The Best of Retina: 2006 in Review

COORDINATED BY LAWRENCE A. YANNUZZI, MD

INTRODUCTION
Retinal Physician invited me to solicit comments from esteemed colleagues and friends on advances in retina during 2006. To that end, I have reviewed the various aspects to the retina subspecialty and invited several thought leaders to highlight most of the important issues, including diabetic retinopathy (DR), dry and wet age-related macular degeneration (AMD), uveitis, genetics, imaging, oncology, and vitreoretinal surgery. While I hoped to avoid redundancies, this has proved difficult because many of the contributors are experts in both the medical and surgical ends of the retinal spectrum. Thus, I request that we be excused in the event of a small degree of repetition. In the event that we have overlooked some important advances, I invite the readers of Retinal Physician to respond to the comments by the experts.
In reviewing the advances of 2006 highlighted by the contributors to this article, one will notice there are a few conspicuously absent topics. For example, no dynamic way yet exists to prevent the progression of neovascularization or atrophy in AMD beyond vitamin therapy. Additionally, there is also no good way to deliver antivasogenic medication without a vitreous administration. It is our hope that 2007 will see the following “blockbusters” in therapy:
• preventative measures for AMD
• methods to reduce apoptotic programmed cell loss
• methods of treating nonexudative disease via elimination of drusen (or some other interventional approach)
• better routes of administration than repetitive intravitreous injections. Please send in your own opinions — agreements, disagreements, additions, and omissions will be welcomed.

MEDICAL MANAGEMENT OF DIABETIC MACULAR EDEMA
Lloyd Aiello,MD, PhD

Associate professor of ophthalmology, Harvard Medical School, director of Beetham Eye Institute, and head of Eye Research, Joslin Diabetes Center, Boston
During the past year there have been numerous advances in novel therapies for diabetic macular edema (DME). Phase 1 and 2 results from studies of ranibizumab (Lucentis, Genentech) and pegaptanib sodium (Macugen, [OSI]Eyetech/Pfizer), respectively, have suggested that anti-vascular endothelial growth factor (VEGF) therapies may help reduce retinal thickening in DME. Several reports suggest that these anti-VEGF approaches, along with bevacizumab (Avastin, Genentech), can cause rapid regression of proliferative DR and iris neovascularization. Numerous clinical trials are currently under way that will shortly yield randomized masked data for the use of Avastin (phase 2), Macugen (phase 3), and intravitreal triamcinolone acetonide (phase 3) in DME. Studies that will be starting imminently include phase 3 trials of Lucentis.

GENETIC LINKS IN AMD
Rando Allikmets, PhD

Acquavella Associate Professor, Departments of Ophthalmology and Pathology and director of cell biology research, Harkness Eye Institute and Columbia University, New York
During 2006, we continued to witness amazing breakout research in determining the genetic cause of AMD. Following the discovery of factor H (CFH) as the first major gene associated with AMD in 2005, the second major locus containing complement pathway genes was identified in 2006. The study determined that variants in 2 other complement regulators — C2 and factor B — were largely associated with AMD, concluding that subtle changes in regulation of the complement response and resulting local inflammation are largely responsible for the disease. Furthermore, another locus containing 3 genes was identified on human chromosome 10q26, which is largely associated with end-stage AMD (choroidal neovascularization [CNV] and geographic atrophy). Together, the 3 loci (CFH, C2/BF, and 10q26) explain the majority of AMD, offer defined targets for early therapeutic intervention, and allow presymptomatic genetic screening.

MULTIMODALITY THERAPY
Mark S. Blumenkranz,MD

Professor and chairman of the Department of Ophthalmology at Stanford University School of Medicine, Stanford, Calif
In my opinion, the principal theme of retina in 2006 revolved around multimodality therapy. This concept was first considered viable several years earlier when photodynamic therapy (PDT) results appeared to be substantially better when accompanied by intravitreal steroid therapy. In the past year, independent investigators began reporting the possible benefits of various combinations of anti-VEGF agents, steroids, and PDT for AMD. Similarly the laser, which only months earlier had already been consigned to the scrap heap of antiquated therapies in the minds of some, re-emerged with the hope that the use of shorter pulses and patterns, particularly when combined with anti- VEGF agents and steroids, might provide additional benefits to patients with DME and proliferative DR. As with all promising new therapies, the confirmation of these hopes will await the initiation and completion of clinical trials, but the remarkable success to date of the Diabetic Retinopathy Clinical Research Network and the development of other similar ad hoc trial groups is a most encouraging sign.

