D R UG TH ERA PY

Drug Therapy
A L A S T A I R J . J . W O O D , M. D. , Editor

A GE -R ELATED
M ACULAR D EGENERATION
STUART L. FINE, M.D., JEFFREY W. BERGER, M.D., PH.D.,
MAUREEN G. MAGUIRE, PH.D., AND ALLEN C. HO, M.D.

GE-RELATED macular degeneration, a deterioration of the central portion of the retina,

is the chief cause of severe and irreversible
loss of vision in developed countries.1,2 There is no
effective treatment for most patients with age-related
macular degeneration, and many patients therefore
resort to experimental treatments. Physicians must
know how to counsel their patients about the limitations and risks of these experimental therapies. Fortunately, several clinical trials sponsored by both the
National Eye Institute and the private sector are evaluating novel prophylactic and therapeutic interventions. In addition, there is much exciting, ongoing
basic research, some of which may lead to major therapeutic advances.

Figure 1. Normal Macula and Optic Nerve (Arrow).

The avascular zone of the fovea (inner circle) is at the center of
the macula. By clinical definition the macula is a circular area,
centered on the fovea, 5 to 6 mm in diameter within the vascular arcades (outer circle).

CLINICAL FEATURES
AND CLASSIFICATION

The macula is the posterior aspect of the retina

and has the highest concentration of photoreceptors,
which facilitate central vision and permit high-resolution visual acuity (Fig. 1). The macula is a circular
area 5 to 6 mm in diameter with the fovea at its center
that lies within the vascular arcades of the retina. Histologically, the macula is the region of the retina with
two or more layers of ganglion cells.3 Age-related
macular degeneration is associated with typical ophthalmoscopic features and usually affects people 60
years of age or older. Because the macula is in the central portion of the retina, advanced age-related macular degeneration often leads to irreversible loss of
the ability to read, recognize faces, and drive. However, most patients, even those with extensive macular
involvement in both eyes, maintain enough peripheral vision to walk unaided.
Age-related macular degeneration can be classified
into early and late stages. The early stage is associat-

From the Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania Health System (S.L.F., J.W.B., M.G.M.), and the Department of Ophthalmology, Wills Eye Hospital, Thomas Jefferson University (A.C.H.) both in Philadelphia. Address reprint requests to Dr.
Fine at the Scheie Eye Institute, University of Pennsylvania Health System,
51 N. 39th St., Philadelphia, PA 19104-2689.
2000, Massachusetts Medical Society.

Figure 2. Early Age-Related Macular Degeneration, Characterized by Large Drusen (Arrows) and Clumps of Pigment (Arrowheads) in the Macula.
This eye has normal visual acuity but is at risk for late agerelated macular degeneration and loss of vision.

ed with minimal visual impairment and is characterized by large drusen and pigmentary abnormalities
in the macula (Fig. 2).4 Drusen are accumulations of
acellular, amorphous debris subjacent to the basement
membrane of the retinal pigment epithelium (Fig.
3).5 Nearly all people over the age of 50 years have
at least one small druse (63 m) in one or both
eyes.6 Only eyes with large drusen (>63 m) are at
risk for late age-related macular degeneration.7
There are two forms of late age-related macular
degeneration: the atrophic form and the neovascular,
exudative form. The atrophic form typically involves
the choriocapillaris, retinal pigment epithelium, and
Vol ume 342

Numb e r 7

483

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

photoreceptor elements (rods and cones) and does not

involve leakage of blood or serum; hence, it is called
dry age-related macular degeneration. The neovascular, exudative form includes serous or hemorrhagic
detachment of retinal pigment epithelium and choroidal neovascularization, which lead to leakage and
fibrovascular scarring; hence, it is called wet age-related macular degeneration.
Loss of vision can occur in either the atrophic or
the neovascular form of the disorder. Patients with the
atrophic form may have good central vision (20/40
or better) but substantial functional limitations, including fluctuating vision, difficulty reading because
of their limited area of good central vision, and limited vision at night or under conditions of reduced
illumination.8,9

The ophthalmoscopic appearance of progressive,

or geographic, atrophy involving the center of the
macula is shown in Figure 4. The histopathological
findings of atrophic age-related macular degeneration
reflect the loss of the photoreceptor layer, the retinal
pigment epithelium, and the choriocapillaris. As the
atrophy progresses, reading vision decreases and text
must be magnified to be perceived.
Figure 5 shows the ophthalmoscopic appearance
of a central fibrovascular scar with exudation in the
macula, which is a typical feature of late, untreated
choroidal neovascularization. The retina surrounding
the scar appears normal. Fibrovascular tissue has replaced the normal anatomical structures in the macula,
including photoreceptors, so there is profound loss
of central vision. Choroidal neovascularization can be
identified before scarring and extensive leakage cause
irreversible loss of vision (Fig. 6 and 7). Among patients with severe loss of visual acuity (20/200 or
worse), choroidal neovascularization is the cause in
at least 80 percent.11
EPIDEMIOLOGY

B
Figure 3. Cross Section of Normal Retina (Panel A) and Retina
with Drusen (Panel B) (Hematoxylin and Eosin).
The asterisks in Panel A identify photoreceptors, and the arrowheads point to retinal pigment epithelium (100). The asterisks
in Panel B identify drusen, or accumulations of eosinophilic
acellular debris subjacent to the basement membrane of retinal
pigment epithelium (400). Panel B was provided by J.D.M.
Gass, Vanderbilt University.

