2. Fish eggs usually coalesce spontaneously within 24 hours. If 1 or 2 bubbles are present, they can usually be left alone, and the patient can adopt a position with the retinal break(s) uppermost the next day.
3. Fish eggs can usually be coalesced by flicking the eye with a cotton-tipped applicator or gloved finger. Rotate the patient's head so that sclera without underlying retinal breaks is uppermost, and this site can be firmly flicked.

3. you thought you knew how to do laser until you arrive at your new fellowship location and they have the new Pascal (Pattern Scan Laser; Optimedica, Santa Clara, CA). Now what?
The PASCAL laser utilizes a 532-nm wavelength laser and was designed to deliver energy rapidly, thus providing better patient comfort. The laser settings are different from those we learned for conventional lasers.

Panretinal photocoagulation (PRP): Typical settings include a 200-µm spot size and 20-ms duration. Start the power low, at 200 mW (some retinal specialists recommend starting at 400 mW), and titrate up to achieve an appropriate burn. You can increase the duration, but that may result in patient discomfort. Be mindful that your burn will be more intense as you treat more anterior retina; be prepared to titrate down as you move anteriorly. As a new retina fellow, consider demarcating the most posterior aspect of the retina you wish to treat and then fill in anteriorly; this will keep you away from the macula if the beautifully unfolding grid hypnotizes you.

Focal: Typical settings include 100-mW power, 100-µm spot size, and 20-ms duration (some retinal specialists recommend 100-ms duration). Titrate outside of the arcade before treating the macula. While some may use the PASCAL's grid function for focal, consider single shots for more control.

When faced with the decision of whether to block the patient, consider that most patients who have experienced PRP from the conventional laser will tell you that the PASCAL is far more comfortable. The use of a retrobulbar block depends on the individual patient's level of comfort throughout the procedure. If you cannot proceed with PRP because of patient pain, however, go ahead and block the patient—he or she will thank you later.

The authors would like to acknowledge John Loewenstein, MD, at Massachusetts Eye and Ear Infirmary for his contribution.

Netan Choudhry, MD, is a first-year vitreoretinal surgery fellow at Massachusetts Eye and Ear Infirmary in Boston, MA. He can be reached at netan.choudhry@gmail.com.

Kristine Pierce, MD, is a first-year vitreoretinal surgery fellow at Casey Eye Institute in Portland, OR. She can be reached at piercekristine@hotmail.com.

Darrell E. Baskin, MD; Jeremy D. Wolfe, MD; and Chirag P. Shah, MD, are second-year vitreoretinal fellows at Wills Eye Institute in Philadelphia, PA, and members of the Retina Today Editorial Board. Dr. Baskin may be reached at darrellbaskin@gmail.com; Dr. Wolfe may be reached at jeremydwolfe@gmail.com; and Dr. Shah may be reached at cshah@post.harvard.edu.

Peter A. Campochiaro, MD, one of the study's investigators, said in an interview with Retina Today that the results suggest that ranibizumab may not be more effective than bevacizumab in the treatment of neovascular AMD, but he cautions that these results should not be generalized to other disease processes such as diabetic macular edema (DME) and macular edema due to retinal vein occlusion (RVO). Dr. Campochiaro is the George S. and Dolores Doré Eccles Professor of Ophthalmology and Neuroscience at the Wilmer Ophthalmological Institute of the Johns Hopkins Hospital School of Medicine. Researchers, including Dr. Campochiaro and Dante Pieramici, MD, stress that these hypotheses—that ranibizumab is more efficacious than bevacizumab or vice versa for any disease process—are just that, hypotheses and the true answer may depend on the disease being treated.

CLINICAL IMPRESSIONS
Currently, comparisons between the two similar anti-VEGF therapies are based purely on clinical impressions rather than firm clinical data. The ongoing Comparison of AMD Treatments Trial (CATT), which is comparing the effects of intraocular injections of 0.5 mg ranibizumab and 1.25 mg bevacizumab, will provide the clinical data to determine if there is a measurable difference in efficacy in treatment of neovascular AMD; however, the findings will not apply to other disease processes. It is possible that ranibizumab has no advantage over bevacizumab in neovascular AMD treatment but does in the treatment of macular edema due to diabetic retinopathy or RVO, as some anecdotal evidence has suggested. Some retina specialists have been disappointed in the effects of bevacizumab in patients with DME and feel that ranibizumab may provide more benefit, Dr. Campochiaro said. Likewise, there is a perceived difference in treating macular edema due to RVO, although probably not as much difference as is felt to be the case in DME, he added.

Good data are not available to support or refute such observations, Dr. Campochiaro stressed. There are positive data from small studies in which ranibizumab was used to treat DME or RVO,^2,3 and these impressive results are being confirmed by larger studies including the 6-month results of the BRAVO and CRUISE studies, he said. Case series reporting results using bevacizumab in patients with macular edema do not seem as impressive, but patient populations in these studies may differ, making it difficult to draw firm conclusions. Understanding that it is not proven that ranibizumab is superior to bevacizumab in treatment of macular edema, it is still useful to ask if there are any characteristics of ranibizumab that could potentially provide advantage.

MOLECULAR SIZE
One possible explanation as to why ranibizumab is said by some to be more effective than bevacizumab in DME and RVO is related to the molecule's size. Dr. Campochiaro speculates that diseases such as DME, in which the retinal vessels are leaking deep in the retina, may require more penetration than was originally believed.

"The transgenic mice study showed that there is a much greater systemic effect from bevacizumab compared with ranibizumab. Bevacizumab is a fairly large molecule, and yet it appears to get out of the eye and maintain levels in the circulation to a greater extent than ranibizumab," Dr. Campochiaro said. A longer half-life in the circulation is well-documented and understandable because bevacizumab contains an Fc domain while ranibizumab does not. The Fc domain may also allow bevacizumab to be transported out of the eye to a greater extent, because there are Fc receptors in the ciliary body which seem to function to transport immunoglobulin-G out of the eye into the circulation, Dr. Campochiaro explained. "However, while bevacizumab may get out of the eye as well as or better than ranibizumab and thus access the subretinal space through the circulation, it may not penetrate into the retina as well as ranibizumab," he said.

BINDING AFFINITY
Dr. Pieramici, of California Retina Consultants in Santa Barbara, CA, is doubtful that there is a clinically significant difference in effectiveness between ranibizumab and bevacizumab in neovascular AMD. Dr. Pieramici said in an interview with Retina Today that his clinical impression is that, for patients with DME as well as macular edema secondary to RVO, ranibizumab may work better than bevacizumab. A Diabetic Retinopathy Clinical Research Network (DRCR.net) study that evaluated intravitreal bevacizumab for DME⁴ produced disappointing results, Dr. Pieramici said, with intravitreal bevacizumab reducing DME in only some eyes. However, data are still needed to definitively prove that ranibizumab is the more effective treatment for DME.

"It is possible that edema may respond more rapidly and to a greater extent with ranibizumab due to its high-binding affinity for VEGF," Dr. Pieramici said.

Ranibizumab is five to twenty times more potent on a molar basis in binding VEGF-A than bevacizumab.⁵ Furthermore, there may be may have higher levels of VEGF in the eye in DME and RVO compared with AMD, Dr. Pieramici pointed out. In AMD, ischemia, with resulting upregulation of VEGF, is localized and occurs in the outer retina. In comparison, ischemia is much more diffuse in diabetic and retinal vascular disease such as RVO and occurs in the inner retina. In the latter case, ranibizumab, with its potent ability to bind to and inactivate more VEGF, would, in theory, be more effective than bevacizumab in disease states with more diffuse ischemia and higher levels of VEGF, Dr. Pieramici speculated.

This observation is counterintuitive to ranibizumab's original purpose, Dr. Pieramici added, "because the molecule was developed to penetrate the retina and treat neovascular macular degeneration, but my impression is that ranibizumab works better in diseases of the inner retina where penetration would be less of an issue, such as for DME and RVO".

1. Miki K, Miki A, Matsuoka M, Muramatsu D, Hackett SF, Campochiaro PA. Effects of intraocular ranibizumab and bevacizumab in transgenic mice expressing human vascular endothelial growth factor. Ophthalmology. 2009;116(9):1748-54.
2. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006:142(6);961-969.
3. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther. 2008;16(4):791-799.
4. Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards AR, Beck RW, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007;114(10):1860-1867.
5. Ferrara N, D'Amico L, Shams N, Lowman H, Kim R Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006;26(8):859-870.
]]> https://retinatoday.com/articles/2009-oct/1009_20-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_20-php How has your involvement with the Houston Ophthalmology Society, the Greater Houston Area American Diabetes Association (ADA), and the Gulf Coast Juvenile Diabetes Research Foundation (JDRF) influenced your approach to practicing medicine?
It is important to support and collaborate with our colleagues in medicine who are seeing patients before they seek tertiary care. It is equally important to support the organizations and foundations that facilitate ongoing research to find new treatments for the diseases that affect our patients.

