American Journal of Ophthalmology
Volume 139, Issue 3 , Pages 405-420, March 2005

Age-related macular degeneration 1969–2004: A 35-year personal perspective

  • Stuart L. Fine, MD

      Affiliations

    • Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania.
    • Corresponding Author InformationInquiries to Stuart L. Fine, MD, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104; fax: 215-662-9676

Accepted 18 November 2004. published online 09 February 2005.

Article Outline

Purpose

To provide a personal perspective concerning diagnosis, treatment, and evaluation of treatment for early and late stages of age-related macular degeneration (AMD) over a 35 year period, 1969–2004.

Design

Literature review, personal recollections, and conversations with investigators who participated in trials to evaluate treatments for AMD.

Methods

The author reviewed the literature pertaining to evaluation and treatment of patients with AMD and conversed with investigators who, over the past 35 years, designed, conducted and participated in trials to assess new and existing treatments for AMD.

Results

In 1969, patients with AMD constituted a small part of a typical ophthalmic practice. From 1969 to 2004, the prevalence of AMD has increased, and the methods of evaluation and treatment have changed dramatically. The emergence of fluorescein angiography and the development of laser photocoagulation and photodynamic therapy have substantially altered clinical practice. Several promising pharmacologic interventions are now being assessed in clinical trials. Nevertheless, AMD remains the leading cause of severe and irreversible vision loss in the United States because there are no highly effective treatments available for most patients.

Conclusions

Because of an aging population and the lack of highly effective treatments, late AMD remains a major unsolved problem. However, there is extensive research being conducted with support from the National Eye Institute and from industry. There is also great interest in prevention trials. Accordingly, the author is optimistic that over the next 35 years there will be significant improvements in our ability to prevent severe vision loss from late AMD.

 

This presentation is a historical perspective on the development of risk factor data and on the evolution of treatments for macular degeneration which have guided patient care since I began my residency in 1969. As depicted in Table 1, the presentation is divided into four eras that coincide with what I consider important milestones.

TABLE 1. Four Eras Representing Milestones in the Development of Risk Factor Data and in Evolution of Treatments for AMD, 1969–2004
1st Era: 1969–1979
• Emergence of fluorescein fundus photography
• Development of argon laser photocoagulation
• Relationship of drusen to age-related macular degeneration
2nd Era: 1979–1994
• Clinical trials to evaluate new treatments, especially laser photocoagulation
• Development of risk factor data from large and small epidemiologic studies
3rd Era: 1994–2004
• Evaluation of radiation therapy for neovascular AMD
• Assessment of pharmacologic interventions for neovascular AMD
• Prevention trials
4th Era: 2004 -
• Completion of ongoing trials for neovascular AMD
• Earlier identification of eyes at risk
• Prevention trials in pre-symptomatic patients

This retrospective begins in the early 1960s with the advent of fluorescein fundus photography, an innovation which facilitated Gass’s seminal 1967 publications demonstrating that leakage from abnormal choroidal vessels was responsible for the exudative manifestations in age-related macular degeneration (AMD). 1 In the early 1970s, few centers were equipped to perform fluorescein fundus photography, and the quality of the angiograms was generally poor. Apart from low vision aids, the most popular treatment was a multivitamin. While there were occasional reports about photocoagulation, there was no agreed upon protocol for performing or evaluating laser treatment.

Figure 1 summarizes the understanding in the 1970s about the pathogenesis of choroidal neovascularization (CNV), specifically, that a break in Bruch’s membrane permitted choroidal blood vessels to penetrate and leak into the sub-retinal pigment epithelial (RPE) space. There was no mention of growth factors or other angiogenic stimuli.

There was correspondingly little information with regard to AMD risk factors, apart from age and family history. The Framingham Eye Study monograph, published in 1980, first identified AMD as a major cause of blindness in the United States. 2 Even the name was different. Until the mid-1980s, the condition was called by the pejorative and medically inappropriate “senile macular degeneration,” a term which had been used for more than 100 years.

With regard to risk factors, the role of genetics, smoking, cardiovascular disease, dietary history, sunlight exposure, and other possible risk factors would be studied and reported on during the next decade by a number of investigative groups led by Drs. Leslie Hyman at the Johns Hopkins School of Hygiene and Public Health, 3 Bressler NM, Bressler SB, West S, et al. from the Chesapeake Bay Watermen Study, 4 Barbara and Ron Klein from the Beaver Dam Eye Study, 5, 6, 7, 8 Paul Mitchell from the Blue Mountains Eye Study, 9 Paulus de Jong from the Rotterdam Study, 10, 11 investigators participating in the NEI-sponsored Eye Disease Case Control Study, 12, 13 and many others. 14, 15, 16

In the 1970s, it would have been unusual for the AAO annual meeting program to have included symposia, courses, posters, or exhibits devoted to AMD. Then, in 1976, a major breakthrough occurred. The April 1976 issue of the American Journal of Ophthalmology described the benefits of panretinal photocoagulation or PRP in the treatment of proliferative and severe non-proliferative diabetic retinopathy. 17 In addition to documenting the substantial benefits of PRP, the 1976 DRS report provided a second lesson of equal importance. It demonstrated the power of the randomized clinical trial in the assessment of new treatments, especially for problems of major public health importance. Nearly 25 years had elapsed since the landmark publications by Arnall Patz et al. which documented that high oxygen in low birth weight premature infants increased the incidence of retrolental fibroplasia (RLF), the original name for retinopathy of prematurity, contributions recognized at the time by the Albert and Mary Lasker Award and most recently by the Presidential Medal of Freedom awarded to Dr. Patz. (Figure 2). 18, 19 Edward Jackson, the educator (Figure 3), would have been interested to know that PRP, the most effective treatment introduced into any area of medicine over the past 30 years, except for vaccines, was preceded by a period in which those who developed the treatment technique were often ridiculed for proposing that a treatment which ablated one quarter or more of the retina actually might be helpful! Patz had encountered similar skepticism in the 1950s when he proposed that high oxygen might contribute to the incidence of RLF.