484

Febr u ar y 17 , 2 0 0 0

The prevalence of age-related macular degeneration

increases dramatically with age. In the populationbased Beaver Dam Eye Study in the United States,
the prevalence of late age-related macular degeneration increased from 0.1 percent among people 43 to
54 years of age to 7.1 percent among those 75 years
of age or older.6 The respective prevalences of early
age-related macular degeneration were 8 percent and
30 percent.
Casecontrol, cross-sectional, and prospective cohort studies have identified several risk factors for agerelated macular degeneration.7,11-17 In addition to older age, they include a family history of the disorder,13,18
cigarette smoking,19-21 low dietary intake or plasma
concentrations of antioxidant vitamins and zinc,15,22,23
and white race (in the case of wet age-related macular degeneration).24,25 Female sex,7 light-colored irises,13 cardiovascular disease,13,14 and increased exposure to sunlight26 have been identified as risk factors
in some studies, but not consistently (Table 1). Among
these factors, diet and smoking are potentially modifiable. The association with cigarette smoking provides another compelling reason to counsel patients
regarding the dangers of smoking. An ongoing clinical trial involving more than 4000 subjects is assessing
the effect of taking antioxidant and zinc supplements
on the development and progression of age-related
macular degeneration.27
COURSE AND VISUAL PROGNOSIS

Patients with only drusen (in one or both eyes)

typically do not have much loss of vision, but they
may require additional magnification of the text and
more intense lighting to read small print. However,
the presence of large drusen, even though not nec-

D R UG TH ERA PY

B
Figure 4. Fundus Photographs Showing Progression of Atrophy
(Arrows) over a Period of Three Years.
In Panel A, atrophy of the retinal pigment epithelium and choriocapillaries makes the subjacent choroidal vessels appear
more prominent. The surrounding fundus is otherwise normal.
Three years later, these features are more pronounced (Panel
B), and the central atrophy is severe enough that reading can
only be accomplished if the text is magnified.

essarily associated with symptoms, is associated with

a risk of the late form of the disease and resultant
loss of visual acuity. Risk factors for late age-related
macular degeneration in patients with drusen in both
eyes include the presence of large drusen, the presence of many drusen, and abnormal pigmental clumping.28 In the Beaver Dam Eye Study, of 2815 patients who initially had no drusen or who had only
hard (small) drusen, just 1 (0.04 percent) had late agerelated macular degeneration during five years of fol-

Figure 5. Fundus Photograph Showing a Central Fibrovascular

Scar (Arrowhead) Surrounded by Subretinal Fluid (Asterisks)
and Subretinal Lipid Exudate (Arrows).
The surrounding retina appears to be normal. Scarring is a typical feature of untreated late age-related macular degeneration.

low-up.7 In contrast, of 197 patients with bilateral

early age-related macular degeneration (defined by the
presence of large drusen), 23 (11.7 percent) had latestage disease in one or both eyes at five years. Fourteen of these patients had neovascular abnormalities,
and nine had geographic atrophy. In selected groups
of high-risk patients over the age of 65 years who
have large drusen and clumping of pigment in both
eyes, the risk of developing late age-related macular
degeneration in one or both eyes over a three-year
period may be as high as 24 percent.28
The progression from large drusen to atrophy is
slow and insidious. However, leakage of blood or serum as a result of choroidal neovascularization may
occur precipitously and is often associated with the
abrupt loss or distortion of vision. Because patients
with large drusen and pigment clumping are at relatively high risk for choroidal neovascularization, the
integrity of central vision in each eye should be carefully evaluated by assessing the vision in each eye
separately while the other eye is closed or covered.
Leakage of fluid or blood beneath the macula may
be manifested as a distortion of vision, a blind spot,
or the inability to read with the affected eye. Use of
Amslers grid may help patients recognize the subtle
distortion in vision caused by subretinal accumulation of fluid in the macula (Fig. 8). Patients may perceive the straight horizontal and vertical lines of the
grid as broken or wavy. However, some patients do
not notice any such changes, despite the onset of
neovascularization.29 Thus, periodic eye examinations
are still an important part of the follow-up of highrisk patients.
Vol ume 342

Numb e r 7

485

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Sensory retina
Subretinal<
fluid

Choroidal neovascularization

Figure 7. Choroidal Neovascularization in Cross Section.

