Download A 76-Year-Old Man With Macular Degeneration

CLINICIAN’S CORNER
CLINICAL CROSSROADS
CONFERENCES WITH PATIENTS AND DOCTORS
A 76-Year-Old Man
With Macular Degeneration
Jorge G. Arroyo, MD, MPH, Discussant
DR SHIP: Dr G is a 76-year-old semiretired surgeon. He is
married, lives in the New York metropolitan area, and has
indemnity insurance and Medicare.
Dr G’s ophthalmologic history was notable for mild
myopia, bilateral drusen, and an episode of self-limited
central serous retinopathy in the left eye at the age of 38
years. Approximately 3 years ago, he noted subtle vision
changes. These symptoms progressed over a 2-month
period and he saw his general ophthalmologist. He was
found to have mild nuclear sclerotic cataracts (right
greater than left), corrected visual acuity of 20/40 in the
right eye and 20/25 in the left eye, and an exudative retinal
detachment in the right eye. He was referred to a retinal
specialist that day.
Since that time, Dr G has received photodynamic therapy
(PDT) to the right eye 5 times, twice with the experimental
addition of intraocular triamcinolone. His visual acuity in the
right eye initially showed some interval improvement, but has
ultimately worsened to “count fingers” vision. His course has
been complicated by chronic dry eyes, for which he has been
unsuccessfully treated with artificial tears and cyclosporine
drops, as well as bilateral nuclear sclerotic cataracts. Cataract surgery for the left eye was aborted 3 months ago when
he sustained an intraorbital hemorrhage during anesthesia
that required treatment by lateral canthotomy.
Dr G’s loss of visual acuity has dramatically altered his
life. While he continues to teach, he stopped performing surgery when he lost depth perception (stereopsis) because of
changes in the right eye. He does not feel he has adequate
binocular vision to drive safely, so has become reliant on
family, friends, and public transportation with the attendant loss of autonomy. He finds variable but occasionally
profound difficulty seeing well enough to do small household repairs, to play the piano, and to read, all activities that
used to occupy his time. He has become depressed.
Dr G’s past medical history is significant for hypertension, osteopenia, mild anemia, and migraine. Fifteen years
See also Patient Page.
CME available online at www.jama.com
2394 JAMA, May 24/31, 2006—Vol 295, No. 20 (Reprinted)
ago his purified protein derivative test converted to positive and he took a course of isoniazid. His surgical history
is notable for a prostatectomy and thymectomy.
His current medications include the following: alendronate (35 mg every week), hydrochlorothiazide (12.5 mg
daily), amlodopine (10 mg daily), aspirin (80 mg every
other day), as well as naproxen and misoprostol (200 µg as
needed for migraine). He has no drug allergies. He has a
remote history of pipe smoking and drinks alcohol
socially.
At his most recent ophthalmologic examination, his visual acuity in the right eye was 20/400, in the left eye 20/
30. The left fundus showed large soft drusen larger than 125
µm, mild pigmentary mottling, but no evidence of subretinal fluid or hemorrhage.
Dr G wonders what he can do to avoid developing similar sight-threatening changes in his left eye and asks if
there are any other treatments for his right eye that he
might consider.
DR G: HIS VIEW
It was during the summer about 3 years ago. I became aware,
while I was driving, of a subtle change in the shape of billboards. The upper right hand corner of the billboard appeared to be sagging. And then I noticed that if I looked at
a page, the upper right hand corner of the page would sag.
And I thought this was most unusual.
My ophthalmologist could not find anything on her examination, so she referred me to a retina specialist. I’ve received 4 treatments, but I’ve had a substantial loss of vision.
The vision changed in spurts. It wasn’t a subtle progression at all. I kept going in to have my prescription changed.
I must have gone through two dozen pairs of glasses in the
last 3 years.
This conference took place at the Medical Grand Rounds of Beth Israel Deaconess Medical Center, Boston, Mass, on December 9, 2004.
Author Affiliation: Dr Arroyo is Assistant Professor of Ophthalmology, Harvard
Medical School, and Retina Service Director, Division of Ophthalmology, Beth Israel Deaconess Medical Center, Boston, Mass.
Corresponding Author: Jorge G. Arroyo, MD, MPH, Division of Ophthalmology,
Shapiro Fifth Floor, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 ([email protected]).
Clinical Crossroads at Beth Israel Deaconess Medical Center is produced and edited by Risa B. Burns, MD, Eileen E. Reynolds, MD, and Amy N. Ship, MD. Tom
Delbanco, MD, is series editor.
Clinical Crossroads Section Editor: Margaret A. Winker, MD, Deputy Editor.
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CLINICAL CROSSROADS
The issue that bothers me most is that I can no longer
work as a surgeon, I can no longer operate. Losing depth
perception has been the most significant thing. It’s been absolutely devastating. My eye-hand coordination was my life.
In the operating room, I can’t demonstrate a procedure. It’s
astoundingly defeating.
I want to protect the vision in my good eye. I’ve always
been a therapeutic nihilist. I never believed that multivitamins and all these extra things are necessary. But I take zinc
and lutein because it isn’t going to do any harm. And maybe
it might help to forestall the development of macular degeneration in the good eye.
I would like to know what else I can do to protect the
vision in that eye and I’d like to do everything I can so that
I can read with greater ease. Because not being able to read,
not being able to write, not able to drive, and not being able
to function with fluidity is a terrible handicap.
QUESTIONS FOR DR ARROYO
What is the epidemiology and pathophysiology of the 2 major types of macular degeneration? What are the risk factors, how do patients typically present, and how is the diagnosis made? What is the natural history of age-related
macular degeneration (AMD)? What treatments exist? What
is known about their effectiveness? What are their complications, if any? What can be done to prevent AMD in those
at risk and/or to delay progression? What does the future
hold? What do you recommend for our patient?
DR ARROYO: As Dr G’s case helps illustrate, AMD is the
leading cause of irreversible vision loss in patients older
than 55 years. As it did for Dr G, AMD often presents with
acute, unilateral central visual distortion and loss. Early
diagnosis and treatment of AMD provide the best chance
of maintaining vision, quality of life, and overall health of
the patient. New treatment options are on the horizon that
promise to improve vision, as opposed to simply reduce
the rate of vision loss. Attention and resources need to be
directed toward understanding the pathophysiology
underlying non-neovascular or dry AMD and formulating
effective treatments that prevent severe vision loss from
geographic atrophy and choroidal neovascularization
(CNV).
Overview of Macular Degeneration
Age-related macular degeneration is a degenerative disease
of the macula (FIGURE 1) that is characterized by the focal
accumulation of yellowish material under the retinal pigment epithelium (RPE) (called drusen) and RPE pigmentary changes in the early stages, and geographic atrophy and
CNV in the advanced stages of the disease. Drusen range
from small, well-defined hard drusen (FIGURE 2), large, illdefined, soft drusen (Figure 2), or crystalline, calcific drusen (Figure 2). The risk of progression to advanced AMD
is 0.5% to 50% over 5 years and increases as the size and
number of drusen increase (⬎125 µm in either eye or ⬎63
©2006 American Medical Association. All rights reserved.
µm in both eyes) and with the presence of RPE pigmentary
disturbances.1
Progression to advanced AMD is usually associated with
severe vision loss due to geographic atrophy of the fovea in
20% of cases (FIGURE 3) or CNV in 80% of cases.2 Neovascular or wet AMD is characterized primarily by growth of
abnormal vessels from the CNV into the sub-RPE and/or subretinal space.3 Less frequently, these abnormal vessels may
originate from the retinal circulation.4 Choroidal neovascular vessels leak, leading to localized exudative retinal detachment and/or bleeding underneath the retina.
Pathophysiology of AMD
Although the exact pathogenesis of non-neovascular AMD
is unknown, a number of theories have been proposed: (1)
photoreceptor and RPE ischemia5-8 and/or decreased diffusion through Bruch membrane9; (2) primary senescence of
the RPE10-12; (3) primary genetic abnormalities in the photoreceptor or RPE13; and (4) decreased scleral elasticity.14
The development of drusen may be a final common pathway that results from any of the above-mentioned etiologies or may be multifactorial in nature.15,16 Factors such as
inflammation17-25 and chronic infection26 may also play a role
in this disease. The ability to develop effective treatments
for non-neovascular dry AMD is hampered by our limited
understanding of its pathophysiology.
In contrast, the molecular events driving neovascularization are much better understood. This insight has allowed
the development of effective antineovascular treatments that
target different molecular events involved in neovascular
AMD.16,27,28
Risk Factors for AMD
Age-related macular degeneration is associated with certain risk factors that may provide insight into its origins as
well as allow for risk modification. These factors include age,2
family history,29 race,30 smoking,31-33 hypertension,34-38 atherosclerosis,38 inflammation,21,22 obesity,39 consumption of
food high in antioxidants,40-42 fish and nuts,43,44 and chronic
infection.26,45-48
Age is the most strongly associated risk factor for AMD.
