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MACULA 2006
New advances make for a memorable meeting.
BY JACQUELINE ZUMMO, MEDICAL EDITOR

MACULA 2006, a combined meeting of the Atlantic Coast Retina Club and the tri-annual New York conference on vitreous-retina and macular diseases, brought together an elite group of researchers and clinicians to present their most recent findings and observations on understanding and attacking macular diseases.

A heightened sense of excitement surrounded the meeting as recent advances on a number of fronts have created promising new possibilities for treating a wide range of macular diseases.

Overall, MACULA 2006 provided a better understanding of current critical issues relating to macular abnormalities and their treatments. The meeting covered imaging and technology, medical and surgical treatment of retina diseases, and new initiatives to approach both the wet and dry forms of age-related macular degeneration (AMD).

Highlights of the meeting were the presentation of impressive new study data from the phase 3 ANCHOR study of ranibizumab (Lucentis, Genentech) for wet AMD, as well as studies that focused on the off-label use of bevacizumab (Avastin, Genentech) for the treatment of wet AMD (for full details of the ANCHOR study please turn to page 19).

The meeting, held at the Uris Auditorium, Weill Medical College, Cornell University, New York, NY, was led by an organizational committee representing the medical school ophthalmologic departments in the greater New York City area, a regionally based and sponsored academic program.

This article focuses on a few presentations given at MACULA 2006.

IMAGING AND TECHNOLOGY

Richard Rosen, MD, of the New York Eye & Ear Infirmary, addressed optical coherence tomography ophthalmoscope (OCT/SLO) in detail. His presentation discussed OCT/SLO being recently commercialized by OTI (Toronto, Ontario,) to provide superior imaging and quantitative studies of the retina.

This technology also utilizes coronal scanning (C scans). Another key discussion point was how OCT/SLO provides pixel-to-pixel registration between simultaneous matching pairs of OCT and SLO images, as well as high-resolution cross-sections (B scans). By scanning parallel to the retinal surface, OCT/SLO produces enhanced views of the vitreoretinal and RPE-choroidal interfaces, and topographic thickness maps, which use vascular patterns to accurately register serial studies. Dr. Rosen also discussed how ultra-high resolution imaging at standard speeds using broadband illumination is also a feature of this technology.

MEDICAL RETINAL DISEASES

With an increase in retinal diseases being seen by many retina specialists, it comes as no surprise that this year's MACULA had a major focus on central serous chorioretinopathy (CSC), AMD, and diabetic retinopathy.

Lawrence Yannuzzi, MD, of the Vitreous, Retina, Macula Consultants of New York, presented on a standard of care for CSC. His presentation highlighted that for more than a century, ophthalmologists have been aware of CSC as a distinct clinical entity. A myriad of clinical manifestations and defining fluorescein angiographic changes have traditionally described the entity. For persistent macular detachment with visual decline and eccentric focal retinal pigment epithelium (RPE) leaks, photocoagulation has been used to treat patients with CSC in the past. However, in recent years other diagnostic and therapeutic modalities have been used in the management of these patients. Dr. Yannuzzi's presentation also reviewed new developments in the diagnosis and treatment of CSC, utilizing the following modalities: OCT, indocyanine green (ICG) angiography, and fundus autofluorescence.

Guy Barile, MD, from the Columbia University College of Physicians & Surgeons, discussed a neurovascular therapeutic target for the prevention and treatment of diabetic complications in the retina. The "RAGE" axis comprises the formation of advanced glycation endproducts (AGEs) and their interaction with a cellular receptor (Receptor for AGEs or RAGE). Chronic hyperglycemia accelerates the development of AGEs, irreversible chemical adducts of proteins, lipids, and nucleic acids. In the vitreous cavity of diabetic eyes, AGE formation results in collagen cross-linking, facilitating diabetic "vitreoschisis" or "vitreopathy." In early diabetic retinopathy, the RAGE axis is amplified within the neural retina and is accentuated along the vitreoretinal interface, with AGEs present in the internal limiting membrane (ILM) where they have contact with the footplates of RAGE-expressing Müller cells. This anatomically close apposition suggests that a possible physiologic benefit of diabetic vitrectomy is the removal of AGE ligands from the posterior vitreous cortex and ILM, down regulating the proinflammatory RAGE axis in adjacent Müller cells. In a murine model of early diabetic retinopathy, antagonism of the RAGE axis reduces neurovascular perturbations, validating this pathway as a therapeutic target for intervention in diabetic retinopathy.

