amd alliance international scientific advisory panel report april 2011

Scientific Advisory Panel Meeting Report 1

Scientific Advisory PanelMeeting Report

April 16th 2011 - New York City, USA

2 AMD Alliance International

Foreword

AMD Alliance International [AMDAI] is a global consortium of more than 70 members. It exists for one reason; to provide hope and help for people all over the world living with macular disease. Our members are organisations that are making an impact in vision rehabilitation research, and seniors’ and vision advocacy. AMDAI was established more than 10 years ago by vision organisations that with great foresight saw the impact that macular disease was going to have on an ageing population. The Alliance’s primary purpose is to create and share resources, disseminate knowledge and encourage research and evidence based practice. AMDAI is fortunate to be aided in its mission by a Scientific Advisory Panel consisting of some of the world’s foremost clinicians and researchers in the field of Macular Disease. They are currently led by the esteemed Dr Alan F. Cruess. The Panel met in New York in April 2011 and discussed a wide range of topics. This document is a record of that meeting and is aimed for the use of the informed reader, and is intended to be used as a resource by member organisations across the globe.

The Alliance thanks contributors for their on-going time and invaluable insight.

Narinder Sharma President & CEOAMD Alliance International

Hugh ParryPresident & CEO Prevent Blindness America


AMD ALLIANCE INTERNATIONALScientific Advisory PanelReport of April 16, 2011, Meeting - New York City, USA

Advances in Imaging and Classification of 4Exudative AMD and CNVK. Bailey Freund, MD

The Role of Nutrition in AMD 8Emily Y. Chew, MD

Risk Assessment Model and AMD 12Emily Chew, MD

Advances in Low Vision Therapy 16Bruce Rosenthal, OD

Anti-VEGF Therapy: Who Really Benefits 20Francesco Bandello, MD

Comparative Effectiveness Trials of Anti-VEGF Therapy 24Alan F. Cruess, MD

Genetics of Age-related Macular Degeneration 26Carel B. Hoyng, MD

Toward a Refined Understanding of Complement and 30Genetics in Age-related Macular DegenerationGregory S. Hageman, PhD

Members in AttendanceDr. Alan Cruess (Chair) Dr. Jose Cunha-VazProf. Au Eong Kah Guan Dr. Gregory S. HagemanProf. Francesco Bandello Dr. Carel B. HoyngDr. Gerald Chader Prof. Peter HumphriesDr. Gilles Chaine Dr. Bruce RosenthalDr. Emily Chew Dr. Lawrence A. YannuzziInvited guest: Dr. K. Bailey Freund

The Scientific Advisory Panel of the AMD Alliance International (AMDAI) met at the offices of Lighthouse International, New York, USA, on April 16, 2011.

Table of Contents


Advances in Imaging and Classificationof Exudative AMD and CNV

Do we need a new classification for choroidal neovascularization?

With advances in imaging technology, specifically optical coherence tomography (OCT), clinicians can examine the structure of the retina with more clarity than previously possible.

As OCT becomes the predominant imaging tool for managing choroidal neovacularization, however, clinicians need a more precise language to communicate its findings. Dr. Freund discussed a proposal to add a third “type” to the Gass neovascularization classifications. Type 3 neovascularization describes retinal angiomatous proliferation (RAP), also known as occult chorioretinal anastomosis (OCRA) or retinal lesion anastomosis (RLA) (Figure 1).

Figure 1. Proposed new classification system forneovascularization.

Is PCV a neovasculopathy or a choroidal vasculopathy?

With advanced imaging and more precise anatomical descriptions, new questions arise, Dr. Freund said. One example involves polypoidal choroidal vasculopathy (PCV), which has been described as a distinct abnormality of the inner choroidal vasculature, consisting of a network of branching vessels with terminal aneurysmal dilatations. Although there is still a general belief that polypoidal lesions are choroidal vascular abnormalities, Dr. Freund noted that recent investigations using advanced imaging show

K. Bailey Freund, MD


Advances in Imaging and Classificationof Exudative AMD and CNV

polyps above Bruch’s membrane, often beneath the retinal pigment epithelium (RPE), suggesting that PCV is a variant of the Type 1 sub-RPE neovascular pattern. “Using spectral domain OCT (SD-OCT) in en face mode, we can isolate a layer of tissue from the branching vascular network that feeds the polyps,” he said. Figure 2 shows the location of the branching vascular network and its relationship to the RPE.

Dr. Freund shared a video created by Szilárd Kiss, MD, showing that the branching vascular network and the polyps seem to localize beneath the RPE but above Bruch’s membrane. Based on recent studies and his own clinical experience, Dr. Freund said he believes polypoidal, for the most part, is a form of Type 1 neovascularization. Having reviewed numerous papers on PCV, he cautioned clinicians: “ When we look at a patient with polypoidal, we should not be entirely focused on the PCV lesions and ignore the other neovascularization, which is usually much more widespread than the polyps. Yes, the polyps at that moment may be causing the vision problem and the serosanguinous complications, but we should not focus only on closing that one polyp. There is a lot more going on in these eyes.”

Figure 2. SD-OCT shows the branching vascular network above the choroid (lower left) and elevating the RPE (lower right).

What has SD-OCT taught us about Type 3 neovascularization (RAP)?

Traditionally, clinicians used indocyanine green (ICG) imaging to confirm the presence of RAP, however, Dr. Freund noted clinicians using SD-OCT can detect RAP much earlier than they can with other imaging modalities. “You are not going to see it on ICG until there is a very well-established lesion with significant leakage.” Dr. Freund also appreciates the active eye-tracking feature of one of the commercially available SD-OCT systems, which enables comparisons of scans taken at different visits to better understand how Type 3 neovascularization develops and why it develops where it does

(Figure 3). Figure 3. SD-OCT enables clinicians to track change over time to learn more about how neovascular tissue develops.


Dr. Freund explained: “What we typically see is thinning of the outer nuclear layer over what looks like a drusenoid pigment epithelial detachment (PED), which may already have neovascularization. Intraretinal pigment migration occurs, presumably with the loss of the outer nuclear layer. The deep retinal circulation comes in close proximity to the RPE cells, which appear to have migrated into the retina. There also appears to be the beginning of angiogenesis.”