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  • FIGURE 2. 

    Arnall Patz (right) and Arnold Palmer (left). Patz received the Presidential Medal of Freedom at the White House in June 2004 for establishing the relationship between oxygen and retinopathy of prematurity in low birth weight infants.

The 1976 DRS publication ushered in the next era, 1979–1994, during which time three randomized trials were conducted to evaluate laser treatment for neovascular AMD. The trials were led by Bird, Chisholm, and colleagues at Moorfields Eye Hospital in London, 20 by Coscas and Soubrane at the University of Creteil in France, 21 and by the Macular Photocoagulation Study (MPS) group at 16 centers in the United States. 22 In 1982, all three groups reported that laser photocoagulation, when employed to treat choroidal neovascularization outside the fovea, reduced the risk of severe vision loss compared to observation (Figure 4). 20, 21, 22 The 60-month visual outcome data from the MPS are shown in Figure 5.

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  • FIGURE 4. 

    Sketch illustrates well-defined choroidal neovascularization outside the fovea. Neovascular lesions in this location were shown to benefit from treatment with laser photocoagulation.

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  • FIGURE 5. 

    Reprinted with permission from Archives of Ophthalmology, Vol 100, p. 916, June 1982, “Cumulative Proportion of Eyes With Event (in MPS Trial of argon laser photocoagulation for extrafoveal choroidal neovascularization). Event has been defined as decrease in visual acuity of six or more lines from baseline. Dashed line indicates no treatment group; solid line, treatment group.”

Despite these favorable reports from three well conducted clinical trials, there are two major limitations to laser treatment for CNV in patients with AMD: (1) Only a small proportion of patients with neovascular AMD is eligible for laser treatment by virtue of having a fluorescein angiographically well defined area of leakage outside the fovea; and (2) There is a high rate of recurrent leakage after initial laser treatment. Notwithstanding these limitations, laser has remained the treatment of choice for patients with extrafoveal new vessels for more than 20 years. One measure of its value is that, in MPS laser-treated eyes that did not develop recurrent leakage, the average visual acuity three years after treatment was 20/50. In comparison, in laser-treated eyes that did develop recurrent leakage, the average visual acuity three years after treatment was 20/250. 23

It is interesting to recall that when these three laser trials were conducted, choroidal neovascularization was diagnosed with certainty only when it had angiographic features of what we now call classic CNV (Figure 6). Although areas of abnormal fluorescence adjacent to classic CNV were considered to represent a variant of neovascularization, the term occult CNV was not yet part of our clinical vocabulary (Figure 7). It would be several years before occult CNV would be acknowledged as the predominant form of neovascularization in patients with AMD.

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  • FIGURE 6. 

    Treatment of choroidal neovascularization in 1970s. Fluorescein angiogram shows well defined area of choroidal neovascularization not involving the foveal avascular zone.

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  • FIGURE 7. 

    Fluorescein angiogram shows area of classic choroidal neovascularization with adjacent area of abnormal fluorescence (arrow) now recognized as occult CNV. (A) Early phase angiogram. (B) Late phase angiogram.

In my role as MPS Chair, I recall two vignettes of interest. First, the grant proposal to the National Eye Institute requesting support to conduct a trial of laser treatment for neovascular AMD was initially disapproved for funding by a study section. The summary statement from the review stated that laser photocoagulation actually caused choroidal neovascularization and therefore could not be considered as a treatment for choroidal neovascularization. This conclusion was based on erroneous extrapolation from two publications. The first article, by Schatz et al., described several patients diagnosed with central serous chorioretinopathy and treated with argon laser photocoagulation who, shortly after laser treatment, were discovered to have choroidal neovascularization, purportedly as a complication of the laser treatment. 24 The second article was a publication by Ryan on the now well known monkey model for producing choroidal neovascularization in primates by delivering short bursts of high intensity laser application to rupture Bruch’s membrane, thereby facilitating the emergence of choroidal new vessels. 25 My co-investigators and I thought that the study section’s conclusions, based on their extrapolations from these two publications, were flawed because, in both these articles, the laser parameters were small diameter laser burns of short duration delivered at moderate to high energy, whereas our laser treatment protocol was proposing larger diameter burns of longer duration. Accordingly, we appealed to the National Advisory Eye Council to support our proposal based not only on the flawed review but also on the public health importance of age-related macular degeneration. Fortunately, the Council agreed with our reasoning, and the Macular Photocoagulation Study was funded beginning in 1978.

The second vignette from the MPS provided an invaluable and never forgotten lesson. Patient enrollment for the MPS began in 1979. A Data and Safety Monitoring Committee appointed by NEI Director, Carl Kupfer, reviewed the accumulating data at six-month intervals. In January 1982, with 224 patients enrolled, this committee noted that, after 18 months of follow up, 60% of untreated eyes compared to only 25% of laser-treated eyes had experienced six or more lines of visual acuity loss. Based on those outcome data, the DSMC voted unanimously to recommend that study enrollment be halted; that all investigators, study patients, and the ophthalmic community be informed; and that all study patients be evaluated to determine their eligibility for laser treatment.

It in was my charge to arrange a meeting of the 16 MPS principal investigators so that the DSMC Chair could present the findings. I was asked not to reveal the outcome data but only to schedule the meeting so that study results could be presented. During telephone conversations, I could not resist asking investigators, all experienced retina specialists, whether they thought the outcome would be in favor of laser or observation. Of the 15 retina specialists representing the other clinical centers, all but one opined that laser treatment probably was not helpful! That response provided a lesson never forgotten, namely, that even experienced clinicians can reach erroneous conclusions based on following a few dozen patients without an appropriate comparison group.