Working with local and national ophthalmic societies allows me to serve as an educator and a resource for the field of retina. Devoting time to such foundations as JDRF and the ADA provides me the opportunity to assist in the fight to eradicate the horrible disease of diabetes, which affects more than half of my patient base. By working with these groups, I am acting in the best interest of my patients.

With several large, multicenter trials on the cusp of completion, how do you envision the treatment of retinal diseases changing over the next 5 years?
Age-related macular degeneration has evolved from a blinding disease to one that is now manageable with anti-vascular endothelial growth factor (anti-VEGF) agents. The downside of these treatments is the necessity for continuous and frequent injections.

Patients with retinal vein occlusion and diabetic eye disease, however, have much higher VEGF production. In cases that are not self-limiting, such as some vein occlusions, it is likely that even monthly injections of the currently available doses of anti-VEGF will not be sufficient to fully control these diseases. I believe that in the future, we will use more of the "art of medicine" approach and rely less frequently on pure clinical trial data to manage these patients.

What do you enjoy most about being a retina specialist?
It changes every day. I really enjoy vitreoretinal surgery, where I can use microsurgical techniques to repair anatomic defects. What's not to like about helping patients while sitting in a comfortable chair listening to country-and-western music and having a great staff that waits on me hand and foot? Beyond surgery, I am thankful for the ability to make a difference in patients' lives through treatments that keep them independent; this is what keeps me coming back to the clinic every day.

What do you find to be the most challenging aspect of being a peer reviewer of ophthalmic journals?
Mark Twain said in his autobiography, "There are three kinds of lies: lies, damned lies and statistics." It is crucial that a peer reviewer discern any underlying bias in the presentation of data to ensure that the presentation is fair and balanced.

I spend more time reviewing large randomized trials, because I know that these will have a significant effect on practice patterns. The individual case series and reports, however, are also important tools in our continuing medical education.

What is the most exciting experience you have had traveling?
I spent Christmas vacation with my wife and my four kids hiking the Shira Plateau region in Kilimanjaro, Tanzania. We spent 8 days hiking there, sleeping in tents. The trip culminated when we reached the summit on Christmas Eve. Although the first 8 days were solid rain, sleet, and snow, we had 30 minutes of brilliant sunlight when we reached the top of Africa. Afterward, we hiked down to Kibo Crater, where we spent the night of Christmas Eve at 18,300 feet. The next morning, we woke up to 3 feet of snow on our tent. Santa Claus had still found us, however, and my 10- and 11-year old daughters were surprised when they woke up with new stuffed animals.

]]> https://retinatoday.com/articles/2009-oct/1009_06-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_06-php In retina surgery, skill and technique are both important factors in determining outcomes. In publications that we read, at conferences we attend, and in conversations we have with our retina colleagues, we can gain insight into specific techniques that can change the way we perform one or more steps in a surgical procedure.

        In this issue of Retina Today, Michael D. Ober, MD, describes the details of a technique that he has used for complicated diabetic vitrectomy. He explains the factors that guide his decision-making process, and he discusses the rationale for using particular surgical tools with this technique.

        We extend an invitation to readers to submit surgical pearls for publication in Retina Today. Please send submissions for consideration to Dean Eliott, MD (deliott@doheny.org), or Ingrid U. Scott, MD, MPH (iscott@psu.edu). We look forward to hearing from you.
        

- Dean Eliott, MD; and Ingrid U. Scott, MD, MPH

                

In several publications, Hugo Quiroz-Mercado, MD, described a modified technique for perfluorocarbon-perfused vitrectomy for repair of complicated retinal detachment and vitreous biopsy.^1-3 I have had the good fortune of performing several of these procedures with Dr. Quiroz-Mercado at the Hospital Dr. Luis S‡nchez Bulnes in Coyocan, Mexico. It is difficult to duplicate this technique exactly in the United States because perfluorocarbon liquid is very expensive and available only in relatively small amounts. I have successfully modified some of the techniques inherent to perfluorocarbon-perfused vitrectomy for complicated cases in my own practice using the limited quantities commercially available. The concept behind this technique is to provide broad countertraction on the relatively delicate retina with perfluorocarbon liquid. This allows peeling of preretinal membranes with a decreased need for cutting individual points of traction. The perfluorocarbon liquid also provides a measure of dissection itself by flowing between the retina and overlying membranes. It tends to suspend the elevated membrane edge as well, thereby allowing for easy regrasping. Furthermore, operating under perfluorocarbon liquid almost always means operating on attached retina. The major advantage of true perfluorocarbon-perfused vitrectomy over the modified technique is the ability to use instruments with suction such as the vitreous cutter. In this article, I explain the technique further via a particularly unusual and difficult case that I encountered. This technique is also similar to what is described by J. Fernando Arevalo, MD.^4,5

        

PREOPERATIVE CONSIDERATIONS
        A 29-year-old woman presented with bilateral macula-off retinal detachments combined with extensive peripheral retinoschisis and multiple outer and inner layer holes (Figures 1-3). She also had advanced diabetic retinopathy with extensive peripheral retinal neovascularization that seemed to be concentrated around the large, mostly outer-layer holes. As expected with her young age, the hyaloid was attached posteriorly.

        

I anticipated that it would be extremely difficult to dissect the hyaloid and fibrovascular membranes from the partial thickness underlying inner retinal layer. Any attempts at countertraction with a lighted pick would likely leave many more holes in the inner retina. Thus, my goal was to use the broad holding power of perfluorocarbon liquid to stabilize the inner retina while I grasped the hyaloid and proliferative membranes with forceps.

        

TOOL SELECTION
        A true perfluorocarbon-perfused vitrectomy is very difficult at my institution because liquid is extremely expensive and not available in the large quantity that would be required. The lack of continuous perfluorocarbon infusion limits my ability to use a vitreous cutter or any instrument that uses a sucking action, and so I used forceps in this case.

        

I first placed an encircling No. 41 band attached with a No. 70 sleeve. It is extremely rare for me to use an encircling buckle in an eye with advanced diabetic retinopathy because of the risk of anterior segment ischemia; however, in this case I wanted to support the vitreous base broadly in the setting of multiple inner and outer layer holes with peripheral proliferative retinopathy.  I chose 20-gauge instrumentation for two reasons. First, the scleral buckle required opening the conjunctiva. Second, I wanted our full complement of instruments including curved horizontal scissors available.  While there are curved horizontal scissors available for small incision vitrectomy, the cannula/trocar system does not allow for an angle between the shaft and blades, thus limiting their effectiveness.

        

CORE VITRECTOMY
        I performed a limited core vitrectomy and then injected triamcinolone (Triesence, Alcon Laboratories, Inc.) over the optic nerve, hoping to stain the posterior hyaloid. I then elevated the posterior hyaloid under fluid in a very limited area around the optic nerve and partially in the macula.

        

I then injected the perfluorocarbon liquid (Perfluoron, Alcon Laboratories, Inc.) into the opening in the posterior hyaloid, filling nearly three-quarters of the eye. The hyaloid was mildly stained with triamcinolone. The posterior hyaloid was grasped with forceps, elevating it from under the perfluorocarbon liquid. The perfluorocarbon liquid helped to dissect the hyaloid away from the retina and also successfully held the retina in a broad fashion flat against the underlying tissues. As the process was extended peripherally, I was able to peel the proliferative membranes away from the inner wall of the retinoschisis.

        

Some areas remained elevated despite the perfluorocarbon liquid because of the fluid trapped within the schisis cavity; the perfluorocarbon, however, held back the inner retina to a level sufficient to allow removal of the preretinal membranes using only forceps. I was unable to remove a small area of residual proliferative tissue surrounding the 12-o'clock position; however, it was peripheral to the large outer hole, and I was able to place laser in a panretinal fashion without difficulty. Additional laser was concentrated around all visible inner- and outer-layer retinal holes.  Some of the trapped fluid was confirmed to be schisis fluid; I still had fairly good laser uptake despite the obvious elevation of the inner retina.

        

AIR-FLUID EXCHANGE
        An air-fluid exchange was then performed including removal of all perfluorocarbon liquid. Additional endolaser was placed to the ora serrata and then silicone oil was injected. I chose silicone oil for several reasons. The patient had multiple inner and outer retinal holes that were difficult to identify, and her vision in the fellow eye was poor (counting fingers). Additionally, the patient had three young children, so it was likely she would be unable to position adequately.

        

POSTOPERATIVE RESULTS
        One week postoperative, uncorrected vision was hand movements with an excellent oil fill (Figure 6). She already began developing a posterior subcapsular cataract, but the view was quite good to the retina. There was shallow subretinal or intraretinal fluid mostly along the inferior arcades and shallowly in the macula, but the periphery and central macula were successfully reattached.

