Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program 

Nutritional Supplements 

for Age-related 

Macular Degeneration:

A Systematic Review

Department of Veterans Affairs

Health Services Research & Development Service

January 2012

Investigators:

Principal Investigator: 

Devan Kansagara, MD, MCR

Co-Investigators: 

Ken Gleitsmann, MD, MPH

Melanie Gillingham, PhD, RD

Michele Freeman, MPH

Ana Quiñones, PhD

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Portland VA Medical Center

Portland, OR

Devan Kansagara, MD, MCR, Director
ii

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

PREFACE

Health Services Research & Development Service’s (HSR&D’s) Evidence-based Synthesis 

Program (ESP) was established to provide timely and accurate syntheses of targeted healthcare 

topics of particular importance to Veterans Affairs (VA) managers and policymakers, as they 

work to improve the health and healthcare of Veterans. The ESP disseminates these reports 

throughout VA.

HSR&D provides funding for four ESP Centers and each Center has an active VA affiliation. The 

ESP Centers generate evidence syntheses on important clinical practice topics, and these reports 

help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient outcomes 

and to support VA clinical practice guidelines and performance measures, and 

• set the direction for future research to address gaps in clinical knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of HSR&D Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of HSR&D field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: Kansagara D, Gleitsmann K, Gillingham M, Freeman M, Quiñones A. 

Nutritional Supplements for Age-related Macular Degeneration: A Systematic Review. VA-ESP 

Project #05-225; 2011

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the Portland VA Medical Center, Portland OR funded by the 

Department of Veterans Affairs, Veterans Health Administration, Office of Research 

and Development, Health Services Research and Development. The findings and 

conclusions in this document are those of the author(s) who are responsible for its 

contents; the findings and conclusions do not necessarily represent the views of the 

Department of Veterans Affairs or the United States government. Therefore, no statement 

in this article should be construed as an official position of the Department of Veterans 

Affairs. No investigators have any affiliations or financial involvement (e.g., employment, 

consultancies, honoraria, stock ownership or options, expert testimony, grants or patents 

received or pending, or royalties) that conflict with material presented in the report.
iii

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

TABLE OF CONTENTS

EXECUTIVE SUMMARY

Background.................................................................................................................................................... 1

Methods......................................................................................................................................................... 1

Results ........................................................................................................................................................... 1

Discussion...................................................................................................................................................... 3

Conclusion..................................................................................................................................................... 3

Executive Summary Table............................................................................................................................. 4

INTRODUCTION............................................................................................................................................... 6

METHODS

Topic Development........................................................................................................................................ 8

Search Strategy.............................................................................................................................................. 9

Study Selection.............................................................................................................................................. 9

Data Abstraction .......................................................................................................................................... 10

Study Quality............................................................................................................................................... 10

Rating the Body of Evidence....................................................................................................................... 11

Data Synthesis............................................................................................................................................. 11

Peer Review................................................................................................................................................. 11

RESULTS

Literature Flow ............................................................................................................................................ 12

Key Question #1. In patients with age-related macular degeneration, do nutritional supplements

containing carotenoids, antioxidants, or omega-3 fatty acids alone or in combination prevent 

functional visual loss? ................................................................................................................................. 13

Key Question #2. In adult populations, what are the harms of carotenoid, antioxidant, and 

omega-3 fatty acid supplementation?.......................................................................................................... 18

DISCUSSION...................................................................................................................................................... 24

Future Studies.............................................................................................................................................. 25

Conclusions ................................................................................................................................................. 26

REFERENCES ................................................................................................................................................... 29

TABLES

Table 1. Characteristics and findings of controlled trials of nutritional supplements 

for age-related macular degeneration......................................................................................... 15

Table 2. Summary of the evidence on the effects of nutritional supplements for 

age-related macular degeneration .............................................................................................. 27

FIGURES

Figure 1. Analytic Framework .................................................................................................................... 9

Figure 2. Literature Flow........................................................................................................................... 12
iv

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

APPENDIX A. Search Strategy ............................................................................................................. 33

APPENDIX B. Inclusion/Exclusion Criteria ................................................................................... 38

APPENDIX C. Assessment of Methodologic Quality and Risk of Bias in Randomized

Controlled Trials of Oral Supplements for Age-related Macular

Degeneration .................................................................................................................... 39

APPENDIX D. Peer Review Comments and Responses.................................................................. 40
6

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

EVIDENCE REPORT

INTRODUCTION

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the 

developed world. In 2004, AMD affected 1.75 million persons in the United States, a number 

which is expected to rise to nearly 3 million by 2020 due to the aging of the population.1 AMD 

is characterized by the appearance of involutional changes (e.g. drusen) in the structure of the 

central retinal pigment epithelium (RPE) leading to the loss of normal central (macular) vision. 

AMD can be categorized as dry (non-exudative) or wet (exudative). Dry AMD represents the 

great majority of AMD patients (90%) and may lead to slow visual loss over many decades, 

with the most severe cases developing geographic atrophy and profound loss of central vision. 

Dry AMD can progress to wet AMD with the development of neovascularization beneath the 

diseased RPE leading to hemorrhage, scarring, and the devastating loss of macular vision over 

a period of months. 

By convention, there are four categories which describe the severity of macular degeneration. 

Category 1 are those patients essentially free of age-related macular abnormalities, with a 

total drusen area less than five small drusen (63 μm), and visual acuity of 20/32 or better in 

both eyes. Category 2 patients have mild or borderline, age-related macular features (multiple 

small drusen, single or nonextensive intermediate drusen (63-124 μm), pigment abnormalities, 

or any combination of these) in one or both eyes, and visual acuity of 20/32 or better in both 

eyes. Category 3 patients require the absence of advanced AMD in both eyes and at least one 

eye with visual acuity of 20/32 or better with at least one large drusen (125 μm), extensive 

(as measured by drusen area) intermediate drusen, or geographic atrophy (GA) that does not 

involve the center of the macula, or any combination of these. Category 4 patients have visual 

acuity of 20/32 or better and no advanced AMD in one eye, with the fellow eye having either 

lesions of advanced AMD, or visual acuity less than 20/32 with AMD abnormalities sufficient 

to explain reduced visual acuity as determined by examination of photographs. “Advanced 

AMD” is defined as having GA involving the center of the macula or features of choroidal 

neovascularization. 