In summary, in addition to detecting Type 3 neovascularization earliest, SD-OCT has revealed valuable information about it. “Type 3 neovascularization appears to be preceded by photoreceptor atrophy, often over a drusenoid PED, and, presumably, there is outer retinal ischemia,” Dr. Freund said. “We tend to see RPE migrate into the retina before these lesions develop and show fluid. There is still uncertainty, however, about where the vessels originate and exactly when retinal choroidal anastomosis develops.”

Can certain forms of CNV protect the retina?

Dr. Freund shared several cases (summarized below) toillustrate the theory that CNV may be protective in some patients.

• A patient presented with an asymptomatic hemorrhage, an occult (Type 1) membrane on fluorescein angiography and good vision. The hemorrhage resolved spontaneously, and the patient was followed. After 7 years, the patient still has neovascular AMD, but his vision improved from 20/40 to 20/30 since his initial visit.

• A patient presented with geographic atrophy in the left eye and geographic atrophy plus Type 1 vessels and leakage in the right eye, which was treated with intravitreal anti-VEGF therapy for 50 months. The right eye had minimal progression of geographic atrophy, whereas the left eye, which did not have neovascularization, developed more profound atrophy.

The right eye is now, by far, the better eye. OCT imaging with eye-tracking over 25 months shows the area of RPE loss in what was the better eye is expanding. “This suggests but does not prove that, in some way, the neovascularization may be helping to perfuse the outer retina in that left eye, keeping those photoreceptors viable,” Dr. Freund said.

• A patient presented with nonexudative changes in the right eye (visual acuity 20/20); in the left eye, there was a large vascularized PED and hemorrhage (visual acuity 20/50). Over 2 years, the right eye worsened more than the left eye, which was treated with intravitreal anti-VEGF therapy. Outer retinal atrophy occurred at the fovea in the right eye, while the photoreceptors in the left eye did well. Visual acuity in the left eye is now 20/25. “Grossniklaus, Green, and others have suggested a potentialcompensatory mechanism in which the Type 1 neovascularization may recapitulate the choriocapillaris and theoretically could be providing


nutrients and oxygen to an ischemic outer retina, helping to preserve photoreceptor viability,” Dr. Freund said.

• A patient was treated with photodynamic therapy with verteporfin from 2002 to 2006. He has been receiving monthly anti-VEGF therapy for 52 months. His visual acuity has remained 20/30.

Based on his and others’ clinical experiences, and with information provided by advanced imaging, Dr. Freund theorized that the Type 1 neovascular pattern may be protective against geographic atrophy. It may develop many years before clinical signs of exudation are evident. Chronic Type 1 neovascular tissue may give rise to the polyps that are part of the polypoidal choroidal vasculopathy, and these may be more appropriately called a neovasculopathy.

During a discussion following Dr. Freund’s presentation, the panelists concurred that OCT is supplanting fluorescein angiography as the primary imaging tool for managing CNV and that better definitions of findings are needed.

Bibliography

Freund KB, Zweifel SA, Engelbert M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration? Retina. 2010;30:1333-1349.[PMID: 20924258]

Grossniklaus HE, Green WR. Choroidal neovascularization. Am J Ophthalmol. 2004;137:496-503.[PMID: 15013874]

Klein ML, Wilson DJ. Clinicopathologic correlation of choroidal and retinal neovascular lesions in age-related macular degeneration. Am J Ophthalmol. 2011;151:161-169. [PMID: 20970772]


The Role of Nutrition in AMD

Updates of the Age-Related Eye Disease Study (AREDS) and AREDS2

On the 10th anniversary of the Age-Related Eye Disease Study (AREDS), Dr. Chew reviewed and updated key findings from this randomized, placebo-controlled clinical trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc. The AREDS had four treatment groups: placebo, antioxidants (vitamin C, E, and beta-carotene), zinc (80 mg zinc, 2 mg copper), and a combination of the antioxidants and zinc, all at very high doses. Patients ranging in age from 55 to 80 years with good vision (20/32or better) in at least one eye and clear media were categorized as having no AMD or early, intermediate, or advanced AMD.

At 5 years, the placebo group’s progression rate was 28% as compared with 20% for the Category 3 and 4 patients, who were given the combination of the two treatments. This was a 25% reduction in the risk of progression. At 10 years, the effect persisted. Based on these findings, Dr. Chew noted, patients with bilateral large drusen and those with advanced AMD in one eye should take the AREDS formulation. These patients should be nonsmokers (defined as having stopped smoking at least 1 year ago) because of the potential for beta-carotene to increase the risk of lung cancer. The formulation is not recommended for Category 2 patients or for offspring of patients with AMD unless they have bilateral large drusen or advanced AMD in one eye. The formulation does not prevent early AMD from progressing. Although there was no treatment effect for patients with geographic atrophy, Dr. Chew believes these patients should take the AREDS formulation because 30% of them will develop neovascularization.

Despite recent reports of increased mortality associated with vitamin E, beta-carotene, and multivitamins, 10-year mortality data from the AREDS showed antioxidants have no effect on mortality; and there was a statistically significant reduction in mortality in patients taking zinc. “What we found was that patients with neovascular AMD had the highest risk of death with cardiovascular disease,” Dr. Chew said. “There was a 60% increased risk of cardiovascular disease in patients with neovascular AMD, and the zinc itself had reduced the cardiovascular disease. We do not know if that is through a mechanism of immune modulation or some other aspect.”

In another important aspect of the AREDS trials, researchers looked at baseline diet, using a 90-item self-administered food frequency questionnaire.

Emily Y. Chew, MD


The Role of Nutrition in AMD They found that lutein and zeaxanthin (found in green leafy vegetables) and omega-3 fatty acids (found in fish products) are important for reducing the risk of progression from early or intermediate AMD to advanced AMD, and they are also protective for geographic atrophy and large drusen. These findings led to the AREDS2 to examine dietary supplementation with lutein and zeaxathin and the omega-3 long-chain polyunsaturated fatty acids (DHA+EPA). Figure 1 illustrates the AREDS2 study design.

According to Dr. Chew, AREDS2 will look at the two components that are problematic in the AREDS formulation: beta-carotene, which increases the risk of lung cancer in smokers, and zinc, which increased the risk of hospitalizations for genitourinary causes and for which there are questions regarding the appropriate dose. “We are testing the classic AREDS supplement versus eliminating betacarotene or lowering the zinc to 25 mg, or the combination of eliminating beta-carotene and decreasing zinc,” Dr. Chew explained. “In this way, the people

who are smokers can be enrolled in a scheme that includes the no beta-carotene group.” She also noted AREDS2 will take place in 82 clinics (versus 11 in AREDS1), which will result in a more geographically diverse population with more diverse diets.