Reprinted from Bressler et al.10 with the permission of the publisher.

B
Figure 6. Choroidal Neovascularization.
Panel A shows choroidal neovascularization (asterisks) temporal to the fovea, surrounded by subretinal blood. In Panel B,
fluorescein dye fills the new blood vessels (asterisks) above the
avascular zone of the fovea.

Eyes with choroidal neovascularization can have

widely varying degrees of visual loss, distortion, and
scotomata (blind spots) depending on the type, location, size, and duration of neovascularization. Much
of the information about the natural course of choroidal neovascularization has been derived from studies of the untreated eyes of patients enrolled in clinical evaluations of laser photocoagulation or other
treatments. Some patients have a rapid decline in vision in the affected eye, with visual acuity changing
from normal to 20/200 or worse within weeks. More
486

Febr u ar y 17 , 2 0 0 0

frequently, visual acuity deteriorates more slowly and

stabilizes within three years. At this time, the average
visual acuity of eyes with the more aggressive, classic form of choroidal neovascularization is usually
between 20/250 and 20/400, but it may be worse
than 20/800. For eyes with the occult form of
choroidal neovascularization, the average visual acuity
is somewhat better, between 20/80 and 20/200.30
Once choroidal neovascularization has developed
in one eye, with or without visual loss, the other eye
is at relatively high risk for the same change. In prospective studies of patients with choroidal neovascularization in one eye, the risk to the second eye can
be predicted by evaluating both systemic and ophthalmoscopic risk factors (Table 2 and Fig. 9). When
all four risk factors more than five drusen, large
drusen, pigmental clumping, and systemic hypertension are present, the five-year risk of choroidal
neovascularization in the second eye is 87 percent,
whereas if none of these risk factors are present, the
risk is 7 percent.31
TREATMENTS EVALUATED
IN CLINICAL TRIALS

Choroidal neovascularization may progress rapidly, and therefore, any sudden change in central vision in a patient with drusen in one or both eyes requires a prompt ophthalmoscopic examination after
dilation of the eyes. The purpose of this evaluation
is to determine whether this sudden loss of vision is
due to leakage from new blood vessels that might be
amenable to treatment with laser photocoagulation
or photodynamic therapy.
Laser Photocoagulation Therapy

Between 1979 and 1994, the Macular Photocoagulation Study Group conducted a number of clinical

TABLE 1. ESTABLISHED AND POSSIBLE RISK FACTORS

FOR AGE-RELATED MACULAR DEGENERATION
IDENTIFIED BY EPIDEMIOLOGIC STUDIES.
ESTABLISHED RISK FACTORS

POSSIBLE RISK FACTORS

Older age (>60 years)

Family history
Cigarette smoking
Low dietary intake or plasma concentrations of antioxidant vitamins and zinc
White race (in the case of wet agerelated macular degeneration)

Female sex
Light-colored iris
Cardiovascular disease
Increased exposure to
sunlight

Percentage of Patients

D R UG TH ERA PY

100
90
80
70
60
50
40
30
20
10
0

87

53
44
25
7

No. of Risk Factors

Figure 9. Five-Year Risk of Choroidal Neovascularization in the
Contralateral Eye, According to the Number of Risk Factors
Present.
Adapted from the Macular Photocoagulation Study Group.31

Figure 8. Amslers Grid.

Amslers grid is used to detect subtle abnormalities in central
vision caused by fluid in the subretinal space. Macular abnormalities may be manifested as distortions in the lines of the grid.

TABLE 2. RISK FACTORS FOR CHOROIDAL

NEOVASCULARIZATION IN THE OTHER EYE OF
A PATIENT WITH THE DISORDER IN ONE EYE.
More than 5 drusen
Large drusen (>63 m)
Focal hyperpigmentation of the retinal pigment epithelium
Systemic hypertension

trials supported by the National Eye Institute that enrolled patients with neovascular lesions of one or both
eyes. Each affected eye was randomly assigned to either
laser treatment or observation. For eligible eyes with
neovascularization in extrafoveal locations (200 m
or more from the center of the macula), juxtafoveal
locations (more than 1 m but less than 200 m
from the foveal center), and subfoveal locations, laser treatment reduced the risk of severe visual loss.32-34
Laser photocoagulation, as performed in the Macular Photocoagulation Study, is the only treatment for
age-related macular degeneration with proven longterm benefit. To identify patients eligible for laser
treatment, intravenous fluorescein angiography is performed. Well-circumscribed new blood vessels identified on the fluorescein angiogram (Fig. 6B) are
treated with laser photocoagulation after topical or
local (retrobulbar or peribulbar) anesthesia. Figure
10 shows the effects of laser photocoagulation immediately after treatment and six months later.
There are three major limitations of laser photocoagulation treatment. First, not more than 10 to 15
percent of all neovascular lesions are small enough
and sufficiently delineated by fluorescein angiography
to be eligible for laser treatment. Second, even if laser
treatment is initially successful that is, the new
blood vessels appear closed on fluorescein angiography there is at least a 50 percent chance that leakage will recur during the next two years. Fortunately, many recurrences are amenable to additional laser
treatment if detected early, thus mandating careful
monitoring after laser treatment. Third, at least half
the patients with sufficiently well-circumscribed neovascular lesions have some initial leakage beneath the
center of the fovea. Laser treatment leads to an immediate reduction in central vision. Even so, with sufVol ume 342