Multiple prospective cohort studies including the Beaver Dam Eye Study, the Blue Mountains 

Eye Study, and the Carotenoids and Age-related Eye Disease Study (CAREDS), have found 

diets higher in zinc, vitamin C, vitamin E and carotenoids are associated with a lower 

risk of AMD progression.2-7 These observational studies, although limited by unmeasured 

confounding and potential recall bias, provided the rationale for controlled trials evaluating the 

efficacy of nutritional supplements in reducing the progression of AMD. 

Our report focuses on the evidence documenting the potential benefits and harms of certain 

dietary supplements in patients with AMD. Recommendations to the Department of Veterans 

Affairs with regard to these supplements will have important implications to that patient 

population as well as to older U.S. adults. We conducted a systematic review of published 

literature to address the following key questions:
7

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

1) In patients with age-related macular degeneration, do nutritional supplements containing 

carotenoids, antioxidants, or omega-3 fatty acids alone or in combination prevent 

functional visual loss?

2) In adult populations, what are the harms of carotenoid, antioxidant, and omega-3 fatty 

acid supplementation?
8

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

METHODS

TOPIC DEVELOPMENT

The review was commissioned by the Department of Veterans Affairs’ Evidence-based Synthesis 

Program. We conferred with VA and non-VA experts to select the patients and subgroups, 

interventions, outcomes, and setting addressed in the review. We addressed the following key 

questions in our review of the literature:

1) In patients with age-related macular degeneration, do nutritional supplements containing 

carotenoids, antioxidants, or omega-3 fatty acids alone or in combination prevent 

functional visual loss?

2) In adult populations, what are the harms of carotenoid, antioxidant, and omega-3 fatty 

acid supplementation?

The criteria for patient population, treatment and comparator interventions, outcomes of interest, 

and patient care setting are outlined below: 

Patients: Adults with nonexudative age-related macular degeneration

Interventions: Carotenoids – zeaxanthin, lutein, beta-carotene

Antioxidants – zinc, vitamin E, vitamin C

Omega-3 fatty acids – alpha linolenic acid (C18:3n-3), docosahexaenoic acid 

(DHA; C22:6n-3), eicosapentaenoic acid (EPA; C20:5n-3)

Comparators: Placebo

Outcomes: Vision loss, defined as visual impairment in the best eye as follows: 

≤ 20/60 by Snellen acuity; or ≤ 6/18 metric acuity; or doubling of the visual angle 

(e.g. 20/50 to 20/100); or ≥ three lines of loss; or ≥ 15 letters lost (ETDRS chart); or, 

progression to advanced disease (either central geographic atrophy or wet macular 

degeneration). Note: A 3-line change in visual acuity (i.e. +/-15 letters) using the ETDRS 

chart is equivalent to a doubling of the visual angle.

Other outcomes: quality of life and functional status

Setting: Outpatient

Figure 1 illustrates the analytic framework that guided our review and synthesis.
9

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Figure 1. Analytic Framework 

Adult with non-exudative 

age-related macular 

degeneration

Treatment interventions:

A. Carotenoids: zeaxanthin, lutein, beta-carotene

B. Antioxidants: zinc, vitamin E, vitamin C

C. Omega-3 fatty acids: alpha linolenic acid (C18:3n-3), 

docosahexaenoic acid (DHA; C22:6n-3), 

eicosapentaenoic acid (EPA; C20:5n-3)

Adverse effects of 

treatment, not limited 

to AMD population

Outcomes:

• Vision loss: visual impairment in 

the best eye of >=20/60 Snellen; 

or >=3 lines or 15 letters loss; or 

progression to advanced AMD

• Quality of life

• Functional status

SEARCH STRATEGY

We conducted a search in Medline® Embase, Scopus, Conference Papers Index, and the 

Cochrane Library (Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews 

of Effects; Cochrane Central Register of Controlled Trials) from 1947 or database inception 

through February 2011. Appendix A provides the search strategy in detail. We obtained additional 

articles from systematic reviews, reference lists of pertinent studies, reviews, editorials, and by 

consulting experts. All citations were imported into an electronic database (EndNote X1).

STUDY SELECTION

Four reviewers assessed for relevance the abstracts of citations identified from literature 

searches. Full-text articles of potentially relevant abstracts were retrieved for further review. 

Each article retrieved was independently reviewed by two authors using the eligibility criteria 

shown in Appendix B. 
10

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Eligible articles had English-language abstracts and provided primary data relevant to the key 

questions. Eligibility criteria varied depending on the question of interest, as described below.

To evaluate the efficacy of oral supplements, we considered prospective, controlled clinical 

trials comparing the effects of carotenoids, antioxidants, or omega-3 fatty acids (alone or in 

combination) with usual care or placebo on clinically significant vision loss, quality of life, or 

functional status among adults with age-related macular degeneration. We defined clinically 

important vision loss as any one of the following based on input from our Technical Expert 

Panel: ≤20/60 by Snellen acuity; or ≤6/18 metric acuity; or doubling of the visual angle (e.g. 

20/50 to 20/100); or ≥ three lines of loss; or ≥15 letters lost; or progression to advanced disease 

(either central geographic atrophy or wet macular degeneration). We did not limit RCTs by 

sample size or duration of treatment. 

We used a similar approach to evaluate the adverse effects of these oral supplements, but we 

also included studies of adults without AMD because the potential harms of oral supplements 

are not specific to those with AMD. Since nutritional supplements for AMD are intended for use 

over long periods of time and because clinically important harms not detected by AMD studies 

are unlikely to be evident in very small studies, we included only those studies with at least 24 

weeks of follow-up and a sample size of 100 or more subjects (Appendix B).

DATA ABSTRACTION

From each study, we abstracted the following: study setting; number of subjects; population 

characteristics (including sex, age, race/ethnicity); treatment type, dosage and duration; type 

of control used; visual outcome results; proportion of subjects who progressed to severe AMD; 

quality of life and functional outcome results; adverse effects or treatments; and funding source. 

STUDY QUALITY

Two reviewers independently assessed the quality of each AMD trial using a tool developed 

by the Cochrane Collaboration (Appendix C).8 This tool asks the following questions about the 

methodologic characteristics of each study to guide assessment of the risk of bias:

• Was the allocation sequence adequately generated?

• Was allocation adequately concealed?

• Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated 

intervention adequately prevented during the study?

• Were incomplete outcome data adequately addressed?

• Are reports of the study free of suggestion of selective outcome reporting?

• Was the study apparently free of other problems that could put it at a high risk of bias? (We 

assessed whether or not there were extreme baseline differences between groups.)