Prevalence data are available from a study of 14 752 people
aged 43 to 99 years, which pooled the results of 3 studies
from the United States, the Netherlands, and Australia.2 Wet
or dry type AMD was found in 1.6% of all people, but in no
one younger than 55 years. Between the ages of 55 and 64
years, 65 and 74 years, 75 and 84 years, and after age 84
years, the rates were 0.2%, 0.9%, 4.6%, and 13.1%, respectively. It is estimated that in 2000 the prevalence of AMD
in US adults aged 40 years and older was 1.47%, affecting
1.75 million people, and by 2020 will affect almost 3 million people as the US population ages.49
Smoking is also strongly associated with an increased risk
of dry and wet type AMD, with relative risks (RRs) ranging
from 2 to 4 compared with individuals who never smoked.31-33
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CLINICAL CROSSROADS
Figure 1. Macula Lutea and Ocular Structures With Age-Related Macular Degeneration (AMD)
A Normal Macula and Optic Nerve
B Cross Section of Normal Retina, Choroid, and Sclera
Superior Temporal Retinal
Vascular Arcade
VITREOUS HUMOR
N E U R O S E N S O RY R E T I N A
Nerve Fiber Layer
Macula
Fovea
Ganglion Cell Layer
Inner Plexiform Layer
Inner Nuclear Layer
Outer Plexiform Layer
Outer Nuclear Layer
Photoreceptor Outer Segments
Retinal Pigment
Epithelium
Bruch
Membrane
Inferior Temporal Retinal
Vascular Arcade
Choriocapillaris
CHOROID
SCLERA
C Age-Related Macular Degeneration
D RY A M D
WET AMD
PHOTORECEPTOR
OUTER SEGMENTS
PHOTORECEPTOR
OUTER SEGMENTS
Subretinal Fluid
With Hemorrhage
RETINAL PIGMENT
EPITHELIUM
HYPERPLASIA
SOFT
DRUSEN
HARD
DRUSEN
RETINAL PIGMENT
EPITHELIUM
CHORIOCAPILLARIS
Bruch Membrane
Choroidal
Neovascular Vessel
A, Fundus photograph of normal retina.The macula is the central part of the retina delimited by the superior temporal and inferior temporal retinal vascular arcades.
The fovea is about the size of the optic nerve (diameter, 1500 µm) and is centered on the foveola (diameter, 350 µm). The foveola is the thinnest part of the retina. It
is devoid of ganglion cells and is responsible for the most acute detailed vision. B, Cross section of normal retina, choroid, and sclera. A photon of light must penetrate
all of the layers of the retina before being absorbed and converted into a neural signal by the photoreceptor outer segments. This retinal transparency results from the
structured organization and orientation of the retinal cell bodies and processes. The retinal photoreceptors and retinal pigment epithelium (RPE) are metabolically active
cells that depend on the choroidal vasculature to supply oxygen and nutrients and remove metabolic waste. C, Dry AMD or nonneovascular AMD is characterized by
nodular, hard drusen, with sharp edges, diffuse soft drusen, and RPE hyperplasia and hyperpigmentation. Histologically, drusenoid material is found between the RPE
and the RPE basement membrane (basal laminar deposits) and/or between the RPE basement membrane and the collagenous layer of Bruch membrane (basal linear
deposits). The risk for progression to wet or neovascular AMD increases with increasing number and size of drusen and the presence of RPE pigmentary abnormalities.
Wet AMD or neovascular AMD is characterized by the intrusion of abnormal new vessels from the choroid into the subretinal (type 2) and/or sub-RPE (type 1) space.
In some cases, neovascularization may originate from the retinal vessels (not shown), with or without a choroidal component. Choroidal neovascularization often
exudes fluid and/or hemorrhage into the subretinal and/or sub-RPE space.
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CLINICAL CROSSROADS
The increased risk of AMD is consistently seen in most studies and may persist even after quitting smoking for 15 to 20
years.32,50
Family history is associated with AMD,29 although the association may be stronger in patients with early onset disease.51 Four recent studies have found that a tyrosinehistodine single protein polymorphism within the AMD locus
of chromosome 1 that is responsible for heparin and
C-reactive protein binding is found in up to 50% cases of
AMD.17-20 This protein polymorphism is thought to regulate the alternative complement pathway and result in increased inflammation. Other investigators have demonstrated that C-reactive protein is elevated in patients with
AMD.21,22 Data on aspirin use and incident AMD is conflicting, although it may decrease the risk of neovascular
AMD.52-54 Calcium channel blockers may be associated with
Figure 2. Types of Drusen in Age-Related Macular Degeneration (AMD)
A
B
C
A, Hard drusen are small, well-defined, homogeneous, yellowish deposits (also known as basal laminar deposits) found under the macula or retinal periphery. These
small lesions (⬍63 µm) are not associated with an increased risk of AMD. B, Soft drusen are medium and large, heterogeneous, yellowish deposits with ill-defined
borders that are associated with AMD. They may result in a focal elevation of the retinal pigment epithelium (RPE) called a pigment epithelial detachment. Note the
subtle RPE mottling near the fovea. The presence of medium-size drusen (⬎63 µm) in both eyes or large drusen (⬎125 µm) in one or both eyes and/or pigmentary
disturbance (hyperpigmentation or hypopigmentation) in one or both eyes is associated with an increasing risk of advanced AMD and severe vision loss: 0.5% (no risk
factors), 3% (1 risk factor), 12% (2 risk factors), 25% (3 risk factors), and 50% (4 risk factors) over a 5-year period.1 C, Calcific drusen are crystalline, refractile, subretinal yellowish lesions that may appear late in AMD. These lesions are typically associated with an increased risk of progression to advanced AMD.
Figure 3. Geographic Atrophy of the Retinal Pigment Epithelium (GARPE), Neovascular or Wet Age-Related Macular Degeneration (AMD),
and Classic Subretinal Choroidal Neovascularization
A
B
C
A, Geographic atrophy of the retina and underlying RPE associated with AMD. Involvement of the center of the fovea by GARPE constitutes advanced AMD and
typically is associated with severe vision loss. B, Neovascular or wet AMD with subretinal fluid and hemorrhage in the macula of a patient with sudden visual distortion
and loss. These findings are typically due to a choroidal neovascular membrane leaking fluid (subretinal fluid) and bleeding (subretinal hemorrhage) under the retina.
C, Fluorescein angiogram showing classic subretinal choroidal neovascularization. Fluorescein dye is injected in the antecubital vein, enters the retinal and choroidal
circulation, and is imaged using a high-resolution fundus camera. Subretinal lesions that hyperfluoresce early in the angiogram and leak late in the angiogram as seen
in this image are consistent with choroidal neovascularization, which is the sine qua non of neovascular AMD.
©2006 American Medical Association. All rights reserved.
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CLINICAL CROSSROADS
Figure 4. Artist Representation of the Acute Central Vision
Distortion and Loss Associated With Subretinal Fluid From a
Choroidal Neovascular Membrane in Age-Related Macular
Degeneration (AMD)
tion of AMD with smoking and family history, the probable association with obesity, hypertension, hyperlipidemia, and cataract surgery, and the possible association with
sun exposure, and may benefit from risk factor modification. Increasing consumption of foods that are rich in vitamin E and C, beta carotene, and zinc, as well as fish (high
in omega-3 fatty acids) and nuts, although not proven to
be effective in a prospective randomized controlled trial
(RCT), is also probably beneficial.
