Macula 2009: Highlights From the Conference
A host of retinal physicians offer the latest tips on treatment and trial results.
ANDREW E. MATHIS, PhD, MEDICAL EDITOR
The Macula 2009 conference was held in New York on January 16 and 17, offering retinal physicians presentations on a number of conditions and medical and surgical techniques for treating retinal disease. Symposia were held on ocular oncology, hereditary disease, ophthalmic technology, OCT imaging, medical, vascular, and surgical retina, and wet and dry AMD. Here we present highlights from the conference.
The first presentation of Macula 2009 was by Jerry A. Shields, MD, from the Oncology Service of the Wills Eye Institute. Dr. Shields presented "pearls" in the differential diagnosis of choroidal melanoma. He mentioned several conditions that present in a similar manner to choroidal melanoma, including choroidal nevus, disciform macular degeneration, peripheral exudative hemorrhagic chorioretinopathy, tumors of the pigment epithelium, choroidal hemangioma, choroidal metastasis, and others. Altogether, in evaluating 12 000 consecutive patients referred to the Oncology Service with the diagnosis of choroidal melanoma, Dr. Shields and his associates found that 1739 of them (14%) had conditions that proved on further examination to be benign lesions that simulated choroidal melanoma. He described subtle clinical features that serve to differentiate these pseudomelanomas from true melanomas.
In the next presentation, Dr. Carol Shields from the Oncology Service of the Wills Eye Institute presented her own pearls on treatment, calling them "black pearls" and making a reference to the movie Pirates of the Caribbean by saying that these pearls "hide in the hollows of the eye." Beginning by citing a meta-analysis by Chirag Shah, MD, that arc welding is related to the development of uveal melanoma, Dr. Shields then pointed to several other important points, including the importance of plaque radiotherapy and genetic testing using fine needle aspiration biopsy to test for monosomy 3, a mutation associated with poor prognosis.
There were also 2 presentations on retinoblastoma (Figure 1), by Brian P. Marr, MD, and David H. Abramson, MD, of the Memorial Sloan-Kettering Cancer Center in New York. Dr. Marr spoke about diagnosis of retinoblastoma, beginning by noting that, as the disease is most common in children, anxious parents pose a challenge for ocular oncologists. The accuracy of diagnosis, Dr. Marr said, depends to a large extent on referring physicians. He that fewer than 1% of eyes enucleated for retinoblastoma nowadays contain something other than retinoblastoma but 38% of eyes referred to him for retinoblastoma do not have retinoblastoma. This figure is similar to what was reported 50 years ago. Dr. Marr also pointed out that, while leukocoria is the most common presenting symptom of retinoblastoma, not all retinoblastoma will present with leukocoria, nor are all cases of leukocoria indicative of malignancy.
Figure 1. Retinoblastoma.COURTESY OF AMY C. SCHEFLER, MD, MARIA ELENA JOCKOVICH, PHD, IZIDORE S. LOSSOS, MD, STUART TOLEDANO, MD, MICHAEL FEILMEIER, MD, SANDER R. DUBOVY, MD, AND TIMOTHY G. MURRAY, MD
Dr. Abramson advocated off-label use of melphalan in treating retinoblastoma, noting that traditional intravenous chemotherapies tend to cause a dramatic change in the size of ocular tumors but rarely actually cure the condition. He also pointed to a recent editorial in Archives of Ophthalmology that argued that two-thirds of the cost of care for ocular tumors is on complications. Intra-arterial melphalan offers a high concentration of chemotherapy to tumors, Dr. Abramson said, but a low dose to the patient. And while Dr. Abramson submitted that although the cost of intra-arterial chemotherapy per session is more expensive than intravenous delivery, two-thirds of the total cancer cost for intravenous chemotherapy is for managing the complications of chemotherapy. Since intra-arterial chemotherapy does not have these problems, the total cost of intra-arterial chemotherapy to the patient is half that of systemic chemotherapy.