According to Dr. Chew, AREDS2 results, including the adverse effect data, such as mortality, should be available in 2013, as the patient follow-ups will be completed by the end of 2012. Other studies that are planned or under way include:

• A genetics study scheduled to launch in 2011

• Phenotype evaluation of AMD with and without peripheral drusen using ultra-widefield retinal imaging

• Phenotype evaluation using spectral domain optical coherence tomography (Bioptigen technology).

During a discussion following Dr. Chew’s presentation, panelists commented on the fact that the AREDS showed a protective effect only in patients with advanced disease, which seems counterintuitive. It was suggested a larger study of longer duration might produce guidelines for patients with early disease; however, such a study is currently not planned. Dr. Chew is hopeful that researchers studying the immunological factors related to AMD will shed some light on potential preventative strategies.

AREDS 2 Study Design


Regarding concerns related to vitamin A, Dr. Chew noted, “Betacarotene is given as beta-carotene. I understand from nutrition specialists that there is little conversion to vitamin A. This is of interest because vitamin A is important for visual function, but another issue with vitamin A is that it increases the risk of fractures in elderly people. … Hopefully with the beta-carotene elimination [in AREDS2], we will learn more.” Dr. Chew later stated that vitamin D levels were not studied in the AREDS. She also noted the U.S. National Institutes of Health is supporting a large trial (about 10,000 participants) looking at cancer and vitamin D, which will likely examine eyes, as well.

In response to a question from a panelist, Dr. Chew noted subjects in the AREDS were offered multivitamins and about twothirds took them. Subjects in AREDS2 were also offered multivitamins, and about 90% are taking them. “We did the analysis in AREDS with and without the multivitamin and it made no difference, except for people with cataracts,” Dr. Chew said. “People taking multivitamins had a protective effect for cataract but not AMD.”

Women’s Antioxidant and Folic Acid CardiovascularStudy and AMD

Dr. Chew next reported on a randomized trial of 5,442 healthy women who are health care professionals 40 years of age and older. Subjects had either risk for or pre-existing cardiovascular disease. They were randomized to a combination of B vitamins or placebo. The primary goal was to reduce cardiovascular disease. These subjects had elevated homocysteine, which may be important in causing vascular endothelial dysfunction. “Interestingly, this elevated homocysteine was also associated with cardiovascular disease, and we have seen it with AMD,” Dr. Chew said. “The Blue Mountains Eye Study showed that elevated homocysteine is a risk factor for maculardegeneration.”

Researchers evaluated the medical records of subjects who reported they had AMD. Most cases showed early changes; there were 19 cases of advanced AMD. In this study, vitamin B was not beneficial for cardiovascular disease; however, researchers reported the risk of macular degeneration was reduced by about 34% to 40%.

Based on results from this study (Figures 2 and 3), Dr. Chew said, no recommendation can be made to the AREDS-type population because these were early changes. In addition, the validation of medical records does not eliminate other eye disease that may have been occurring at the same time. Although the results of this randomized trial deserve further evaluation, Dr. Chew said, the recommendation for patients with AMD is to continue taking the AREDS formulation.


Bibliography

Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular 11 degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436. Erratum in: Arch Ophthalmol. 2008;126:1251. [PMID: 11594942]

Christen WG, Glynn RJ, Chew EW, Albert CM. Folic acid, pyridoxine, and cyanocobalamin combination treatment and agerelated macular degeneration in women: the Women’s Antioxidantand Folic Acid Cardiovascular Study. Arch Intern Med. 2009;169:335- 341. [PMID: 19237716]

Krishnadev N, Meleth AD, Chew EY. Nutritional supplements for age-related macular degeneration. Curr Opin Ophthalmol. 2010;21:184-189. Review. [PMID: 20216418].

Rochtchina E, Wang JJ, Flood VM, Mitchell P. Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol. 2007;143:344-346. [PMID: 17258528]

Total Confirmed AMD

Visually Significant AMD

Figure 2

Figure 3


Risk Assessment Model and AMD

AREDS researchers, led by Michael L. Klein, MD, are developing a risk assessment model for AMD. According to Dr. Chew, researchers are looking at demographic and environmental risk factors, ocular phenotype risk factors, and the genetic variants. Demographic and environmental risk factors include:

• Age• Sex• Race• Body mass index• Educational level• Tobacco smoking• Diet• Sunlight exposure• History of hypertension, cardiovascular disease, diabetes, arthritis, and skin cancer• Current and past medications• Dietary supplements.

Researchers are using the AREDS Simple Scale to phenotype AMD. Genetic variants include: CFH, LOC/HTRA1, C2, C3, CFI and CFB.

Dr. Chew noted key eye studies have found that people who are current smokers have a 2.8 increased risk of geographic atrophy as compared with people who never smoked (Figure 1). For every 10mg/dL increase in total cholesterol, there is a 20% increased risk of geographic atrophy. There is at least a two-fold increased risk of AMD in people who smoke. In a multiple study of different countries on the French-Mediterranean Sea border, researchers found that former smokers and current smokers have increased risk (Figure 2); however, they also had an interesting dose response (Figure 3). As Dr. Chew explained, “Comparing someone who had smoked more than 40 pack-years to someone who never smoked or had fewer pack years, a gradation of the risk increases, so clearly, smoking is something we find in every study. It is a very important risk factor.”

Emily Chew, MD


Risk Assessment Model and AMD

Smoking and AMD

Smoking--Dose Response

Figure 1

Figure 2

Figure 3


Phenotyping is particularly problematic, Dr. Chew noted. “It is difficult to use AMD categories from the AREDS because of the heterogeneity of Category 3, so we are using the AREDS Simple Scale, which is somewhat more user-friendly,” she said. The AREDS Simple Scale grades both eyes and uses only two baseline factors: presence of large drusen (125 microns) and pigmentary changes (hypo- or hyperpigmentary changes, including geographic atrophy that is not in the center). Figure 4 shows an example of the Simple Scale grading, and Figure 5 shows the 5-year risk of developing AMD using this scale.