The initial MPS outcome data were presented at a national press conference arranged by the National Eye Institute and convened at the National Institutes of Health in Bethesda in May 1982. The data were reported in an expedited publication in the Archives of Ophthalmology in June 1982. 22 The press conference received national attention from the three major television networks as well as from the New York Times, the Wall Street Journal, and print and broadcast media across the United States. Although efforts were made to inform the ophthalmic community about these findings by means of a pre-publication manuscript mailed to all ophthalmologists in the United States in advance of the press conference, a number of practitioners heard about the MPS findings on the evening news before they had a chance to read the manuscript. Understandably, many patients called their ophthalmologists, asking about laser treatment, despite having had vision loss for years attributable to macular disciform scars, glaucoma, and other irreversible conditions.

Since the treatment benefit of argon laser for neovascular AMD was reported during approximately the same time period by investigators in the United Kingdom, 20 France, 21 and the United States, 22 the retina communities on both sides of the Atlantic and around the world quickly adopted recommendations for treating patients with CNV outside the fovea. In the weeks and months following the 1982 publications, large numbers of patients, including all MPS participants who had been assigned to the observation group, were evaluated to determine their eligibility for laser treatment. Unfortunately, only a small proportion of patients with neovascular maculopathy secondary to AMD actually have well defined extrafoveal choroidal neovascularization. Thus, there was understandably a great deal of frustration among patients and their ophthalmologists.

During the 1979–1994 era, many investigators around the globe contributed data, provided insights, and developed or applied technology to assist with diagnosis and study design. Among these contributions are those by Flower, Yannuzzi, and Guyer on ICG angiography, 26 Puliafito and colleagues on optical coherence tomography, 27 Bird and the International Classification of AMD Group, 28 the MPS investigators on classification of choroidal neovascularization, 29 and many others. Never to be forgotten or taken for granted are the patients who volunteered as subjects for these studies.

The years between 1979 and 1994 also witnessed the emergence of important risk factor data beginning with the 1980 Framingham Eye Study monograph and continuing with information from many population-based epidemiologic studies whose principal authors already have been acknowledged. In my corner of the world, colleagues who at the time were medical students, and I conducted risk factor studies on several categories of AMD patients.

•Susan and Neil Bressler reported that, among untreated eyes with juxtafoveal neovascularization, 89% had visual acuity of 20/200 or worse within 24 months. 30

•David Guyer reported that 64% of eyes with untreated subfoveal neovascularization lost 6 or more lines of vision within 24 months. 31

These natural history data provided impetus for the MPS investigators to assess laser treatment for juxtafoveal and subfoveal neovascularization in trials supported by the National Eye Institute. These trials concluded that laser treatment, compared to observation, reduced the risk of severe vision loss. In the trial evaluating krypton red laser treatment for juxtafoveal neovascular lesions (496 eyes in 494 patients), treatment reduced the risk of severe vision loss compared to observation when comparing all treated eyes with all untreated eyes. 32 The treatment benefit was particularly strong in normotensive patients and of no demonstrable benefit in hypertensive patients. 33

The trial evaluating laser treatment for subfoveal neovascular lesions, known as the Foveal Photocoagulation Study (FPS), enrolled 373 eyes in 371 patients in the new subfoveal membrane study and 209 eyes in 209 patients in the recurrent subfoveal membrane study. In the trial of recurrent-subfoveal neovascular lesions (Figure 8), laser treatment proved to have a significant advantage over observation in terms of reducing the risk of severe vision loss. After two years, 8% of laser-treated eyes compared to 29% of observed eyes experienced severe vision loss. 34 Moreover, this treatment benefit was obtained irrespective of the size of the recurrent neovascularization as long as the eye met all the eligibility criteria for enrollment; for example, lesions could be no greater than six disk areas in extent, including the area of prior laser photocoagulation.

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  • FIGURE 8. 

    Fluorescein angiogram shows marginal recurrent leakage under the fovea (arrow) in eye previously treated with laser for extrafoveal choroidal neovascularization.

In the trial evaluating laser photocoagulation for new (previously untreated) subfoveal lesions, eyes which began with smaller neovascular lesions and worse visual acuity derived the greatest benefit from laser treatment. The benefit typically was a reduction in the rate of progression to severe vision loss. 35, 36 In almost all cases, however, especially in patients with subfoveal neovascular lesions, laser treatment caused an immediate and usually irreversible decrease in central vision, an outcome not appreciated by patients or by their ophthalmologists. These trials, while successful with regard to design, conduct, completion, data analysis, and demonstration of a laser treatment benefit, provided additional impetus to search for less destructive treatments for AMD patients with subfoveal neovascularization.

In the 1980s, medical students with whom I collaborated also conducted studies which quantified the risk of progressing from drusen to neovascularization. Ellen Strahlman et al. identified drusen number, drusen size, and macular pigment clumping as risk factors for progression from drusen to CNV in fellow eyes of patients who already had developed CNV in their first eye. 37 These observations were subsequently confirmed and quantified among the MPS patient cohort with second eyes at risk. 38 The MPS also documented that systemic hypertension was an independent risk factor for progression from drusen to CNV (Table 2). The magnitude of this risk varies substantially according to the number of risk factors, information of great import in identifying patients with fellow eyes at greatest risk of vision loss who might be candidates for prevention trials (Figure 9).