The oncology presentations ended with a lecture by J. William Harbour, MD, of Washington University in St. Louis, sponsored by the Fund for Ophthalmic Knowledge. Dr. Harbour's presentation, "New Molecular Observations in Melanoma," indicated 6 future directions for the treatment of ocular melanoma: (1) targeted molecular therapy; (2) genetic approaches to treatment; (3) the inhibition of proliferation and induction of apoptosis of cancer cells; (4) induction of dormancy of micrometastases; (5) better prediction of response to therapy based on increasing genetic knowledge; and (6) noninvasive molecular imaging, similar to that seen with fluorescein angiography.
Gregory S. Hageman, PhD, of the University of Iowa, Rando Allikmets, MD, of Columbia University, and Johanna M. Seddon, MD, of Tufts University School of Medicine, each gave presentations on our current understanding of the genetics of AMD. In the first lecture, Dr. Hageman focused on the role of aberrant complement activation, working within a thesis that AMD is an ocular manifestation of a larger systemic immune condition. In the eye, he singled out the membrane attack complex (MAC) as existing both at high levels at the RPE-choroid interface in AMD donors and present when significant levels of complement factor H (CFH) exist. The model that Dr. Hageman suggested was one in which CFH is activated at the RPE-choroid interface, leading to RPE and retinal cell death as a consequence of local "bystander damage."
Dr. Allikmets' presentation summarized our current knowledge of AMD-associated genes and alleles with particular emphasis on loci containing complement genes CFH, CFB/C2, and C3. He also discussed the major non-complement locus on human chromosome 10q, summarized the data for the ABCA4 gene and presented evidence of extremely variable genetic susceptibility in major ethnic groups. Notably, Dr. Allikmets closed his presentation by stating that there are no major genetic loci left to find in AMD; however, there is still a lot of careful work to do to complete the genetic analysis of this complex disorder.
|The Lighthouse International Schupf Lectureship|
During the meeting, Alan Bird, MD, of Moorefields Eye Hospital in London (pictured, second from left) gave the Lighthouse International Schupf Lectureship, "The Role of Retinal Pigment Epithelial Dysfunction in Retinal Disease." Dr. Bird, a pioneer in ophthalmic research and teaching, has made significant contributions on retinal vascular disease, generalized rod-cone dystrophies, and neuro-opthalmological disorders. His lecture discussed how to gauge the integrity of the RPE and the predictive value that autofluorescence confers on outcome assessment in choroidal neovascularization treated with anti-VEGF therapy.
Pictured (left to right) are Donald J. D'Amico, MD, professor and chair of ophthalmology at Weill Cornell Medical College and ophthalmologist-in-chief at New York Presbyterian Hospital; Dr. Bird; Tara A. Cortes, RN, PhD, president and CEO of Lighthouse International; and Dr. Lawrence A. Yannuzzi, professor of clinical ophthalmology at Columbia University, vice-chairman and director of the Retinal Research Center of the Manhattan Eye, Ear & Throat Hospital, and founder and president of The Macula Foundation, Inc.
Dr. Seddon lectured on the roles of nature vs nurture in AMD. Citing several notable studies going back 15 years, she indicated the clear link between smoking and AMD. Furthermore, she noted that oxidative stress plays a role and the Dietary Ancillary Study of the 1980s and, more recently the AREDS study and other research, indicate that nutrition can have an effect on prevention. Conversely, she said, there is less clinical evidence that sun exposure or alcohol intake play any significant role in AMD pathogenesis. She closed her presentation by pointing to studies on familial aggregation of AMD, noting that several genetic variants are related to both the development and progression of this disease. Behavioral factors add to the genetic risk. CFH risk alleles may compromise the body's ability to respond to nutritional supplements. She has developed an algorithm for predicting AMD risk combining these variables.
The first session on January 17 was on ophthalmic technology. Richard B. Rosen, MD, of the New York Eye & Ear Infirmary, spoke first on microperimetry and imaging correlates, particularly the combined spectral OCT and scanning laser ophthalmoscopy with microperimetry, which, Dr. Rosen suggested, was the closest retinal physicians have come so far to a virtual biopsy. He spoke about a study that he undertook searching for a correlation between retinal thickness and visual sensitivity measurements using microperimetry. This study showed that microperimetry correlated with retinal thickness changes most consistently in cases involving cystic changes of the inner retina and cicatricial loss of inner retinal layers.