AREDS Clinical Severity Scale for AMD

Patient Severity Scale

Right EyeLarge Drusen

Pigment Changes

Yes = 1

Yes = 1

No = 0

No = 0-

-

1

1

Left EyeLarge Drusen

Pigment Changes

Yes = 1

Yes = 1

Yes = 1

No = 0

No = 0

-

-

-

1

1

1

Patient Severity Score = 4

AREDS Clinical Severity Scale for AMDEventRate

30%

40%

50%

5-Year Risk of Developing Advanced AMD

0.5% 3% 12% 25% 50%

1 2 3 400%

30%

20%

10%

Patient Severity Score

Figure 4

Figure 5


Dr. Chew noted some of the limitations of the AREDS Risk Assessment Model include:

• Incomplete knowledge– Lack of fundus autofluorescence, drusen area, types of drusen, ie, reticular or pseudodrusen for phenotyping– Complexity of genetics (other variants or gene-to-gene interactions may play a role)• Difficulty analyzing dietary information• Lack of serum or other biomarkers that may be useful in the future.

A paper describing this risk assessment model is currently in press.

During a discussion following Dr. Chew’s presentation, it was noted risk factors in families may be different from those in individuals. “The family studies are difficult, unless you can truly verify that a particular family member has AMD,” Dr. Chew said. “For example, in the Physician Health Study, we asked for self-reports for AMD. When we verified the medical records, a number of the participants, all of whom were physicians, did not have macular degeneration. They had epiretinal membranes or macular holes, but they called it macular degeneration, so we have to be very careful with family history.”

Dr. Cruess asked the panelists how they are counseling their patients about nutrition and dietary supplements in light of current information. Responses were varied, often reflecting clinical practice in different parts of the world, and highlighting a need for specific recommendations for early disease. Some panelists reported the original AREDS formulation is not available over-the-counter in some countries because of government regulations restricting the dosage of vitamin A and zinc. In those countries, if the dosage of a vitamin is higher than a specified maximum, it is considered a medication. The panelists agreed that smokers should not use the AREDS formulation with beta-carotene.

Bibliography

Klein ML, Francis PJ, Rosner B, et al. CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology. 2008;115:1019-1025. [PMID: 18423869] 16


Advances in Low Vision Therapy

Low Vision: A treatment modality in the continuum of care of age related macular degeneration and moving into thehi-tech age

Dr. Rosenthal is encouraged by a worldwide commitment to low vision services. “We have seen the medical literature begin to quantify the importance of low vision services around the world,” he said. For example, in a paper published in Investigative Ophthalmology and Vision Science, the authors cite a substantial increase in the need for social services for visually impaired elderly women. Their findings also reinforce the importance of early preventative and rehabilitative efforts to prevent longitudinal deterioration in vision loss. Dr. Rosenthal noted that Lighthouse International has responded to this worldwide need through education and by establishing centers of excellence in the Dominican Republic, Egypt, India, Mexico and Saudi Arabia.

The aging population worldwide is a concern, Dr. Rosenthal said. Increased life expectancy in developed countries means eye doctors will be seeing more patients over the age of 80 who have end-stage disease. He has noticed this trend in his own clinic. “In one period last week, 10 out of 20 patients I saw were over the age of 90 years,” he said, “and many of these people are still working.”

Depression is a serious concern for people with AMD. Quoting former AMDAI Chairman Don Curran, Dr. Rosenthal noted, “Even clinicians and pharmaceutical companies don’t understand how [AMD] can cause such depression. Simple blindness is far easier to comprehend than this kind of partial-sightedness.” According to Dr. Rosenthal, the artist Adam Hahn, whose paintings depict how people who have AMD perceive themselves, is helping to raise awareness of the impact of this disease. The late Henry Grunwald, a former editorin-chief of Time Inc.’s magazines, wrote “Twilight Losing Sight, Gaining Insight” after developing AMD, which also provides insight into the emotional and psychological impact of the disease.

According to Dr. Rosenthal, Lighthouse International has studied depression in the visually impaired. A long-term study by Horowitz and colleagues showed clinical depression is higher in people who have AMD than in people who are visually impaired from other causes.

Dr Bruce Rosenthal


Dr. Rosenthal also recognized Lawrence A. Yannuzzi, MD, the recipient of the 2010 Lighthouse International Pisart Vision Award, for raising awareness of the need for low vision services and for “bringing the ophthalmologic, optometric, and research communities to the table.”

Tools for clinicians

Low vision specialists are incorporating high-tech equipment, such as optical coherence tomography (OCT), into their practices, which enables them to be active partners with retina specialists in their patients’ care. As Dr. Rosenthal explained, “When I am examining a patient I have not seen in 6 months, and, all of a sudden, he has lost three lines on the ETDRS chart and his contrast has decreased, I can do an OCT, and if necessary, refer that patient immediately to the retina specialist. As a low vision clinician, I have to recognize that these patients may be undergoing some severe changes.”

Evaluating contrast sensitivity is another important part of the low vision specialist’s examination. Dr. Rosenthal has found the Mars Letter Contrast Sensitivity Test beneficial. The test can help clinicians gauge a patient’s ability to use low vision devices and determine if he will benefit from optical or electronic devices. One of the challenges is to improve contrast sensitivity outdoors to minimize the risk of falls. Dr. Rosenthal also noted some patients have difficult recognizing facial features, which contributes to their feeling of isolation. “I feel very passionate about contrast sensitivity as being a very important visual function, along with visual acuity and the visual field,” he said.

Tools for patients

As clinicians’ tools have advanced, so have optical aids for patients, however, not every optical device is acceptable for every patient. As an example, Dr. Rosenthal recalled a patient who refused to wear eyeglasses. “In this modern era, we have to find out, realistically, what a young person will use,” he said. “On the other hand, all of a sudden, we have many new high-tech electronic devices. These are off-the-shelf devices that became available to low vision patients mainly because they were used for video games.” He cited the introduction of the iPad as an advance that has benefited some low vision


patients. “These types of devices are leveling the playing field for the visually impaired, helping them to feel ‘normal’ in public. All of a sudden, their icons are talking to them, and they can use earphones so nobody knows they cannot see the screen. They can stretch the screen, change the font, or even make the font bold. They can take a picture of a page with the iPad2, and it will speak the page. I think Steve Jobs changed the world.”