Disagreements were resolved through discussion. Each study was then given an overall summary 

assessment of low, high, or unclear risk of bias. The risk of bias within a given study can vary 

according to outcome. For instance, the risk of bias associated with lack of blinding might be low 

for mortality outcomes, but high for more subjective outcomes such as quality of life or symptom 

scores. 
11

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

RATING THE BODY OF EVIDENCE

We assessed the overall body of evidence for each outcome by considering the consistency, 

coherence, and applicability across studies, as well as the internal validity of individual studies, 

using a method developed by the Grades of Recommendation, Assessment, Development, and 

Evaluation (GRADE) Working Group.9

DATA SYNTHESIS

We critically analyzed the strength of the evidence regarding both efficacy and adverse treatment 

effects, and compiled a qualitative synthesis of findings. We could not conduct a quantitative 

synthesis because the outcome measures, treatments, and populations differed substantially 

across trials. 

PEER REVIEW

A draft version of this report was sent to the Technical Expert Panel and additional peer 

reviewers. We revised the report based on peer review feedback (Appendix D).
12

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

RESULTS

LITERATURE FLOW

We reviewed 4,335 titles and abstracts from the electronic search, and identified 22 additional 

references through manual searching of reference lists or from input from technical advisors. 

After applying inclusion/exclusion criteria at the abstract level, 347 full-text articles were 

reviewed, as shown in Figure 2. Of the full-text articles, we rejected 308 that did not meet our 

inclusion criteria.

Figure 2. Literature Flow

4,768 Citations initially identified from 

electronic database searches 

• 4,037 from MEDLINE®

• 254 from EMBASE

• 26 from the Cochrane Library

• 382 from Scopus

• 69 from Conference Papers Index

4,010 Citations excluded due to lack of 

relevance in title or abstract

433 Duplicate citations excluded

4,357 Potentially relevant citations 

identified for further review

4,335 Citations resulting 

from electronic searches

308 Articles excluded

Non-English language = 2

Studied outcomes not in scope = 35

Study design or article type out of scope = 80

Trial of supplements but does not supply data about 

adverse effects = 67

Duplicate publication of a single study = 15

Used for contextual purposes only = 127

Note: Multiple exclusion codes may apply

347 Potentially relevant articles identified for further review

Key Question 1: 7 RCTs of nutritional supplements 

(carotenoids, antioxidants, or omega-3 fatty acids) to 

prevent functional visual loss in AMD patients

Key Question 2: 7 systematic reviews and 26 RCTs 

reported adverse effects of carotenoids, antioxidants, 

and omega-3 fatty acid supplementation in adults with 

or without AMD

39 articles addressing benefits or harms

22 Citations identified from manual searches, 

reference lists, or suggested by experts
13

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

KEY QUESTION #1. In patients with age-related macular degeneration, 

do nutritional supplements containing carotenoids, antioxidants, or 

omega-3 fatty acids alone or in combination prevent functional visual 

loss?

Summary of findings 

We identified seven randomized controlled trials (RCTs) of nutritional supplements in AMD 

patients. A significant effect in preventing functional loss was found only in the two largest 

trials.10, 11 The weight of evidence was dominated by the Age Related Eye Disease Study 

(AREDS)10 in terms of sample size (N=3640) and duration of follow-up (seven years). The 

sample sizes in the other six studies ranged from 60 to 164 subjects, with follow-up ranging 

from 6 to 24 months. Given that progression of AMD occurs slowly and with low frequency, the 

smaller studies might have been of insufficient duration or power to detect a treatment effect. 

In the AREDS study, a beneficial effect was only observed among subjects with Categories 3 and 

4 AMD, while no significant change was reported in mild AMD subjects (Category 1 or 2) in any 

of the three treatment arms compared with placebo. The protective effect of greatest magnitude 

among all of the supplement treatment arms was noted in the zinc plus antioxidant group 

OR=0.63 (99% CI; 0.44-0.92).

Detailed findings 

Table 1 shows the detailed characteristics and findings of included studies. 

Carotenoids

One randomized trial reported the effects of a supplemental carotenoid, lutein (10 mg/d), among 

subjects with AMD.12 Subjects were randomized to lutein alone (N=29), lutein + antioxidants 

(OcuPower®; N=30) or placebo (N=31) for 12 months. The authors report very small increases 

in visual acuity in the lutein and lutein + antioxidants groups, but these changes were not 

clinically significant (<15 letters) after a one-year follow-up. 

Antioxidants

Six RCTs evaluated the effects of antioxidant supplements in patients with Categories 2 to 4 

AMD.10-15 Three of these examined a mixture of antioxidant nutrients, including vitamin C, 

vitamin E, and some carotenoids such as beta carotene or quercetin. The remaining three studies 

used zinc alone in the form of zinc sulfate (200 mg/d),11, 13 or as zinc monocysteine (50 mg/d).14

By far, the largest study was the multicenter AREDS trial which randomized 3,640 patients 

with Categories 2, 3 and 4 AMD into four treatment groups: antioxidants with carotenoids, 

zinc alone, antioxidants with carotenoids + zinc, or placebo.10 The primary outcome was 

progression to advanced AMD (central geographic atrophy or choroidal neovascularization) 

and at least moderate functional visual loss, defined as the loss of ≥15 letters on the ETDRS 

logMAR chart. A secondary visual outcome was a decrease in the best corrected visual acuity 

score from baseline of 30 or more letters in a study eye (six lines or a quadrupling of the initial 

visual angle) and progression of disease to a visual acuity score worse than 20/100 in one or 

both eyes. Overall, in analyses limited to only those with Category 3 or 4 AMD, a reduction in 

functional visual loss was noted with either supplement alone or in combination.10 Specifically, 
14

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

after five years of follow-up, the zinc/antioxidant combination significantly decreased the degree 

of functional vision loss (OR 0.63; 99% CI 0.44-0.92). A similar but smaller effect was noted 

with either supplement alone (zinc alone OR 0.75; 99% CI 0.53-1.07; antioxidants alone OR 

0.79; 99% CI 0.55-1.13). On the other hand, antioxidants were not associated with benefit in 

the large subgroup of patients with Category 2 AMD (N = 1063) over seven years of followup. Of note, there was a very low rate of progression from Category 2 AMD to more advanced 

disease. Of patients with Category 2 AMD at baseline, 13 progressed to advanced AMD and 316 

progressed to Category 3 or 4 AMD during the study. No significant differences in demographics, 

socioeconomic status, smoking status, or comorbidities were noted between the Category 2, 3 or 

4 participants. 