Natural History of AMD
The central vision becomes distorted, straight lines become curved (metamorphopsia), images may appear smaller (micropsia) or larger (macropsia), a grayish
spot often obscures the central vision (central scotoma). Central visual distortion
and blurring is one of the earliest symptoms associated with wet AMD and should
prompt urgent ophthalmologic evaluation within 24 to 48 hours. Photograph reproduced with permission by Carole Uminski, Beth Israel Deaconess Medical Center, Boston, Mass.
an increased incidence of AMD, although the evidence is
not very strong.53 Finally, Chlamydia pneumoniae may be a
possible infectious trigger of inflammation associated with
AMD; however, serological and pathological data are
contradictory.26,45-48
Hypertension, level of elevated blood pressure, and increased pulse pressure are also associated with AMD.34-38
Thermal laser photocoagulation appears to be less successful in patients with hypertension,55 and hypertension may
increase the risk of developing AMD in the second eye among
those who have one eye affected by the disease.56
A number of epidemiological studies have suggested a protective effect of consuming foods rich in carotenoids, particularly dark green leafy vegetables, and fruit.41,42 A recent
study of 560 participants followed up for a mean of 8 years
found that high dietary intake of beta carotene, vitamins C
and E, and zinc was associated with a 35% reduced risk of
incident AMD, from 16.3% of those with below-median intake developing advanced AMD to 9.7% for those with abovemedian intake.40 Fat intake has been associated with the risk
of progression of AMD, although this risk appears to decrease with consumption of fish and nuts.43,44 Obesity may
also be associated with progression to advanced AMD.39
All individuals who have a diagnosis of AMD or a family
history of AMD should be informed of the definite associa2398 JAMA, May 24/31, 2006—Vol 295, No. 20 (Reprinted)
As with Dr G’s right eye, distortion of straight lines is one
of the earliest symptoms associated with neovascular or wet
AMD (FIGURE 4).57 In the primary care setting, a complaint of visual disturbance should prompt questions regarding the rate of vision loss, whether one or both eyes are
involved, and whether the vision loss is for distance vision,
near vision, or both. Unilateral vision loss that has occurred acutely over a period of days or weeks may represent an urgent condition and requires ophthalmologic evaluation within 24 to 48 hours.
Patients with acute distortion or loss of central vision require a dilated fundus examination. The macula is easily visualized using slit-lamp biomicroscopy. The presence of subretinal fluid associated with exudative retinal detachment,
subretinal hemorrhage, or a gray subretinal membrane are
all strongly suggestive of a CNV (Figure 3). A fluorescein
angiogram is needed to precisely delineate the location and
type of CNV present (Figure 3).
Treatment Options for AMD
Antioxidants. Antioxidants have been proposed to prevent
cellular damage in the RPE by limiting the damaging effects of free radicals produced in the process of light absorption.58 The Age-Related Eye Disease Study (AREDS) studied 3640 patients aged 55 to 80 years who were randomly
assigned to 1 of 4 treatment groups: (1) antioxidants (500
mg of vitamin C, 400 IU of vitamin E, 15 mg of beta carotene); (2) 80 mg of zinc as zinc oxide and 2 mg of cupric
oxide (copper); (3) antioxidants plus zinc; or (4) placebo.
During an average follow-up of 6.3 years, the following findings were reported: patients with no AMD (category 1) or
mild or borderline AMD (category 2) did not benefit from
antioxidant and/or zinc supplementation. Patients with moderate and advanced AMD (categories 3 and 4) had a lower
risk of progression to advanced AMD and visual acuity loss
in the good eye if they took both zinc and antioxidants compared with placebo for 7 years (odds ratio [OR], 0.72; 99%
confidence interval [CI], 0.52-0.98). Therefore, patients with
extensive intermediate-size drusen, at least 1 large druse,
or noncentral geographic atrophy in one or both eyes benefited from this treatment combination.59 In patients who
were at the highest risk for AMD progression, both zinc and
antioxidants plus zinc significantly reduced the odds of developing advanced AMD (antioxidants plus zinc: OR, 0.66
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CLINICAL CROSSROADS
[99% CI, 0.47-0.91]; absolute risk reduction [ARR] in the
proportion of eyes developing advanced AMD in 5 years,
0.06; number needed to treat [NNT] to prevent 1 case of
progression to advanced AMD, 17; zinc: OR, 0.71 [99% CI,
0.52-0.99]; ARR, 0.036, NNT=27; antioxidants: OR, 0.76
[99% CI, 0.55-1.05]). It is estimated that if all individuals
in the United States who are at high risk for developing advanced AMD used the recommended antioxidant and zinc
supplementation, approximately 300 000 of these individuals would avoid developing severe vision loss during the next
5 years.60
Based on the results of this RCT, to detect potentially treatable disease, all individuals older than 55 years should have
a dilated fundus examination of both eyes to determine if
they have signs of moderate AMD. Individuals who have extensive intermediate-size drusen, at least 1 large druse or
noncentral geographic atrophy in one or both eyes, should
consider treatment with vitamin A, C, and beta carotene,
plus zinc.
However, patients should be aware that beta-carotene
supplementation has been linked to an increased risk of lung
cancer in patients who smoke.61 Two large chemoprevention trials (Alpha-Tocopherol, Beta Carotene Cancer Prevention Study [ATBC] and Beta-Carotene and Retinal Efficacy Trial [CARET]) found an excess incidence of lung cancer
and overall mortality in patients who smoked and were taking high doses of beta carotene.62,63 The relative increase in
lung cancer incidence was 17% within the first 3 years following study termination in the ATBC trial (absolute risk
increase, 0.00084 lung cancer cases per person-year; number needed to harm to produce 1 case of lung cancer, 1190)
and 12% in the first 6 years following study termination in
the CARET trial (absolute risk increase, 0.0033 lung cancer cases per person-year; number needed to harm, 294).
Given these findings and the fact that zinc alone was found
to have a beneficial effect (although less pronounced) in patients who were at high risk of AMD progression, it seems
prudent not to recommend beta carotene treatment in
smokers.
High doses of vitamin E (ⱖ400 IU/d) in patients with heart
disease or diabetes was associated with a significant increase in the rate of heart failure (RR, 1.13 [95% CI, 1.011.26]; P = .03) in the Heart Outcomes Prevention Evaluation (HOPE) trial. 64 A large meta-analysis of 135 967
participants in 19 clinical trials of vitamin E found that the
pooled all-cause mortality risk difference in high-dose (ⱖ400
IU) vitamin E trials was 39 per 10 000 persons (95% CI, 3-74
per 10 000 persons; P = .035).65 The proven risk reduction
in AMD progression and vision loss derived from taking highdose antioxidants plus zinc needs to be weighed against the
increased risk of heart failure and all-cause mortality associated with high-dose vitamin E.
Laser Treatment. Thermal laser photocoagulation uses
high-intensity thermal laser energy to cause coagulation of
the CNV and localized damage to the overlying retina. It is
©2006 American Medical Association. All rights reserved.
an outpatient procedure that requires only topical anesthetic drops. Several large RCTs found that thermal laser photocoagulation of well-defined extrafoveal CNV associated
with AMD reduced the RR of severe visual loss (loss of ⱖ6
lines of vision or a quadrupling of the visual angle) over 5
years.66-72 Specifically, at 5 years of follow-up, 47% of treated
eyes vs 65% of control (untreated) eyes experienced severe
vision loss. Unfortunately, CNV typically recurs within 2 years
in approximately one half of patients treated. Thermal laser photocoagulation is restricted to use in patients with welldefined CNV, which is present in only 15% of patients who
develop wet AMD. The CNV in Dr G’s right eye was subfoveal at presentation and thus would not have been eligible for thermal laser treatment.
Photodynamic therapy involves intravenous injection of
a photosensitive dye such as verteporfin 5 minutes prior to
application of a cool photoactivating laser.73,74 Animal studies have shown that the wavelength, intensity, and duration of treatment used do not appreciably affect the retina,
but instead activate the verteporfin that is preferentially adsorbed to the CNV.75-77 The activated dye forms reactive free
radicals that damage vascular endothelium, which results
in thrombosis of the damaged vessels. However, with time,
some of these vessels may reopen, requiring retreatment. Photodynamic therapy does not usually restore good vision.
As in Dr G’s case, PDT is indicated for patients who have
a subfoveal CNV. The efficacy of this approach has been demonstrated in placebo-controlled RCTs. In an analysis of 2
such trials including 609 patients, PDT was associated with
a significant benefit in visual acuity at 1-year follow-up compared with placebo.78 Compared with baseline, 246 (61%)
of 402 eyes assigned to receive PDT vs 96 (46%) of 207 eyes
assigned to receive placebo had lost fewer than 15 letters of
visual acuity (doubling of the visual angle or a 3-line loss
of vision on a logMAR visual acuity chart). In subgroup analysis, this benefit was limited to patients with predominantly
classic CNV (well-defined lesions that hyperfluoresce early
and leak late on the fluorescein angiogram). Open-label follow-up of this cohort for up to 3 years found that vision outcomes remained relatively stable and that PDT could be safely
repeated.79
Another trial that extended follow-up to 2 years noted similar benefits of PDT compared with placebo.80 In this study,
however, benefits also extended to CNV that was less than
50% classic or 100% occult. Subgroup analyses of 100% occult lesions with no classic CNV at baseline demonstrated
a greater treatment benefit in cases with either smaller lesions (ⱕ4 disc areas) or lower levels of visual acuity (20/50
or worse) at baseline. Patients received on average 3 treatments in the first year and 5 treatments over 2 years of
follow-up.