LUCENTIS AND PDT
Neil Bressler,MD

James P. Gills Professor of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore
The most important advance in retina for 2006 is the FDA approval of Lucentis. Specifically, the evidence indicates that outcomes with monthly Lucentis injections are clearly better than every 6 week injections with Macugen or PDT with verteporfin as often as every 3 months for patients who have subfoveal CNV in AMD when fluorescein angiography demonstrates a minimally classic or occult with no classic lesion composition and presumed recent disease progression or a predominantly classic lesion composition.Whether adding PDT to Lucentis leads to better outcomes than Lucentis alone remains to be determined.

ALTERNATIVES FOR INDOCYANINE GREEN
Stanley Chang,MD

Edward Harkness Professor and Chair, Department of Ophthalmology, Columbia University
Controversy persists over the issue of potential retinal toxicity of indocyanine green (ICG) for macular surgery.^1,2 It is known that ICG dye may persist on the retina for over 1 year following macular hole surgery and that the greatest uptake is in the exposed retinal pigment epithelial (RPE) cells lying in the crater of the hole. Because of the long persistence of ICG dye, a long-term, follow-up study (1-2 years) is necessary to see if the persistence of ICG is related to the late postoperative development of RPE atrophy directly in the fovea. This is especially relevant after cataract surgery, when the retina has increased levels of irradiance. Surgeons have tried to minimize the exposure of the foveal RPE during surgery by using a viscoelastic, perfluorocarbon liquid, or other means to limit access of ICG to the central area of the macular hole. Other investigators are looking for new vital stains that may offer greater safety. In 2006, Enaida and colleagues³ reported their experience in Retina with what may be the most promising alternative — brilliant blue G, also known as acid blue 90 or Coomassie blue. Using a concentration of 0.25 mg/mL, they reported on a series of 20 eyes treated by vitrectomy for macular hole and epiretinal membranes. Visual acuity improved in 85% of eyes postoperatively. The stain appears to be taken up in the internal limiting membrane, and is more visible that trypan blue. Clinical trials to further investigate brilliant blue G are being planned.

AREDS 2
Emily Y.Chew,MD

Deputy director, Division of Epidemiology and Clinical Research, National Eye Institute, Bethesda, Md On the fifth anniversary of the announcement of the results of the Age-Related Eye Disease Study (AREDS), the National Eye Institute announced the start of the AREDS2, a study designed to assess the effects of oral supplementation of lutein and zeaxanthin and/or omega-3 long chain polyunsaturated fatty acids (LCPUFAs, known as DHA and EPA) for the treatment of AMD and cataract. The primary objective of AREDS2 is to evaluate these supplements for reducing the risk of progressing to advanced AMD, geographic atrophy affecting the center, or neovascular AMD. All AREDS2 participants will be offered the AREDS formulation. AREDS2 will use this opportunity to evaluate the possibility of deleting beta carotene and decreasing the original levels of zinc in the AREDS formulation for the treatment of AMD. AREDS2 is now recruiting participants (n=4000) with bilateral large drusen or advanced in 1 eye in up to 100 clinical centers (http://www.areds2.org). The AREDS formulation of vitamins C (500 mg), E (400 IU), beta carotene (15 mg), zinc (80 mg of zinc oxide) and copper (2 mg of cupric oxide) remains the standard of care for patients with intermediate risk of AMD (bilateral large drusen) or with advanced AMD in 1 eye. The public health impact of this treatment is significant, as it can decrease the risk of progression to advanced AMD by 25%. Recent analyses showed the therapeutic effects are maintained with long-term follow-up of 10 or more years.