R.V. Paul Chan, MD, from Weill Cornell Medical Center, spoke next about ocular ultrasound using postimaging processing techniques, notably wavelet analysis. Dr. Chan stated that using wavelets was the application of a "finite element to look at a finite structure," thus resulting in less imaging artifacts. He then presented comparisons of OCT and wavelet analyses in patients with several conditions. Finally, Dr. Chan described how wavelet analysis provides numerical descriptors for tissue characterization.
Frank G. Holz, MD, of the University of Bonn, Germany, lectured on new perspectives in fundus autofluorescence (FAF) imaging using confocal scanning laser ophthalmoscopy. He addressed various applications of FAF, including measurement of geographic atrophy, and identification of patterns of abnormal FAF signals based on diseased RPE surrounding atrophic patches preceding occurrence and spread of atrophy. He then presented several images of eyes of patients suffering from a variety of retinal diseases correlating FAF imaging with simultaneous spectral-domain optical coherence tomography (SD-OCT). Dr. Holz addressed some of the shortcomings of FAF, such as quantification of autofluorescence signals, but maintained that the technology still holds great promise as it develops.
The session also included 2 presentations on drug delivery, given by Karl G. Csaky, MD, of Duke University, and William F. Mieler, MD, of the University of Illinois, Chicago. Dr. Csaky began by talking about intravitreal injections and implants and whether they penetrate the retina and choroid. Several studies he cited indicated that Avastin can reach the choroid, possibly by first exiting the eye into the systemic circulation through a mechanism specific for antibodies. Dr. Csaky also spoke about eyedrops and their ability to penetrate the back of the eye. Episcleral delivery, Dr. Csaky said, is the "holy grail" of drug delivery, but using the AART trial failure as an example, he urged caution before drawing conclusions. Implants, Dr. Csaky said, will probably be the wave of the future, along with nanoparticles.
Dr. Mieler picked up where Dr. Csaky left off, discussing thermo-reversible hydrogels as a possible drug-delivery system. After discussing the pharmacokinetics of these gels, Dr. Mieler spoke about studies describing how these gels are capable of delivering anti-VEGF agents such as bevacizumab and ranibizumab (Lucentis). He described delivery up to 3 weeks, though he showed that substantial drug was still embedded in the hydrogel at that timeframe, and that longer delivery (3 to 6 months) was currently being studied. He also reported on several animal models utilized to assess possible adverse effects. He reported no evidence of toxicity and also noted that the released anti-VEGF agents appeared to be biologically active.
Robert W. Flower, PhD, of the University of Maryland, gave the last lecture of the technology session on the topic of erythrocyte movement in the retinal capillaries. He pointed out that use of indocyanine green and fluorescein angiography exploits not erythrocytes, but plasma. To get data that better represent the metabolic capacity of blood flow, Dr. Flower said, it makes sense to change the association of the indicator dye from plasma to the red blood cells. He showed comparative angiograms of ICG-stained plasma vs ICG-loaded erythrocytes. The stalled erythrocytes shown in capillaries, Dr. Flower said, indicate presence of vasomotion, which has been found in all other organ systems studied. However, because the retina lacks lymphatic vessels, it appears that vasomotion accounts for absorption of the excess fluid from capillaries predicted by Starling's hypothesis. Unabsorbed, that fluid would result in tissue edema, as in diabetic macular edema (Figure 2), suggesting reduced vasomotion may be an early indicator of incipient tissue swelling.
Figure 2. Clinically significant diabetic macular edema.