Thermal laser treatment directed toward an extrafoveal
choroidal feeder vessel supplying a CNV has been proposed. These studies require specialized high-speed fluorescein and indocyanine green scanning laser angiography
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CLINICAL CROSSROADS
to accurately identify potentially treatable CNV feeder vessels.81 Further results are needed prior to making treatment recommendations.82,83
Pharmacological Treatment. Vascular endothelial growth
factor (VEGF) is a potent endothelial mitogen and vascular permeability factor that plays a pivotal role in neovascularization.28 Antagonists to this important growth factor
may help mitigate the growth and permeability of CNV.84 A
number of VEGF inhibitors have been developed and are
under investigation.85 These agents are typically injected in
the eye every 4 to 6 weeks.
Two concurrent phase 3 trials of the VEGF antagonist pegaptanib have been published.86,87 A total of 1186 patients with
wet AMD were treated with 3 doses of intravitreous pegaptanib or placebo. Overall, patients who received intravitreous pagaptanib injection every 6 weeks lost less than 3 or more
lines of visual acuity vs control patients (70% treated; 55%
controls; P⬍.001). Adverse effects included endophthalmitis (1.3% per year), traumatic cataract (0.7%), and retinal detachment (0.6%).86 Pegaptanib is the first anti-VEGF drug for
the treatment of neovascular AMD approved by the US Food
and Drug Administration (FDA).
Vascular endothelial growth factor antagonists block neovascularization, an end-stage event in the overall pathophysiology of AMD. Anti-VEGF therapy may need to be continued indefinitely to treat recurrent neovascularization. The
long-term complications associated with chronic VEGF inhibition in the eye are unknown.
Surgical Treatment. Two surgical procedures are under
investigation: submacular surgery and macular translocation surgery. Submacular surgery involves the removal of abnormal subretinal neovascularization and, if present, large
submacular hemorrhages. Macular translocation surgery involves surgically detaching the fovea and moving it from a
more diseased area of RPE to a less diseased area.
The Submacular Surgery Trials studied submacular surgery for subfoveal CNV associated with AMD.88 These investigators found that submacular surgery for new subfoveal lesions with less than 50% blood did not improve or
preserve visual acuity for 24 months in more eyes (41%) than
observation (44%) and is not recommended for patients with
wet AMD.89 In addition, submacular surgery for group B lesions (⬎50% blood) did not increase the chance of stable
or improved (ⱖ2 lines of vision) visual acuity (56% in the
surgery group vs 59% in the observation group) and was associated with a high risk of rhegmatogenous retinal detachment (16% in the surgery group vs 2% in the control group).
However, it did reduce the risk of severe visual acuity loss
(loss of ⱖ6 lines of vision) compared with observation (21%
vs 36%, P=.004).90
Macular translocation is a complicated surgical procedure that relocates the fovea on healthier RPE and has the
potential of preserving foveal photoreceptor function. Results from recent case series with macular translocation surgery are encouraging,91-94 but no RCT has been performed.
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These consecutive, noncomparative case series of 15 to 90
patients followed for at least 1 year demonstrated an overall improvement in vision in 0% to 66%, and loss of vision
in 6% to 32% of patients.91,93-96 The most recent of these case
series of 64 patients demonstrated an improvement of median distance vision from 20/125 before surgery to 20/80 at
1 year (P=.03) and median reading speed of 71 to 105 words
per minute (P⬍.001).94 Eleven percent of patients had a
greater than 3-line loss of vision, and 13% of patients ended
up with less than 20/200 vision; both are consistent with
the natural history of wet AMD. The learning curve for acquiring the skills needed to perform this surgery is substantial and has thus limited the number of surgeons who perform it. Due to the complexity and risks associated with this
surgery, 360° macular translocation surgery is only considered in patients whose disease is unresponsive to other treatment or who are ineligible (eg, having large submacular hemorrhages) for nonsurgical treatment.96
None of the currently available AMD treatments, except
perhaps 360° macular translocation, has been shown to improve average visual acuity.
Future Treatment Options for AMD
AMD Prevention. The primary objective of the AREDS II
chemoprevention trial is to evaluate the effect of antioxidants (10 mg/d lutein and 2 mg/d zeaxanthin with or without 1 g/d of omega-3 long-chain polyunsaturated fatty acids) on the progression to advanced AMD. The secondary
objective is to establish the effects of these supplements on
moderate vision loss and to study the effects of eliminating
beta carotene and reducing zinc in the original AREDS formulation (TABLE).
Anecortave acetate is a steroid derivative that has antiangiogenic properties, but lacks glucocorticoid activity.97 This
drug is administered in a peribulbar fashion using a special
cannula and lasts approximately 6 months. Initial studies
of this drug and technique suggest a good safety profile.98
A large preventive clinical trial is currently under way to
evaluate whether peribulbar anecortave acetate can decrease the risk of progression from dry to wet AMD.
Therapeutic apheresis is an extracorporeal blood purification method that is being studied in patients with dry
AMD.99 The proposed mechanism of action of this technique is that removal of high-molecular-weight proteins and
lipids reduces plasma viscosity and enhances endothelial cell
function, which leads to improvement of choriocapillary perfusion. A double-masked RCT (the Multicenter Investigation of Rheopheresis for AMD [MIRA-1]) of double filtration plasmapheresis or rheopheresis in patients with dry AMD
is currently under way and enrolling patients.100 Interim results for 43 patients with 1 year of follow-up revealed a greater
than 3-line improvement in vision (16% vs 0%) and reduced vision loss of 3 or more lines (4% vs 16%) in rheopheresis vs control subjects, respectively.101 Although the initial results look promising, further work is needed to clarify
©2006 American Medical Association. All rights reserved.
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CLINICAL CROSSROADS
the precise benefits and risks associated with this expensive and complicated treatment.102
Finally, drusen have been shown to spontaneously disappear and reappear in up to 30% of patients with dry AMD121
and have been noted to disappear soon after thermal laser
photocoagulation treatment.122 The reasons for the disappearance of drusen are unknown. Investigators have hypothesized that laser-induced regression of high-risk drusen may reduce the risk of developing advanced AMD.
Unfortunately, initial results from the Choroidal Neovascularization Prevention Trial (CNVPT) demonstrated that eyes
receiving prophylactic scatter laser treatment were more likely
to develop neovascularization than were control eyes.103-106
Final results from the CNVPT and the Complications of Agerelated Macular Degeneration Prevention Trials (CAPT)107
are needed to clarify the exact benefits and risks of this procedure.
Laser Treatment. Rostaporfin is a photoactive drug that
is being used with PDT in patients with neovascular AMD
in studies outside the United States. Transpupillary thermotherapy does not appear to provide a significant benefit
to patients with neovascular AMD.
Pharmacological Treatment. Future pharmacological treatments for wet AMD are directed at different sites in the mo-
Table. Completed and Ongoing Trials for Age-Related Macular Degeneration (AMD)
Study and
Related
References
Treatment
Design
Inclusion
Outcome
AMD Prevention Trials
Moderate AMD
Progression to
advanced AMD
AREDS II41
Lutein/zeaxanthin ±
omega-3 fatty acids
RCT
Retaane risk
reduction97,98
Peribulbar anecortave
acetate
RCT
Moderate AMD
Rheopheresis99-102
Blood apheresis
RCT
CNVPT103-106
Laser to drusen
CAPT107
Laser to drusen
Stage
Comments
Enrollment
N = 4000
Progression
Follow-up
N = 2500
Moderate AMD
Progression
Visual acuity
Analysis
N = 180; preliminary
findings nonsignificant
RCT
Moderate AMD
Progression
Analysis
Nonsignificant findings
RCT
Moderate AMD
Progression
Analysis
Nonsignificant findings
Laser Treatment Trials
Photrex108
Rostaporfin PDT
RCT
CNVM
Visual acuity
Recruitment
N = 660; outside United
States
TTT4CNV109,110
Transpupillary thermotherapy
RCT
CNVM
Visual acuity
Analysis
N = 305; nonsignificant
findings
ANCHOR111
Ranibizumab vs verteporphin
PDT
RCT
Predominantly
classic CNVM
Maintained or
improved visual
acuity
Follow-up
N = 423; significant
difference at 1 y
MARINA112
Ranibizumab every mo ⫻ 24
RCT
Minimally
classic/occult
CNVM
Maintained or
improved visual
acuity
Follow-up
N = 716; significant
difference at 1 y
FOCUS113
Verteporphin PDT ±
ranibizumab
RCT
Predominantly
classic CNVM
Maintained or
improved visual
acuity
Follow-up
N = 162; significant
difference at 1 y
SAILOR114
Ranibizumab every mo ⫻ 3
then as needed
RCT
New or previously
treated CNVM
Safety, moderate
visual acuity loss,
time to retreatment
Enrolling
N = 5000
PIER111
Ranibizumab every mo ⫻ 3
then every 3 mo x 6
RCT
Any CNVM
Maintained or
improved visual
acuity
Follow-up
N = 184
siRNA115,116
Cand5
RCT
CNVM
Maintained visual
acuity
Follow-up
N = 120
PEDF117,118
Ad PEDF
Open-label
CNVM
Safety
Complete
N = 20
Retaane119
Anecortave acetate vs PDT
RCT
CNVM
Maintained visual
acuity
Complete
N = 511
Retaane119
Anecortave acetate every
3 mo vs every 6 mo
RCT
CNVM
Maintained visual
acuity
Enrolling
N = 288
Squalamine PK120
Intravenous squalamine
RCT
CNVM
Maintained visual
acuity
Enrolling
N = 40
Pharmacological Treatment Trials
Abbreviations: Ad PEDF, adenoviral pigment epithelium-derived factor; ANCHOR, Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD;
AREDS II, Age-Related Eye Disease Study II; CAPT, Complication of AMD Prevention Trial; CNVM, choroidal neovascular membrane; CNVPT, Choroidal Neovascularization Prevention
Trial; FOCUS, RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety; MARINA, Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab in the
treatment of Neovascular AMD; PDT, photodynamic therapy; PIER, Phase IIIb, Multi-center, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety
of Ranibizumab; RCT, randomized controlled trial; SAILOR, Safety Assessment of Intravitreal Lucentis for AMD; siRNA, small interfering RNA; TTT4CNV, transpupillary thermotherapy
for choroidal neovascularization.