Numb e r 7

487

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Figure 10. Choroidal Neovascularization in the Absence of and after Laser Treatment.
In Panel A, choroidal neovascularization (asterisks) has caused new blood vessels to penetrate Bruchs membrane (arrowheads).
The arrows identify the retinal pigment epithelium (periodic acidSchiff, 775). In Panel B, immediately after laser treatment, there
is opacification of the normally clear retina over the treated area. In Panel C, six months after treatment, there is a circumscribed
laser scar with no accompanying blood or subretinal fluid. In Panel D, a fluorescein angiogram obtained six months after treatment
shows no leakage from the treated blood vessels. Panel A was provided by W.R. Green, Wilmer Eye Institute, Johns Hopkins Medical
Institution. Panel B was reprinted from Bressler et al.10 with the permission of the publisher.

ficient follow-up, the extent of visual loss is less in

laser-treated eyes than in untreated eyes.34,35
Photodynamic Therapy

Photodynamic therapy is a nonthermal process leading to the localized production of reactive oxygen
species, including singlet oxygen, superoxide anions,
and hydroxyl radicals, which may mediate local cellular, vascular, and immunologic injury, and ultimately result in the partially selective destruction of new
488

Febr u ar y 17 , 2 0 0 0

blood vessels.36 The process of destruction can be

confined to the area of choroidal neovascularization
by the intravenous administration of a photosensitizer and irradiation of this region. Typically, the new
blood vessels will remain closed for a few weeks, and
then treatment should be repeated on the basis of the
appearance of the region on fluorescein angiography.
In a recent, large clinical trial, photodynamic therapy with verteporfin as the photosensitizer delayed
or prevented loss of vision during at least one year

D R UG TH ERA PY

of follow-up in patients with predominantly classic

neovascular lesions.37 This type of lesion is typically
well delineated on fluorescein angiography. Patients
assigned to treatment with verteporfin photodynamic
therapy received an average of 3.4 treatments in the
first year. Treatment was beneficial only in the group
of patients with predominantly classic choroidal neovascularization. Within that subgroup, only 33 percent of the patients who received verteporfin had substantial loss of vision, as compared with 61 percent
of those given a placebo photosensitizer.
Photodynamic therapy extends the group of eyes
that can benefit from some type of treatment. The
long-term benefit of this promising therapy, as well
as the refinement of the treatment regimen, awaits
further study. Clinical trials of verteporfin in patients
with poorly defined areas of choroidal neovascularization and of other photosensitizing agents in all
sorts of lesions are currently under way.
Interferon Alfa-2a

Although preliminary data in animals and anecdotal reports in humans had suggested that interferon alfa-2a was beneficial in patients with choroidal
neovascularization, the results of a large, multicenter,
international trial of interferon alfa-2a were negative.38 Indeed, patients treated with high-dose interferon alfa-2a had more rapid loss of vision than did
those given placebo.
INVESTIGATIONAL TREATMENTS
Submacular Surgery

Advances in microsurgical techniques have permitted the development and refinement of surgical methods for the treatment of age-related macular degeneration. Areas of choroidal neovascularization can be
excised and blood extracted from the subretinal space
by means of vitreous surgery. The efficacy of this procedure is now being evaluated in a trial supported by
the National Eye Institute.39
External-Beam Radiation Therapy

External-beam radiation therapy is being considered as a treatment for the neovascular lesions in patients with age-related macular degeneration because
of the radiosensitivity of vascular endothelial cells,
especially proliferating vascular endothelial cells. Since
1993, when the results of the first series were published,40 many large studies have been conducted, but
none included a control group. A recent small, randomized clinical trial in the Netherlands found that
patients who received external-beam radiation therapy had a smaller decrease in visual acuity than did
untreated patients one year after enrollment.41
Thalidomide

Thalidomide is being evaluated as a treatment for

age-related macular degeneration because of its effi-

cacy in controlling growth factorinduced corneal

angiogenesis in rabbits and mice.42 Accordingly, a
small clinical trial (<75 patients) is being conducted.
TREATMENTS NOT YET EVALUATED
IN CLINICAL TRIALS
Indocyanine GreenGuided Laser Treatment