TABLE 2. Risk Factors for Progression From Drusen to Choroidal Neovascularization in the Second (Fellow) Eyes of Patients with CNV in the First Eye
• Drusen number (>10)
• Drusen size (>125)
• Macular pigment clumping
• Systemic hypertension

In patients with drusen and good visual acuity in both eyes, Smiddy et al. and Holz et al. at Moorfields, independently reported that drusen number, drusen size, and macular pigment clumping were risk factors for progression to vision loss or choroidal neovascularization or both. 39, 40 These risk factor data were useful in designing the Age-Related Eye Diseases Study (AREDS) by identifying patients at greatest risk of progression from drusen and good visual acuity to advanced AMD or vision loss.

The next era, which extends from 1994 to 2004, is characterized by pharmacologic intervention trials, radiotherapy trials, and prevention trials. The first trial evaluated oral thalidomide in patients with subfoveal neovascularization. The rationale for this trial was based on experiments conducted by Robert D’Amato, MD, PhD. After completing a residency at the Massachusetts Eye and Ear Infirmary, D’Amato was mentored by Dr. Judah Folkman at Children’s Hospital Boston. For several decades, an important objective for the Folkman laboratory had been to discover or develop drugs that would inhibit angiogenesis in patients with cancer. This objective was based on the assumption that solid tumors deprived of a blood supply would be less likely to grow. Both Folkman and D’Amato recognized the similarities between tumor angiogenesis and ocular angiogenesis. During a comprehensive literature review to identify drugs that might have anti-angiogenic activity, D’Amato encountered thalidomide, a drug that inhibited menstruation and caused birth defects. Since 1963, the sale of thalidomide had been banned because of its teratogenic effect on fetal development if taken by pregnant women during the first trimester. After a literature review, D’Amato concluded that thalidomide crossed the placental barrier and inhibited blood vessel growth in the limbs of the developing fetus. He reasoned that it would likely cross the blood-brain and blood-ocular barriers as well.

To test the hypothesis that thalidomide might be an effective angio-inhibitory drug in the eye, D’Amato performed experiments in rabbits in which pellets impregnated with basic fibroblast growth factor (bFGF) were placed in a central corneal pocket to induce ingrowth of vessels from the corneal limbus. Rabbits treated with thalidomide experienced a 65% reduction in corneal neovascularization compared to controls (Figure 10). 41 These experiments, which confirmed the angio-inhibitory properties of thalidomide, also explained the dysmelia that occurred in infants whose mothers had taken thalidomide during the first trimester of pregnancy; specifically, if angiogenesis in the limb is inhibited, the limb does not develop properly.

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  • FIGURE 10. 

    Rabbit corneas eight days after implantation of bFGF pellets in central corneal pocket. (A) Control. (B) Thalidomide-treated. (Photographs courtesy of Robert D’Amato, MD, PhD, Harvard Medical School, Children’s Hospital of Boston.)

During the 1994 ARVO meeting, D’Amato described to me the results of the thalidomide experiments using the rabbit cornea model. I learned at that time that thalidomide had been used for many years as an effective treatment for patients with leprosy, severe rheumatoid arthritis, and for some patients with graft vs host disease. In each of these conditions, the drug was reported to be well tolerated with only minimal side effects consisting of drowsiness, constipation, and a largely reversible peripheral neuropathy which reportedly occurred in approximately 5% of treated patients. In view of these data and in recognition of the urgent need for a more effective treatment for AMD patients with subfoveal neovascularization, it seemed appropriate to evaluate thalidomide for patients with subfoveal CNV. The reported side effects seemed manageable, and the issue of fetal toxicity would be non-existent since the average age of patients with neovascular AMD was 70 to 75 years.

Thus, with approval of a protocol by the FDA, my colleagues and I began a trial of low dose thalidomide in AMD patients with subfoveal neovascular lesions. However, only 22% of 18 patients assigned to thalidomide continued their medication throughout 12 months compared to 65% of 20 patients assigned to the placebo group. The trial could not be completed as designed because the peripheral neuropathy and other side effects proved to be considerably more frequent and more disabling than previously reported, despite the fact that the patients started with a low dose (150 mg) at bedtime and increased to 150 mg twice daily if the initial dose was well tolerated. The conclusion from the AMD Thalidomide Study was that, because of the disabling side effects, thalidomide could not be considered as a treatment for patients with neovascular AMD (unpublished data).

The 1990s witnessed the completion of two concurrent multicenter trials conducted worldwide to evaluate interferon alfa-2a as a treatment for AMD patients with subfoveal CNV. These trials were conducted after a relatively small number of patients who had been treated with interferon appeared to improve more often than historical controls. The two multicenter trials showed that interferon, when administered according to study protocol, was not an effective treatment for neovascular AMD. 42 In one sub-group, interferon-treated patients actually experienced a worse visual outcome than observed patients.

The 1994–2004 decade also witnessed the conduct of several radiotherapy trials. In the United Kingdom, Chakravarthy and colleagues had demonstrated that radiation impaired proliferation of vascular endothelial cells. 43 Two well conducted trials, one in the U.K. and one in Germany, failed to show that low dose radiation was an effective treatment. 44, 45 The German collaborative trial, which involved nine centers, concluded that 16 Gy of radiation therapy, administered in 8 doses of 2 Gy each, was not beneficial in preventing vision loss among AMD patients with subfoveal CNV. 45 A point to emphasize is that this well conducted trial could draw a conclusion only about the radiation dose that was evaluated. 46

Another group of investigators chose to evaluate a dose of 20 Gy of external beam radiation therapy administered as 5 divided doses of 4 Gy each, in a similar group of AMD patients with subfoveal CNV. This AMD Radiotherapy Trial (AMDRT), supported by the National Eye Institute, found that after six months of follow up, 26% of radiation-treated eyes compared to 50% of eyes not radiated, lost ≥3 lines of visual acuity (P = .04). At 12 months, 43% of radiated and 50% of observed eyes lost ≥3 lines of visual acuity (P = .60). Also at 12 months, the radiation-treated group demonstrated smaller lesions and less fibrosis than the observed group (P = .05 and .004 respectively). 47 Although this dose of radiation may have a modest treatment benefit of short duration, the treatment benefit is not overwhelming, thus it seems unlikely at this time that radiotherapy will become a major therapeutic option for AMD patients with subfoveal CNV.