©2006 American Medical Association. All rights reserved.
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CLINICAL CROSSROADS
lecular cascade that drives neovascularization. Most of these
potential drugs target the VEGF pathway: they degrade VEGF
or VEGF receptor messenger RNA using small interfering
RNAs,123 sequester and neutralize VEGF itself,124 block the
VEGF receptor, or block the downstream tyrosine kinase signaling pathways.125
The most promising anti-VEGF drug currently under investigation is ranibizumab. The 2-year Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal
Neovascularization in AMD (ANCHOR),111 Minimally Classic/
occult Trial of the Anti-VEGF Antibody Ranibizumab in the
Treatment of Neovascular AMD (MARINA),112 and RhuFab
V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety (FOCUS)113 trials are investigating the effect of
monthly intravitreous injection of ranibizumab (0.3-mg and
0.5-mg doses) vs verteporphin PDT, alone, or in combination with verteporphin PDT, respectively, for neovascular AMD.
The 1-year results for each of these trials have demonstrated
that ranibizumab maintained or improved visual acuity significantly better than the corresponding control treatment.
The Safety Assessment of Intravitreal Lucentis for AMD
(SAILOR)114 and the Phase IIIb, Multicenter, Randomized,
Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab (PIER)111 trials are investigating the effects of less frequent injection protocols in patients with neovascular AMD.
Although ranibizumab is not FDA-approved or commercially available, it is a fragment of the humanized antibody
bevacizumab, which is FDA-approved for use in the treatment of colorectal cancer.126 Initial reports of off-label intravitreous bevacizumab in patients with neovascular AMD
have been encouraging, but further studies are needed to
better understand the precise risks and benefits associated
with intravitreous injection of this drug.127,128
The mechanisms by which steroids inhibit neovascularization are manifold. They include alterations in extracellular matrix turnover, inhibition of plasminogen activator,
inhibition of inflammation and macrophage activation, and
decreased vascular permeability.97,129,130 A number of steroid compounds are currently being studied in patients with
wet AMD. These include intravitreous or periocular injection of triamcinolone acetonide and implantation of sustained-release steroid implants.131 Intravitreous administration of triamcinolone acetonide is associated with a risk of
moderate to severe increase in intraocular pressure in 15%
of patients and an increased risk of significant cataract progression requiring surgery in 20% of patients.132,133 The risk
of endophthalmitis with intravitreous triamcinolone acetonide injection is estimated to be 0.1%.134 The long-term
ocular sequelae of intravitreous steroids are not precisely
known, thus extended follow-up studies are needed.
The C-01-99 phase 3 clinical trial of anecortave acetate
found that the drug did not meet the primary end point of
noninferiority to verteporfin PDT in the treatment of neovascular AMD.119 Forty-five percent of the patients in the
2402 JAMA, May 24/31, 2006—Vol 295, No. 20 (Reprinted)
anecortave group lost fewer than 3 lines of vision compared with 49% of patients in the PDT group. Other trials
of anecortave acetate using a new injection protocol that minimizes reflux of the drug and using varying injection intervals and doses are under way.
Squalamine is a cationic steroid isolated from the dogfish shark Squalus acanthius that has both antimicrobial and
antiangiogenic properties.120 A phase 3, double-masked RCT
of intravenous injection weekly for 1 month and monthly
for 1 year of squalamine lactate in patients with neovascular AMD is currently under way.131
Combination Treatments. Due to the limited success of
monotherapy for wet AMD, many investigators are turning
to combination treatment targeting various points in the molecular cascade responsible for neovascularization to improve outcomes. For example, PDT with verteporfin is being
studied in combination with the following agents: posterior
subtenons or intravitreous triamcinolone acetonide, intravitreous squalamine lactate, intravitreous pegaptanib sodium, and
intravitreous ranibizumab, and vatalanib (ADVANCE: Study
of Vatalanib and Photodynamic Therapy With Verteporfin in
Patients With Subfoveal Choroidal Neovascularization [CNV]
Secondary to Age-Related Macular Degeneration131).
Radiation Treatment. External beam radiation therapy
has been studied in patients with AMD, but RCTs have not
found a benefit to date.135-137 The safety and efficacy of ocular brachytherapy system (temporary radioactive plaque
placement on the sclera directly behind the macula) is currently under investigation in patients with wet AMD (www
.clinicaltrials.gov).
RECOMMENDATIONS FOR DR G
Dr G has reached a crossroads with regard to his vision. Despite a proven course of treatment with PDT and intravenous verteporphin, as well as experimental adjuvant intravitreous steroids, Dr G has lost central vision in his right
eye and has developed a disciform scar. Since the neovascularization process has reached its final cicatricial stages,
no further treatment is possible in the right eye. Although
his vision is still good in his left eye, the visual disability
caused by his AMD has had a dramatic impact on Dr G’s
ability to work and his quality of life, and consequently has
resulted in a reactive depression.
Given the fact that he has both large soft drusen and pigmentary RPE abnormalities in his good eye and that his fellow eye has a disciform scar, Dr G has a 50% risk of progression to severe AMD in his good eye over the next 5
years.59
I would recommend first that Dr G obtain the best possible refraction for his good eye to maximize his distance
and near vision. He may also want to be seen by a visual
rehabilitation specialist who may provide him with adaptive strategies for overcoming his functional limitations.
Second, Dr G should aim at minimizing the 10% risk per
year that his good eye will progress to advanced AMD. In
©2006 American Medical Association. All rights reserved.
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CLINICAL CROSSROADS
addition to encouraging a diet of fruits and vegetable (high
in antioxidants and zinc), fish (high in omega-3 fatty acids), and nuts, and addressing any cardiovascular risk factors, such as smoking, hypertension, and elevated cholesterol, I would also recommend that he begin taking the
AREDS-recommended antioxidant and zinc formulation on
a daily basis. Based on the results of the AREDS study, we
would expect that his risk of developing advanced AMD
would drop from 10% to 7.5% per year, a 25% risk reduction, by taking these supplements. Dr G and his primary care
physician should consider the proven benefits of these highdose antioxidants and zinc with the small risk associated
with beta carotene in someone with a remote history of smoking and high-dose vitamin E. He should be aware that there
is some evidence that calcium channel blockers may increase the risk of progression to advanced AMD.
Third, Dr G should seriously consider joining one of the
AMD prevention trials listed above. Such a trial intervention may possibly decrease his risk of AMD progression and
would help push forward our understanding of this insidious disease.
Fourth, Dr G should be aware of the early symptoms of
early subretinal CNV such as acute, unilateral loss or distortion of vision. He should test his vision daily using an
Amsler grid and should seek immediate ophthalmologic care
if he develops any of these visual changes in his good eye.
Finally, if Dr G has not already been evaluated for symptoms of his depression, he should be assessed to determine
what treatment is indicated.
DR ARROYO: As mentioned previously, hypertension and
level of hypertension is associated with increasing risk of
AMD.34-38 The association between cholesterol/lipid levels
and AMD has been mixed.36,38,138,139 The relationship between statin use and AMD has also been quite variable, with
the largest studies suggesting no association,140,141 and smaller
studies reporting contradictory findings.54,142 Unfortunately, there are no prospective randomized studies that have
studied the benefit of controlling high blood pressure or cholesterol on the incidence or progression of AMD.