The lineup for the session on OCT imaging was the most packed of Macula 2009, with lecturers offering presentations on using OCT for a variety of disorders. Many of the lectures dealt with spectral domain (SD)–OCT. For instance, Philip J. Rosenfeld, MD, PhD, of the Bascom Palmer Eye Institute, spoke about the ability of SD-OCT to provide fundus images of geographic atrophy and RPE segmentation. A key point of Dr. Rosenfeld's presentation was that using SD-OCT along with FAF allows the retinal physician to better measure the area of geographic atrophy. In addition, SD-OCT also allows the the physician to follow the volumetric changes in drusen as they evolve into geographic atrophy.
Yale L. Fisher, MD, of Manhattan Ear, Eye, and Throat Hospital, followed Dr. Rosenfeld's presentation by commenting on automated drusen detection using SD-OCT. Dr. Fisher compared the distance-measuring ability of OCT vs ultrasound. He pointed out the algorithms for measurement are device-dependent and, thus, measurement correlation between different devices should be considered when assessing studies. Dr. Fisher presented a series of pie charts to demonstrate the ability of SD-OCT to detect drusen, noting that, if large drusen are more troublesome, then the detection ability of SD-OCT is particularly useful.
Duke University's Cynthia A. Toth, MD, gave the talk "The Secret Life of Drusen," in which posed the question "What, really, are drusen?" She laid out a classification scale for drusen with regard to their interior, eg, while 67% of the drusen examined were homogenous, a full third had either no cores or differing cores. Then she stressed that quantitative measurements of drusen were as important as qualitative ones. She reported an ongoing ancillary study to the AREDS 2 that will provide longitudinal in vivo data on SD-OCT imaging of drusen.
Speaking next was Giovanni Staurenghi, MD, from the University of Milan in Italy. Dr. Staurenghi stated that, with SD-OCT, retinal physicians have begun to see new things on fundus photographs that cannot be identified. He spoke about angioid streaks and pathological myopia, showing cases of successful treatment of each condition but noting certain aspects of the imaging that could not be explained. However, Dr. Staurenghi stressed that there needs to be a point-to-point correlation between images to better understand what is being seen.
Edoaro Midena, MD, of the University of Padova, also in Italy, spoke next and talked about the ability to distinguish different phenotypes of diabetic macular edema using SD-OCT. While OCT, he said, is the gold standard of assessing the progression of DME, he warned the audience not to oversimplify; rather, he said, retinal physicians should try to contribute to individual diagnostic assessment of DME.
K. Bailey Freund, MD, of Vitreous-Retina-Macula Consultants of New York, gave a presentation on a new OCT finding detected in the outer retinal layers of patients with various degenerative macular disorders. He termed this apparent reorganization of the photoreceptor layer "outer retinal tubulation" or ORT. Dr. Freund found that by curving OCT C-scans, one could see a branching networks of tubules confined to the outer nuclear layer, thus the name he has given to the condition. He showed OCT images of patients with neovascular AMD demonstrating how ORT could be misinterpreted as evidence of leakage from underlying choroidal neovascularization, possibly prompting unnecessary interventions. He finished by showing these tubules occurring in several retinal disorders.
John T. Thompson, MD, of the Greater Baltimore Medical Center, spoke about vitrectomy for epiretinal membranes with visual acuities of 20/50 or better and lamellar macular holes guided by OCT. He presented a case series of 40 patients with relatively good visual acuities from epiretinal membranes, showing that OCT was helpful in determining whether surgery was warranted. Dr. Thompson said that OCT was also helpful in deciding when not to perform surgery, eg, if the OCT looks good in eyes with epiretinal membranes, surgery should probably be avoided. OCT is also helpful in determining which patients with lamellar macular holes should receive vitrectomy.
Richard F. Spaide, MD, also of Vitreous-Retina-Macula Associates in New York, spoke next on the topic of choroidal imaging. Dr. Spaide began by showing how inverted images can provide more information about the choroid than noninverted images. He then presented his own case series of patients scanned using OCT, focusing on age-related choroidal atrophy as seen in several scans. He also spoke about cases of central serous chorioretinopathy and how that condition appears on OCT, both when it is comorbid with glaucoma and when it is not. Dr. Spaide closed with a short presentation of pathologic myopia as seen on OCT, noting the thinning of the choroid in such patients.