Inexpensive smartphone applications are also available, including one that speaks the denomination of paper money and another that speaks the color of an item when scanned. In the realm of specialized devices, an implantable miniature telescope (VisionCare Ophthalmic Technologies Inc., Saratoga, Calif.) gained approval by the US Food and Drug Administration in 2010.

Dr. Rosenthal reported a unique assistive device is under investigation by BrainPort Technologies Wicab Inc., in Middletown, Wis. According to the company’s website, “The BrainPort vision device is an investigational, nonsurgical, assistive visual prosthetic device that translates information from a digital video camera to the tongue through gentle electrical stimulation.” Dr. Rosenthal has personally seen a patient use the device. “A young patient who was shot through his optic nerves and is totally blind was instructed how to use the device and then walked around the block,” he said. “He had the biggest smile because, all of a sudden, he was traveling independently.”

Also on the horizon is a new edition of “The Lighthouse Ophthalmology Resident Training Manual,” which will be translated into several languages, and Low Vision University™, an educational program developed to educate US professionals at a statewide level.

Bibliography

Finger RP, Fenwick E, Marella M, et al. The impact of vision impairment on vision-specific quality of life in Germany. Invest Ophthalmol Vis Sci. 2011;52:3613-3619. [PMID: 21357395]

Finger RP, Fimmers R, Holz FG, Scholl HP. Incidence of blindness and severe visual impairment in Germany: projections for 2030. Invest Ophthalmol Vis Sci. 2011;52:4381-4389. [PMID: 21447690]

Finger RP, Fimmers R, Holz FG, Scholl HP. Prevalence and causes of registered blindness in the largest federal state of Germany. Br J Ophthalmol. 2011;95:1061-1067. [PMID: 21378005]

Howowitz A, Reinhardt JP, Boerner K. The effect of rehabilitation on depression among visually disabled older adults. Aging Ment Health. 2005;9:563-570. [PMID: 16214704]

Horowitz A, Reinhardt JP, Kennedy GJ. Major and subthreshold depression among older adults seeking vision rehabilitation services. Am J Geriatr Psychiatry. 2005;13:180-187. [PMID: 15728748]


Anti-VEGF Therapy: Who Really Benefits?

Prof. Bandello and his coworkers at the Department of Ophthalmology, Scientific University Institute San Raffaele, Milan, Italy, recently conducted a literature review to better understand which eyes are most likely to respond to anti-VEGF therapy and why as many as 10% do not respond. They learned that nonresponders in the MARINA and the ANCHOR trials had the following factors in common:

• Increasing age• Larger CNV lesion size at baseline• Higher baseline visual acuity score

Figures 1 and 2 provide brief explanations of the predictive values ofthese factors.

Francesco Bandello, MD

Figure 1

Figure 2


Anti-VEGF Therapy: Who Really Benefits?


Similarly, data from the pegaptanib study showed visual acuity stabilized for 47% of treated eyes with early lesions, but thepercentage dropped to 33% for all lesions. A significant improvement was seen in 20% of the eyes with early lesions, but only 6% of the eyes with any kind of lesion (Figure 3). Thus, treating early lesions will achieve the best response. “This study also found that an improvement in visual acuity within 3 months of a patient’s first injection is a good sign regarding the evolution of the disease,” Prof. Bandello said. He also noted, genetic factors and the photoreceptor layer, as seen on spectral domain optical coherence tomography images, may also be predictive of a patient’s response to treatment.

A recent retrospective analysis by Rosenfeld and co-workers reported in part:

• After 2 years, 9% of ranibizumab-treated patients in the MARINA study and 10% in the ANCHOR study had lost 15 or more letters.• 30% of the patients treated with ranibizumab in the MARINA study and 38% in the ANCHOR study gained at least 15 letters.• Baseline characteristics associated with loss of visual acuity at 2 years included: older age, better visual acuity and larger lesions.• After 2 years, increased area of retinal pigment epithelium abnormality and increased total lesion area were associated with visual acuity loss in both studies.

Prof. Bandello and colleagues performed a randomized, doubleblind study (NCT01327222) to compare the effectiveness of intravitreal bevacizumab injection to observation in patients with subfoveal CNV secondary to AMD, presenting at baseline with BCVA less than 20/200. They presented their findings at the 2011 meeting of the Macula Society in Boca Raton, USA. They found no treatment benefit over a 6-month follow-up period. Even subjectively, patients did not report a significant improvement in visual function or quality of life.

Figure 3


In summary, Prof. Bandello noted, many factors can limit the functional gain from anti-VEGF therapy. Future efforts should focus on determining the best therapeutic approach for each type of CNV lesion to preserve photoreceptor RPE cell viability. In a subsequent discussion on response to treatment, somepanelists suggested patients diagnosed with AMD in their 40s and 50s may, in fact, have a macular dystrophy that is mimicking AMD, which, therefore, may not respond to anti-VEGF therapy. It was also suggested that genetic factors may play a role in early-onset AMD.

Bibliography

Brown DM, Kaiser PK, Michels M, et al.; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.[PMID: 17021319]

Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431. [PMID: 17021318]

Rosenfeld PJ, Shapiro H, Tuomi L, Webster M, Elledge J, Blodi B; MARINA and ANCHOR Study Groups. Characteristics of patients losing vision after 2 years of monthly dosing in the phase IIIranibizumab clinical trials. Ophthalmology. 2011;118:523-530. [PMID: 20920825]


Comparative Effectiveness Trials ofAnti-VEGF Therapy

(Editor’s note: This report was presented prior to the 2011 meeting of the Association for Research in Vision and Ophthalmology.)

Dr. Cruess reported that results from the Comparison of Agerelated Macular Degeneration Treatments Trials: Lucentis-Avastin Trial (CATT) will be released and discussed at the 2011 meeting of the Association for Research in Vision and Ophthalmology (ARVO). This study evaluates the relative efficacy and safety of treatment of neovascular AMD with ranibizumab versus bevacizumab on a fixed schedule and a variable schedule. The primary outcome measure is mean change in visual acuity at 1 year. Secondary outcome measures include:

• Number of treatments in each group• Proportion of eyes with a three-line change in visual acuity• Change in subretinal and intraretinal fluid on optical coherencetomography• Mean change in lesion size on fluorescein angiography• Incidence of eye-related treatment complications• Incidence of systems adverse events• Relative cost of treatments.