        

Michael D. Ober, MD, practices with Retina Consultants of Michigan and is a member of the Adjunct Teaching Faculty, Department of Ophthalmology, Henry Ford Health Systems, Detroit, MI. Dr. Ober states that he is a paid consultant for Alcon Laboratories and OD-OS. He can be reached at obermike@gmail.com.

        

Dean Eliott, MD, is a Professor of Ophthalmology and Director of Clinical Affairs, Doheny Eye Institute, Keck School of Medicine at University of Southern Carolina and is a member of the Retina Today Editorial Board. He may be reached by phone: +1 323 442 6582; fax: +1 323 442 6766; or via e-mail: deliott@doheny.org.

        

Ingrid U. Scott, MD, MPH, is a Professor of Ophthalmology and Public Health Sciences, Penn State College of Medicine, and is a member of the Retina Today Editorial Board. She may be reached by phone: +1 717 531 4662; fax: +1 717 531 5475; or via e-mail: iscott@psu.edu.

        
            
1. Quiroz-Mercado H, Guerrero-Naranjo J, Agurto-Rivera R, et al. Perfluorocarbon-perfused vitrectomy: a new method for vitrectomy–a safety and feasibility study. Graefes Arch Clin Exp Ophthalmol. 2005;243(6):551–562.
            
2. Quiroz-Mercado H, Garcia-Aguirre G, Ustáriz-Gonz‡lez O, Mart'n-Aviˆ J, Martinez-Jardon S. Perfluorocarbon-perfused vitrectomy using a transconjunctival 25-gauge system. Retina. 2007;27(7):926–931.
            
3. Quiroz-Mercado H, Suarez-Tat‡ L, Magdalenic R, et al. Perfluorocarbon perfused vitrectomy: animal studies. Am J Ophthalmol. 2004;137(2):287–293.
            
4. Arevalo JF. En bloc perfluorodissection for tractional retinal detachment in proliferative diabetic retinopathy. Ophthalmology. 2008;115(6):e21–25.Ê
            
5. Arevalo JF.En bloc perfluorodissection in vitreoretinal surgery: a new surgical technique. Retina. 2008;28(4):653–656. Erratum in: Retina. 2008 Jun;28(6):913.
        
]]> https://retinatoday.com/articles/2009-oct/1009_18-pdf Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_18-pdf https://retinatoday.com/articles/2009-oct/1009_08-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_08-php The CLEAR-IT 2 trial was a phase 2 study of the safety and efficacy of VEGF Trap-Eye (Regeneron Pharmaceuticals) in patients with neovascular age-related macular degeneration (AMD). The results of the phase 2 trial were presented at the 2008 Retina Society meeting.¹ An extension of the CLEAR-IT 2 trial followed patients from the original trial; 6-month results of the extension stage of the study were presented at the Association for Research in Vision and Ophthalmology (ARVO) earlier this year.² This article reviews results of the initial CLEAR-IT 2 as well as data from the extension stage.

CLEAR-IT 2
VEGF Trap-Eye is a purified formulation of VEGF Trap, a vascular endothelial growth factor (VEGF) receptor fusion protein that binds all forms of VEGF-A (Figure 1). VEGF Trap-Eye, formulated for intraocular use, is being developed for the treatment of neovascular AMD, diabetic macular edema, and other ocular pathologies.

CLEAR-IT 2 was a double-masked multicenter trial in which patients with neovascular AMD were randomly assigned to receive monthly intravitreal injections of VEGF Trap-Eye 0.5 mg or 2.0 mg or quarterly injections of 0.5, 2.0 or 4.0 mg for an initial 3-month fixed-dose period, after which they received the same doses on an as needed basis at monthly visits out to 1 year. Subgroups of patients were established based on age, best-corrected visual acuity (BCVA) at baseline, lesion size at baseline, and previous treatment for neovascular AMD.

At 1 year, for all treated groups combined (n=157), there was a significant improvement in BCVA from baseline (mean improvement 5.3 letters; P<.0001). Patients who received three monthly doses of 2.0 mg followed by as-needed dosing achieved mean improvements in BCVA of 9.0 letters from baseline (P<.0001 vs baseline). Those who received three monthly doses of 0.5 mg followed by as-needed dosing achieved mean improvements of 5.4 letters from baseline (P<.085 vs baseline) at the end of 1 year. Patients who received initial quarterly dosing followed by as-needed dosing also achieved gains in BCVA, but they were generally not as robust as those achieved with initial monthly dosing.

Patients receiving initial monthly doses of VEGF Trap-Eye achieved mean decreases in retinal thickness vs baseline at 1 year. In addition, treatment with VEGF Trap-Eye was associated with a reduction in the size of the total active choroidal neovascular membrane (CNV).

Subgroup analyses were presented at this year's ARVO meeting. Patients 75 years old or less achieved greater BCVA gains than those older than 75 years. Other differences between subgroups did not achieve statistical significance.

EXTENSION STUDY
Six-month results for 117 patients who elected to enter the extension stage of the CLEAR-IT 2 study were also presented at this year's ARVO. All patients received 2.0 mg VEGF Trap-Eye on an as-needed basis.

In the original study, the mean gain in BCVA from baseline for the 117 patients who entered the extension stage was 7.3 letters (P<.0001 vs baseline) at the 3-month primary endpoint of the original study, 8.4 letters (P<.0001 vs baseline) at 1 year, and 7.1 letters (P<.0001 vs baseline) at month 6 of the extension study. Over the 15-month course of the PRN dosing phase, from month 3 of the original study to month 6 of the extension phase, patients received a mean 3.5 injections of VEGF Trap-Eye.

The treatment was generally well tolerated throughout the study, and there were no drug-related serious adverse events. One case of culture-negative endophthalmitis/uveitis was reported in a study eye, and there were two arterial thrombotic events that were deemed not to be related to the drug. Three deaths were reported, two related to cancers and one in a patient with pre-existing pulmonary hypertension. The most common adverse events were those typically associated with intravitreal injections, including conjunctival hemorrhage at the injection site and transient increased intraocular pressure following injection.

CONCLUSION
The extension study demonstrates that patients with neovascular AMD achieved and maintained significant improvement in BCVA for 18 months with initial fixed dosing followed by 15 months of as-needed administration. On average, only 3.5 injections were given during the PRN dosing phase. Patients continue to be seen and treated in the extension stage of the CLEAR-IT 2 study.

Jeffrey S. Heier, MD, is a Clinical Ophthalmologist specializing in diseases of the retina and vitreous at Ophthalmic Consultants of Boston. He reports that is a consultant or Regeneron, Inc. Dr. Heier is a member of the Retina Today Editorial Board. He can be reached at jsheier@eyeboston.com.

1. Brown D. One year results of a phase 2, randomized, controlled dose- and interval-ranging study of intravitreal VEGF Trap-Eye in patients with neovascular age-related macular degeneration. Paper presented at: Retina Society annual meeting; September 25-28, 2008; Scottsdale, AZ.
2. Heier JS, CLEAR-IT 2 Investigators. CLEAR-IT 2: Phase 2, randomized, controlled dose-and interval-ranging study of intravitreal VEGF Trap Eye in patients with neovascular age-related macular degeneration: predictive factors for visual acuity outcome at one year. Paper presented at: Association for Research in Vision and Ophthalmology annual meeting; May 4, 2009; Fort Lauderdale, FL.
]]> https://retinatoday.com/articles/2009-oct/1009_10-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_10-php There is currently no effective or approved treatment for vision loss associated with geographic atrophy (GA) in nonexudative age-related macular degeneration (AMD). Ciliary neurotrophic factor (CNTF) is a neurotrophic factor that has been shown to increase thickness of the retina, in particular the outer nuclear layer of photoreceptors, in animal models. NT-501 (Neurotech) is an intraocular implant containing encapsulated cells genetically modified to secrete CNTF and deliver it to the posterior segment.

A phase 2, randomized, double-masked, controlled, multicenter dose-ranging study was performed to assess the safety profile of the NT-501 encapsulated cell technology in subjects with geographic atrophy. A secondary purpose of the study was to identify efficacy trends in terms of structure and function, to help determine primary endpoints for future clinical studies of efficacy.

The study included 51 subjects at eight sites, randomized 2:1:1 to receive a high- or low-dose NT-501 intravitreal implant or sham surgery. After 1-year follow-up, the primary study endpoint, the investigator could remove the device if the patient so desired. Then patients were followed for an additional 6 months. Patients were included if they were 50 years old or more, had best corrected visual acuity (BCVA) of 20/50 to 20/200, and had GA-associated vision loss in the study eye. GA was defined as one or more well-defined circular patches of pigmented retinal pigment epithelium greater than 350 µm in diameter.

Optical coherence tomography (Stratus OCT; arl Zeiss Meditec, Jena, Germany) scans were analyzed at the Duke Reading Center for quantitative and morphologic changes. Quantitative measures included average thickness at center point, total macular volume, and average thickness in nine subfields. Morphologic factors included intraretinal cysts, subretinal fluid, choroidal neovascularization (CNV), epiretinal membrane (ERM), and vitreomacular traction.