Duke's Glenn J. Jaffe, MD, finished the sessions with a lecture concerning artifacts on SD-OCT scans. Dr. Jaffe said that the expectation of artifact-free scans with SD-OCT — as opposed to time-domain OCT, which had the problem of containing many artifacts — was greater than the reality. In fact, a majority of the scans he presented in a case study had some artifact on their SD-OCT scans. Motion artifacts were less common, Dr. Jaffe noted that AMD cases tended to include the most artifacts. He showed several examples in a number of different pathologies. Dr. Jaffe reminded physicians to review their scans, and to provide feedback to technicians to minimize artifacts.
Douglas A. Jabs, MD, of Mount Sinai Medical Center in New York, opened the session with a talk on management of posterior uveitis. Discussing a variety of forms of uveitis, he talked about immunosuppressive drug therapy as a means of treating disorders. Eg, with birdshot chorioretinitis complicated with macular edema, immunosuppression resulted in an 86% reduction in edema — far better than with steroids, as well as an improvement in visual field loss. Immunosuppression is "the way to go," according to Dr. Jabs.
Lee M. Jampol, MD, of Northwestern University, spoke next, giving an update on the use of RU-486 for central serious chorioretinopathy. While photodynamic therapy is still the most common treatment for recalcitrant cases, Dr. Jampol described a case series he is currently directing using RU-486 and measuring outcomes in visual acuity using OCT and fluorescein angiogram. Dr. Jampol said that the drug, approved by the FDA for abortion and not eye disease and very expensive, seems to work in 40% of cases and its effect wears off with time. He suggested that adjuvant use of anecortave acetate should be studied in refractory cases.
Next, Mark W. Johnson, MD, of the University of Michigan, lectured on a syndrome in older patients that resembles acute multifocal placoid pigment epitheliopathy (APMPPE). Dr. Johnson presented a case series of 6 patients over the age of 50 who presented with acute APMPPE-like lesions limited to the posterior pole. The lesions faded to pigment mottling in 1 to 2 weeks with substantial initial improvement in vision. However, on long-term follow-up, most eyes developed geographic atrophy and/or choroidal neovascularization, with a poor final visual outcome. Recurrence of acute lesions was seen in just over half the eyes. Admitting that the cause of the syndrome is unknown, Dr. Johnson suggested either idiopathic choroidal vasculitis or choroidal hypersensitivity reaction with subsequent death of senescent RPE.
The Beaumont Eye Institute's George A. Williams, MD, followed with a talk on new concepts in retinal neuroprotection. He began by pointing out that that a significant problem with anti-VEGF therapy is that it improves ocular anatomy, but it leads to photoreceptor death. Neuroprotection, Dr. Williams suggested, is a way of directing treatment at neuronal loss, thus lessening effects on the retina. Agents that could act in this manner, according to Dr. Williams, include combination therapies, as well as encapsulated cell technology using ciliary neurotrophic factor and the glaucoma drug brimonidine.
Harry W. Flynn, Jr., MD, of Bascom Palmer, lectured next, presenting a 4-year retrospective case series of endophthalmitis in patients who had received intravitreal injections of 3 anti-VEGF agents. Dr. Flynn noted that, over the course of anti-VEGF therapy, cases of endophthalmitis are generally rare. In his own case series, Dr. Flynn found 9 cases of endophthalmitis in 34 000 injections, and of these, 5 were culture positive and 4 were culture negative. Dr. Flynn noted that the culture-negative cases might have been related to a batch of Avastin similar to cases reported from Canada. The culture-positive cases had a poorer prognosis, with Streptococcus infections having worse visual outcomes. Dr. Flynn suggested that exposure of syringes to moisture droplets from breathing of doctors and techs was a possible contributing factor to strep infections.