One additional trial found benefit from supplement use.11 In this small trial, 174 patients with 

Category 3 or 4 AMD were randomized to either zinc sulfate supplements (200 mg/day) or 

placebo. Seventy-one subjects in the placebo and 80 subjects in the zinc group completed the 

two-year follow-up. Most patients had Category 3 or 4 AMD at baseline, and half the participants 

had baseline evidence of geographic atrophy. The placebo group was twice as likely as the zincsupplemented group to demonstrate clinically significant vision loss (15.5% vs. 7.5%).

The other four studies were small (N = 56 or less), of relatively short duration (6 to 24 months), 

and did not report a clinically significant reduction in visual loss from supplement use.12-15 Two 

of these trials were conducted in VA settings. One of the VA trials found the combination of 

lutein + antioxidants improved visual acuity, but not to a clinically significant degree.12 Another 

small, multicenter VA trial evaluated the effects of a tablet containing a number of antioxidants 

and, similarly, found non-clinically significant improvement in visual acuity.15 One small, nonVA trial of zinc supplementation found intervention patients had better visual acuity compared 

to the placebo group, but the difference was <15 letters on the ETDRS chart.14 One other small 

single center trial found no difference in visual acuity between zinc supplement and placebo 

groups.13

Omega-3 fatty acids

One study examined the effects of supplemental omega-3 fatty acids, L-carnitine and coenzyme 

Q10 among subjects with AMD.16 Most (93.6%) subjects in this study had “early” AMD at 

baseline; only 6.4 percent had Category 3 or 4 AMD. The study randomized subjects to omega-3 

fatty acid supplement (N=52), or placebo (N=55). The change in visual acuity was measured 

after 12 months of supplementation. The report noted that omega-3 fatty acids slowed visual 

acuity loss, but not to a clinically significant degree (0.5 line change in Snellen acuity). 
15

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

ngs of controlled trials of nutritional supplements for age-related macular degeneration

Baseline visual acuity;

% of population with Category

3 or 4 AMD at baseline

Treatment arms (daily dosage 

unless otherwise specified);

N of subjects;

duration of treatment Visual acuity outcomes

Progression to 

severe AMD,

% of subjects

Assessed

risk of 

bias

Mean logMAR by treatment group: Lutein alone: R0.359 L0.279Placebo: R0.445 L0.286 

Lutein alone (10 mg nonesterified), N=29Lutein plus antioxidants (OcuPower®), N=30Placebo, N=3112 months

Lutein alone: +5.4 Snellen (95% CI 2.7-9.0) p-value=0.01/Placebo: -2.1 Snellen (95% CI -6.7-2.4) p-value not reportedEffect size < 15 letters (i.e. not statistically nor clinically significant, p-values not reported)

NR Low

with carotenoids, or other supplements

All eligible pts had signif AMD in one eye but the best eye had at least 20/32 vision; visual acuity was assessed by ETDRS chart. Younger pts 55-59 yrs were eligible only if they had Cat 3 or 4 AMD. Ocular media had to be clear and no other lesions as confounders present.29% of subjects had Cat 240.2% had Cat 322.4% had Cat 4

Antioxidants alone (vit C, 500mg; vit E, 400 IU; beta carotene, 15mg), N=945Antioxidants plus zinc, N=888Placebo, N=9038 years

(Reported only for Cat 3 & 4 at 5 years) Note: This data is reported as probability (or absolute event rate) of visual loss at 5 years; p-values are presented here for equivalent odds ratios reported in Table 5 of this AREDS report.

Visual loss from 20/32 to <20/50 vision per ETDRS 

(a decrease in BVA from baseline of >=15 letters): Antioxidants alone: 26% p-value=0.07Antioxidants plus zinc: 23% p-value=0.008Placebo: 29% p-value not reported

Marked Visual Loss from 20/32 to 20/100 in one 

eye (p-values not reported; rather odds ratios with 99% CI were reported): Antioxidants alone: 14% (OR, 0.80; 99% CI, 0.55-1.16)Antioxidants plus zinc: 12% (OR, 0.68; 99% CI, 0.46-1.01)Placebo: 17% (p-values not reported)

Subjects with Cat 3 & 4 who develop advanced AMD at 5 years:Antioxidants alone: 23%Antioxidants plus zinc: 20%Placebo: 28%Outcomes in Cat 2 subjects, treatment group NR: 15/1063 (1.4%) progressed to advanced AMD over 5 years; 316 (29.7%) advanced to Cat 3 or 4; no effect of treatment observed

Low

Placebo: R eye logMAR 0.24 +/-0.03; L eye 0.24 +/- 0.03; Ocuguard: R eye 0.27 +/- 0.04; L eye 0.19 +/- 0.03

Ocuguard (20000 IU beta-carotene; 200 IU vit E; 750 mg vit C; 50 mg quercetin; 12.5 zinc; 50 ug selenium; 100 mg taurine; 25 mg vit B12; 100 ug chromium), N=39Placebo, N=32

Placebo: -4 Snellen R eye; -15 Snellen L eyeAntioxidant: -5 Snellen R eye; no change L eyeEffect size <3 linesp-values not reported

NR Low
16

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

Baseline visual acuity;

% of population with Category

3 or 4 AMD at baseline

Treatment arms (daily dosage 

unless otherwise specified);

N of subjects;

duration of treatment Visual acuity outcomes

Progression to 

severe AMD,

% of subjects

Assessed

risk of 

bias

Mean logMAR by treatment group: Lutein plus antioxidants: R0.324 L0.303Placebo: R0.445 L0.286 

Lutein (10 mg non-esterified) plus antioxidants (2500 IU vit A; 15,000 beta carotene; 1500 mg vit C; 400 IU vit D; 500 IU vit E; 50 mg vit B1; 10 mg vit B2; 70 mg vit B3; 50 mg vit B5; 50 mg vit B6; 500 ug B12; 800 ug folic acid 200 ug biotin; 500 mg ca++; 300 mg Mg; 75 ug Iodine; 25 mg zinc; 1 mg Cu; 2 mg Mn; 200 ug Se; 200 ug Cr; 75 ug Mb; 600 mg lycopene; 150 mg lipoic acid), N=30Placebo, N=3112 months

Lutein plus antioxidants: +3.5 Snellen (95% CI 0.8-6.1) Placebo: -2.1 Snellen (95% CI -6.7-2.4)effect size < 3 linesp-values not reported

NR Low

See AREDS, 2001 under Antioxidants

Zinc alone (80 mg as zinc oxide and 2 mg copper as cupric oxide), N= 904Placebo, N=903 8 years

(Reported only for Cat 3 & 4 at 5 years)Note: This data is reported as probability (or absolute event rate) of visual loss at 5 years; p-values are presented here for equivalent odds ratios reported in Table 5 of this AREDS report.