WELL-TOLERATED
The NT-501 was well-tolerated. No serious adverse events were attributed to the implant. No endophthalmitis or retinal detachment occurred, and there was no increase in intraocular pressure, CNV, or serum antibodies to either the CNTF or the encapsulated cells.

CNTF treatment resulted in dose-dependent changes in retinal thickness as early as 4 months after implantation, with changes maintained through 6 and 12 months. There was a statistically significant increase in total macular volume in the group with high-dose–releasing implants compared with the low-releasing group and the sham surgery group.

The significant increase in retinal thickness persisted when possible mitigating factors were controlled for, including toxic effects related to cysts, ERM, CNV, and vitreomacular traction. These results are consistent with the preclinical studies. The increase could have been due to increases in size of photoreceptor cells or in the number of cells, but with the resolution of the time-domain Stratus OCT it was not possible to determine this.

STABILIZED BCVA
The anatomic changes were associated with stabilization of BCVA (less than 15 letters lost) in the high-dose group compared with low-dose and sham groups at 12 months. In post-hoc subgroup analysis, in the eyes that started with better BCVA at baseline (20/63 or better), there was a greater difference between the high-dose group and the other two groups in preservation of visual acuity. None of the eyes in the high-dose group lost 15 letters of BCVA, and the mean BCVA in the high-dose group was 10.5 letters greater than the BCVA in the low-dose and sham groups combined.

Five patients allowed their implants to be explanted after 1 year, and those implants were evaluated. All of them contained viable cells and continued to release CNTF for up to 18 months.

In summary, safe, sustained intraocular delivery of CNTF with encapsulated cell technology was demonstrated in a multicenter clinical trial. A potential for a therapeutic effect in eyes with GA in nonexudative AMD was identified in terms of both retinal thickness change and visual function, especially in eyes with better BCVA at baseline. These data should be helpful in designing subsequent clinical trials in larger patient populations.

Glenn J. Jaffe, MD, is a Professor of Ophthalmology in the Vitreoretinal Service at Duke University Eye Center, Durham, NC. He reports that he is a consultant to Neurotech. Dr. Jaffe may be reached at jaffe001@mc.duke.edu.

]]> https://retinatoday.com/articles/2009-oct/1009_12-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_12-php

The ability of vascular endothelial growth factor (VEGF) inhibitors to improve visual acuity in most patients with neovascular age-related macular degeneration (AMD) has been well established in clinical trials and clinical practice. In most of these patients, however, choroidal neovascularization (CNV) is stabilized but does not regress. Anti-VEGF drugs control angiogenesis and leakage, but they do not effect vascular remodeling.

Platelet-derived growth factor (PDGF) is a protein that regulates cell growth and is involved in angiogenesis. An anti-PDGF pegylated aptamer (E10030, Ophthotech) has been shown in experimental models of neovascularization to "strip away" pericytes from neovascular tissue.^1,2

A phase 1 clinical trial was conducted to evaluate intravitreal combination therapy of the PDGF inhibitor E10030 plus the VEGF inhibitor ranibizumab (Lucentis, Genentech).³ This dose-escalation study included 22 patients at multiple sites, with 0.03-, 0.3-, 1.5-, and 3.0-mg doses of E10030 given in combination with ranibizumab once monthly for 3 months. All eyes in the study had subfoveal CNV with some classic component and a total lesion size of five disc areas or less. Pre- and post-treatment fluorescein angiography were analyzed for CNV vascular area and qualitative patterns.

Results of this phase 1 study were compared with a retrospective group of 24 patients treated with ranibizumab or bevacizumab (Avastin, Genentech) induction therapy, once a month for 3 to 5 months, from 2007 to 2009.3 These patients had mostly predominantly classic CNV lesions secondary to AMD with total lesion size of five disc areas or less.

With anti-PDGF/anti-VEGF combination therapy, partial regression of CNV lesions occurred in 91% of patients. Vascular regression of CNV was observed to leave a hypofluorescent plaque. No patients receiving combination therapy experienced progression of CNV in the trial. In contrast, in patients treated with anti-VEGF monotherapy, CNV regressed in 16% of patients, but most remained stable and some progressed. Stable inactivity was observed in 9% of eyes treated with combination therapy, compared with 68% of eyes treated with anti-VEGF monotherapy.

These preliminary data suggest that combination therapy with an anti-PDGF aptamer plus a VEGF inhibitor produces regression of CNV lesions. Fluorescein and indocyanine green angiography is useful in evaluating the regression of CNV lesions in response to treatment.

Scott W. Cousins, MD, is Director of the Center for Macular Diseases at Duke University Eye Center. Dr. Cousins reports that he is a consultant to Ophthotech. He may be reached via email at scott.cousins@duke.edu; phone: 919-684-3090; fax: 919-681-6474.

1. Mitchell TS, Bradley J, Robinson GS, Shima DT, Ng YS. RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis. 2008;11(2):141-151.
2. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. 2006;168(6):2036-2053.
3. Cousins SW, Csaky KG, Ophthotech Study Group. Patterns of CNV fluorescein and indocyanine green angiographic regression responses after anti-VEGF monotherapy or anti-VEGF plus anti-PDGF combotherapy. Paper presented at: Association for Research in Vision and Ophthalmology annual meeting; May 4, 2009; Fort Lauderdale, FL.
]]> https://retinatoday.com/articles/2009-oct/1009_13-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_13-php

Patients are becoming increasingly aware of age-related macular degeneration (AMD) through affected family members and personal experiences, as well as through increased media coverage due to the growing prevalence of the disease. This awareness has been a driving force in the development of new therapies and technologies to improve their care.

Our understanding of AMD's epidemiology has also grown considerably over the years. With that increased knowledge, we have gained the ability to help our patients prevent both the atrophic nonexudative (dry) AMD and conversion to exudative (wet) AMD. Through risk identification, behavior modification, and nutritional supplementation, our patients have more control over their ocular health than ever before. Even with this improved understanding of AMD risk modification, however, it is inevitable that preventive measures will not work for all patients. Despite the best efforts to prevent conversion, some of our patients will progress to exudative AMD and require treatment. Although this is an unfortunate reality, we have an increasing number of tools at our disposal to improve treatment success.

EFFECTIVE MONITORING OF THE DISEASE
Choosing the best therapy protocols for your practice and each patient is imperative. With drugs that inhibit vascular endothelial growth factor (VEGF), we have the ability to truly help many of our AMD patients gain better visual acuity. However, implementing treatment in a timely manner is just as important in order to obtain the best outcomes. As retinal specialists, our ability to provide patients with treatment at the optimal time can depend on several factors, including proper referral timing, accurate reporting of symptoms by the patient, and meticulous at-home and in-office monitoring protocols to identify conversion early. All of the above issues—and more—can affect our ability to apply treatment as early as possible.

The Amsler grid has long been the basis of AMD monitoring both in-office and at home. However, new technologies now allow us to provide more accurate and in-depth monitoring capabilities to our patients. The Amsler grid's benefits and weaknesses lie in its simplicity. It is easy to use and an inexpensive way to monitor AMD. It has low sensitivity scores, however, and when used for at-home monitoring, patient compliance becomes a concern.^1,2 My practice has implemented several technologies additive to our use of the Amsler grid that have improved our ability to enhance treatment success through timelier implementation.

Preferential Hyperacuity Perimetry (Foresee PHP; Sightpath Medical, Bloomington, MN) is one tool we use in my office regularly to monitor at-risk patients for conversion. Based on hyperacuity, the test can identify subtle changes in the macular field that affect the ability to perceive minute differences in the alignment of visual stimuli. The PHP technology offers greater sensitivity and specificity than the Amsler Grid and can also compensate for limitations of the Amsler grid such as completion, fixation and crowding.^1,3 The test has also been shown to differentiate between intermediate dry AMD and wet AMD.⁴ Often, patients are referred to us for treatment of CNV in one eye while the fellow eye has only small drusen. Because of the likelihood that the fellow eye will convert, PHP technology has become essential in monitoring these high-risk patients.

After the PHP technology indicates an abnormality, we follow up with optical coherence tomography (Cirrus Spectral Domain HD-OCT; Carl Zeiss Meditec, Dublin, CA) The OCT takes cross-sectional images of the retina and allows us to identify subtle areas of change within the macula. Its ability to indicate slight accumulations of fluid is essential in confirming the presence of CNV. Additionally, when patients are unable to accurately describe their symptoms, the device can help us determine exactly what they are experiencing and locate the pathology. The OCT imaging has come a long way over the years and is now offered in several models by several manufacturers in various price ranges and levels of image clarity.

Finally, one of the most beneficial tools developed for retinal diagnosis is the fluorescein angiogram (FA). This diagnostic test has become widely used because of its ability to provide information about the condition of the back of the eye and the circulation within the eye. For our patients with AMD, it is particularly useful in confirming the presence of CNV. The fluorescein dye injected into the bloodstream collects in areas of leakage due to CNV and appears highlighted in the photographic results.