Dr. Cruess noted that Usha Chakravarthy, MD, will present a report, “Fluctuating Levels of Circulating VEGF in a Subset of Patients as Part of the Multicenter IVAN Study,” at the ARVO meeting. IVAN is a randomized, controlled trial of alternative treatments to inhibit VEGF in age-related choroidal neovascularization.

Researchers for these trials are stressing health-related quality outcomes and costs, and they are performing serum and DNA testing.

Dr. Cruess also noted new data from the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (VIEW1) and VIEW2 trials are expected to be released at the ARVO meeting, as well. Other trials under way around the world include:

• Austria: Avastin Versus Lucentis in Age Related Macular Degeneration (MANTA)• Brazil: Bevacizumab Versus Ranibizumab in Age Related Macular Degeneration (AxL-2009)

What Can We Expect from CATT and IVAN?Alan F. Cruess, MD


Comparative Effectiveness Trials ofAnti-VEGF Therapy

• France: French Evaluation Group Avastin Versus Lucentis (GEFAL)• Germany: Prevention of Vision Loss in Patients With Age- Related Macular Degeneration (AMD) by Intravitreal Injection of Bevacizumab and Ranibizumab (VIBERA)• Netherlands: Equivalence of three monthly intravitreal injections and additional injections as needed of bevacizumab and ranibizumab on visual acuity in patients with exudative age-related macular degeneration (EQUAL)• Norway: Lucentis Compared to Avastin Study (LUCAS)

Following Dr. Cruess’s presentation, the panelists discussed the potential ramifications among governments, regulatory agencies, and payers if results show ranibizumab and bevacizumab are equivalent. Although speculative, comments by panelists from various countries with diverse health care systems sparked lively debate on safety, efficacy, and costs.


Genetics of Age-relatedMacular Degeneration

What is the role of ARMS2/HTRA1 in AMD?

Dr. Hoyng presented data derived from EUGENDA, the European Genetic Database, which is an online database of more than 3,500 entries (patients and controls). Participants complete questionnaires about lifestyle, family history, and so on. Visual acuities are measured, and fundus photographs, fluorescein angiograms, and optical coherence tomography images are taken and graded at a reading center. Blood samples are collected for serum, plasma, DNA, cell line, and clinical chemistry. According to Dr. Hoyng, the database now includes more than 100 families with AMD, with two or more members affected, making for a robust resource for genetic study.

In genetic studies of AMD, Dr. Hoyng noted, the first risk variant was found in complement factor H (CFH), which is an inhibitor of the alternative pathway of the complement system (Figure 1). “Looking at published odds ratios,” he said, “we see that CFH and ARMS2, each with an odds ratio between 3 and 7, are the most important genes (Figure 2). After analyzing our database, we found a correlation with apolipoprotein B (ApoB) in thousands of our patients compared to about a thousand controls (Figure 3). These ApoB levels are associated with the ABCA1 genotype.”

Carel B. Hoyng, MD

Figure 1


According to Dr. Hoyng, ApoB plays a role in the pathogenesis of AMD. The primary apolipoprotein of LDL, ApoB acts as a ligand for allele receptors and cells, and it is a better indicator of heart disease than total cholesterol or LDL. Transgenic mice overexpressing ApoB in the retinal pigment epithelium (RPE) develop AMD. Elevated ApoB levels stimulate inflammation, so something may be present that also plays a role in the development of AMD. “We also analyzed complement activation and complement regulators to learn what these genetic changes mean,” Dr. Hoyng said. “We do not exactly know what the ARMS2 gene does, how it works; however, we see complement activation in patients who arehomozygous for the ARMS2 allele. It comes back to inflammation.” Dr. Hoyng and his coworkers are also hoping to develop a predictive model based on their findings.

Figure 2

Figure 3


Is AMD one disease, or are there specific subtypes?

According to Dr. Hoyng, dry AMD has numerous subtypes. “In our genetic analyses, we found five new mutations, not only in the CFH gene but also in other genes, mostly in the complement system, that lead to basal laminar drusen (BLD), a dry type of AMD.” (Figure 4) About 10% of dry AMD is characterized by BLD, which can develop neovascularization, Dr. Hoyng noted. The CFH allele occurs much more frequently in BLD than in AMD. Mutations in CFH can cause BLD, and other genetic risk factors and mutations are being studied. Other clinical subtypes of AMD are retinal angiomatous proliferations (RAPs) and late-onset Stargardt disease, which Dr. Hoyng believes is underestimated in dry AMD.

Are the factors that lead to AMD the same factors that influence progression of AMD?

In looking at 108 patients with AMD, Dr. Hoyng and his coworkers found that smoking most definitely influences progression of AMD. CFI and LPL also were associated with progression, while CFH and ARMS2 were not.

Another study was designed to find out which factors influence the response to treatment. As Dr. Hoyng explained: “We looked at the pharmacogenetics of AMD, which is the study of genetic variation that gives rise to differing response to drugs. We know that approximately 10% to 20% of AMD patients do not respond to anti-VEGF treatment, and our question was: Can genetic variants explain this response? Our preliminary results suggest ARMS2 and BMI are correlated with a poor outcome.”

Based on research to date, Dr. Hoyng said, “We conclude that the complement system is systemically activated in AMD patients. The currently known AMD risk factors are good predictors of disease. We have to look for clinical subtypes, such as BLD, and that is especially important when we want to advise our patients. For AMD progression, several risk

Figure 4


factors influence second eye involvement, but not ARMS2 and CFH. For pharmacogenetics, ARMS2 genotype and BMI are associated with response to ranibizumab treatment.”

Dr. Hoyng also briefly discussed a paper by Kaneko and colleagues published in the journal Nature in March (DICER1 Deficit Induces Alu RNA Toxicity in AMD). The investigators found that Alu RNA transcripts accumulate only in the RPE cells of patients with geographic atrophy, and that elevated levels of Alu RNA in the RPE were due to DICER1 depletion. The messenger RNA was reduced in the RPE by about 65% compared to control eyes. Investigators concluded that, so far, the evidence supports the theory that DICER1 disregulation is involved in the pathogenesis of geographic atrophy.


Toward a Refined Understanding ofComplement & Genetics inAge-related Macular Degeneration

Early studies showed that a host of complement pathway components, regulators, cofactors, inhibitors, and activators characterize the retinal pigment epithelium (RPE)-choroid interface in eyes derived from donors with early AMD. “For better or for worse, at the time of these early discoveries, we pursued the concept that activation of complement at the RPE-choroid interface was at the root of early-stage AMD,” Dr. Hageman said. “These initial observations led to the hallmark discovery that the Complement Factor H (CFH) gene on chromosome 1 is associated with approximately 50% risk of developing AMD. We have since learned that a number of additional genes in the complement pathway are associated with macular degeneration.”