Although laser photocoagulation as guided by fluorescein angiography is the only treatment of proven
long-term benefit for age-related macular degeneration, several other imaging methods are contributing to our understanding of the structure, function,
natural history, and response to treatment of eyes
with this disorder. One such approach is indocyanine
green angiography. Indocyanine green differs from
fluorescein in that it absorbs and fluoresces in the
near-infrared portion of the spectrum and is more
completely bound to plasma proteins, potentially conferring advantages for the study of choroidal circulation.43 Several groups have attempted to use indocyanine green angiography to guide treatment of
choroidal neovascularization in patients whose eyes
are deemed ineligible for treatment on the basis of
fluorescein angiography.44,45 The usefulness of this
technique awaits validation.
Retinal Transplantation and Transplantation of Retinal
Pigment Epithelium

Retinal transplantation and transplantation of retinal pigment epithelium are still many years away from
clinical use. However, investigators are now attempting to transplant photoreceptor elements and retinal
pigment epithelium cells as a means of restoring visual function or at least slowing the progression of
visual loss resulting from processes potentiated in
part by abnormal retinal and retinal pigment epithelium cells.46
Retinal Translocation

Surgical innovators are exploring the potential benefits and complications of translocating the retina
with respect to the retinal pigment epithelium and
choroid.47,48 The goal of one experimental procedure
is to move otherwise functional sensory retina away
from subfoveal areas of choroidal neovascularization
so that laser photocoagulation can obliterate the new
blood vessels without destroying the overlying retina.
Early reports have described both successes with this
approach and adverse effects, including retinal detachment with loss of vision. With experience, advanced
methods of vitreoretinal surgery may prove effective.
Perhaps the optimal approach is to combine techniques; for example, excision of subfoveal areas of
choroidal neovascularization could be combined with
transplantation of retinal pigment epithelium or photoreceptors and possibly with the intravitreal instillation of a suitable drug to inhibit further choroidal
neovascularization.
Vol ume 342

Numb e r 7

489

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Retinal Prosthesis

Efforts to transplant or regenerate retinal neural

and supportive elements have not been successful.
Therefore, stimulated by advances in microelectronics and biomaterials science and buoyed by the success of cochlear implants, several groups are developing and evaluating an electronic retinal prosthesis.49,50
The challenges are formidable and include the need
for biocompatible materials that will not be rejected
by the host, the need to devise microsurgical methods and materials that will allow stable fixation of the
device, the establishment of a successful interface between neural elements and electronic materials, and
the design and implementation of appropriate strategies to stimulate neurons with signals that allow
visual perception. There is tempered optimism with
respect to the use of this treatment for degenerative
conditions such as retinitis pigmentosa. In such conditions a treatment may be deemed successful if visual acuity improves from light perception to 20/400
vision, restoring a patients ability to walk unaided.
Since peripheral vision is usually preserved in patients
with age-related macular degeneration, an implant
must do far more to be deemed effective.
Gene Therapy

Advances in molecular genetics, in concert with

epidemiologic studies and analyses of blood samples
from patients and families with age-related macular degeneration, are beginning to increase our understanding of the molecular basis of this disorder.51,52 Putative genes responsible for some forms of the disorder
are being identified,53 and several groups are exploring the potential of gene therapy to reverse or slow the
progression of the disorder.54 Better characterization
of the genetic aspects of age-related macular degeneration may lead to the identification of some forms
of the disorder that are amenable to gene therapy.
VISUAL REHABILITATION
AND COUNSELING

Most patients with even moderate loss of vision as

a result of age-related macular degeneration, regardless of the stage, can benefit from the use of low-vision
aids. Patients with even mild degrees of vision loss
should be encouraged to see a low-vision specialist for
evaluation and a prescription for various types of
magnifying devices, lighting intensifiers, or computerassisted reading devices. Such early intervention is
likely to improve the quality of life and to lead to
more effective use of these devices should visual loss
progress.55
In addition, all physicians should be alert for clinical depression in patients with recent loss of vision
from age-related macular degeneration. Losing ones
ability to read or drive a car often results in a depression similar to that experienced with the loss of a
loved one, and treatment for depression may be more
490

Febr u ar y 17 , 2 0 0 0

effective than the treatment for macular degeneration.

Patients who are thought to be depressed should be
encouraged to see their primary care physician or a
psychiatrist so that their depression can be diagnosed accurately and treated effectively. Often treatment for depression can be discontinued once the
patients have adjusted to their visual loss.
PROPHYLAXIS
Laser Treatment