Combining the PHP technology, OCT, and FA helps practitioners to more accurately identify progression to CNV, implement treatment in a timely fashion and provide patients with confidence in their ocular care (see accompanying case study).

Our knowledge of and ability to manage AMD have come a long way in recent years. Treatment success is greatly improved through better therapeutic options and monitoring capabilities. With improved education, patients are maintaining their vision far longer than ever before. Until there is an absolute cure for this disease, however, these improvements must continue. We owe it to our patients to improve their knowledge of AMD as well as our referral processes, therapeutic offerings and office technologies so they can obtain the best visual outcomes possible.

Paul Garfinkle, MD, is a retina and comprehensive ophthalmologist at Ohio EyeAlliance. He has experience in the diagnosis and treatment of medical retinal disease, age-related macular degeneration, and small incision cataract surgery. He states that he has no financial interest in the companies or products mentioned. He may be reached at eyedoc7@neo.rr.com

1. Zaidi FH, Cheong-Leen R, Gair EJ, et al. The Amsler chart is of doubful value in retinal screening for early laser therapy of subretinal membranes. The West London Survery. Eye. 2004;18:503–508.
2. Trevino R. Recent progress in macular function self-assessment. Ophthal Physiol Opt. 2008 28:183–192.
3. Preferential Hyperacuity Perimetry Research Group. Preferential hyperacutiy perimeter for detecting choroidal neovascularization study. Ophthalmology. 2005:112:1758–1765.
4. Loewenstein A, Malach R, Goldstein M, et al. Replacing the Amsler grid: a new method for monitoring patients with age-related macular degeneration. Ophthalmology. 2003;110(5):966–970.
]]> https://retinatoday.com/articles/2009-oct/1009_14-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_14-php

The stimuli for choroidal neovascularization (CNV) in age-related macular degeneration (AMD) are not completely defined. However, it has been confirmed that the vitreous plays a role in the pathogenesis of exudative AMD. We have been interested in the relationship between traction from the posterior vitreous and the development of AMD, and we have performed a number of studies exploring that relationship.

Three comparative studies were performed to evaluate the relationship of the posterior vitreous to the macula in AMD. The first evaluated vitreomacular adhesion (VMA) and posterior vitreous detachment (PVD) in eyes with exudative AMD, nonexudative AMD, and age-matched controls.¹ A second study, designed to eliminate potential influences of genetics and environment, compared VMA and PVD in patients with wet AMD in one eye and dry AMD in the fellow eye.² The first two studies were done in collaboration with Jerry Sebag, MD, of the VMR Institute, and Lawrence Yannuzzi, MD, of Vitreous-Retina-Macula Consultants of New York. A third study examined differences in these conditions between active and end-stage AMD.²

In the first study, in a total of 163 eyes, ultrasound revealed a significantly lower percentage of complete PVD in eyes with exudative AMD (17 of 50; 34%), in comparison with eyes with nonexudative AMD (41 of 57; 71.9%) and control eyes (34 of 56; 60.7%). Optical coherence tomography (OCT) showed persistent central VMA surrounded by a detached posterior vitreous cortex in more eyes with exudative AMD (18 of 50; 36%) than in nonexudative AMD (4 of 57; 7%) and control eyes (6 of 56; 10%).

In the second study, in patients with wet AMD in one eye and dry AMD in the other (Figure 1), similar results were seen. Again, VMA was significantly higher in eyes with wet AMD compared with dry AMD, and complete PVD was higher in eyes with dry AMD than wet AMD. In the third study, examining advanced disease, the difference did not continue to be significant because of an increased incidence of PVD and decreased incidence of VMA in eyes with disciform scars.

Taken together, our conclusion from these studies was that PVD was highly associated with dry AMD, as confirmed by ultrasound, and that a high percentage of eyes with wet AMD have vitreomacular adhesions, with OCT providing useful information about the relationship of vitreous and retina. Genetic and environmental factors did not influence these observations, and the differences did not persist into end-stage disease.

3-D OCT STUDY
Others have suggested that persistent attachment of the posterior vitreous cortex to the macula may be a risk factor for the development of exudative AMD due to chronic low-grade inflammation induced by vitreoretinal traction,³ due to macular exposure to cytokines or free radicals in the vitreous gel,⁴ and/or due to interference with oxygenation and nutrition of the macula from the vitreous.⁵

In light of our own studies and these observations, we formed the hypothesis that vitreomacular traction might play a role in the development of neovascularization, and we sought to examine this hypothesis using high-definition 3-D imaging technologies.

This most recent study was designed to examine tractional forces in the development of exudative AMD. We wanted to determine whether spectral domain high-definition OCT, with its higher resolution, faster scan acquisition, and raster scanning capability, could contribute additional information about the localization and direction of vitreomacular traction.

We examined a consecutive series of patients, who presented with different types and stages of exudative AMD and vitreoretinal adhesions, using a 3-D display system that allowed enhanced visualization of subtle structures of the vitreoretinal interface.⁶ Eyes were imaged with the macular cube 512x128 program of the Cirrus HD OCT (Carl Zeiss Meditec, Jena, Germany) and with the high speed mode of the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany), oversampled twice, and with a single high-resolution line placed through the center of the lesion. Visualization was further improved by ray-traced 3-D reconstruction using a custom-made subprogram in the Cinema 4D XL 11.0 software program (Maxon Computer, Friedrichsdorf, Germany). A pseudo-segmentation algorithm was implemented using noise-reduction filtering and a stepped color gradient. Finally, the ray-traced shading was backed directly into the texture, resulting in real-time visualization using OpenGL.

Using this system, 25 eyes of 20 patients, mean age 76.6 years, were examined. Most of the patients (62%) were under treatment with vascular endothelial growth factor (VEGF)-inhibiting therapy; 38% were treatment-na•ve.

Vitreomacular adhesions surrounded by shallow detachment of the posterior hyaloid were localized in the fovea in 52.4% and were juxtafoveal in 47.6% of eyes. In 93% of the juxtafoveal lesions, a retinal angiomatous proliferation (RAP) was present.

The area of the adhesion in each eye corresponded with localization of a "hot spot" shown in that eye's indocyanine green angiography, even if the lesion extended under the foveal avascular zone. Overall, the area of adhesion corresponded in 100% of eyes with the localization of the CNV.

In 72% of eyes, traction of the posterior hyaloid on the retina was visible, and the traction forces were directed toward the CNV, which could be visualized in the 3-D images. Tight adhesion and traction could also be detected on the temporal margins of the optic disc. Adhesions and traction forces were visible with both OCT machines.

CONCLUSIONS
Using 3-D spectral domain OCT technology from two manufacturers with this image-enhancement system, we were able to gain further insights into the precise location of VMAs, the direction of traction, and the forces of the vitreous, as well as the development of CNV. Visualization of the tractions and 3-D post-processing were possible in real time regardless of the spectral domain OCT hardware used.

Further studies will be required to confirm interesting aspects of the current study, such as the high incidence of RAP lesions associated with vitreoretinal traction, traction on the margin of the optic disc, and persistence of adhesions during anti-VEGF therapy. Subsidiary pharmacologic vitreolysis or sutureless, nonvitrectomizing posterior-hyaloid–lifting surgery might be potential avenues to improve the treatment of exudative AMD.

Susanne Binder, MD, is Professor and Chairman in the Department of Ophthalmology of the Ludwig Boltzmann Institute for Retinology and Biomicroscopic Laser Surgery, Rudolf Foundation Clinic, in Vienna, Austria. She may be reached at +43 1 71165 4607; fax: +43 1 71165 4609; e-mail: susanne.binder@wienkav.at.

Carl Glittenberg, MD; Christiane Falkner-Radler, MD; and Ilse Krebs, MD; are with the Ludwig Boltzmann Institute for Retinology and Biomicroscopic Laser Surgery, Department of Ophthalmology, Rudolf Foundation Clinic, Vienna, Austria.

The authors state that they have no proprietary interests in the products or companies discussed in this article.

1. Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? Am J Ophthalmol. 2007;144(5):741-746.
2. Robison CD, Krebs I, Binder S, et al. Vitreomacular adhesion in active and end-stage age-related macular degeneration. Am J Ophthalmol. 2009;148(1):79-82.
3. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134(3):411-431.
4. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina. 2005;25(2):111-118.
5. Holz FG, Pauleikhoff D, Klein R, Bird AC. Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol. 2004;137(3):504-510.
6. Glittenberg C, Krebs I, Falkner-Radler C, et al. Advantages of using a ray-traced, three-dimensional rendering system for spectral domain Cirrus HD-OCT to visualize subtle structures of the vitreoretinal interface. Ophthalmic Surg Lasers Imaging. 2009;40(2):127-134.
]]> https://retinatoday.com/articles/2009-oct/1009_15-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_15-php

In retinal detachment (RD), fluid can accumulate in the subretinal space, between the sensory retina and the retinal pigment epithelium (RPE). Current treatments for RD include scleral buckling, pneumatic retinopexy, and vitrectomy with tamponade.