UVEITIS
Emmett T. Cunningham, Jr.,MD, PhD, MPH

Clinical professor of ophthalmology, Stanford University School of Medicine, and director of the Uveitis Service, California Pacific Medical Center, San Francisco
2006 was an exciting year for uveitis with a number of important therapeutic advances. Jaffe and colleagues⁴ reported the 34-week data from the 3-year intravitreous fluocinolone acetonide (Retisert, B&L, Rochester, NY) implant trial, showing clearly that the device can, in appropriately selected patients with noninfectious posterior uveitis, result in a marked and sustained improvement in intraocular inflammation. A number of studies have addressed the use of biologic agents for ocular inflammation, most notably the TNF inhibitors infliximab (Remicade, Centocor), etanercept (Enbrel, Amgen/Wyeth), and adalimumab (Humira, Abbott). The studies support what is now the consensus opinion among uveitis experts that TNF inhibitors can provide real benefit in select patients with moderate to severe sight-threatening inflammation, but that given the incidence of drug-related adverse events, they are probably best reserved for patients who are either incompletely responsive to or intolerant of more conventional immunotherapies. Other biologics, such as the VEGF-blocking agents Macugen, Lucentis, and Avastin, are also beginning to be investigated for the treatment of inflammation and its complications, most notably cystoid macular edema (CME) and inflammatory ocular neovascularization, with impressive early results. Lastly, surgical therapies for uveitis are gaining acceptance. For example, a well-designed prospective, randomized controlled trial by Tranos and colleagues⁵ at Moorfields Eye Hospital provided strong evidence for the use of pars plana vitrectomy to treat uveitic CME that is refractory to medical therapy. The numbers were small, but the results were clear and generally confirmed claims made in earlier retrospective reports that pars plana vitrectomy can play an important role in the management of refractory uveitic CME.

DIAGNOSTIC IMAGING
Yale Fisher,MD

Clinical professor of ophthalmology at the New York Hospital Cornell Medical Center and director of the surgical retinal service and surgeon director, Manhattan Eye, Ear & Throat Hospital
Last year was stellar for the evolutionary development in diagnostic imaging for the fundus. The race is on for a spectral domain system, and there are now at least 6 entries — companies with the technology to provide or register high-resolution OCT images in combination with a 3-D scan with point-to-point correlation and accurate reproducibility. In the coming year, the systems should be commercially available, and 1 or more will likely become part of the standard diagnostic adjunct armamentarium of the retinal specialist. Nonmydriatic and noncontact fundus cameras are also emerging for both patient screening and management. No 1 system seems to satisfy all needs, and widefield and highresolution represent technologies that, in a sense, are optically diametrically opposed. However, the use of such cameras for diabetic and AMD screening, and possibly the integration of other imaging modality including angiography, is on the horizon. Finally, fundus autofluorescence has become a practical and meaningful diagnostic adjunct beyond AMD. Following original observations and encouragement by our European colleagues, several US centers are now using this form of imaging for diagnosing and monitoring agerelated disease and for identifying disease entities, as well as manifestations of certain disorders, such as central serous chorioretinopathy. My prediction is that fundus autofluorescence will be a standard method of imaging in the near future for all retinal specialists.

SMALL-GAUGE VITRECTOMY
Harry W. Flynn, Jr,MD

Professor and J. Donald Gass Distinguished Chair of Ophthalmology, Bascom Palmer Eye Institute, Miami
The year 2006 has been a time of transition for most vitreoretinal surgeons regarding instrumentation. At the beginning of the year, most surgeons incorporated 25-g vitrectomy into more than 50% of their surgical cases. Access to 23-g vitrectomy was limited in early 2006, but there has been growing interest in 23-g vitrectomy because of the limitations with 25-g instrumentation. Most surgeons experienced in the use of 23-g vitrectomy systems report a more controlled removal of the formed vitreous, better peripheral vitreous dissection, and easier separation of the posterior hyaloid (as in macular hole surgery) compared with the 25-g systems. The use of 23-g instrumentation is quite similar to 20-g with no bending of instruments and more rapid fluid-gas exchange when indicated. A growing concern in both small-gauge vitrectomy approaches is the issue of postoperative endophthalmitis. In traditional 20-g vitrectomy, the number of reported cases is low (fewer than 1 in 2000 cases). At the September 2006 combined meeting of the American Society of Retina Specialists and and European VitreoRetinal Society, several centers reported endophthalmitis rates as high as 1 in 100 cases after small-gauge surgery. Risk factors for endophthalmitis include persistent vitreous wick in the sclerotomy sites, postoperative hypotony, nonuse of subconjunctival antibiotics, and increasing use of intravitreal adjuvants such as triamcinolone acetonide.