Lee Jampol, MD, of Feinberg School of Medicine, Northwestern University, focused on an epidemiologic study of white dot syndromes and "the black mucula".

Dr. Jampol presented a case of reactive lymphoid hyperplasia involving the retina and choroid (leopard spots), both orbits, the lids, the pancreas, kidneys, and many lymph nodes including the mediastinum. The diagnosis of this systemic pseudolympohoma was discussed. Possibilities included Castleman's disease, an unusual prelymphoma disease that is often seen in HIV-positive patients (this patient was not). Another possibility was atypical sarcoid.

Dr. Jampol's presentation also involved 4 cases of a new disease, which is now tentatively being called white geographic maculopathy. The patients have serpiginous bilateral macular lesions but initially have good vision (unless there is choroidal neovascularization [CNV]). The white changes last months or years. The hypofluoresent changes on the FA and ICG last many months or years, and CNV is very common.

Michael J. Cooney, MD, MBA, from the Manhattan Eye, Ear & Throat Hospital, discussed emerging concepts in nutritional supplementation for diabetic retinopathy. He presented that Diabetes mellitus has become a worldwide scourge and a medical pandemic. He also asserted that preventive strategy for diabetic retinopathy could have significant public health impacts by decreasing the incidence of vision loss and decreasing the costs to society.

The AREDS study provided the proof of principle that nutritional supplementation can positively impact retinal disease progression and slow vision loss. He also discussed Genistein, an isoflavone derived from soybeans, as having a multiple biological mechanisms of action, a wide therapeutic index, and has been studied in many disease states. Genistein inhibits tyrosine kinase and aldose reductase pathways, both of which are pathophysiological pathways that have been implicated in diabetic retinopathy. Genistein has been studied in several animal models of retinal ischemia and diabetic retinopathy and can significantly inhibit the upregulation of tyrosine kinase pathways found in these animals. Gensitein also protected against retinal morphologic changes associated with these disease states in animals. He concluded by adding that a clinical development program for genistein as a nutritional supplement for diabetic retinopathy is underway.

SURGICAL RETINA

Donald J. D'Amico, MD, of Harvard Medical School, discussed his perspectives on evolutionary and revolutionary trends in vitreoretinal surgery over the past 25 years. He considers evolutionary trends to be those that extend naturally from previous instrumentation and techniques, and described the following as evolutionary trends in vitreoretinal techniques and instrumentation: 1) the use of fine forceps, as opposed to membrane pics, for membrane peeling; 2) small-guage vitrectomy; 3) temporary keratoprosthesis; 4) endoscopy; 5) the progression from lens removal to retention to IOL implantation at the time of vitrectomy; 6) ICG and other tissue stains for tissue visualization; and 7) the shift from buckling to vitrectomy for many detachments.

Revolutionary trends are those that could not have been easily foreseen 25 years ago, and arise almost disruptively. He included as revolutionary trends: 1) retinotomy/retinectomy for retinal reattachment, drainage; 2) perfluorchemical techniques; 3) wide-angle and noncontact viewing; 4) permanent keratoprosthesis for ocular rehabilitation; 5) adjuvant pharmaceuticals at vitrectomy; and 6) the shift from either scleral buckling or vitrectomy to pneumatic retinopexy for primary retinal detachments.

He considers the endolaser and tamponades to be the most substantial advances in that period, and although they are currently without demonstrated clinical success, he believes retinal vascular surgery (CRVO, BRVO) techniques have been revolutionary in their attempt. He suggested that trends for the future will be 1) increasing attention to combined IOL and vitreoretinal surgery; 2) research to find alternatives to eye-filling tamponades for retinal break closure; 3) continued advancement in permanent keratoprosthesis, and most importantly; 4) extraordinary refinement in adjuvant pharmaceuticals at the time of vitreoretinal surgery.

Carl Regillo, MD, from Wills Eye Hospital, discussed how 25-g pars plana vitrectomy (PPV) offers several potential advantages over the traditional 20-g approach, including sutureless sclerotomy sites, shorter operating time, reduced surgical trauma, improved patient comfort after surgery, and faster postoperative healing.