Dr. Hageman further explained that, in addition to CFH, the chromosome 1 locus also contains five CFH-related genes. “We have just discovered a sixth gene in that locus,” he said, “as well as Factor 13B (F13B), which is structurally similar to other complement genes. The other important locus that is strongly associated with risk for AMD is the ARMS2/HTRA1 gene complex located on chromosome 10.”

Questions remain, Dr. Hageman noted, among them:• What do we know about the local activation and regulation of complement at the level of the RPE-choroid interface?• What do we know about the participation of secondary immune pathways?• Is the complement-mediated disease process really a manifestation of a more global systemic problem?

As Dr. Hageman explained, the complement cascade, when activated, produces the small peptides, C3a and C5a, which recruit cells associated with the immune system. The large molecule complex C5b-9 (the membrane attack complex [MAC]) inserts itself indiscriminately into cell membranes and lyses cells and bacteria, most often killing them. “With this knowledge, new questions arise,” Dr. Hageman said. “Is MAC produced in large quantities as a result of complement activation? If so, is it causing damage to healthy, local cells and tissues? One of the real problems at this interface is that the RPE is not capable of replacing dead cells. So if MAC is indeed killing the RPE cells as suspected, the result will be the slow degeneration of the macula that is observed in AMD.” Dr. Hageman proposed that the RPE cells

Gregory S. Hageman, PhD


do the best they can to defend themselves by expressing other complement inhibitors, but theyeventually lose the game over time.

Researchers in Dr. Hageman’s laboratory were able to show that high levels of MAC at the RPE-choroid interface were associated with decreased densities of cells associated with the RPE and choriocapillaris. “That observation suggested MAC was likely damaging and killing these cells, very much like the situation that occurs in Alzheimer disease,” Dr. Hageman said. “The environment is such that I think we know a lot about complement activation and its ultimate role in cellular destruction at that interface.”

Dr. Hageman emphasized that the phenomenon he described is not true in a proportion of patients with geographic atrophy, suggesting that complement activation at the RPE-choroid interface may not be at the root of the disease process in some forms of geographic atrophy.

“We have spent a lot of time characterizing local ocular regulation of the complement system at the level of the eye,” he noted. The major take-home messages include:

• There is a lack of evidence for differential expression of complement components by the neural retina, RPE, and choroid in AMD.• The prominent source of most complement components is the choroid, and to a lesser extent, the RPE, not the neural retina.• Expression by the retina and the RPE is limited to a few regulatory molecules, including CFH.

“Again, these findings suggest we should be considering systemic manipulation from a therapeutic standpoint,” Dr. Hageman said. It is still unknown what triggers activation of complement at the RPE-choroid interface. According to Dr. Hageman, any number of candidates have been suggested, including cholesterol, lipofuscin and amyloid beta protein, all of which are capable of triggering complement in other conditions. “My colleagues and I have also described some unique structural entities in drusen,” he said. “They are as hard as rocks, and they have a spectacular morphology. We call them ‘spherules’ for lack of better terminology. … Not all drusen phenotypes contain these structures, so we need to know more about their role in the disease. They do contain the Aβ peptide and some of the earliest complement activation products, such as iC3b, suggesting they may be a great candidate for triggering complement at the RPE-choroid interface.”

Dr. Hageman and his coworkers recently completed a global gene expression study that strongly suggests a role for secondary cellmediated inflammation pathways at the level of the choroid. Further studies will be required to better define the role(s) of these pathways in disease etiology. “I think AMD really is a systemic disease, and we have suspected this for some time,” he said. “Clinicians and epidemiologists have provided data that show comorbidities between AMD and other systemic diseases. … Along these lines, it is interesting that some of the same CFH haplotypes that cause AMD are associated with disparately different diseases, such as dense deposit disease, various cardiovascular conditions, and hemolytic uremic syndrome. We need to understand more about how one can have the same genetic predilection but develop different diseases in different organsat different times in life.”


In a large liver transplant study he conducted, Dr. Hageman noted that when a protective factor H homozygote received a liver from a donor who was homozygous risk, AMD developed rapidly after the time of transplant in many cases, suggesting a systemic influence of liver-produced CFH.

Although we have learned a great deal about the genetic background of AMD, Dr. Hageman feels the precise influences of these genes has not been resolved. “We have some in vitro observations with respect to proteins made from risk-associated genes,” he said, “but from an in vivo perspective, our knowledge is limited. We know that protective and risk factor H can act differently in certain assays in the test tube, but we are not sure that is how they are functioning in patients with disease. We clearly need to make more progress on this front. In the search for frank genetic causality, Dr. Hageman is also looking at different ethnic groups worldwide, hoping the assessment of populations with different AMD phenotypes or disease prevalence will help refine the understanding of the genetics of AMD causality and protection.“We typically treat AMD as a bucket—a single disease entity—but the more we learn about the disease, especially the genetics, I think we are learning it is not the bucket we think it is,” Dr. Hageman said. Calling current research efforts an “era of refinement,” Dr. Hageman proposed that the following questions need focus:

• Have we identified the causal and protective variants/genes/haplotypes within the major AMD-associated loci?• Are there multiple causal and/or protective variants/haplotypes within each AMD-associated gene/locus?• What of diplotype and gene-gene associations?• Can we better characterize disease phenotypes to aid in more robust disease stratification for genetic analyses and treatment?

Dr. Hageman also noted that, interestingly, the majority of gene associations being studied are in regions of genetic duplication. For example, the CFH locus contains six highly duplicated genes; the C2/FB locus contain two paralogous, or almost identical, genes; and ARMS2 share regions of homology with HTRA1. “What is it about these duplications that has caused this incredible prevalence of AMD in Caucasians particularly?” Dr. Hageman asked, noting the answer will likely come from a more in-depth assessment of other ethnic groups and whole genome sequencing efforts.