PHARMACOTHERAPY FOR AMD AND DR
Peter K.Kaiser,MD

Director, Clinical Research Center and Digital OCT Reading Center (DOCTR), Cole Eye Institute and Cleveland Clinic Foundation
The approval of Lucentis in June 2006 represented a huge leap forward in our ability to treat patients with exudative AMD. Lucentis is a humanized Fab fragment of a mouse monoclonal antibody against VEGF-A that also formed the backbone for Avastin. Intravitreal Lucentis is the first approved drug where 70% of patients improved vision with, on average, a 1.5 line improvement after 12 months, irrespective of CNV lesion composition. Forty percent of patients had a 3-line improvement in vision, and a similar percentage had better than 20/40 vision at 12 months.⁶ However, as impressive as these results are, physicians and patients are faced with the practice management nightmare of monthly injections because less frequent mandated dosing did not have as impressive results in the PIER study.⁷ Combination treatments and reinjection based on OCT criteria are being evaluated to decrease the treatment burden and maintain efficacy. Although the treatment is expensive, a cost-utility analysis demonstrated that Lucentis conferred the greatest improvement in patient value (17.7%), which is similar to the value associated with first-eye cataract surgery (20.8%), and significantly greater than any other AMD approved treatment. Given its potent pan-VEGF-A extracellular blockade, Lucentis is also being evaluated to treat DME and retinal vein occlusions in early clinical testing. Other FDA-approved anti-VEGF drugs are also being tested in these diseases. Macugen, an aptamer that specifically inhibits the 165 isoform of VEGF-A, has been shown to be efficacious in a phase 2 DME study. Additional studies are ongoing.

DRUG DELIVERY
William F. Mieler,MD

Professor of Ophthalmology & Visual Science and Chair of the Department of Ophthalmology, University of Chicago Hospitals

Jennifer J.Kang Derwent, PhD

Assistant professor, Illinois Institute of Technology, Pritzker Institute of Biomedical Science and Engineering
During 2006, we saw significant changes in the management of patients with exudative AMD. Not only was Lucentis approved for clinical usage by the FDA, but there also has been increasing employment of intravitreal Avastin.With the abovenoted agents, there is the need to have patients return for treatment every 4 to 6 weeks. This frequency of treatment has had a significant impact not only on our patients and their families, but also on all of our retina practices. It has been readily recognized that while the current treatments offer substantial hope for the vision and lifestyle of our patients, it would be ideal if we were able to offer effective treatment either on a less frequent basis or with a prolonged duration of activity. This can be accomplished via one of several means: development of even more effective monotherapy treatments, combination therapy treatments, or enhancement of drug delivery to the eye. Interest in enhanced drug delivery to the eye continues to grow.While intravitreal injections offer an effective means of placing drug directly in the eye, this method has an impact both logistically, as noted above, but also medically. There are significant ocular risks associated with such injections, particularly endophthalmitis. Already on the market are several non-biodegradable solid intravitreal implants, primarily offering extended delivery of corticosteroids. Additionally, there is ongoing research in the realm of anti-VEGF drug delivery via microspheres or nanoparticles, along with thermosensitive gels. Our research team has extensive interest in thermosensitive gels, from the standpoint of trans-scleral and/or intravitreal delivery of these gels embedded with anti-VEGF agents. This type of delivery system offers the possibility of extended delivery of drug to the eye for 3 to 6 months, which should help to ease the burden of repetitive intravitreal injections.We all look forward to extensive progress in the realm of drug delivery to the eye in 2007 and beyond.

LUCENTIS AND AVASTIN
Philip J. Rosenfeld,MD, PhD

Professor of ophthalmology, Bascom Palmer Eye Institute
There is no doubt that 2006 was the breakout year for pan-VEGF blockade in the treatment of neovascular and exudative eye diseases. One could argue it was the year of Lucentis, the first treatment for neovascular AMD to improve vision through 2 years as proven in large, controlled multicenter randomized clinical trials. In these trials, Lucentis was proved to be safe and effective. But Lucentis must share center stage with Avastin, its litter-mate and first cousin found within the stable of exceptional drugs manufactured by Genentech. In 2006, Avastin became the most widely used drug in the world for the treatment of neovascular and exudative eye diseases. Notably, Avastin’s rise to global prominence was not fueled by mass marketing but by word of mouth; the overall opinion among eyecare specialists is that intravitreal Avastin is an inexpensive, cost-effective therapy that appears to be safe. This consensus is supported by 58 separate reports published in National Library of Medicine indexed journals in 2006. Even the National Institutes of Health considers the evidence so compelling that they have agreed to spend millions of dollars and perform a head-to-head trial comparing Lucentis to Avastin.When talking about these 2 drugs, Lucentis and Avastin, they are similar in so many ways that, for the sake of simplicity, perhaps 2006 should be known as the year of “LuVastin.”