In complex cases of RD, aspiration of subretinal fluid may be performed to allow immediate apposition of the detached retina. A range of cannula sizes can be used for aspiration of subretinal fluid. Current 39- or 40-gauge cannulas can leave behind a self-sealing retinotomy, but they do not allow efficient aspiration of fluid.

In selected cases of RD, I have begun using the iScience Subretinal Aspiration Cannula (iSRAC; iScience Interventional, Menlo Park, CA), which is a Class 1 device in the United States. The device uses a concentric coaxial vacuum design, attaching to retinal tissue with an outer 25-gauge vacuum ring while using an inner 40-gauge vacuum cannula to aspirate subretinal fluid (Figure 1).

FLUID DRAINAGE
The main application for the iSRAC is for drainage of subretinal fluid, used in conjunction with standard three-port vitrectomy. At the end of a complex case—for example, vitrectomy in a diabetic patient with a long-standing tractional retinal detachment—there may still be a reservoir of chronic subretinal fluid. In that situation, the iSRAC can be used to drain the fluid with minimal trauma and without the need to create any laser burns.

A very small hole is made with the beveled tip of the 40-gauge cannula (125 µm) that forms the core of the iSRAC. The outer 25-gauge cannula keeps the retina engaged, elevated, and stabilized under an annulus of suction, while the inner coaxial suction allows aspiration of the subretinal fluid through the 40-gauge cannula. The device is extremely atraumatic in terms of causing scotomas; it makes very small scars with hardly any bleeding (Figures 2-6).

The iSRAC may not be needed in every case, but it can be valuable in selected situations. For instance, it may be called into play after a normal suction device has been used for the majority of a case. After drainage of most of the subretinal fluid, a pool of subretinal fluid may be seen to have tracked posteriorly. A drainage hole can be made to drain the residual fluid, but a big hole in the posterior retina is undesirable. In a case like this, with a small pocket of residual fluid, the 40-gauge inner cannula is perfect because it is so atraumatic. The iSRAC is also helpful for making drainage spots very close to the macula when needed, without the need to place extra laser spots in that crucial area.

Many times, when a soft-tipped cannula is used to aspirate fluid through a retinal hole, the surgeon can spend more time engaging and disengaging the retina around the hole than actually aspirating the fluid. The result can be a widening of the original hole, as well as a risk of hemorrhage. The iSRAC instrument has the advantage that it is not as traumatic to the retina. The sides of the retinotomy stay the same, and the resulting hole is smaller and in most cases does not need extra laser.

The device is easy to use, operated basically the same as a standard aspiration cannula. The surgeon must get used to the proportional control of suction with the foot pedal. Also the 40-gauge cannula takes longer to aspirate fluid than a standard suction instrument; however, this is a fair tradeoff for the ability to achieve minimally traumatic drainage of subretinal fluid.

SUBRETINAL BIOPSY
I have recently used the iSRAC to perform a subretinal biopsy.¹ A 48-year-old man presented with lesions in the lungs and both ocular fundi. The device was used to obtain subretinal aspirates with minimal trauma to the retina.

A diagnosis was made in this complex case through multiple biopsies and wedge resections. The iSRAC was a small part of the case, but it was a good illustration of the ability to adapt this new instrument to novel uses. The film shows how easy the device was to use and how small the resulting scars were. On an area of flat retina, only a tiny scar was left, with a very small hemorrhage.

PROMISE FOR THE FUTURE
The iSRAC is a handy tool to have in one's surgical arsenal. It may not be deployed for every case, but in selected cases it definitely has value.

The device brings a host of potential benefits to the management of RD. It allows efficient and thorough removal of subretinal fluid with improved tissue reapproximation. It broadens the current treatment options for RD to include more complex detachments, inferior detachments, and the potential for removal of subretinal tamponading agents. It reduces trauma from the surgical procedure, with the possibility of multiple minimally traumatic retinotomies. It also may simplify postoperative management and expedite visual rehabilitation.

iScience Interventional is currently working on additional applications for the iSRAC. Over time, as surgeons learn to take advantage of the instrument's abilities, more and more creative uses for the device will emerge.

Michael A. Singer, MD, is the Managing Partner and Director of Clinical Trials at Medical Center Ophthalmology Associates, in San Antonio, TX. He is also Assistant Clinical Professor at the University of Texas Health Science Center of San Antonio. He can be reached at msinger@mcoaeyecare.com.

1. Singer MA, Bell DJ. A new minimally invasive retinal biopsy technique. Film presented at: Retina Congress 2009 Film Festival; September 30-October 4, 2009; New York, NY.

Dr. Singer's award-winning video, A New Minimally Invasive Retinal Biopsy Technique, is now available on the Retina Channel at http://www.eyetube.net. The video is located within the Therapeutic Drug Delivery selection.

]]> https://retinatoday.com/articles/2009-oct/1009_16-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_16-php Although diabetic retinopathy was one of the first conditions for which pars plana vitrectomy (PPV) was employed, vitreoretinal surgery for complications of diabetes remains a challenge. In general, success rates for visual improvement are 90% for vitreous hemorrhage, 60% for those with tractional retinal detachment and may be as low as 30% to 40% for those with combined tractional and rhegmatogenous retinal detachment. Much of this reduction in success rate is due to the underlying condition of diabetic retinopathy with ischemia and cystoid macular edema (CME) implicated in poor visual recovery however surgical complications also contribute.¹ Complications for surgery can be divided into preoperative complications and postoperative complications but the two are inter-linked. It is therefore easier to consider the eye from its anterior segment to posterior segment.

ANTERIOR SEGMENT COMPLICATIONS
Commencing with the cornea, these patients have a loose corneal epithelium that is prone to separation. The surgical use of a contact lens system for visualization of the retina in prolonged surgery may cause corneal edema, reducing the surgeon's ability to view the retina. In such cases, debridement of the epithelium is performed to clear the cornea. The more frequent use of noncontact visualization systems, however, has significantly reduced the need to remove the corneal epithelium during surgery.

Cataract after vitrectomy is common, particularly in patients older than 50 years. For reasons that are not clearly understood, however, patients with diabetes are less likely to develop cataracts post-vitrectomy. Thus, for these patients a combined vitrectomy/phacoemulsification procedure is unnecessary. It has been postulated that cataracts do not form in these patients because of reduced oxidative stress on the lens proteins in the ischemic diabetic eye.² Performing vitrectomy increases the partial oxygen pressure (PO2) in the vitreous. It is possible that the vitreous functions to keep oxygen tension low around the lens, and that this reduces the oxidative stress on the lens fibers.³ In ischemic eyes, such as in patients with diabetes, the PO2 is lower—and remains lower than normal—even after vitrectomy. For this reason, the diabetic eye may be protected from postoperative cataract. The reduced performance of combined cataract and vitrectomy surgery in these patients translates to a risk of lens touch, in my series 1.3% in these patients.

POSTERIOR SEGMENT COMPLICATIONS
Early Vitreous Hemorrhage
Postoperative vitreous hemorrhage in these patients can be divided into early (within 2 months of surgery) and late.^4-6 Early hemorrhage can be present in up to 60% of patients in the postoperative period. Surgical technique is important; dissection of neovascular membranes can cause preoperative hemorrhage, which reduces the ability of the surgeon to perform further membranectomy (reduces the view and fibrin adheres to retina). In very rare cases bleeding can be uncontrollable leading to risk of abandonment of surgery. In order to control bleeding during diabetic surgery I recommend the following:

• Elevate the infusion bottle to try to minimize the bleed from vessels but to watch the optic nerve which has a fragile circulation and is prone to shut down with raised intraocular pressure.
• Apply pressure to the bleeding point with a blunt instrument such as a flute needle tip. The pressure must be applied for enough time to allow the blood to clot (Figure 1). Perioperatively, this may seem like a very long time as the instrument must be kept still on the blood vessel to avoid tearing of the retina. I generally suggest a 1-minute minimum application of pressure to allow the hole in the blood vessel to plug.
• Endodiathermy can be applied; technically it has a tendency to damage the retina in the area of application. Removal of the endodiathermy tip can be associated with removal of the plug of fibrin causing a recurrence of bleeding. Thus, I use do not use endodiathermy frequently.

Once a clot has been formed, it can become very adherent to the fragile diabetic retina. It may be tempting to aspirate the clot and pull if off the bleeding blood vessel. This removes the plug of fibrin, however, which allows hemostasis. It is therefore more appropriate to trim the blood clot down to the bleeding point leaving a small piece of clot at the blood vessel to maintain the plugging effect of the thrombus.