The mid-point of the 1994–2004 decade, 1999, marked the first of a series of publications on Verteporfin-Photodynamic Therapy (PDT) as treatment for neovascular AMD and related maculopathies. 48 The biologic basis of photodynamic therapy (PDT) is based on the interaction between a light absorbing chromophore which, when activated by a particular wavelength, leads to the initiation of a chemical reaction of therapeutic benefit. Some investigators who pioneered the application of photodynamic therapy to the treatment of choroidal neovascularization were Drs. Joan Miller, Evangelos Gragoudos, and Ursula Schmidt-Erfurth who performed their basic research at the Wellpoint Photobiology Lab at Harvard and at the Massachusetts Eye and Ear Infirmary. 49 Their findings, which informed the clinical protocols, provided critical information concerning dosage of drug, duration of light exposure, frequency of treatment, and intervals between treatment. When the phase I/II trials showed that PDT with verteporfin (Novartis Pharma AG, Basel, Switzerland) could cause temporary cessation of fluorescein leakage from CNV, that recurring leakage could be halted with repeat application of PDT, and that intravenously injected verteporfin appeared to be safe, two large multicenter phase III trials were launched. 50

The initial report from these trials documented that verteporfin photodynamic therapy was beneficial for patients with subfoveal choroidal neovascularization that had evidence of classic CNV. Subgroup analyses suggested that the benefit was mainly in those with a predominantly classic composition on fluorescein angiography. Subsequent reports have documented the benefit of PDT for eyes with occult with no classic choroidal neovascularization with recent disease progression and for eyes with relatively small, minimally classic choroidal neovascularization. 51 Ongoing analyses have shown that lesion size is an important factor in determining the efficacy of photodynamic therapy in patients with minimally classic or purely occult neovascularization. 52 Lesions less than four disk areas in extent have the most favorable prognosis.

In all the studies of PDT for choroidal neovascularization secondary to AMD, only individuals with subfoveal neovascular lesions were eligible for enrollment because thermal laser photocoagulation has remained the treatment of choice for patients with extrafoveal neovascular lesions. However, since only a minority of choroidal neovascular lesions in AMD is extrafoveal, photodynamic therapy has by default become the treatment of choice for the majority of AMD patients with CNV who might be considered for any form of treatment. As was the case after the benefits of thermal laser treatment were first documented in trials and adopted in clinical practice, both ophthalmologists and patients recognize the limitations of PDT and eagerly anticipate treatments for neovascular AMD that are more effective.

Several ongoing trials are evaluating drugs which inhibit angiogenesis. Treatment regimens currently under investigation include Retaane (Alcon, Fort Worth, Texas, USA), Lucentis (Genentech, South San Francisco, California, USA), and Macugen (Eyetech Pharmaceuticals, New York, New York, USA). Ongoing reports from these studies, as well as from continuing efforts to refine the role of PDT, with and without triamcinolone, will be featured presentations at meetings over the next 12 to 24 months. Future reports should place each of these treatments in perspective. If any of these interventions has a beneficial effect, it would seem incumbent to compare its advantages and limitations with existing treatments by means of a controlled trial.

Trials to evaluate prophylactic interventions evolved in the 1994–2004 era with the conduct of a micronutrient supplementation trial, two laser trials, and a pharmacologic intervention trial. The possibility of prophylaxis has been a most exciting development because an effective intervention for early AMD almost certainly would have a far greater impact on reducing vision loss than any intervention for late AMD. 53

The first prevention trial was AREDS whose initial outcome data were published in 2001. 54 AREDS initially was conceived as a natural history study. Two considerations promoted its evolution to a trial. First was the recognition that many elderly patients already were taking micronutrient supplements based on marketing instead of evidence. Second was the notion that providing patients with a pill might bond the patients to a study with a prolonged follow-up period. After an average of 6.3 years of follow-up, the group of patients with large drusen in both eyes (AREDS Group 3) as well as the cohort of patients who already had experienced vision loss from late AMD in one eye and had a second eye at risk (AREDS Group 4), experienced a 20% relative reduction in the risk of three lines of vision loss and a 25% relative reduction in the risk of progressing to advanced AMD if they had been assigned to take the study formulation which included antioxidant vitamins, zinc, and copper (Figure 11). When patient enrollment began, not even the study leaders, Drs. Frederick Ferris and Emily Chew, could envision that micronutrients actually might have such a significant impact. Again we witness the power of the randomized trial to provide unassailable information that guides patient care, especially for important public health problems. Appropriately, the ophthalmic community has adopted the AREDS recommendations that patients with high risk drusen or unilateral advanced AMD benefit substantially by taking the formulation which includes antioxidant vitamins, zinc, and copper.

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  • FIGURE 11. 

    (A) Probability of developing visual acuity loss of at least 15 letters in at least one study eye of AREDS participants in AREDS Categories 3 and 4 by treatment group. (AREDS photographs courtesy of F.L. Ferris, MD, National Eye Institute). (B) Probability of developing advanced AMD in at least one eye of AREDS participants according to treatment group.