ADVANCES IN OCULAR ONCOLOGY
Jerry A. Shields,MD

Professor of ophthalmology , Thomas Jefferson University, and director, Oncology Service, Wills Eye Hospital, Philadelphia
During 2006 we continued to observe advances in the diagnosis and management of retinal and choroidal tumors, in particular, the two most important malignant tumors of the ocular fundus: retinoblastoma and posterior melanoma. For retinoblastoma, enthusiasm continues regarding the use of chemoreduction (CRD) followed by supplemental treatment with transpupillary thermotherapy, cryotherapy, plaque radiotherapy and sub-tenon’s injection of chemotherapeutic agents. Plaque radiotherapy has been reported to be an excellent method of salvaging the eye after failure of CRD in selected cases. Refinements in ultrasound biomicroscopy for uveal melanoma now allow closer measurement of small ciliary body tumors that were previously difficult to follow because of their anatomic location. OCT has allowed better evaluation of small melanocytic choroidal lesions and to determine their effects on the adjacent retina. It provides more detailed assessment of the extent of radiation retinopathy following plaque or charged-particle radiation. Radiation papillopathy and CME are better evaluated with OCT and intravitreal corticosteroids, and anti-VEGF agents are being employed more often to manage such occurrences. A particularly exciting development is the determination of genetic changes in uveal melanoma. In several centers around the world, tumor tissue is harvested directly at the time of enucleation or by fine needle biopsy at the time of plaque radiotherapy. The tumors are studied by fluorescent in situ hybridization (FISH) or microarray techniques. Monosomy of chromosome 3 has been found to impart a worse prognosis, compared with normal disomy of chromosome 3. The information reaped from such studies will most certainly influence how patients are followed and managed in the future from a systemic standpoint.

CLOSED-SYSTEM VITRECTOMY
Richard Spaide,MD

Assistant clinical professor, New York Medical College, Manhattan Eye, Ear and Throat Hospital
Modern vitrectomy has long been considered a “closed” system. This term was used to contrast standard 3-port technique against the open-sky approach. However, 20-g vitrectomy invariably used wounds in the eye that now seem large and were not watertight. The longer the case, the more the wounds enlarged, and subsequently, the leakage from the wounds increased.To replace this loss we used larger and larger amounts of irrigating solution, and a lengthy vitrectomy would require 1000 mL or 1500 mL of irrigation flowing through the 4-mL vitreous cavity. The excessive flow caused extreme movement of the retina and lens changes.Overflow of gas had its own problems, such as cataract formation and retinal damage. A flow of 4 cc/sec results in a jet of gas traveling more than 60 MPH at the tip of the infusion cannula. Recently, new valves have been described for vitrectomy surgery, the two more prominent ones were for 25-g and 23-g vitrectomy. These valves were made to be part of the cannulas used for small-incision vitrectomy surgery. These valves allow free passage of instruments in and out of the eye, but they restrict free flow of fluid and gas. Vitrectomy has truly become a “closed” approach. This simple development will mean fewer bottle changes and reduced cataract formation, and it should eliminate retinal damage induced by gas jets in the eye during vitrectomy surgery.

REFERENCES
1. Ashikari M, Ozeki H, Tomida K, Sakurai E, Tamai K, Ogura Y. Long-term retention
of dyd after indocyanine green-assisted internal limiting membrane peeling. Jpn
J Ophthlamol. 2006;50:349-353.
2. Kampik A, Haritoglou C, Gandorfer A. What are vitreoretinal surgeons dyeing
for? Retina. 2006;26:599-601.
3. Enaida H, Hisatomi T, Hata Y. Brilliant blue G selectively stains the internal limiting
membrane/brilliant blue G-assisted membrane peeling. Retina.
2006;26:631-636.
4. Jaffe GJ, Martin D, Callanan D, et al; Fluocinolone-Acetonide Uveitis Study
Group. Fluocinolone acetonide implant (Retisert) for noninfectious posterior
uveitis: thirty-four-week results of a multicenter randomized clinical study.
Ophthalmology. 2006;113:1020-1027. Epub 2006, May 9.
5. Tranos P, Scott R, Zambarajki H, Ayliffe W, Pavesio C, Charteris DG. The effect of
pars plana vitrectomy on cystoid macular oedema associated with chronic
uveitis: a randomized, controlled pilot study. Br J Ophthamol. 2006;90:1107-
1110. Epub 2006, May 24.
6. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for
neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-
1433.
7. Brown DM. Lucentis PIER data. Presented at: The Second Annual Retinal
Physician Symposium; June 2, 2006; Paradise Island, Bahamas.

 

Lawrence A. Yannuzzi, MD, is vice chairman of the Department of Ophthalmology and director of retinal services at Manhattan Eye, Ear & Throat Hospital, and professor of clinical ophthalmology at the College of Physicians and Surgeons, Columbia University, New York.