Other strategies have been described to deal with perioperative bleeding such as heparin infusion into the eye to prevent clotting and allow washout of any bleeding. In addition, some surgeons have described inserting adrenaline into the infusion bottle, although this carries a distinct risk of shutting down vessels.

Late Vitreous Hemorrhage
Late vitreous hemorrhage occurs in 12% to 27% of patients treated for diabetic retinopathy; I warn my patients that there is a 10% chance of a repeat vitrectomy for removal of postoperative blood. It is worth informing your patient that over the long term—1 year to 18 months—some patients will experience small bleeds which last a few a days at a time. Gradually, these reduce with frequency; however, a few may require a further vitrectomy. More laser therapy can be applied and is usually enough to prevent further bleeding.

Sclerotomy Site Neovascularization
There are a number of descriptions of sclerotomy site neovascularization in these patients. This remains a controversial topic as a potential cause of late postoperative bleeding. Some surgeons will perform dissection of the sclerotomy site neovascularization in an attempt to reduce further bleeding. These patients, however, are also having repeat vitrectomy and more laser application—I personally find this is enough to prevent further bleeds without specific dissection of the sclerotomy sites.^7-9 Other types of potential hemorrhage in this kind of surgery remain very low. In my series of 264 tractional retinal detachments I had no choroidal hemorrhages, small or large.

Iatrogenic Breaks
Iatrogenic breaks are common in patients receiving delamination surgery with en bloc dissection of neovascular membranes, caused by traction on membranes, direct incision of the retina from scissors or cutters or insertion of instruments into sclerotomy entry sites.^10-12 Some patients have schitic retina from traction from neovascular membranes—a feature that is prone to retinal breaks during delamination (Figure 2).

Segmentation or En Bloc
Originally, segmentation of difficult-to-remove membranes was performed. It was then determined, however, that it would be more advantageous to remove all membranes from the retina, i.e, en bloc dissection. One school of thought suggests complete removal of membranes, dealing with the consequences of any iatrogenic breaks that are created afterward. The other school suggests segmentation of membranes too difficult to remove in an attempt to reduce the iatrogenic break rate. The described rates of breaks vary from 20% to 35% and in my practice, I choose to create the iatrogenic break and deal with it rather than leave membrane behind on the retina. Persistent membrane may cause reproliferation of the membrane and further traction on the retina. If the membrane is close to the disc or the macula, contraction causes striae in the macula, reducing vision. Once a break is created, the membrane close to the break must be removed, as traction of the membrane on the breakage postoperatively will cause lifting and retinal detachment. Instead, flatten the break, laser, and tamponade with intraocular gas.

Rhegmatogenous Retinal Detachment
Rhegmatogenous retinal detachment postoperatively can occur despite panretinal photocoagulation and multiple laser scars.^4,13,14 Retinal detachment rates have been described in 1% to 9% of patients. These patients usually have iris neovascularization (83%).^15,16 The surgeon should reoperate as quickly as possible because proliferative vitreoretinopathy (PVR) occurs rapidly and can lead to an inoperable situation. In a patient who develops this complication without PVR, vitrectomy and gas can be performed. However more often, PVR has been initiated and the patient will require vitrectomy and oil. In general, silicone oil is not ideal for use in a diabetic eye and I prefer to never use it as a first-line tamponade in these patients.^17-19 It is impenetrable to oxygen and may exacerbate the ischemic condition.²⁰ It appears to be associated with enlargement of retinal breaks, proliferation of membranes, and a high risk of subretinal silicone oil if used at the first surgery. It may however, be necessary to insert at subsequent surgery if the patient's eye is complicated by retinal detachment. The risk of these catastrophic outcomes with silicone oil appears to be lower at the second surgery, possibly because the laser has had a chance to reduce the relative ischemia of the retina. Silicone oil remains a risky agent, however, to use in a diabetic eye and should only be used when absolutely necessary. Maneuvers, such as retinectomy in these eyes, are fraught with risk but may sometimes be necessary if the retina will not reattach with tamponade alone.

Much remains that we do not know about the response of the diabetic eye to surgery. In simple cases of vitreous hemorrhage, success rates are high but in patients with tractional retinal detachment, with dissection off the delicate retina and optic nerve, there may be residual effects on the retina that we as yet cannot quantify. Often a good surgical result is not followed by a good visual result. Optic atrophy is commonly seen and the retina is often thin.

PREOPERATIVE MEASURES
Intravitreal antivascular endothelial growth factor agents (anti-VEGF), such as bevacizumab (Avastin, Genentech, Inc.), have been successfully used preoperatively to reduce perioperative complications, such as perioperative bleeding, in tractional retinal detachments.²¹ Injected 1 week before tractional retinal detachment surgery, anti-VEGF agents can reduce the blood flow in membranes and contraction of the membrane.

Surgical innovations include the development of high-speed cutters with cutting orifices that are nearer the end of the cutter tip. These may allow closer dissection of membranes from the retina, and may reduce the need for scissor-delamination prior to the removal of the membranes. Surgery for very complex tractional retinal detachments and those with rhegmatogenous retinal detachment can be aided by surgery with a bimanual approach. The use of chandelier illumination systems allows the surgeon to use forceps in one hand and scissors in the other to remove membranes from mobile retina, hopefully reducing iatrogenic tear formation in these complex cases.

The catastrophe rate in these patients is 3% to 4% for phthisis bulbi and 7% for risk of no perception of light in some series.^4,22 The risk of no perception of light is increased in those who have iris neovascularization, postoperative hemorrhage and macular ischemia. These patients with often severe diabetic complications systemically have a reduced 5 year survival to somewhere between 68% and 80%.^23-25

In conclusion, vitrectomy for complications of diabetic retinopathy is complex surgery. Although cataract formation is reduced postoperatively this is replaced by an increased rate of postoperative vitreous hemorrhage and iatrogenic tear formation, especially in patients with traction retinal detachment. If patients develop retinal detachment postoperatively iris neovascularization is common.

Tom H. Williamson, MD, MBChB, FRCS, FRCOphth, MD, is a Senior Consultant Ophthalmologist at St. Thomas' Hospital, London, Queen Mary's Hospital, Sidcup, Kent, and is an Honorary Clinical Lecturer at King's College, London. Dr. Williamson states that he has no financial relationships to disclose. He can be reached at +1 44 207 188 4320; or via e-mail at retinasurgery.co.uk@googlemail.com.