QUESTION: Do you see a role for stem cell transplantation?
DR ARROYO: As you know, the retina is the most accessible part of the brain and is partially immunoprivileged.
Because of these features, the retina will be a particularly
good place to deliver stem cells in patients with retinal degeneration associated with AMD, retinitis pigmentosa, and
retinal detachment. The treatment of ophthalmic disorders
with stem cells is one of the most exciting and promising
areas for future research.
QUESTIONS AND ANSWERS
QUESTION: If you have an illness that is of consequence and
affects 15% of the people over 85 years of age and you’ve
got some evidence that you can slow its progression with
this cocktail that you talked about, isn’t there an argument
that you should give this prophylactically to people with good
vision?
DR ARROYO: The AREDS study found that daily highdose antioxidants and zinc supplements were associated with
a 25% reduction in the risk of progression from moderate AMD
to advanced AMD.59 They did not, however, find a benefit in
patients with less severe AMD. Since high-dose beta carotene and vitamin E have been associated with an increased
risk of lung cancer in smokers and mortality in patients with
heart disease or diabetes, respectively, indiscriminant use is
not advised. I recommend that patients who are older than
50 years of age be examined for evidence of macular degeneration, and that patients with at least moderate AMD should
consider taking daily high-dose antioxidant and zinc supplements as per the AREDS study. Any patient who has a family
history of AMD or has any sign of AMD should be aware of
the risk factors associated with AMD and should be encouraged to modify risks accordingly.
QUESTION: Can you show us the data regarding control
of high blood pressure and cholesterol levels?
REFERENCES
©2006 American Medical Association. All rights reserved.
Financial Disclosures: Dr Arroyo reported serving as a paid consultant for Amgen
and as a clinical investigator for the Submacular Surgery Trials, Eyetech Pharmaceutical Macugen Trials, and the AREDS-2 trial.
Funding/Support: This Clinical Crossroads was made possible in part by a grant
from the Sidney and Esther Rabb Charitable Foundation. Dr Arroyo is a recipient
of an NIH K-23 grant.
Role of the Sponsor: The funding organization did not participate in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Acknowledgment: We thank the patient for sharing his story. We also thank Carole Uminski, Beth Israel Deaconess Medical Center, Boston, Mass, for her assistance with Figure 4.
1. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for agerelated macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123:
1570-1574.
2. Smith W, Assink J, Klein R, et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology. 2001;108:697-704.
3. Grossniklaus HE, Miskala PH, Green WR, et al. Histopathologic and ultrastructural features of surgically excised subfoveal choroidal neovascular lesions: submacular surgery trials report No. 7. Arch Ophthalmol. 2005;123:914-921.
4. Gass JD, Agarwal A, Lavina AM, Tawansy KA. Focal inner retinal hemorrhages
in patients with drusen: an early sign of occult choroidal neovascularization and
chorioretinal anastomosis. Retina. 2003;23:741-751.
5. Friedman E, Krupsky S, Lane AM, et al. Ocular blood flow velocity in agerelated macular degeneration. Ophthalmology. 1995;102:640-646.
6. Friedman E. A hemodynamic model of the pathogenesis of age-related macular degeneration. Am J Ophthalmol. 1997;124:677-682.
7. Grunwald JE, Metelitsina TI, Dupont JC, Ying GS, Maguire MG. Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci. 2005;46:1033-1038.
8. Ciulla TA, Harris A, Kagemann L, et al. Choroidal perfusion perturbations in
non-neovascular age related macular degeneration. Br J Ophthalmol. 2002;86:209213.
9. Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Arch Ophthalmol.
1994;112:402-406.
10. Zarbin MA. Age-related macular degeneration: review of pathogenesis. Eur J
Ophthalmol. 1998;8:199-206.
11. Hogan MJ. Role of the retinal pigment epithelium in macular disease. Trans
Am Acad Ophthalmol Otolaryngol. 1972;76:64-80.
12. Young RW. Pathophysiology of age-related macular degeneration. Surv
Ophthalmol. 1987;31:291-306.
13. Zack DJ, Dean M, Molday RS, et al. What can we learn about age-related
macular degeneration from other retinal diseases? Mol Vis. 1999;5:30.
14. Friedman E, Ivry M, Ebert E, Glynn R, Gragoudas E, Seddon J. Increased scleral
rigidity and age-related macular degeneration. Ophthalmology. 1989;96:104-108.
(Reprinted) JAMA, May 24/31, 2006—Vol 295, No. 20 2403
Downloaded from jama.ama-assn.org at Beth Israel Deaconess Medical Center on June 16, 2011
CLINICAL CROSSROADS
15. Ciulla TA. Evolving pathophysiological paradigms for age related macular
degeneration. Br J Ophthalmol. 2001;85:510-512.
16. Zarbin MA. Current concepts in the pathogenesis of age-related macular
degeneration. Arch Ophthalmol. 2004;122:598-614.
17. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in agerelated macular degeneration. Science. 2005;308:385-389.
18. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;
308:421-424.
19. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.
20. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the
complement regulatory gene factor H (HF1/CFH) predisposes individuals to agerelated macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227-7232.
21. Seddon JM, George S, Rosner B, Rifai N. Progression of age-related macular
degeneration: prospective assessment of C-reactive protein, interleukin 6, and other
cardiovascular biomarkers. Arch Ophthalmol. 2005;123:774-782.
22. Vine AK, Stader J, Branham K, Musch DC, Swaroop A. Biomarkers of cardiovascular disease as risk factors for age-related macular degeneration. Ophthalmology.
2005;112:2076-2080.
23. Yeh DC, Bula DV, Miller JW, Gragoudas ES, Arroyo JG. Expression of leukocyte adhesion molecules in human subfoveal choroidal neovascular membranes
treated with and without photodynamic therapy. Invest Ophthalmol Vis Sci. 2004;
45:2368-2373.
24. Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH. A potential role
for immune complex pathogenesis in drusen formation. Exp Eye Res. 2000;70:441449.
25. Patel N, Ohbayashi M, Nugent AK, et al. Circulating anti-retinal antibodies as
immune markers in age-related macular degeneration. Immunology. 2005;115:422430.
26. Kalayoglu MV, Bula D, Arroyo J, Gragoudas ES, D’Amico D, Miller JW. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. Graefes Arch Clin Exp
Ophthalmol. 2005;243:1080-1090.
27. Folkman J. Endogenous angiogenesis inhibitors. APMIS. 2004;112:496-507.
28. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress.
Endocr Rev. 2004;25:581-611.
29. Klein BE, Klein R, Lee KE, Moore EL, Danforth L. Risk of incident age-related
eye diseases in people with an affected sibling: The Beaver Dam Eye Study. Am J
Epidemiol. 2001;154:207-211.
30. Klein R, Rowland ML, Harris MI. Racial/ethnic differences in age-related maculopathy: Third National Health and Nutrition Examination Survey. Ophthalmology.
1995;102:371-381.
31. Smith W, Mitchell P, Leeder SR. Smoking and age-related maculopathy: The
Blue Mountains Eye Study. Arch Ophthalmol. 1996;114:1518-1523.
32. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA. 1996;276:
1141-1146.
33. 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;276:1147-1151.
34. Age-Related Eye Disease Study Research Group. Risk factors associated with
age-related macular degeneration: a case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology.
2000;107:2224-2232.
35. Klein R, Peto T, Bird A, Vannewkirk MR. The epidemiology of age-related macular degeneration. Am J Ophthalmol. 2004;137:486-495.
36. Klein R, Klein BE, Franke T. The relationship of cardiovascular disease and its
risk factors to age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology.
1993;100:406-414.
37. Klein R, Klein BE, Jensen SC. The relation of cardiovascular disease and its risk
factors to the 5-year incidence of age-related maculopathy: the Beaver Dam Eye
Study. Ophthalmology. 1997;104:1804-1812.
38. van Leeuwen R, Ikram MK, Vingerling JR, Witteman JC, Hofman A, de Jong
PT. Blood pressure, atherosclerosis, and the incidence of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol Vis Sci. 2003;44:3771-3777.
39. Seddon JM, Cote J, Davis N, Rosner B. Progression of age-related macular
degeneration: association with body mass index, waist circumference, and waisthip ratio. Arch Ophthalmol. 2003;121:785-792.
40. van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA. 2005;294:3101-3107.
41. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C,
and E, and advanced age-related macular degeneration. JAMA. 1994;272:1413-1420.
42. Cho E, Seddon JM, Rosner B, Willett WC, Hankinson SE. Prospective study of
intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related
maculopathy. Arch Ophthalmol. 2004;122:883-892.
43. Seddon JM, Rosner B, Sperduto RD, et al. Dietary fat and risk for advanced
age-related macular degeneration. Arch Ophthalmol. 2001;119:1191-1199.