Two ongoing trials are evaluating whether low intensity laser photocoagulation can reduce progression from drusen to advanced AMD and vision loss. Efforts at prevention of disease progression in AMD using laser began as early as the 1970s when several investigators including Gass, Cleasby, Little, and Wetzig reported at various meetings that treating drusen directly with xenon arc, argon laser, or ruby laser photocoagulation, led to their partial or complete disappearance. All of these reports and presentations described relatively small numbers of patients with relatively short follow-up, and most suffered from the absence of controls achieved by means of randomization. If there were merit, anatomic or visual, to applying laser treatment as a preventive strategy in eyes with drusen, a large controlled clinical trial would be necessary to establish the benefit or lack thereof.

My interest in a trial of preventive laser treatment for eyes with high risk drusen was kindled in 1992. At that time, during a routine follow-up visit, I examined a 60-year-old patient with visual acuity of 20/15 in each eye, large confluent drusen in each macula, and a small hemorrhage accompanied by lipid exudates in the left papillomacular bundle (Figure 12). A fluorescein angiogram showed subtle but definite abnormal fluorescence in the area adjacent to the hemorrhage and exudates (Figure 13). Biomicroscopy showed slight elevation of the retinal pigmented epithelium (RPE) in this area. Because I strongly suspected that this RPE elevation, associated hemorrhage and lipid, and abnormal fluorescence was caused by a small tuft of extrafoveal choroidal neovascularization, I recommended argon laser photocoagulation despite the fact that this was an asymptomatic lesion in an eye with 20/15 visual acuity. The patient agreed with my recommendation, and laser treatment (two overlapping burns) was carried out uneventfully. In a few weeks, the blood disappeared, the RPE flattened, and the laser-induced paracentral scotoma became asymptomatic. Nine months after laser treatment, the drusen in the untreated right eye were still large, confluent, and as numerous as nine months previously, whereas the drusen in the laser-treated left eye had largely disappeared except for a few drusen 180 degrees opposite the area treated with laser (Figure 14). I speculated that the laser application to the small neovascular lesion in the left eye might have promoted resolution of the macular drusen by some unknown mechanism. Several months later, while still pondering this question, I read a report describing 20 patients who showed some resolution of drusen under the fovea and in the nasal portion of the macula after low intensity laser photocoagulation had been applied directly only to drusen located in the temporal portion of the macula. 55 On average, drusen in the temporal macula treated directly with laser disappeared within two months, whereas nasal drusen and foveal drusen, presumably as a result of indirect laser treatment, required an average of 10 months for resolution. To investigate further the possible relationship between laser photocoagulation and drusen resolution, the MPS Reading Center evaluated a group of patients who had been treated successfully with laser in their study eyes, who had not developed recurrent leakage in the treated study eye, and who had drusen in the fellow eye. Over a follow-up period of three years, laser treated eyes were far more likely to show drusen resolution than untreated fellow eyes (unpublished data).

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  • FIGURE 12. 

    Fundus photographs of 60-year-old woman with large, confluent macular drusen in both eyes and a small hemorrhage with lipid exudates in the papillomacular bundle. (A) Right eye. (B) Left eye.

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  • FIGURE 13. 

    Fluorescein angiogram of patient showing subtle but definite hyperfluorescence (arrow) adjacent to macular hemorrhage, left eye. (A) Early phase angiogram. (B) Late phase angiogram

There was now information from several sources suggesting that photocoagulation or laser treatment in the macular region was followed by the disappearance of or reduction in the extent of drusen. These data, when considered in the aggregate, provided the impetus to consider a clinical trial to evaluate the ability of low intensity laser treatment, not only to promote drusen resolution but more importantly to reduce the risk of disease progression and its attendant risk of vision loss in eyes with high risk drusen.

My colleague, Dr. Maureen Maguire, Professor of Ophthalmology and Director of the Center for Preventive Ophthalmology and Biostatistics at the Scheie Eye Institute of the University of Pennsylvania, and I proposed a pilot study, the Choroidal Neovascularization Prevention Trial or CNVPT. This trial, consisting of two sub-studies, the Fellow Eye Study and the Bilateral Drusen Study, was conducted at 16 participating clinical centers between 1994 and 1998 (Figure 15). Beginning in 1994, 120 patients enrolled in the Fellow Eye Study, and 156 patients enrolled in the Bilateral Drusen Study. The CNVPT treatment protocol stipulated the placement of a total of 20 relatively low intensity lesions, each 100 microns in diameter, in three concentric arcs temporal to the fovea in the eye assigned to treatment (Figure 16). Six months later, if the eye assigned to laser treatment still would be eligible to be enrolled in CNVPT, 20 additional laser lesions were placed in three concentric arcs on the nasal side of the fovea.

Prior to beginning patient enrollment in the CNVPT, Dr. Maguire and I appointed a Data and Safety Monitoring Committee (DSMC) to review the protocol as well as the data that would be accumulating with regard to both safety and possible efficacy. In planning this pilot, it never was intended that a sufficient number of patients would be enrolled to answer the study question definitively with regard to efficacy. While the CNVPT ophthalmologists felt confident from the outset that the protocol laser treatment would promote at least partial resolution of drusen, they also thought that the risk of toxicity from the relatively low intensity laser application required by the study protocol was extremely small, absenting an inadvertent laser burn to the fovea. Thus, the investigators were surprised when the DSMC reported in December 1996, two years after patient enrollment began, that in the Fellow Eye Study only, laser-treated eyes were more likely than observed eyes to have progressed to choroidal neovascularization, the opposite of the anticipated effect of preventive laser treatment (Figure 17). Fortunately, in this group of laser-treated fellow eyes in the Fellow Eye Study, there was no accompanying increase in the frequency of vision loss compared to the group of observed fellow eyes. Nevertheless, on advice from the Data and Safety Monitoring Committee, the CNVPT investigators took the following actions:

•Halt the enrollment of all new patients in both the Fellow Eye Study and the Bilateral Drusen Study

•Inform all patients in both the Fellow Eye Study and Bilateral Drusen Study of this unexpected finding in the Fellow Eye Study

•Halt all preventive laser treatments, including protocol follow-up treatments, in both studies

•Inform the ophthalmic community about this unexpected finding, in an effort to discourage practicing ophthalmologists from performing similar preventive treatments in patients not enrolled in the CNVPT studies 56

•Follow all patients in the Fellow Eye Study for up to four years

All of the aforementioned recommendations were carried out. By the time patients in the Fellow Eye Study had been followed up for four years, it was clear that, 30 months after enrollment, the rates of choroidal neovascularization in treated eyes and untreated eyes in the Fellow Eye Study were identical (Figure 17). 57

  • View full-size image.
  • FIGURE 17. 