1. Yorston D, Wickham L, Benson S, et al. Predictive clinical features and outcomes of vitrectomy for proliferative diabetic retinopathy. Br J Ophthalmol. 2008;92(3):365–368.
2. Holekamp NM, Shui YB, Beebe D. Lower intraocular oxygen tension in diabetic patients: possible contribution to decreased incidence of nuclear sclerotic cataract. Am J Ophthalmol. 2006;141(6):1027–1032.
3. Williamson TH, Grewal J, Gupta B, et al. Measurement of PO2 during vitrectomy for central retinal vein occlusion, a pilot study. Graefes Arch Clin Exp Ophthalmol. 2009;247(8):1019–1023.
4. Brown GC, Tasman WS, Benson WE, et al. Reoperation following diabetic vitrectomy. Arch Ophthalmol. 1992;110(4):506–510.
5. Novak MA, Rice TA, Michels RG, Auer C. Vitreous hemorrhage after vitrectomy for diabetic retinopathy. Ophthalmology. 1984;91(12):1485–1489.
6. Tolentino FI, Cajita VN, Gancayco T, Skates S. Vitreous hemorrhage after closed vitrectomy for proliferative diabetic retinopathy. Ophthalmology. 1989;96(10):1495–1500.
7. West JF, Gregor ZJ. Fibrovascular ingrowth and recurrent hemorrhage following diabetic vitrectomy. Br J Ophthalmol. 2000;84(8):822–825.
8. Sawa H, Ikeda T, Matsumoto Y, et al. Neovascularization from scleral wound as cause of vitreous rebleeding after vitrectomy for proliferative diabetic retinopathy. Jpn.J Ophthalmol. 2000;44(2):154–160.
9. Lewis H, Abrams GW, Williams GA. Anterior hyaloidal fibrovascular proliferation after diabetic vitrectomy. Am J Ophthalmol. 1987;104(6):607–613.
10. Abrams GW, Williams GA. "En bloc" excision of diabetic membranes. Am J Ophthalmol. 1987;103(3 Pt 1):302–308.
11. Carter JB, Michels RG, Glaser BM, de BS. Iatrogenic retinal breaks complicating pars plana vitrectomy. Ophthalmology. 1990;97(7):848–853.
12. Oyakawa RT, Schachat AP, Michels RG, Rice TA. Complications of vitreous surgery for diabetic retinopathy. I. Intraoperative complications. Ophthalmology. 1983;90(5):517–521.
13. Virata SR, Kylstra JA. Postoperative complications following vitrectomy for proliferative diabetic retinopathy with sew-on and noncontact wide-angle viewing lenses. Ophthalmic Surg Lasers. 2001;32(3):193–197.
14. Wand M, Madigan JC, Gaudio AR, Sorokanich S. Neovascular glaucoma following pars plana vitrectomy for complications of diabetic retinopathy. Ophthalmic Surg. 1990;21(2):113–118.
15. Kadonosono K, Matsumoto S, Uchio E, et al. Iris neovascularization after vitrectomy combined with phacoemulsification and intraocular lens implantation for proliferative diabetic retinopathy. Ophthalmic Surg Lasers. 2001;32(1):19–24.
16. Helbig H, Kellner U, Bornfeld N, Foerster MH. Rubeosis iridis after vitrectomy for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 1998;236(10):730–733.
17. Pearson RV, McLeod D, Gregor ZJ. Removal of silicone oil following diabetic vitrectomy. Br J Ophthalmol. 1993;77(4):204–207.
18. Heimann K, Dahl B, Dimopoulos S, Lemmen KD. Pars plana vitrectomy and silicone oil injection in proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 1989;227(2):152–156.
19. Wilson-Holt N, Gregor Z. Spontaneous relieving retinotomies in diabetic silicone filled eyes. Eye. 1992;6 (Pt 5):461–464.
20. de Juan E, Jr., Hardy M, Hatchell DL, Hatchell MC. The effect of intraocular silicone oil on anterior chamber oxygen pressure in cats. Arch Ophthalmol. 1986;104(7):1063–1064.
21. Gandhi JS, Tan LT, Pearce I, Charles SJ. Bevacizumab (Avastin) as a surgical adjunct in diabetic vitrectomy for fibrovascular disease. Eye. 2008;23(3):742–743. Epub 2008 Apr 11.
22. Oldendoerp J, Spitznas M. Factors influencing the results of vitreous surgery in diabetic retinopathy. I. Iris rubeosis and/or active neovascularization at the fundus. Graefes Arch Clin Exp Ophthalmol. 1989;227(1):1–8.
23. Gollamudi SR, Smiddy WE, Schachat AP, et al. Long-term survival rate after vitreous surgery for complications of diabetic retinopathy. Ophthalmology. 1991;98(1):18–22.
24. Summanen P, Karhunen U, Laatikainen L. Characteristics and survival of diabetic patients undergoing vitreous surgery. Acta Ophthalmol. (Copenh). 1987;65(2):197–202.
25. Helbig H, Kellner U, Bornfeld N, Foerster MH. Life expectancy of diabetic patients undergoing vitreous surgery. Br J Ophthalmol. 1996;80(7):640–643.
]]> https://retinatoday.com/articles/2009-oct/1009_17-php Thu, 01 Oct 2009 00:00:00 GMT https://retinatoday.com/articles/2009-oct/1009_17-php

How would you like to have your main office—a brand-new state-of-the-art facility—located one floor above the ambulatory surgery center (ASC) where you do most of your surgery? That is now the situation for Tennessee Retina, the seven-surgeon, retina-only practice in which I am a partner.

In April we moved into a new 18,000 sq ft office that we designed with the help of an architectural firm with ophthalmology office expertise. Moving three practices into a new facility was a herculean task, but well worth it. We take pride in the facility, which we think is optimally designed for a busy clinical private practice involved in clinical research.

We would not be in this brand-new facility if we had not recently expanded our original four-surgeon practice. In July 2008, two surgeons from another local practice joined our group, and in January 2009 an additional solo practitioner came on board. We consider this a merger of equals, although for practical reasons we maintained the corporation of the largest group, but with a new name – Tennessee Retina. The addition of our new partners was done in stages, determined by the expiration of their leases. For the first few months, we were a single legal entity but were still practicing in our original offices. Now we are all under one roof, so to speak, and are enjoying the interaction and cooperation of our new partnership.

Our newly expanded physician contingent allowed us to become the first ophthalmologists to use the multispecialty ASC above which we are located. This ASC was previously not doing any ophthalmic surgery; now it has opened up an operating room just for vitreoretinal surgery. That provision was made economically feasible through our ability to offer the ASC a sufficient volume of cases. With seven of us, we were easily able to provide the surgical volume necessary to establish this new service.

EFFICIENCIES
Our larger practice has led to new efficiencies in a number of areas. As separate entities, the three groups practiced in 20 locations. Now that we are together, we have eliminated geographic overlap and competition, and we now have 16 offices. We have hired a seasoned ophthalmology practice manager as our chief executive officer with the objective of freeing the physicians' time to do what they do best – practice medicine. Of course, we remain actively engaged in the management of the practice, but the benefit of having an experienced administrator in place is already obvious.

In addition, we have gained efficiency through proximity to the ASC. Before the practices combined, all of our surgery was hospital-based. Now we perform a substantial number of our cases in an ASC one flight of stairs below our main office. We do not yet have an ownership stake in the ASC, although we have plans to acquire a small share. But even without an ownership interest, the efficiency that we have gained by operating in the ASC environment is tremendously valuable. Time is money, and we have more time in our schedules with this arrangement.

The increase in the number of surgeons brings its own efficiencies of scale for the practice, as well as better coverage for weekends, meetings, and so on. It also leads, we believe, to a higher quality of patient care. Whenever physicians are in a better position to learn from one other, the quality of the group is elevated.

REACHING CONSENSUS
Working with a group of seven surgeons entails compromise. The core practice had been in business for over 30 years and the others a minimum of 15 years. After that amount of time, there is a tendency to get set in one's ways; things work well, and there is no real motivation to scrutinize practice patterns. The merger has given us a reason to evaluate the major and even minor elements of our practice, and our goal is eventually to optimize and standardize each one.

With every change we make in the ways each of us has been practicing, our goal is to agree on the method that will work the best — whether it is a long-standing habit of one doctor or a novel method for all of us.

It is possible, believe it or not, to get seven surgeons to agree. We have a collegial group, and thus far everyone has been willing to compromise, with the understanding that it is better to come to an agreement, to institute change, and to refine a process than to seek the perfect solution before instituting change. For example, although we expect one day to make the transition to electronic medical records, we decided to stick with paper charts for now. This forced us to assess and rework the charts and forms that we had each been accustomed to. There are new abbreviations, different colors, and revised layouts for all, but the compromise has been a huge benefit to our staff, who had struggled for the first few months with three completely different sets of forms and charts.

We have not run into any issue that we have not been able to resolve collectively. By no means has every decision been unanimous, but every decision has been accepted by discussion and vote.

PLENTY OF ROOM
We designed our new facility with a goal of providing high-quality, efficient care in an elegant but practical space. This includes, of course, the requirement of handling the increased patient volume that most retina practices have seen with the introduction of intravitreal injections for exudative age-related macular degeneration (AMD). We have taken into account that our patients are mostly older, often in wheelchairs, and often accompanied by family members.

The office is spacious, with halls much wider than the typical office and comfortable waiting areas with large flat-screen televisions for patients and family members. It is also set up to facilitate the efficient movement of doctors and technicians (Figures 1-3). I often describe the clinical area as a "retina hospital," as opposed to a retina office. There are no dedicated injection rooms—the equipment needed to do an injection is not specialized, so we can do them in the exam lanes—but we have enough lanes that we can run a busy "injection clinic" with ease.

Seven physicians never practice in the office at the same time. On any given day no more than three doctors see patients in the main office, although the office is designed to handle up to six working doctors in a pinch. Most of our 15 other locations are satellite offices that we serve anywhere from a half day to 3 days a week. At least one surgeon is in the operating room each day.

Our practice has a commitment to clinical research; we participated in all the pivotal clinical trials for AMD in recent years, for example. Therefore, we have a large number of patients coming in for clinical trial visits, which are typically time- and space-consuming. Dedicated interview areas and exam lanes for study patients allow us to treat these patients as VIPs while not impeding the function of the regular clinic.

We look forward to further growth, whether that comes from adding more doctors or locations or simply working more effectively with the team that we have. These are issues that we will continually evaluate.

THE TIMING
Our decision to merge was years in the making and was independent of current social and economic events. With the economy suffering and recent uncertainty about the future of national health care policies, however, the fact that we now have a larger group is reassuring. The efficiencies brought about by our new arrangement can only help us to deal with these issues.

Medical practices face constant challenges. We have competition locally with other groups, we face the economic pressures common to all medical practices, and we never know when an upheaval in our practice pattern will be brought about by some revolutionary change in treatments, as with the advent of antiangiogenic injections.

We can never be complacent. One of the pitfalls of larger groups is the tendency to assume that "someone else" is watching the details. To date, we have done a good job of keeping focused on our mission: providing world-class care to our patients and to our referring doctors. We look forward to many years of continued growth here too—but no more office moves!

Carl C. Awh, MD, practices at Tennessee Retina in Nashville, TN. Dr. Awh states that he has no financial interests relevant to the topics discussed in this article. He may be reached at +1 615 983 6000; e-mail: cawh@aol.com.]]>