Visual loss from 20/32 to <20/50 vision per ETDRS 

(a decrease in BVA from baseline of >=15 letters):Zinc alone: 25% p-value=0.04Placebo: 29% p-value not reported

Marked Visual Loss from 20/32 to 20/100 in one 

eye(p-values not reported; rather odds ratios with 99% CI were reported):Zinc alone: 13% (OR, 0.75; 99% CI, 0.52-1.08),Placebo: 17% (p-values not reported)

Progression from baseline Cat 3 & 4 at 5 years:Zinc: 22% Placebo: 28%

Low

Zinc group: VA >20/25 in 25/80Placebo: VA >20/25 in 23/84

Zinc sulfate (200 mg/day; 100 mg bid) N=90Placebo, N=8424 months

Zinc vs placebo,Gain of 10 letters: 3/80 v 1/71Loss of 10-14 letters 5/80 v 13/71Loss of 15-19 letters 4/80 v 6/71Loss of >20 letters 2/80 v 5/71(p-values not reported)

NR Low
17

ge-related Macular Degeneration: A Systematic Review Evidence-based Synthesis Program

Baseline visual acuity;

% of population with Category

3 or 4 AMD at baseline

Treatment arms (daily dosage 

unless otherwise specified);

N of subjects;

duration of treatment Visual acuity outcomes

Progression to 

severe AMD,

% of subjects

Assessed

risk of 

bias

Placebo visual acuity (ETDRS logMAR) R eye: 40.297 +/-0.649L eye: 39.270 +/-0.516Treatment group visual acuity:R eye: 39.027 +/-0.672 L eye: 39.257 +/-0.585

Zinc monocysteiene (50 mg/day; 25 mg bid), N=37Placebo (bid), N=376 months

Zinc: 20/50 at baseline improved to 20/46 right eye and 20/47 left eye at 6 months (p-value=0.0001)Placebo group baseline vision 20/50 with no change over 6 months (p-value=0.0001)

NR Low

LogMAR(mean +-SD)Zinc: 0.073 +/-0.12Placebo: 0.076 +/-0.13 72% high risk AMD22% low risk AMD*

Zinc sulfate (200 mg), N=56Placebo, N=5624 months

LogMAR at 24 months trt N=37 0.046 +/-0.12 (p-value=0.52 ; placebo N=41 0.027 +/-0.14effect size <15 letters (p-value not reported)Zinc: 20/22 at baseline to 20/22 at 24 monthsPlacebo: 20/22 at baseline to 20/21 at 24 months

25% after 44.8 +-8.2 months

Low

20/25-20/50 in worse eye; all had early AMD as part of inclusion criteria. 8/92 (8.7%) treatment grp and 4/96 (4.2%) of placebo had Cat 3 AMD at baseline (both eyes were considered for AMD progression, whereas only the worse eye was considered for visual acuity outcome)

Phototrop (proprietary compound of Acetyl-L-carnintine, ALC; n-3 FAs; and CoQ10), N=52Placebo, N=5512 months

Change in mean Snellen acuity, Phototrop vs placebo:Improved in 77% vs 55% (by .05 Snellen decimal) Deteriorated in 23% vs 45% (also by 0.05 Snellen decimal), p=0.015; OR 2.78 for deterioration, placebo vs active Tx.

Not reported...outcomes were measured as changes in drusen covered areas by photography

Low

ular degeneration; C = control; CA = cancer; ETDRS = Early Treatment Diabetic Retinopathy Study; logMAR= logarithm of the minimum angle of resolution, a 

Treatment; HTN = hypertension; N = number of subjects; NOS = not otherwise specified; NR = not reported.

 eyes with a predominant drusen size of more than 125 /Ltm and/or a large drusen size of more than 250 /m and/or definite evidence of focal RPE 

of drusen confluence. Eyes that did not exceed these limits were classified as “low-risk AMD” eyes.13 Definitions of AREDS categories for AMD severity (AREDS 

ed macular abnormalities, with a total drusen area less than 5 small drusen (<63 μm), and visual acuity of 20/32 or better in both eyes. 

ted macular features (multiple small drusen, single or nonextensive intermediate drusen (63-124 μm), pigment abnormalities, or any combination of these) in 1 

 or better in both eyes. 

 in both eyes and at least 1 eye with visual acuity of 20/32 or better with at least 1 large drusen (125 μm), extensive (as measured by drusen area) intermediate 

t did not involve the center of the macula, or any combination of these. 

tter and no advanced AMD (GA involving the center of the macula or features of choroidal neovascularization) in the study eye, and the fellow eye had either 

ty less than 20/32 and AMD abnormalities sufficient to explain reduced visual acuity as determined by examination of photographs at the reading center.
18

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Ongoing studies

The National Institute of Health (NIH) has commissioned the National Eye Institute to conduct 

the Age-Related Eye Disease Study 2 (AREDS II), and the trial is currently underway.17

Enrollment of subjects began in September 2006 and is now complete. Approximately 4,200 

subjects will be followed for five years with an estimated completion date of December 2012. 

Subjects between ages 50 and 85, with clear enough media for retinal photography (e.g. no 

significant cataracts), and who had various stages of macular degeneration are included. The 

study design is a double-blinded RCT of five-year duration, with the primary outcome measure 

of progression to advanced AMD in subjects at moderate to high risk for progression (e.g. 

Categories 3 and 4 AMD). Secondary outcome measures pertinent to our review are: progression 

to moderate vision loss; adverse events; and, effect of DHA/EPA on cardiovascular morbidity 

and mortality. The purpose of the study is to evaluate the effect of lutein and zeaxanthin (two 

dietary xanthophylls), and two omega-3 fatty acids DHA and EPA on these outcome measures. 