The Mayo Clinic's Jose S. Pulido, MD, presented 5 cases of autoimmune syndromes that were properly diagnosed using a single blood test. Among the cases Dr. Pulido described were a patient with neuromyelitis optica, diagnosed with a blood test to detect antibodies to aquaporin, and a patient with cells in the eye in a case of small-cell lung cancer who was given a collapsin response mediator protein (CRMP)–5 antibody test. Dr. Pulido noted that a recent paper in the New England Journal of Medicine noted that the induction of interferon for melanoma caused the development of autoimmunity, so Dr. Pulido's team tried to intentionally induce autoimmunity to cause antitumor activity. It remains to be seen whether autoimmunity can be used to treat cancer.
Lawrence A. Yannuzzi, MD, of Vitreous-Retina-Macula of New York, gave the last presentation in the medical retina session, speaking about a collaborative study of acute zonal occult outer retinopathy (AZOOR). Dr. Yannuzzi described the typology of AZOOR and cited a broad array of research done on this family of disorders, punctuating this research with slides of different patients.
Michael J. Cooney, MD, of Vitreous-Retina-Macula of New York, opened the retinal vascular session at Macula 2009 with a presentation on advances in diabetic pharmacotherapeutics. Dr. Cooney noted that, while lasers remain the standard of care for diabetic retinopathy, they slow vision loss by 50%, but visual acuity continues to decline. With intravitreal triamcinolone acetonide, there are good short-term effects, but there are also significant side effects of glaucoma and cataract. Dr. Cooney comments on such treatments as Avastin, ruboxistaurin, and Macugen, noting that the jury is still out on all these treatments. However, Dr. Cooney did state that he sees vitreolysis using microplasmin as holding promise for treating DME.
Philip J. Ferrone, MD, from Long Island Vitreoretinal Consultants in Great Neck, NY, presented 6-month interim data from a Lucentis trial involving diabetic macular edema. Dr. Ferrone stated that there have been no serious adverse events and the mean number of injections in each treatment arm have been just under 4. There was a statistically significant difference between the 0.5 and 1.0 mg doses of 5.7 letters in mean visual acuity improvement at 6 months. Dr. Ferrone also noted that the maximal drug effect lasted sometime between 4 and 8 weeks independent of the dose of Lucentis used.
The next 3 speakers were from Johns Hopkins. Peter A. Campochiaro, MD, discussed how topical mecamylamine is being used to treat DME, providing data from a phase 1/2 trial sponsored by the Juvenile Diabetes Research Foundation. Topical drug was administered tid for 12 weeks to 23 patients. Of 21 patients for whom data were available at 12 weeks, 13 showed improvement in foveal thickness and 8 showed improvement of at least 1 line in VA. Dr. Campochiaro concluded that topical mecamylamine showed evidence of biologic activity and deserves further study.
Neil M. Bressler, MD, delivered the next presentation, on the topic of whether diabetic retinopathy progresses after cataract surgery. He began by citing ETDRS report #25, which had concluded that there was no increased risk of macular edema following cataract surgery and no increased risk of progression of diabetic retinopathy. Dr. Bressler advised the audience to treat DME before surgery if at all possible, and to follow surgery with laser right after surgery is finished if needed for any DME uncovered after cataract surgery. He then addressed the value of pre-, intra-, and postoperative anti-VEGF treatment in patients with diabetes undergoing cataract surgery. While preoperative bevacizumab was reported by some investigators to prevent macular edema in 1 study compared with no treatment in a small randomized clinical trial, it was not a masked study. Dr. Bressler stated only the subjective assessments of the severity of edema or retinopathy were better in the bevacizumab group, and he noted that no differences were noted for objective outcomes with respect to changes in retinal thickness OCT or visual acuity.
Quan Dong Nguyen, MD, gave the last lecture of the session, on 1-year data from the READ 2 trial of Lucentis for DME. Dr. Nguyen indicated that, at the 6-month mark, the Lucentis arm of the study showed the greatest improvement, but as the months passed, the combination arm had outperformed the Lucentis monotherapy arm. Patients were followed up with laser and/or Lucentis, depending on the arm of the trial. At month 12, the laser arm continued to improve, while the visual acuity in the Lucentis arm declined. Dr. Nguyen suggested that increased combination treatment of Lucentis with laser may help those patients whose visual acuity declined.