The Wills Experience consisted of 70 eyes of 70 patients having 25-g PPV for a variety of indications. Both the entire study population and the individual subgroups had a statistically significant visual improvement at final follow-up compared with the baseline preoperative acuity. There were no intraoperative or postoperative complications that affected the final visual outcome in any eye. Two eyes (2.8%) had intraoperative retinal breaks detected and treated without further sequelae. Four eyes (6%) had postoperative hypotony (IOP <6 mm Hg) the day after surgery, but all cases resolved within 1 week and no choroidal detachments or other problems occurred. One eye (1.4%) had a postoperative limited retinal detachment. Overall, rates of intraoperative and postoperative problems were very low and comparable to previously published studies on 25-g surgery. Furthermore, significant complications such as retinal tear and detachment appeared no greater than what has been reported for 20-g vitrectomy surgery.

Richard Spaide, MD, of Vitreous, Retina, Macula Consultants of New York, presented his experience with 23-g vitrectomy. He described the rationale for minuturization in vitrectomy surgery, including obviating the need for sutures, reducing postoperative recovery times, sparing of the conjunctiva with reduction in scarring, and decreasing operating room times. Like 25-g systems, 23-g systems provide a sutureless, transconjunctival approach to vitrectomy. Twenty-three-g systems provide several additional possible advantages, including tunnelled sclerotomies to avoid postoperative hypotony, stiffer instrumentation, larger bore cutters with greater suction forces to create a posterior vitreous detachment, and brighter light pipes. With more than 1 year's experience with the system, no safety issues were found.

ANTI-VEGF
Avastin: The Miami Experience

Andrew Moshfeghi, MD, of Bascom Palmer Eye Institute, discussed his use of bevacizumab in Miami.

He described how in May of 2005 the Bascom Palmer group first started using off-label intravitreal bevacizumab (Avastin) as salvage therapy for patients with advanced and refractory neovascular AMD. Dr. Moshfeghi noted the similarity between bevacizumab and ranibizumab (Lucentis), and the availability of bevacizumab (FDA-approved for metastatic colorectal cancer), as strong rationales for intravitreal use of bevacizumab.

Dr Moshfeghi said his experience with intravitreal bevacizumab has been clinically indistinguishable from the open-label experience with intravitreal ranibizumab. He estimates that at least 500 patients have been treated at the Bascom Palmer Eye Institute with intravitreal Avastin since May 2005, and it has been found to be a well-tolerated treatment with no serious ocular or systemic complications reported. Until Lucentis is granted FDA approval, bevacizumab is nicely filling the AMD treatment-gap, primarily as salvage therapy, he noted.

ANCHOR Study

At MACULA 2006, Genentech announced positive 1-year results from its second pivotal phase-3 study of the investigational drug Lucentis in patients with wet AMD. Data from the ANCHOR study comparing ranibizumab to verteporfin (Visudyne, Novartis) photodynamic therapy (PDT) showed a difference in mean change in visual acuity of 18 letters for patients treated with 0.3 mg of ranibizumab and 21 letters for patients treated with 0.5 mg of ranibizumab from study entry compared to those treated with PDT at 12 months. Overall, the data show that ranibizumab maintained or improved vision in approximately 95% of patients at 1 year.

Pegaptanib Sodium

In an off-site interview with Lawrence Singerman, MD, of Retina Associates of Cleveland and Carl Regillo, MD, of Wills Eye Hospital, pegaptanib sodium was presented as the foundation therapy for wet AMD. Recent data suggest that pegaptanib sodium (Macugen, OSI (Eyetech)/Pfizer) used as early treatment may result in optimal vision outcomes. In clinical practice, it appears that the clinical value of pegaptanib sodium is greater than that demonstrated in the original pivotal trials, as the original trials included more difficult cases that may have had previous treatment with PDT. Additionally, because there are potential safety issues with the use of nonapproved anti-VEGF therapies, pegaptanib sodium should be a strong consideration for treatment based on demonstrated 2-year safety data. Because pegaptanib sodium is the only approved anti-VEGF therapy for wet AMD, reimbursement for pegaptanib sodium will likely not be a challenge for the retinal clinician.