    Reprinted with permission from Ophthalmol Vol 110, No. 5 p. 974, May 2003. Rates of choroidal neovascularization in CNVPT Fellow Eye Study “Estimated cumulative proportion of eyes developing choroidal neovascularization by treatment group.” At no time was there a significant difference in visual outcome in treated fellow eyes vs untreated fellow eyes.

Among the 156 patients enrolled in the Bilateral Drusen Study, there was never an indication that laser-treated eyes were more likely than untreated eyes to develop choroidal neovascularization. Accordingly, once it became clear that there was no evidence of long term toxicity from low intensity laser treatment in the CNVPT Fellow Eye Study, the investigators again considered the possibility of conducting a definitive trial, sufficiently powered with respect to the number of patients to be enrolled, to determine whether laser treatment could reduce the likelihood of progression from high risk drusen to late AMD and accompanying loss of vision in patients with large, confluent drusen in both eyes.

In designing that definitive trial of preventive laser treatment, we used information learned from the CNVPT and from another trial with a similar study design, the Prophylactic Treatment for Age-Related Macular Degeneration Study (PTAMD), chaired by Dr. Thomas Friberg of the University of Pittsburgh. The information that was used to plan the next trial is summarized below.

(1)The intensity of the laser burn, as applied to eyes with high risk drusen, was positively correlated with the risk of developing CNV in laser treated eyes. 58

(2)Since eyes with high risk drusen that develop CNV following laser treatment most often exhibit the occult form of CNV, with little or no accompanying vision loss, annual fluorescein angiograms would be necessary to detect the primary endpoint CNV that was often asymptomatic.

(3)A larger number of low intensity laser burns delivered to the macular region was not associated with any significant toxicity and might be more effective in reducing the extent of drusen.

Accordingly, the definitive protocol for the new trial incorporated what had been learned from the CNVPT and from the PTAMD studies. 59 In this new NEI-supported trial, known as the Complications of AMD Prevention Trial (CAPT), the study question is whether, in patients with high risk drusen in both eyes, low intensity laser treatment applied to one eye selected at random, could reduce the risk of vision loss and the risk of progression to either choroidal neovascularization or geographic atrophy. Between 1999 and 2001, the CAPT enrolled 1052 patients at 22 clinical centers (Figure 18). One eye of each patient was assigned randomly to receive the protocol laser treatment (Figure 19A). One year after treatment, patients who had less than 50% reduction in the extent of drusen were eligible for a second protocol laser treatment (Figure 19B) unless they had developed CNV or geographic atrophy in the eye assigned to treatment or CNV in the fellow (untreated) eye. A Data and Safety Monitoring Committee has been meeting at six-month intervals to monitor the effects of treatment with respect to safety and efficacy. At its most recent meeting, in April 2004, the DSMC confirmed that the CAPT study is sufficiently powered to provide an answer concerning the efficacy of the intervention under study by the anticipated study closing date in the spring of 2006. The PTAMD study expects to have outcome data available within the same time frame.

  • View full-size image.
  • FIGURE 19. 

    Protocol laser treatment for Complications of AMD Prevention Trial (CAPT). (A) Initial laser treatment protocol. (B) Follow-up treatment protocol at one year.

In the meantime, several ongoing analyses of CAPT patients already have been reported. Stoltz and associates reported that drusen remodeling, pigmentary alterations, and foveal atrophy which does not achieve the CAPT criteria for a diagnosis of geographic atrophy are responsible for most vision loss of ≥ three but ≤ six lines on an ETDRS chart. (Stoltz RA, et al. Fundus features of untreated eyes with visual acuity loss in CAPT. April 26, 2004 presentation at ARVO. IOVS 1389, B200). Alexander and associates have confirmed that most of the CNV which occurs is of the occult type. (Alexander J, et al. Characteristics of exudation in patients with bilateral large drusen. April 27, 2004 presentation at ARVO. IOVS 2989, B624).

Of more than passing interest is a recent publication from Sweden which reported that in a randomized pilot study involving 38 patients with soft drusen maculopathy, preventive laser treatment reduced the rate of exudative complications to a statistically significant degree. However, because of the small sample size and despite eight years of follow-up, the authors urged caution in the interpretation of the results. 60

A pharmacologic intervention, recently launched, is evaluating whether juxtascleral anecortave acetate, compared to sham injection, can reduce the rate of progression from extensive drusen and pigment clumping to neovascularization in the second eye of patients who already have lost vision from late AMD in the first eye. Anecortave acetate is thought to work by inhibiting the action of cellular proteases that are needed for the migration of vascular endothelial cells. In a 12-month Phase II trial involving 128 patients, treated eyes were less likely to experience vision loss than untreated eyes. 61 Recruitment of over 500 patients was completed in August 2003 for a Phase III trial of anecortave acetate vs PDT for predominantly classic subfoveal CNV. Twelve-month outcome data were reported by Carl Regillo at the pre-Academy Retina Subspecialty Day meeting on October 22, 2004.