Five presentations on surgical retina were of great interest. Stanley Chang, MD, of Columbia university opened the session with presentation on vitrectomy for retinoschsis/detachment in high myopia. He presented a case series of 20 eyes in 19 patients, all of which underwent vitrectomy and ILM peeling with gas tamponade. In 12 eyes had no preoperative macular holes on OCT, Dr. Chang found 60% of the eyes on which he operated improved in visual acuity to 20/50 or better, though 5 patients developed macular holes postoperatively. When the foveoschisis was associated with a macular hole, the visual outcome was less favorable. He ended by stressing the need to follow fellow eyes with OCT.
Julia A. Haller, MD, from Wills Eye, followed with a presentation on vitrectomy for DME. Dr. Haller stated that, while laser photocoagulation remains the gold standard in treating DME, disease persistence and lack of VA improvement are still problems. An approach that has been used over the years for persistent DME is vitrectomy, which has both an anatomic and a theoretical physiologic rationale, but little strong prospective evidence-based support. Dr. Haller discussed the results of a study by the DRCRN, on which she is the principal investigator. Outcomes in a group of patients with DME and vitreomacular traction showed retinal thickness decreasing over 6 months and 37% of patients experiencing a 10-letter or better improvement in visual acuity at 6 months. Still, 23% of patients experienced a decline in visual acuity, and Dr. Haller reminded the audience that 1-year interim data and subset analyses were still pending.
Steve Charles, MD, of the eponymous Charles Retina Institute in Memphis, spoke about 25-g macular surgery, giving an update on technique and stressing the need for using Alcon DSP end-grasping ILM forceps for epiretinal membrane and ILM peeling. He argued strongly against using indocyanine green for ILM visualization and advocated for ILM peeling on the basis of its ability to reduce recurrences, eliminate striae, as well as completely remove the epiretinal membrane and residual posterior vitreous membrane. Dr. Charles also warned against doing simultaneous phacoemulsification, reminding the audience that refractive outcomes and intra-operative visualization suffer.
Mark S. Blumenkranz, MD, of Stanford University gave a talk entitled "Why Macular Holes Close: A Working Hypothesis." The impact of high-resolution OCT has confirmed the return to normal architecture in many successful cases but the question remains as to the precise mechanism. Dr. Blumenkranz suggested a unifying hypothesis based upon previously under-recognized retinal plasticity and the capability of retinal supporting and neuronal elements to migrate and restratify in response to mechanical or thermal stimulation. The conclusions are based on observation of eyes undergoing retinal prosthesis insertion and gentle short pulse duration laser injury. In the former case, Dr. Blumenkranz cited research stating that retinal cells migrate through opening after implantation of fenestrated mylar membranes with the vigor of the response, based on aperture size. He also cited research on short pulse duration laser injury that indicates that repair occurs causing near normalization of the outer retinal layers including. He then quoted data from other labs using serial analysis of gene expression (SAGE) to demonstrate that following retinal injury there is a specific sequence of genes activated that contribute to retinal wound healing that are likely the initiators of these changes.
Greater Baltimore Medical Center's C. Pat Wilkinson, MD, spoke about surgically reattached maculas and the "mysteries" surrounding them. VA results after successful repair of macula-off retinal detachments remain relative poor and the data are "mysteriously inconsistent," he said. One of the variables Dr. Wilkinson addressed was the length of time that the macula has been detached. Other variables that he touched on while reviewing several published studies were height of macular detachment and preoperative visual acuity, the latter of which Dr. Wilkinson deemed the best clinical indicator of operative visual success. He also discussed nonclinical indicators, such as electrophysiology and OCT. Electroretinograms were not correlated with visual acuity, while OCTs were inconsistent in terms of determining VA.