2404 JAMA, May 24/31, 2006—Vol 295, No. 20 (Reprinted)
44. Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch
Ophthalmol. 2003;121:1728-1737.
45. Klein R, Klein BE, Knudtson MD, Wong TY, Shankar A, Tsai MY. Systemic markers of inflammation, endothelial dysfunction, and age-related maculopathy. Am J
Ophthalmol. 2005;140:35-44.
46. Robman L, Mahdi O, McCarty C, et al. Exposure to Chlamydia pneumoniae
infection and progression of age-related macular degeneration. Am J Epidemiol.
2005;161:1013-1019.
47. Miller DM, Espinosa-Heidmann DG, Legra J, et al. The association of prior
cytomegalovirus infection with neovascular age-related macular degeneration. Am
J Ophthalmol. 2004;138:323-328.
48. Kalayoglu MV, Galvan C, Mahdi OS, Byrne GI, Mansour S. Serological association between Chlamydia pneumoniae infection and age-related macular
degeneration. Arch Ophthalmol. 2003;121:478-482.
49. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122:564-572.
50. Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L. Smoking and age-related
macular degeneration: the POLA Study: Pathologies Oculaires Liees a l’Age. Arch
Ophthalmol. 1998;116:1031-1035.
51. Hammond CJ, Webster AR, Snieder H, Bird AC, Gilbert CE, Spector TD. Genetic influence on early age-related maculopathy: a twin study. Ophthalmology.
2002;109:730-736.
52. Christen WG, Glynn RJ, Ajani UA, et al. Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol. 2001;
119:1143-1149.
53. Klein R, Klein BE, Jensen SC, et al. Medication use and the 5-year incidence
of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol.
2001;119:1354-1359.
54. Wilson HL, Schwartz DM, Bhatt HR, McCulloch CE, Duncan JL. Statin and
aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration. Am J Ophthalmol.
2004;137:615-624.
55. Jampol LM. Hypertension and visual outcome in the macular photocoagulation study. Arch Ophthalmol. 1991;109:789-790.
56. 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;115:741-747.
57. Quillen DA. Common causes of vision loss in elderly patients. Am Fam Physician.
1999;60:99-108.
58. Christen WG Jr. Antioxidants and eye disease. Am J Med. 1994;97(3A):14S17S.
59. Age-Related Eye Disease Study Research Group. A randomized, placebocontrolled, clinical trial of high-dose supplementation with vitamins C and E, beta
carotene, and zinc for age-related macular degeneration and vision loss: AREDS
report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
60. Bressler NM, Bressler SB, Congdon NG, et al. Potential public health impact
of Age-Related Eye Disease Study results: AREDS report no. 11. Arch Ophthalmol.
2003;121:1621-1624.
61. Duffield-Lillico AJ, Begg CB. Reflections on the landmark studies of betacarotene supplementation. J Natl Cancer Inst. 2004;96:1729-1731.
62. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The
effect of vitamin E and beta carotene on the incidence of lung cancer and other
cancers in male smokers. N Engl J Med. 1994;330:1029-1035.
63. Goodman GE, Thornquist MD, Balmes J, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality
during 6-year follow-up after stopping beta-carotene and retinol supplements. J
Natl Cancer Inst. 2004;96:1743-1750.
64. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA.
2005;293:1338-1347.
65. Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E.
Meta-analysis: high-dosage vitamin E supplementation may increase all-cause
mortality. Ann Intern Med. 2005;142:37-46.
66. Macular Photocoagulation Study Group. Occult choroidal neovascularization: influence on visual outcome in patients with age-related macular degeneration.
Arch Ophthalmol. 1996;114:400-412.
67. Macular Photocoagulation Study Group. The influence of treatment extent
on the visual acuity of eyes treated with Krypton laser for juxtafoveal choroidal
neovascularization. Arch Ophthalmol. 1995;113:190-194.
68. Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization: five-year results from randomized clinical trials.
Arch Ophthalmol. 1994;112:500-509.
69. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration: updated findings
from two clinical trials. Arch Ophthalmol. 1993;111:1200-1209.
70. Macular Photocoagulation Study Group. Five-year follow-up of fellow eyes
©2006 American Medical Association. All rights reserved.
Downloaded from jama.ama-assn.org at Beth Israel Deaconess Medical Center on June 16, 2011
CLINICAL CROSSROADS
of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol. 1993;111:1189-1199.
71. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: five-year results from randomized clinical trials. Arch
Ophthalmol. 1991;109:1109-1114.
72. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: three-year results from randomized clinical trials. Arch
Ophthalmol. 1986;104:694-701.
73. Schmidt-Erfurth U, Hasan T. Mechanisms of action of photodynamic therapy
with verteporfin for the treatment of age-related macular degeneration. Surv
Ophthalmol. 2000;45:195-214.
74. Woodburn KW, Engelman CJ, Blumenkranz MS. Photodynamic therapy for
choroidal neovascularization: a review. Retina. 2002;22:391-405.
75. Husain D, Miller JW, Michaud N, Connolly E, Flotte TJ, Gragoudas ES. Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy
of experimental choroidal neovascularization. Arch Ophthalmol. 1996;114:978985.
76. Kramer M, Miller JW, Michaud N, et al. Liposomal benzoporphyrin derivative
verteporfin photodynamic therapy: selective treatment of choroidal neovascularization in monkeys. Ophthalmology. 1996;103:427-438.
77. Miller JW, Walsh AW, Kramer M, et al. Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin. Arch
Ophthalmol. 1995;113:810-818.
78. Treatment of Age-related Macular Degeneration With Photodynamic Therapy
(TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results
of 2 randomized clinical trials–TAP report. Arch Ophthalmol. 1999;117:1329-1345.
79. Blumenkranz MS, Bressler NM, Bressler SB, et al. Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: threeyear results of an open-label extension of 2 randomized clinical trials–TAP Report
No. 5. Arch Ophthalmol. 2002;120:1307-1314.
80. Verteprofin in Photodynamic Therapy Study Group. Verteporfin therapy of
subfoveal choroidal neovascularization in age-related macular degeneration: twoyear results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization–verteporfin in photodynamic therapy report 2. Am
J Ophthalmol. 2001;131:541-560.
81. Flower RW. Optimizing treatment of choroidal neovascularization feeder vessels associated with age-related macular degeneration. Am J Ophthalmol. 2002;
134:228-239.
82. Shiraga F, Ojima Y, Matsuo T, Takasu I, Matsuo N. Feeder vessel photocoagulation of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 1998;105:662-669.
83. Desatnik H, Treister G, Alhalel A, Krupsky S, Moisseiev J. ICGA-guided laser
photocoagulation of feeder vessels of choroidal neovascular membranes in agerelated macular degeneration: indocyanine green angiography. Retina. 2000;20:
143-150.
84. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina. 2005;25:111-118.
85. van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA. 2005;293:1509-1513.
86. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:
2805-2816.
87. Eyetech Study Group. Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. Ophthalmology. 2003;110:979-986.
88. Bressler NM, Hawkins BS, Sternberg P Jr, McDonald HR. Are the submacular
surgery trials still relevant in an era of photodynamic therapy? Ophthalmology.
2001;108:435-436.
89. Hawkins BS, Bressler NM, Miskala PH, et al. Surgery for subfoveal choroidal
neovascularization in age-related macular degeneration: ophthalmic findings: SST
report No. 11. Ophthalmology. 2004;111:1967-1980.
90. Bressler NM, Bressler SB, Childs AL, et al. Surgery for hemorrhagic choroidal
neovascular lesions of age-related macular degeneration: ophthalmic findings: SST
report No. 13. Ophthalmology. 2004;111:1993-2006.
91. Pertile G, Claes C. Macular translocation with 360 degree retinotomy for management of age-related macular degeneration with subfoveal choroidal
neovascularization. Am J Ophthalmol. 2002;134:560-565.
92. Lai JC, Lapolice DJ, Stinnett SS, et al. Visual outcomes following macular translocation with 360-degree peripheral retinectomy. Arch Ophthalmol. 2002;120:13171324.
93. Abdel-Meguid A, Lappas A, Hartmann K, et al. One year follow up of macular translocation with 360 degree retinotomy in patients with age related macular
degeneration. Br J Ophthalmol. 2003;87:615-621.
94. Mruthyunjaya P, Stinnett SS, Toth CA. Change in visual function after macular translocation with 360 degrees retinectomy for neovascular age-related macular degeneration. Ophthalmology. 2004;111:1715-1724.
95. Aisenbrey S, Bartz-Schmidt U. Macular translocation with 360-degree reti-
©2006 American Medical Association. All rights reserved.
notomy for management of age-related macular degeneration with subfoveal choroidal neovascularization. Am J Ophthalmol. 2003;135:748-749.