Perhaps the most promising approach for the future is prophylactic treatment. Even if the rate of efficacy of prophylaxis were only 30 percent, such a response would still reduce by half the rate of legal
blindness from age-related macular degeneration.56
On the basis of the encouraging results of pilot studies in the United States and elsewhere,57-61 the National Eye Institute recently funded a clinical trial to
evaluate the effect of low-intensity laser application
as prophylaxis in high-risk patients with numerous
large drusen in both eyes the Complications of
Age-Related Macular Degeneration Prevention Trial.
In each patient in this study, one eye will be randomly
assigned to receive laser photocoagulation of the macula in a grid pattern and the other eye to observation. Patients will be followed for at least five years.
In addition, an industry-sponsored, clinical trial of
prophylaxis with the infrared diode laser is being conducted in patients with bilateral drusen and patients
who already have choroidal neovascularization in one
eye and in whom the other eye is at risk.
Although prophylactic laser treatment can promote the resolution of drusen and, in some patients,
improve visual function moderately, it is not clear
whether the ophthalmoscopic resolution of drusen is
accompanied by a reduction in the risk of severe visual loss from atrophy or neovascularization.56 In fact,
in a pilot study of moderate-intensity laser treatment
(the Choroidal Neovascularization Prevention Trial), which was conducted from 1994 to 1999 to prepare for the large-scale study, the risk of choroidal
neovascularization in prophylactically treated fellow
eyes was increased.57
Nutrition and Dietary Supplements

Nutritional factors have been a subject of great interest among patients with age-related macular degeneration and their physicians. In casecontrol studies, subjects who habitually consumed large quantities
of leafy green vegetables and other foods containing
antioxidant vitamins had a decreased risk of age-related macular degeneration.62 Can people who begin to
consume antioxidant vitamins in their 60s and 70s
alter their risk of age-related macular degeneration?
For the past decade, the National Eye Institute has
supported the Age-Related Eye Disease Study, which
is assessing whether supplementation with antioxidant vitamins alone or in combination with zinc can

D RUG TH ERA PY

reduce the risk of adverse outcomes in patients with

early age-related macular degeneration.63
In addition to antioxidant vitamins and zinc, patients ask about a wide variety of unproven and often untested nutritional supplements. These include
bilberries, shark cartilage, and Ginkgo biloba extract.
Unfortunately, little is known about the effect of these
products on age-related macular degeneration; no
clinical trials have been conducted. Other treatments
currently being promoted include electroshock therapy and plasma-exchange therapy. Patients with agerelated macular degeneration who are offered these
often expensive and sometimes risky treatments are
given little information as to their benefit or risk. Patients should be advised to avoid unproven treatments.
CONCLUSIONS

In the next few years, we anticipate that many genetic mutations will be discovered in patients with
the various forms of macular degeneration. In some
instances, it may be possible to modify environmental factors, such as diet, in carriers of a mutation before macular degeneration develops. Even if the onset
of age-related macular degeneration could be delayed
by only 5 to 10 years, such a delay could profoundly
decrease the rate of blindness, because some patients
would not survive long enough to lose their vision.
Although effective treatment is currently limited, research being conducted in many areas, including
prophylaxis, offers hope for the future to the many
affected patients and their offspring.
Supported in part by an unrestricted grant from Research to Prevent
Blindness (to Drs. Fine, Berger, Maguire, and Ho), a Career Development
Award from Research to Prevent Blindness (to Dr. Berger), and a grant
from the Paul and Evanina Bell Mackall Foundation Trust (to Drs. Fine,
Berger, Maguire, and Ho). Drs. Fine, Maguire, and Ho have received a grant
from Entremed, and Dr. Ho has received grants from CibaVision and Pharmacia & Upjohn and served as a consultant for Nexstar Pharmaceuticals.

REFERENCES
1. Tielsch JA. Vision problems in the U.S.: a report on blindness and vision impairment in adults age 40 and older. In: Prevent blindness America.
Schaumburg, Ill.: Prevent Blindness America, 1994.
2. Evans J, Wormald R. Is the incidence of registrable age-related macular
degeneration increasing? Br J Ophthalmol 1996;80:9-14.
3. Gass JDM. Stereoscopic atlas of macular diseases: diagnosis and treatment. 4th ed. St. Louis: Mosby, 1997.
4. Bird AC, Bressler NM, Bressler SB, et al. An international classification
and grading system for age-related maculopathy and age-related macular
degeneration. Surv Ophthalmol 1995;39:367-74.
5. Bressler NM, Silva JC, Bressler SB, Fine SL, Green WR. Clinicopathological correlation of drusen and retinal pigment epithelial abnormalities in
age-related macular degeneration. Retina 1994;14:130-42.
6. Klein R, Klein BEK, Linton KLP. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933-45.
7. Klein R, Klein BEK, Jensen SC, Meuer SM. The five-year incidence and
progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997;104:7-21.
8. Sunness JS, Rubin GS, Applegate CA, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology 1997;104:1677-91.
9. Steinmetz RL, Haimovici R, Jubb C, Fitzke FW, Bird AC. Symptomatic
abnormalities of dark adaptation in patients with age-related Bruchs membrane change. Br J Ophthalmol 1993;77:549-54.

10. Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration.
Surv Ophthalmol 1988;32:375-413.
11. Ferris FL III. Senile macular degeneration: review of epidemiologic
features. Am J Epidemiol 1983;118:132-51.
12. Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham
Eye Study monograph: an ophthalmological and epidemiological study of
cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual
acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 1980;24:Suppl:335-610.
13. Hyman LG, Lilienfeld AM, Ferris FL III, Fine SL. Senile macular degeneration: a case-control study. Am J Epidemiol 1983;118:213-27.
14. Goldberg J, Flowerdew G, Smith E, Brody JA, Tso MOM. Factors associated with age-related macular degeneration: an analysis of data from
the first National Health and Nutrition Examination Survey. Am J Epidemiol 1988;128:700-10.
15. The Eye Disease Case-Control Study Group. Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol 1992;110:1701-8.
16. Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related
maculopathy in Australia: the Blue Mountains Eye Study. Ophthalmology
1995;102:1450-60.
17. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of agerelated maculopathy in the Rotterdam Study. Ophthalmology 1995;102:
205-10.
18. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol 1997;123:199-206.
19. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective
study of cigarette smoking and age-related macular degeneration in women. JAMA 1996;276:1141-6.
20. Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE. A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA 1996;276:1147-51.
21. Klein R, Klein BEK, Moss SE. Relation of smoking to the incidence
of age-related maculopathy: the Beaver Dam Eye Study. Am J Epidemiol
1998;147:103-10.
22. Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc
in macular degeneration. Arch Ophthalmol 1988;106:192-8.
23. VandenLangenberg GM, Mares-Perlman JA, Klein R, Klein BE,
Brady WE, Palta M. Associations between antioxidant and zinc intake and
the 5-year incidence of early age-related maculopathy in the Beaver Dam
Eye Study. Am J Epidemiol 1998;148:204-14.
24. Sommer A, Tielsch JM, Katz J, et al. Racial differences in the causespecific prevalence of blindness in East Baltimore. N Engl J Med 1991;325:
1412-7.
25. Klein R, Rowland ML, Harris MI. Racial/ethnic differences in agerelated maculopathy: Third National Health and Nutrition Survey. Ophthalmology 1995;102:371-81. [Erratum, Ophthalmology 1995;102:1126.]
26. Cruickshanks KJ, Klein R, Klein BEK. Sunlight and age-related macular
degeneration: the Beaver Dam Eye Study. Arch Ophthalmol 1993;111:514-8.
27. Clinical trials supported by the National Eye Institute. Bethesda, Md.:
National Institutes of Health, 1993. (NIH publication no. 93-2910.)
28. Holz FG, Wolfensberger TJ, Piguet B, et al. Bilateral macular drusen
in age-related macular degeneration: prognosis and risk factors. Ophthalmology 1994;101:1522-8.
29. Fine AM, Elman MJ, Ebert JE, Prestia PA, Starr JS, Fine SL. Earliest
symptoms caused by neovascular membranes in the macula. Arch Ophthalmol 1986;104:513-4.
30. Maguire MG. Natural history. In: Berger JW, Fine SL, Maguire MG,
eds. Age-related macular degeneration. St. Louis: Mosby, 1999:17-30.
31. Macular Photocoagulation Study Group. Risk factors for choroidal
neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Arch Ophthalmol 1997;115:741-7.
32. Idem. Argon laser photocoagulation for neovascular maculopathy: fiveyears results from randomized clinical trials. Arch Ophthalmol 1991;109:
1109-14. [Erratum, Arch Ophthalmol 1992;110:761.]
33. Idem. Laser photocoagulation for juxtafoveal choroidal neovascularization: five-year results from randomized clinical trials. Arch Ophthalmol
1994;112:500-9.
34. Idem. Laser photocoagulation for subfoveal neovascular lesions of agerelated macular degeneration: updated findings from two clinical trials.
Arch Ophthalmol 1993;111:1200-9.
35. Idem. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration:
the influence of initial lesion size and initial visual acuity. Arch Ophthalmol
1994;112:480-8.
36. Miller JW, Walsh AW, Kramer M, et al. Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin. Arch Ophthalmol 1995;113:810-8.
37. Treatment of Age-Related Macular Degeneration with Photodynamic
Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal

Vol ume 342

Numb e r 7

491

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

neovascularization in age-related macular degeneration with verteporfin:

one-year results of 2 randomized clinical trials TAP report. Arch Ophthalmol 1999;117:1329-45.
38. Pharmacological Therapy for Macular Degeneration Study Group. Interferon alfa-2a is ineffective for patients with choroidal neovascularization
secondary to age-related macular degeneration: results of a prospective randomized clinical trial. Arch Ophthalmol 1997;115:865-72.
39. Bressler NM. Submacular surgery: are randomized trials necessary?
Arch Ophthalmol 1995;113:1557-60.
40. Chakravarthy U, Houston RF, Archer DB. Treatment of age-related
subfoveal neovascular membranes by teletherapy: a pilot study. Br J Ophthalmol 1993;77:265-73.
41. Bergink GJ, Hoyng CB, van der Maazen RWM, Vingerling JR, van
Daal WAJ, Deutman AF. A randomized controlled clinical trial of the efficacy of radiation therapy in the control of subfoveal choroidal neovascularization in age-related macular degeneration: radiation versus observation.
Graefes Arch Clin Exp Ophthalmol 1998;236:321-5.
42. DAmato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is
an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994;91:40825.
43. Bischoff PM, Flower RW. Ten years experience with choroidal angiography using indocyanine green dye: a new routine examination or an epilogue? Doc Ophthalmol 1985;60:235-91.
44. Regillo CD, Benson WE, Maguire JI, Annesley WH Jr. Indocyanine
green angiography and occult choroidal neovascularization. Ophthalmology 1994;101:280-8.
45. Slakter JS, Yannuzzi LA, Sorenson JA, Guyer DR, Ho AC, Orlock
DA. A pilot study of indocyanine green videoangiography-guided laser
photocoagulation of occult choroidal neovascularization in age-related
macular degeneration. Arch Ophthalmol 1994;112:465-72.
46. Kaplan HJ, Tezel TH, Berger AS, Wolf ML, Del Priore LV. Human
photoreceptor transplantation in retinitis pigmentosa: a safety study. Arch
Ophthalmol 1997;115:1168-72.
47. Machemer R, Steinhorst UH. Retinal separation, retinotomy, and
macular relocation. I. Experimental studies in the rabbit eye. Graefes Arch
Clin Exp Ophthalmol 1993;231:629-34.
48. de Juan E Jr, Lowenstein A, Bressler NM, Alexander J. Translocation
of the retina for management of subfoveal choroidal neovascularization.
II. A preliminary report in humans. Am J Ophthalmol 1998;125:63546.
49. Rizzo JR III, Wyatt J. Prospects for a visual prosthesis. Neuroscientist
1997;3:251-62.

50. Humayun MS, de Juan E Jr, Dagnelie G, Greenberg RJ, Propst RH,
Phillips DH. Visual perception elicited by electrical stimulation of retina in
blind humans. Arch Ophthalmol 1996;114:40-6.
51. Allikments R, Shroyer NF, Singh N, et al. Mutation of the Stargardt
disease gene (ABCR) in age-related macular degeneration. Science 1997;
277:1805-7.
52. ABCR gene and age-related macular degeneration. Science 1998;279:
1107.
53. Stone EM, Lotery JA, Munier FL, et al. A single EFEMP1 mutation
associated with both Malattia Leventinese and Doyne honeycomb retinal
dystrophy. Nat Genet 1999;22:199-202.
54. Bennett J, Maguire AM. Gene therapy. In: Berger JW, Fine SL, Maguire MG, eds. Age-related macular degeneration. St. Louis: Mosby, 1999:
395-412.
55. Steinberg JD. Principles of low-vision rehabilitation. In: Berger JW,
Fine SL, Maguire MG, eds. Age-related macular degeneration. St. Louis:
Mosby, 1999:433-42.
56. Lanchoney DM, Maguire MG, Fine SL. A model of the incidence and
consequences of choroidal neovascularization secondary to age-related
macular degeneration: comparative effects of current treatment and potential prophylaxis on visual outcomes in high-risk patients. Arch Ophthalmol
1998;116:1045-52.
57. Choroidal Neovascularization Prevention Trial Research Group. Laser
treatment in eyes with large drusen: short-term effects seen in a pilot randomized clinical trial. Ophthalmology 1998;105:11-23.
58. Little HL, Showman JM, Brown BW. A pilot randomized controlled
study on the effect of laser photocoagulation of confluent soft macular
drusen. Ophthalmology 1997;104:623-31.
59. Figueroa MS, Regueras A, Bertrand J. Laser photocoagulation to treat
macular soft drusen in age-related macular degeneration. Retina 1994;14:
391-6.
60. Frennesson C, Nilsson SEG. Prophylactic laser treatment in early age
related maculopathy reduced the incidence of exudative complications. Br
J Ophthalmol 1998;82:1169-74.
61. Ho AC, Maguire MG, Yoken J, et al. Laser-induced drusen reduction
improves visual function at 1 year. Ophthalmology 1999;106:1367-74.
62. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA
1994;272:1413-20. [Erratum, JAMA 1995;273:622.]
63. Sperduto RD, Ferris FL III, Kurinij N. Do we have a nutritional treatment for age-related cataract or macular degeneration? Arch Ophthalmol
1990;108:1403-5.

ELECTRONIC ACCESS TO THE JOURNAL S CUMULATIVE INDEX

At the Journals site on the World Wide Web (http://www.nejm.org) you can search an
index of all articles published since January 1990. You can search by author, subject, title,
type of article, or date. The results will include the citations for the articles plus links to the
abstracts of articles published since 1993. Single articles and past issues of the Journal can
also be ordered for a fee through the Internet (http://www.nejm.org /customer/).

492

Febr u ar y 17 , 2 0 0 0

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.