Additionally, the treatment arms will evaluate the effects of eliminating beta-carotene from the 

original AREDS formulation of antioxidants (500 mg vitamin C; 400 IU vitamin E; and 15 mg 

beta carotene), and/or lowering the zinc component of the supplement (previously 80 mg zinc 

as zinc oxide, and 2 mg copper as cupric oxide). All participants are offered additional treatment 

with the original AREDS formulation (now considered the standard of care). It is doubtful 

whether this study will be able to address the more subtle loss of functional vision in lower risk 

patients upon which our review was focused. This is the result of the natural history of early 

AMD, which is characterized by long duration and slow progression of the disease. The sample 

size of the AREDS II will again cause this study to statistically dominate similar studies of these 

outcome measures for the foreseeable future.

Key Question #2. In adult populations, what are the harms of carotenoid, antioxidant, and omega-3 fatty acid supplementation?

Seven systematic reviews examined the adverse effects of oral supplements in 56 RCTs. One 

review included trials of adults with AMD,18 while other reviews included a range of study 

populations. One review examined mortality in trials of vitamin E.19 Two reviews examined 

the risk of lung cancer in trials of beta-carotene,20, 21 and one of these reviews also examined 

prospective observational studies of carotenoids for lung cancer incidence.20 Three reviews 

included studies of various supplements (B-carotene, vitamin A, vitamin C, vitamin E, alphatocopherol, zinc), alone or in combination, to examine the effects on colorectal adenoma,22

gastrointestinal cancers,23 and prostate cancer.24

Thirty-three large (N >1000) RCTs with more than one year of follow-up were accounted for by 

the prior systematic reviews. Because of their size and length of follow-up, these trials provide 

the richest source of information about potential harms of these supplements. As their results 

are well represented in prior reviews, we focus below on the findings of previous evidence 

syntheses, supplemented with data from our own review of primary studies of this added new 

information. In addition to existing systematic reviews, we examined 173 publications from 41 

trials for reports of adverse effects of oral supplements in adults, not limited to patients with 

AMD. 
19

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Summary of findings 

Vitamin E at high doses (>=400 IU/day) may be associated with increased risk of mortality, 

congestive heart failure, and prostate cancer. 

Beta-carotene may be associated with an increased risk of lung cancer among active smokers. 

In the Beta-Carotene and Retinol Efficacy Trial (CARET) and Alpha-Tocopherol and BetaCarotene (ATBC) trials, beta-carotene was associated with increased mortality and increased risk 

of lung cancer among smokers. Two other large trials, the Women’s Health Study (WHS) and the 

Physicians’ Health Study (PHS), did not find an excess risk of lung cancer among smokers using 

beta-carotene, but a meta-analysis combining these four studies determined that the overall risk 

of lung cancer among current smokers treated with beta-carotene was significantly elevated (OR 

1.24 (95% CI, 1.10-1.39)). No increase in lung cancer incidence was observed among former 

smokers and nonsmokers in these studies. In prospective cohort studies that used lower doses 

than RCTs, a small inverse association between carotenoids and lung cancer among current 

smokers has been observed. 

Zinc was associated with urinary tract infections and hospital admissions due to genitourinary 

causes in one study. 

Yellowish discoloration of the skin was frequently reported in trials of beta-carotene, and has 

also been noted in trials of lutein. Gastrointestinal symptoms were also commonly reported in 

trials of various supplements. 

Detailed findings

Mortality

A systematic review of various supplements (beta-carotene, vitamin A, vitamin C, vitamin 

E, and selenium in combination) found that the relative risk (RR) of all-cause mortality was 

significantly increased with antioxidants compared with placebo (RR 1.05, 95% CI 1.02-

1.07), in a meta-analysis that combined 13 trials with low risk of bias.23 There was significant 

heterogeneity among the trials, however, and the combined estimate appeared to be driven by 

two large studies of beta-carotene that contributed 52 percent of the weight in the analysis: the 

ATBC study,25 which included 29,133 male smokers; and the CARET study,26 which enrolled 

18,314 smokers, former smokers, and workers exposed to asbestos. 

In ATBC, there were marginally significant increases in mortality after 6.1 mean years of 

treatment in the group that received 20 mg/day beta-carotene alone (RR 1.08 (95% CI 0.99-

1.19)) and the group that received 20 mg/day beta-carotene plus a low dose (50 IU/day) of 

vitamin E (RR 1.10 (95% CI 1.00-1.21)), whereas mortality was not elevated in the group 

that received vitamin E alone (RR 1.02, 95% CI 0.93-1.12).25 In the CARET study, the active 

treatment group combined 30 mg beta-carotene together with 25,000 IU vitamin A and was 

associated with a 17 percent increase in mortality compared with placebo after four years of 

treatment (RR 1.17, 95% CI 1.03-1.33).26 A post-intervention analysis of the CARET study 

determined that the increase in all-cause mortality in the beta-carotene/vitamin A group remained 

elevated six years after the trial had ended, although the magnitude of risk had diminished and 

become less significant (RR 1.08, 95% CI 0.99-1.17).26
20

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

A systematic review of vitamin E included 19 trials stratified by dosage (<400 IU/day or >=400 

IU/day).19 Low-dose vitamin E (16.5 to 330 IU/day) had no significant effect on all-cause 

mortality in a meta-analysis of eight trials. High-dose vitamin E (400 to 2000 IU/day) was 

associated with a significant increase in all-cause mortality in a meta-analysis of 11 trials. The 

risk ratio was 1.04 (95% CI 1.01-1.07, p=0.035) and the pooled risk increase was 39 deaths 

per 10,000 persons (95% CI 3-74 per 10,000, p=0.035) compared with controls. The reviewers 

conducted a dose-response analysis that showed a statistically significant trend of increased 

mortality with vitamin E dosage >150 IU/day.19

Cancer 

Lung cancer

A systematic review of four RCTs examined the effects of beta-carotene (20 to 30 mg/day) 

on lung cancer incidence, stratified by smoking status.21 Among current smokers, lung cancer 

incidence was significantly increased with beta-carotene supplementation in the ATBC27 and 

CARET28 studies, but not significantly increased in the PHS29 and WHS30 studies. Although the 

WHS study was terminated early after a median beta-carotene exposure of 2.1 years, (compared 

with 4 years in CARET, 6.1 years in ATBC, and 12 years in PHS) a meta-analysis combining 

the four studies determined that the overall risk of lung cancer among current smokers treated 

with beta-carotene was significantly increased (OR 1.24 (95% CI 1.10-1.39)).21 Three of the 

studies (CARET, PHS, and WHS) included former smokers, and in this subgroup there was no 

association between beta-carotene and lung cancer incidence in any of the three studies (pooled 