96. Koh SS, Arroyo J. Macular translocation with 360-degree retinotomy for treatment of exudative age-related macular degeneration. Int Ophthalmol Clin. 2004;
44:73-81.
97. Penn JS, Rajaratnam VS, Collier RJ, Clark AF. The effect of an angiostatic steroid on neovascularization in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2001;42:283-290.
98. D’Amico DJ, Goldberg MF, Hudson H, et al. Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular
degeneration: twelve-month clinical outcomes. Ophthalmology. 2003;110:23722383.
99. Bosch T. Therapeutic apheresis-state of the art in the year 2005. Ther Apher
Dial. 2005;9:459-468.
100. Pulido J, Sanders D, Winters JL, Klingel R. Clinical outcomes and mechanism
of action for rheopheresis treatment of age-related macular degeneration (AMD).
J Clin Apher. 2005;20:185-194.
101. Pulido JS. Multicenter prospective, randomized, double-masked, placebocontrolled study of Rheopheresis to treat nonexudative age-related macular degeneration: interim analysis. Trans Am Ophthalmol Soc. 2002;100:85-106.
102. Pulido JS, Winters J. Rheopheresis for macular degeneration: the data is not
there yet to justify it. J Clin Apher. 2005;20:168.
103. Hsu J, Maguire MG, Fine SL. Laser prophylaxis for age-related macular
degeneration. Can J Ophthalmol. 2005;40:320-331.
104. Choroidal Neovascularization Prevention Trial Research Group. Laser treatment in fellow eyes with large drusen: updated findings from a pilot randomized
clinical trial. Ophthalmology. 2003;110:971-978.
105. Choroidal Neovascularization Prevention Trial Research Group. Choroidal neovascularization in the Choroidal Neovascularization Prevention Trial. Ophthalmology.
1998;105:1364-1372.
106. 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.
107. Complications of Age-Related Macular Degeneration Prevention Trial Study
Group. The Complications of Age-Related Macular Degeneration Prevention Trial
(CAPT): rationale, design and methodology. Clin Trials. 2004;1:91-107.
108. Rostaporfin: PhotoPoint SnET2, Purlytin, Sn(IV) etiopurpurin, SnET2, tin ethyl
etiopurpurin. Drugs R D. 2004;5:58-61.
109. Mainster MA, Reichel E. Transpupillary thermotherapy for age-related macular degeneration: principles and techniques. Semin Ophthalmol. 2001;16:55-59.
110. Reichel E. Results from the TTT4CNV Clinical Trial. Paper presented at: Macula
Society meeting; February 24-26, 2005; Key Biscayne, Fla.
111. Preliminary data from phase III trial show Lucentis is the first investigational
therapy to demonstrate clinical benefit over Visudyne. Foundation Fighting Blindness Web site. http://www.blindness.org/press/pressDetails.asp?ID=137. Accessibility verified May 4, 2006.
112. Ho A. Ranibizumab for age-related macular degeneration: 1-year subanalysis results of the MARINA study. Paper presented at: Macula Society 29th Annual
Meeting; February 22-25, 2006; North San Diego, Calif.
113. Heier JS; Focus Study Group. Intravitreal ranibizumab with verteporfin photodynamic therapy for neovascular age-related macular degeneration: year 1 results. In: Program and abstracts of the American Society of Retina Specialists 23rd
Annual Meeting; July 16-20, 2005; Montreal, Quebec.
114. Ranibizumab in naı̈ve and previously treated subjects with CNV secondary
to AMD. ClinicalTrials.gov Web site. http://www.clinicaltrials.gov/ct/show
/NCT00299078. Accessibility verified May 4, 2006.
115. Tolentino MJ, Brucker AJ, Fosnot J, et al. Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina. 2004;
24:132-138.
116. Barik S. Development of gene-specific double-stranded RNA drugs. Ann Med.
2004;36:540-551.
117. Auricchio A, Behling KC, Maguire AM, et al. Inhibition of retinal neovascularization by intraocular viral-mediated delivery of anti-angiogenic agents. Mol Ther.
2002;6:490-494.
118. Reich SJ, Bennett J. Gene therapy for ocular neovascularization: a cure in
sight. Curr Opin Genet Dev. 2003;13:317-322.
119. Regillo C. Results from the C-01-99 phase III clinical trial of anecortave acetate.
Paper presented at: American Academy of Ophthalmology meeting; October 2326, 2004; New Orleans, La.
120. Brunel JM, Salmi C, Loncle C, Vidal N, Letourneux Y. Squalamine: a polyvalent drug of the future? Curr Cancer Drug Targets. 2005;5:267-272.
121. Bressler NM, Munoz B, Maguire MG, et al. Five-year incidence and disappearance of drusen and retinal pigment epithelial abnormalities: Waterman study.
Arch Ophthalmol. 1995;113:301-308.
122. Abdelsalam A, Del Priore L, Zarbin MA. Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced
regression. Surv Ophthalmol. 1999;44:1-29.
(Reprinted) JAMA, May 24/31, 2006—Vol 295, No. 20 2405
Downloaded from jama.ama-assn.org at Beth Israel Deaconess Medical Center on June 16, 2011
CLINICAL CROSSROADS
123. Campochiaro PA. Potential applications for RNAi to probe pathogenesis and
develop new treatments for ocular disorders. Gene Ther. 2006;13:559-562.
124. Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP. Age-related macular
degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol.
2003;48:257-293.
125. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors.
Nat Med. 2003;9:669-676.
126. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized antiVEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun.
2005;333:328-335.
127. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography
findings after an intravitreous injection of bevacizumab (avastin) for neovascular
age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36:331335.
128. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study.
Ophthalmology. 2005;112:1035-1047.
129. Ciulla TA, Walker JD, Fong DS, Criswell MH. Corticosteroids in posterior segment disease: an update on new delivery systems and new indications. Curr Opin
Ophthalmol. 2004;15:211-220.
130. Ingber DE, Madri JA, Folkman J. A possible mechanism for inhibition of angiogenesis by angiostatic steroids: induction of capillary basement membrane
dissolution. Endocrinology. 1986;119:1768-1775.
131. List of macular degeneration trials. ClinicalTrials.gov Web site. http://www
.clinicaltrials.gov/ct/search;jsessionid=A599CA0D51D26639ABD34A40F00574D1
?term=macular+degeneration. Accessibility verified May 2, 2006.
132. Gillies MC, Simpson JM, Billson FA, et al. Safety of an intravitreous injection
of triamcinolone: results from a randomized clinical trial. Arch Ophthalmol. 2004;
122:336-340.
133. Smithen LM, Ober MD, Maranan L, Spaide RF. Intravitreal triamcinolone acetonide and intraocular pressure. Am J Ophthalmol. 2004;138:740-743.
134. Westfall AC, Osborn A, Kuhl D, Benz MS, Mieler WF, Holz ER. Acute endophthalmitis incidence: intravitreous triamcinolone. Arch Ophthalmol. 2005;123:
1075-1077.
135. Char DH, Irvine AI, Posner MD, Quivey J, Phillips TL, Kroll S. Randomized
trial of radiation for age-related macular degeneration. Am J Ophthalmol. 1999;
127:574-578.
136. Ciulla TA, Danis RP, Klein SB, et al. Proton therapy for exudative agerelated macular degeneration: a randomized, sham-controlled clinical trial. Am J
Ophthalmol. 2002;134:905-906.
137. Bergink GJ, Hoyng CB, van der Maazen RW, Vingerling JR, van Daal WA,
Deutman AF. A randomized controlled clinical trial on 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;
236:321-325.
138. Tomany SC, Wang JJ, Van Leeuwen R, et al. Risk factors for incident agerelated macular degeneration: pooled findings from 3 continents. Ophthalmology.
2004;111:1280-1287.
139. Paunksnis A, Cimbalas A, Cerniauskiene LR, et al. Early age-related maculopathy and risk factors of cardiovascular disease in middle-aged Lithuanian urban population. Eur J Ophthalmol. 2005;15:255-262.
140. Klein R, Klein BE, Tomany SC, Danforth LG, Cruickshanks KJ. Relation of statin
use to the 5-year incidence and progression of age-related maculopathy. Arch
Ophthalmol. 2003;121:1151-1155.
141. Smeeth L, Cook C, Chakravarthy U, Hubbard R, Fletcher AE. A case control
study of age related macular degeneration and use of statins. Br J Ophthalmol.
2005;89:1171-1175.
142. McGwin G Jr, Owsley C, Curcio CA, Crain RJ. The association between statin
use and age related maculopathy. Br J Ophthalmol. 2003;87:1121-1125.
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