Frederick L. Ferris, MD, of the NEI opened the session on dry AMD (Figure 3) with a presentation on new findings on geographic atrophy from the AREDS study. He discussed a natural history case series of AREDS patients who developed geographic atrophy at the 4-year visit or thereafter. Virtually all of them had large drusen. Pigmentary changes ultimately gave way to either mild RPE atrophy or geographic atrophy. Dr. Ferris then posed a series of questions, ie, whether size can be estimated, how fast the atrophy will progress, whether size is related to progression, etc. He then discussed a study of 251 eyes, which concluded that bilaterality becomes more common over time, that geographic atrophy is likely to become central, and that CNV frequently complicates the course of geographic atrophy.
Figure 3. Dry age-related macular degeneration.
Kang Zhang, MD, PhD, from the University of California–San Diego, followed with a presentation on genetic links to geographic atrophy. First, Dr. Zhang spoke about complement factor H, which apparently confers similar risks of geographic atrophy and CNV. However, because not all soft drusen patients progress to wet AMD, Dr. Zhang's team concluded other genetic variables must be involved. They found the HTRA1 gene indicating higher AMD risk in populations in both Utah and Hong Kong. Combined with CFH, this gene incurs great risk of developing AMD. Dr. Zhang then discussed the newly identified TLR3 receptor, stimulation of which can confer protection against GA.
The NEI's Emily Y. Chew, MD, and Susan B. Bressler, MD, of Johns Hopkins, both gave presentations on the relationship between cataract surgery and the development of advanced AMD. Dr. Chew pointed out that several population-based studies have indicated an increased risk of mostly CNV and rarely geographic atrophy with cataract surgery. But these studies have very small numbers of advanced cases of AMD. In the large AREDS study, thousands of cataract surgeries were performed and the presence of AMD was documented before and after cataract surgery with fundus photos. In this prospective study, there are no statistically significantly differences in the rates of development of advanced AMD in those participants undergoing cataract surgery compared with those who did not have cataract surgery. Neither CNV nor geographic atrophy was found to have increased following cataract surgery in the largest study to date. In addition, these patients have a high risk of developing advanced AMD because of the natural course of the condition and should have vigilant follow-up after cataract surgery.
Dr. Bressler's presentation took up the issue of cause and effect in the previous lecture, noting that several small case series have been done to try to determine whether a link between cataract surgery and progression of AMD exists, but they have been inconsistent. Dr. Bressler then turned to data from the Wilmer Institute's Retinopathy After Cataract Surgery study of 108 subjects. Although it appeared that roughly 10% of patients progressed to neovascular AMD after cataract surgery, most of these eyes manifested CNV on images obtained within 1 week of the surgery — suggesting that the pathology was likely present pre-operatively despite failure to identify it on pre-operative images through the cataract. The lesion characteristics suggested that the CNV likely had been present for a longer period of time as well. Similar observations were made for geographic atrophy.
Lucian V. Del Priore, MD, of Columbia University, spoke next on the topic of pharmacological vitreolysis for dry AMD. Dr. Del Priore indicated a clear relationship between posterior vitreous detachment (PVD) and AMD and a high incidence of vitreous attachment in eyes with recurrent CNV. He suggested that enzymes such as plasmin and microplasmin can induce PVD, with possible therapeutic benefit. Also in the pipeline is a vitreolysing agent called dispase, which is in commercial development with Drs. Tongalp Tezel and Henry Kaplan at the University of Louisville.
Finally, James M. Klancnik, Jr., MD, also of Vitreous-Retina-Macula Consultants of New York, discussed current treatments for dry AMD. He discussed complement inhibition and stressed that several stages of the disease could be treated with several agents either in development or in clinical trials. He spoke specifically about the ASaP trial of POT-4, which blocks C3. At therapeutic doses, it forms a gel-like deposit in the vitreous, offering potential sustained delivery with a single injection. Currently in phase 1 trials, the treatment appears safe. Dr. Klancnik closed with a brief overview of treatments in the pipeline, including autologous RPE transplant, stem cells, gene therapy, and even computer chips.
Macula 2009 ended with several presentations on wet AMD; you can read the coverage of that session on 'Going Beyond Anti-VEGF' of this issue. The society will meet next in a combined congress with ASRS and the Retina Society. The congress will be also be in New York and will take place from September 30 to October 4. RP