OR 1.10, 95% CI 0.84-1.45).21 Former smokers were defined in the CARET study as individuals 

who smoked within the past 15 years but quit smoking more than six years prior to the study28, 

whereas individuals were classified as former smokers in PHS and WHS if they had smoked in 

the past but had quit at the onset of the study. No significant increase in lung cancer incidence 

was observed among nonsmokers (OR 0.73, 95% CI 0.33-1.59).21

Another review of carotenoids and lung cancer incidence examined data from six RCTs and 24 

prospective observational studies.20 The review noted the increased risk of lung cancer among 

smokers in the CARET and ATBC studies, but found a small inverse association between 

carotenoids and lung cancer among current smokers in prospective cohort studies. The reviewers 

noted that the RCTs used beta-carotene at doses 5 to 10 times greater than normal dietary 

intake, and suggested that beta-carotene may accelerate the growth of already initiated cells if 

administered in later stages of the carcinogenic process.20

A follow-up analysis of the ATBC study containing updated cancer data determined that the 

excess risk of lung cancer associated with beta-carotene during the trial period was attenuated 

(RR 1.16, 95% CI 0.97-1.40)25 compared with the initial findings (RR 1.19, 95% CI 1.04-1.36)27

that were used in the meta-analysis cited above.21 The follow-up of the ATBC study examined 

post-intervention cancer incidence and determined that the excess risk of lung cancer among 

beta-carotene recipients was no longer evident four to six years after ending the intervention (RR 

1.06, 95% CI 0.94-1.20).25

Prostate cancer

A systematic review and meta-analysis examined the incidence of prostate cancer with vitamin E 

in five large RCTs (N of subjects ranging from 9,541 to 35,533) with treatment duration of four 
21

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

to eight years.24 The pooled analysis showed no significant findings (HR 0.96, 95% CI 0.85-1.08) 

although the dosage and effects of vitamin E varied among the trials. The ATBC trial used a low 

dose of vitamin E (50 IU daily) and found a significantly protective effect against prostate cancer,27

while the Selenium and Vitamin E Cancer Prevention Trial (SELECT) administered 400 IU/day and 

found a marginally elevated risk.31. The other three trials of vitamin E included in the meta-analysis 

administered 400 IU daily or every other day, and found neutral effects on prostate cancer incidence. 

Data from follow-up studies of the ATBC and SELECT trials showed an upward shift in the risk 

of prostate cancer associated with vitamin E. The initial analysis of the SELECT trial based on 

235,689 person-years of follow-up reported a 13 percent increased risk of prostate cancer with 

vitamin E (HR 1.13, 99% CI 0.95-1.35).31 A post-trial analysis, which included an additional 

54,464 person-years since the primary report, determined that the overall risk of prostate cancer 

among men in the Vitamin E group had increased to 17 percent above placebo (HR 1.17, 99% 

CI 1.004-1.36, p=0.008).32 The study investigators determined that the absolute increase in 

risk of prostate cancer per 1000 person-years was 1.6 for subjects treated with vitamin E. The 

significantly protective effect of vitamin E on prostate cancer (RR 0.66, 95% CI 0.52-0.86) 

initially observed in the ATBC study diminished to non-significance during the six-year post-trial 

observation period (RR 0.88, 95% CI 0.76-1.03).25

No significant effects on incidence or mortality from prostate cancer were found in two RCTs of 

vitamin C, and in three RCTs of beta-carotene.24

Gastrointestinal cancer

A systematic review that examined the effects of various supplements (beta-carotene, vitamin A, 

vitamin C, vitamin E, and selenium, alone or in combination) among 20 RCTs found no effect on 

incidence of gastrointestinal cancers among 12 good-quality trials.23

Colorectal adenoma

A systematic review of various supplements (beta-carotene, vitamin A, vitamin C, vitamin E, 

and selenium, alone or in combination) found mixed effects on the development of colorectal 

adenoma among eight RCTs. Stratifying the studies by methodological quality, the review 

determined that antioxidant supplements appeared to increase the risk of colorectal adenoma in 

three low-bias risk trials (RR 1.2, 95% CI 0.99-1.4) while an opposite, significantly protective 

effect was observed in five high-bias risk trials (0.59, 95% CI 0.47-0.74).23

Cardiovascular disease

In the ATBC trial, low-dose vitamin E supplementation (50 IU/day alpha-tocopherol) decreased 

the risk of cerebral infarction but increased the risk of fatal hemorrhagic stroke among 

smokers. The study authors noted that the overall net effects of vitamin E on total stroke were 

nonsignificant.33 A systematic review that included 10 trials of vitamin E (alone or combined 

with other supplements) concluded that vitamin E did not significantly affect the risk of 

hemorrhagic stroke (RR 1.01, 95% CI 0.82-1.23).23

In the GISSI-Prevenzione trial of post-infarction patients, vitamin E (300 mg/day for 3.5 years, 

open-label) increased the risk of the combined outcome of CHF hospitalization or death in 

patients with left ventricular dysfunction (HR 1.50, 95% CI 1.03-2.20) but not in those with 

preserved systolic function.34
22

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

In the HOPE trial, a double-blinded RCT of vitamin E (400 IU daily for a mean of 4.5 years) 

in 9,541 patients with DM, CVD, or renal insufficiency, CHF (i.e., hospitalization or death due 

to CHF, or use of an ACE inhibitor for the diagnosis of CHF) was increased with vitamin E 

supplementation (RR 1.13, 95% CI 1.01-1.26).35 The increased CHF risk associated with vitamin 

E was found at extended follow-up (median 7 years; RR 1.19, 95% CI 1.05-1.35).35

An open-label trial of fish oil consumption in 3,114 men with angina observed a marginally 

significant increased risk of cardiac death at three to nine years among subjects advised to 

consume oily fish or fish oil capsules twice a week.36 This study was methodologically limited 

by the lack of blinding, and the inability to determine the level of compliance with the dietary 

advice and other confounding factors. 