There is also a need to understand which genes in these highly duplicated regions are causal (or protective). The CFH locus is a good case in point, Dr. Hageman said. “CFH is comprised of 20 similar domains made up of approximately 60 amino acids each, but the homology to other CFH-related genes that lie downstream is strong. In fact, it is a difficult locus to work in, and we are not even sure the reference genome in this region is correct. I think, in some ways, we tried to make the story too simple. …


of all the variations in CFH that have been highly associated with AMD, the most highly associated variants are protective. Many people assume a 10-29 association is on the risk side of the equation, but it is not. It is on the protective side. We need to understand that.”

Another example that this locus may be more complicated than once thought is the observation that two of the CFH-related genes, CFHR1 and CFHR3, are absent in approximately 20% of Caucasian chromosomes, and their absence is highly associated with protection.

In Africans, the deletion occurs in about 70% of chromosomes. “In other words,” Dr. Hageman said, “maybe this is not a deletion in Caucasians but rather a duplication, and maybe these genes evolved in Caucasians to fight off the plague or some other threat that was common in western Europe, but now these genes compete directly with CFH for binding sites. We need to understand the interplay among all of these proteins.”

Over the last 2 years, Dr. Hageman and his coworkers rebuilt haplotypes across the entire locus, from CFH to Factor 13B (F13B) (Figure 1). “For example, the blue-shaded region is the risk that is the original H1 haplotype,” he explained, “but by extending that into F13B, we split that haplotype into two fairly prevalent haplotypes. Interestingly, the majority of AMD risk is associated with the new H2 haplotype. … At face value, it may suggest that CFH is not the causal gene, and the true causality lies somewhere more distal in CFHR5 or F13B. Maybe this is true, or maybe it is not true, but we are expending a lot of effort to decipher the differences between the new H1 and H2 haplotypes.

“So the unthinkable is that CFH is not the causal gene,” Dr. Hageman continued. “The other alternative is that there is an as-yet undiscovered genetic ‘secret’ that differentiates H1 from H2 in CFH: small inversions, copy number variations, methylation patterns. Our approach has been to take homozygote H1s and homozygote H2s. We are doing whole genome sequencing across all regions, trying to uncover that piece of causality. We are tackling those one-by-one, and I can tell you that it is not copy number variation. We are convinced about this. We have also not found many inversions that would explain the difference.”

Dr. Hageman and his coworkers have also been studying populations where either the phenotypes of AMD are different or the prevalence of disease is different. For example, they have found thatAfricans have a high percentage of the CFHR3/1 deletion, suggesting that deletion may be protective

Figure 1


against AMD. “Maybe we are all at risk,” Dr. Hageman said, “and whether or not we get the disease depends on the degree of protection we have.

“It will also be important to gain a better understanding of diplotype and gene-gene associations,” he said. “What happens if you carry one risk and one protective allele of CFH? What is your risk for developing AMD in this situation? We need to address this issue, and I think that is where a lot of the genetic work is headed.”Chromosome 10 is strongly associated with the late-stage forms of the disease, Dr. Hageman said. “Individuals who are homozygous risk at the chromosome 10 locus typically manifest reticular pseudodrusen, and this phenotype is highly predictive for severe disease, including a majority of geographic atrophy and almost all of choroidal neovascularization,” he said. “This begs the question: Is AMD at least two very distinctly different biological diseases, one complement-driven and the other driven by the pseudodrusen phenotype?”

For drusen-mediated disease, Dr. Hageman suggested that the complement pathway—particularly the AP amplification loop—is a realistic target upon which to base the development of treatment modalities. The therapeutic pathway to pursue for chromosome 10-mediated disease is less clear at this time, although this is a major focus of efforts being conducted at the John A. Moran Center for Translational Medicine that is directed by Dr. Hageman. (See Figure 2 for a summary of research activities.)

Figure 2


AMD Alliance International (AMDAI)

is a global consortium of more than 70 members. It exists for one reason; to provide hope and help for

people all over the world living with macular disease. Our members are organisations that are making an

impact in vision rehabilitation research, and seniors’ and vision advocacy.

About AMD Alliance International

Chair: Mr. Hugh Parry President & CEOPrevent Blindness America(United States) Immediate Past Chair: Mr. MacDonald (Don) Curran Hon. Life Chair: Dr. Robert (Bob) Thompson Treasurer: Dr. Jane Barratt Secretary General International Federation on Ageing (Canada) Secretary: Ms. Julie Heraghty Chief Executive Officer Macular Degeneration Foundation (Australia) Executive at Large: Dr. Keith Gordon Head of Research The Canadian National Institute for the Blind (Canada) Executive at Large: Mr. Luc Licari Interim Executive Director Retina France (France) Executive at Large: Ms. Lesley-Anne Alexander Chief Executive Officer Royal National Institute of Blind People (United Kingdom)

Executive at Large: Mr. Tiziano Melchiorre International Agency for the Prevention of Blindness (Italy) Executive at Large: Dr. Alan Cruess Dalhousie University Halifax (Canada) Ms. Judith Delgado Director Macular Degeneration Partnership (United States) Mr. Mark Ackermann President and Chief Executive Officer Lighthouse International (United States) Ms. Helen Jackman Chief Executive Officer The Macular Disease Society (United Kingdom) Ms. Gretel Schmitz-Moormann Pro Retina Deutschland (Germany) Mr. Peter Lynch Executive Director Lions Clubs International Ms. Christina Fasser President Retina International (Switzerland) Mr. K. P. Tsang President Retina Hong Kong (Hong Kong)

Dr. Tracy Williams Executive Director Spectrios Institute for Low Vision (United States) Mr. Giusseppe Castronovo President International Agency for the Prevention of Blindness (Italy) Ms. Maryanne Diamond President World Blind Union Chief Executive Officer: Narinder Sharma AMD Alliance International (United Kingdom) Global Office 6th Floor City Gate East/ Toll House Hill Nottingham United Kingdom NG1 5FS +44 115 935 [email protected] USA 600 Wyndhurst Avenue/Suite 300 BaltimoreMaryland 21210-2413 Japan 1-31-1-502, Kaminoge Setagaya-ku, Tokyo 158-009

The Alliance’s Board consists of:

6th Floor City Gate East/ Toll House Hill I Nottingham I United Kingdom NG1 5FS Tel: +44 115 935 2100 I Email: [email protected] I www.amdalliance.org

amd alliance international scientific advisory panel report april 2011

Documents

meeting new york city

classificationof exudative

new classification

vision organisations

alliance thanks contributors

emily chew

field of macular disease

low vision therapy