During the fourth era, which begins in 2004, several ongoing trials will be completed and the results with indications for patient care will be published. Recently, the Submacular Surgery Trials Group reported that submacular surgery in eligible AMD patients did not improve the overall chance for stable or improved visual acuity compared to observation. 62, 63 More detailed analyses may identify one or more subgroups that derive a benefit from this intervention. During the next decade, I expect that the role of anti-VEGF therapy, including combination therapy, will be sorted out by means of clinical trials (Table 3). I expect that prevention trials will be conducted for patients with very early AMD. I expect that new information, being developed in laboratories around the world, will shed light on the pathogenesis of AMD. Hahn and associates have found that AMD retinas exhibit iron overload. 64 While this finding does not prove that iron overload is a cause of AMD, several additional findings from that laboratory support this possibility. First, a line of mice with retinal iron overload attributable to mutations in the iron transporters, ceruloplasmin and hephaestin, develop some features of AMD, including neovascularization in the subretinal space. 65 Second, a patient with the rare autosomal recessive disease, aceruloplasminemia, which results in retinal iron overload, developed drusen at the young age of 47 (Dunaief JL, written communication, August 19, 2004). Third, ceruloplasmin is upregulated in mouse retinas exposed to photo-oxidative stress, possibly as a defense against iron induced oxidative stress. 66 Dunaief’s lab is now testing whether an iron chelating agent can reduce the retinal iron overload in the ceruloplasmin/hephaestin deficient mice (Figure 20). If so, could iron chelation become another non-surgical intervention for AMD?

TABLE 3. Important Features of Clinical Trials
• Accurate description of disease
• Understanding natural history
• Well defined treatment protocol
• Adequate sample size
• Informed consent by eligible study participants
• Controls achieved by randomization
• Appropriate length of follow up
• Biometric data analysis
• Independent data and safety monitoring committee

Another recent finding, that of amyloid-beta in drusen, first reported in Anderson’s lab and subsequently confirmed by Dunaief’s lab, suggests that drusen may have some features of extracellular plaques found in Alzheimer’s Disease brains (Figure 21). 67, 68 A potential link between the pathogenesis of AMD and Alzheimer’s Disease suggests that anti-amyloid-beta therapies under development for Alzheimer’s may prove useful for AMD.

  • View full-size image.
  • FIGURE 21. 

    Figure reprinted with permission from Molecular Vision, September 2003; Vol 9, p. 188. Photomicrograph shows that anti-amyloid-beta-antibody 2332 detects a single vesicle and punctuate granular deposits within drusen.

In looking to the future, other lines of investigation include creating animal models for both drusen and choroidal neovascularization by overexpression of certain genes, and exploring the role of genetics, altered blood flow, inflammation, and the role of PEDF and growth factors other than VEGF. Remarkably, psychophysicists now can detect subtle disturbances in macular function before there are visible macular abnormalities. If nontoxic interventions are shown to be of value in presymptomatic patients, these psychophysical assessments could identify the subjects who should be evaluated. Once effective pharmacologic treatment becomes available, the next hurdle will be to develop a delivery system which ideally would not require repeated retrobulbar, periocular, or intravitreal injections. An effective treatment delivered as an eye drop or through a slow release polymer injected into the vitreous cavity would be a significant advantage over routes of administration currently employed in most ongoing eye trials.

During my 35 years in ophthalmology, AMD has moved from the rear balcony to center stage. In 1969, when I first heard the term senile macular degeneration from my University of Florida mentor, Dr. Melvin Rubin, I had to look it up. The Framingham Eye Study had not yet issued its first report on the prevalence of AMD as a cause of vision loss. But despite the plethora of trials and the emergence of treatments of some value, AMD remains the major cause of severe and irreversible vision loss in the United States and throughout the developed world. Each year, 200,000 AMD patients in the United States develop choroidal neovascularization and that number will rise considerably as the population ages, absent the introduction of one or more highly effective interventions. 69, 70 Thus AMD remains the greatest unsolved problem in ophthalmology in the developed world. On the positive side is the enormous interest of the National Eye Institute, large pharmaceutical companies, and the many investigators actively conducting research. These endeavors, and the emphasis on prevention trials, provide much hope for the future. In the meantime, we must acknowledge our current limitations in treating AMD patients and remember that low vision rehabilitation, treatment for depression, when appropriate, and the empathetic ophthalmologist are crucial components of patient care. My fervent wish is that the next Jackson lecturer who selects AMD as a topic will describe the quantifiable benefits of a highly effective treatment that is broadly applicable to the universe of patients at risk for vision loss from AMD. In the meantime, the honor of this Edward Jackson Memorial lectureship is dedicated to all the patients still suffering from AMD and to all the investigators laboring to find better treatments. With their continued efforts, AMD may no longer be the scourge of the elderly.

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biography

Stuart Fine’s career at Johns Hopkins (1972–1991) and at University of Pennsylvania (1991–present) has focused on leadership of randomized clinical trials. These include the Macular Photocoagulation Study, the AMD and Thalidomide Trial, the AMD Radiotherapy Trial, the Choroidal Neovascularization Prevention Trial, and the Complications of AMD Prevention Trial. Among his proudest accomplishments is that many of his former students and fellows are now participating in and leading controlled clinical trials.

 Supported, in part, by Research to Prevent Blindness, Inc., New York, New York, National Eye Institute grant No. U10-EY-012261, (Complications of AMD Prevention Trial), the Paul Mackall and Evanina Evans Bell Mackall Trust, the Scheie Eye Institute Macular Degeneration Research Fund, the F.M. Kirby Foundation, and the Rosanne Silbermann Foundation.

PII: S0002-9394(04)01413-8

doi:10.1016/j.ajo.2004.11.050

American Journal of Ophthalmology
Volume 139, Issue 3 , Pages 405-420, March 2005

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