In a double-blinded RCT of fish oil supplementation (6 g/day of n-3-fatty acids) for six months 

following coronary angioplasty in 205 patients, restenosis was non-significantly increased in 

the fish oil group (RR 1.7, 95% CI 0.9-3.4).37 This effect was not observed in other studies of 

restenosis after coronary angioplasty38, 39 or atrial fibrillation.40

Other adverse effects

Respiratory tract infections

In a double-blinded RCT of vitamin E (200 mg/dL/day for 15 months) among noninstitutionalized individuals aged 60+, the incidence of respiratory tract infections did not differ 

with treatment. Among those who experienced a respiratory infection, however, individuals 

who received vitamin E had longer illness duration, more symptoms, and a higher frequency of 

fever and restriction of activity.41 The authors of the study suggested that supplementation with 

vitamin E may improve immune response, and that the observed effect of vitamin E on illness 

severity might reflect a more active immune response.41

Urinary tract infections

Subjects treated with zinc (80 mg as zinc oxide and 2 mg copper as cupric oxide, daily, with 

6.3 years mean follow-up) in the AREDS study experienced significantly more urinary tract 

infections compared with non-zinc treated subjects, particularly women (2.3% vs 0.4%, RR 5.77, 

95% CI 1.30-25.66, p=0.013). There were more hospital admissions due to genitourinary causes, 

particularly among men (RR 1.26, 95% CI 1.07-1.50, p=0.008).42

Yellowish discoloration of the skin (carotenodermia)

Beta-carotene was significantly associated with yellowing of the skin in a systematic review 

that included five RCTs of beta-carotene,24 as well as the AREDS study.10 Another systematic 

review that included nine RCTs of beta-carotene determined that transient yellowing of the skin 

was increased but not to a statistically significant degree (RR 1.85, 95% CI 0.74-4.67).23 In a 

trial of beta-carotene (15,000 IU), vitamin C (250 mg), and vitamin E (350 IU) taken together 

(2 capsules/2x daily) for six months following coronary angioplasty, yellow skin pigmentation 

was observed in 56 percent of patients taking multivitamins, but the significance of this finding 

relative to the placebo group in this study was not specified.43

Lutein has also been associated with carotenodermia. A narrative review of carotenoids44 cited 

two trials of lutein in which this effect occurred, at daily doses of 15 mg for 4 to 5 months.45, 46
23

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Gastrointestinal symptoms

A systematic review of 10 RCTs of antioxidant supplements to prevent or delay progression 

of AMD reported that gastrointestinal symptoms were the most common adverse effect that 

led to withdrawal from studies.18 In a trial of beta-carotene (15,000 IU), vitamin C (250 mg), 

and vitamin E (350 IU) taken together (2 capsules/2x daily) for six months following coronary 

angioplasty, diarrhea occurred more frequently among the multivitamin group compared to 

placebo.43 A systematic review of beta-carotene trials found increases in minor gastrointestinal 

(GI) symptoms.24 A greater incidence of GI upset was also reported in at least two other trials: a 

trial of fatty acid supplementation (2 capsules/2x daily containing 280 mg of gamma-linolenic 

acid and 45 mg eicosapentaenoic acid) in patients with intermittent claudication,47 and in a trial 

of beta-carotene (15,000 IU), vitamin C (250 mg), and vitamin E (350 IU) taken together (2 

capsules/2x daily) for six months following coronary angioplasty.43

Anemia

More zinc-treated subjects self-reported the occurrence of anemia (13.2 vs 1.2%, p=0.004) in the 

AREDS study. This perceived effect was not supported by laboratory values, however, as serum 

hematocrit levels showed no significant differences between treatment groups.10
24

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

DISCUSSION

We conducted a systematic review of the benefits and harms of nutritional supplements for 

treatment of AMD. We found good evidence mainly from one large RCT that supplementation 

with carotenoids and antioxidants decreased the risk of functional vision loss among patients 

with Category 3 or 4 AMD. One smaller RCT also found zinc supplementation may decrease the 

risk of clinically significant visual loss among patients with Category 3 or 4 AMD, but six other 

RCTs found no clinically significant benefit from nutritional supplements in AMD patients. The 

effects of carotenoids or omega-3-fatty acids alone have not been well-studied. 

It is likely that the discrepant findings reflect, at least in part, the size, length of follow-up, and 

patient characteristics in these six studies not finding benefit. These studies all included fewer 

than 200 patients each, were conducted over a relatively short time frame, and included large 

proportions of patients with mild AMD. 

We also found evidence of significant potential harm from some nutritional supplements. 

Carotenoids such as beta-carotene have been associated with an estimated 24 percent increased 

risk of lung cancer among smokers. Similar to the studies of potential benefits, the evidence 

for harms is driven primarily by two large trials, ATBC and CARET. The release of the results 

regarding beta-carotene and lung cancer risk from ATBC in 199427 and CARET in 199628 caused 

an amendment to be made to the ongoing AREDS study, in which smokers were offered a chance 

to change their randomization of treatment supplements category to one which included either 

zinc alone or placebo. This concern also has been addressed in the subsequent AREDS II study, 

now underway, which is discussed below under Future Studies.48

Higher doses of vitamin E (>400 IU per day) have been associated with an estimated four percent 

increase in mortality; a 13 to 17 percent increase in risk of prostate cancer; and a 13 to 50 percent 

increase in risk of congestive heart failure among those with existing CVD risk factors such as left 

ventricular dysfunction, diabetes mellitus, recent myocardial infarction, or renal insufficiency. 

Whether the balance of benefits and harms favors supplementation in AMD patients likely 

depends on the population being considered. There is strong evidence for benefit in patients 

with more advanced AMD; and in these patients, the very small risk of harm is likely to be 

outweighed by the potential benefit. Using the AREDS data, one can calculate the number 

needed to treat with supplements to prevent one patient from developing clinically significant 

visual loss, as 33 over five years. In a population of patients with comorbid cardiovascular 

disease, 256 would need to be treated with supplements (which include vitamin E) to cause one 

excess death.19

The role of nutritional supplementation in patients with mild AMD is unclear. The natural history 

of mild AMD is one of slow progression. Among 1,117 participants with Category 1 AMD at 

baseline in the AREDS study, only five (0.45%) participants developed advanced AMD during 

6.3 mean years of follow-up. Among 1,063 subjects with Category 2 AMD at baseline, only 13 

(1.2%) subjects had significant vision loss related to AMD, and 28 (2.6%) participants progressed 

to Category 3 or 4.10 There was no detectable effect on vision loss in any of the treatment arms 

among these subjects, given the very slow rate of disease progression in mild AMD. It is unclear, 

however, whether the rate of progression from mild to advanced AMD increases with age. It 
25

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

is possible that nutritional supplementation for mild AMD may yield more detectable benefit 

to those over age 85 compared with younger individuals. These aged individuals make up the 

fastest growing demographic in the United States. The natural progression of AMD in this age 

group warrants further study. 

Since AMD patients are likely to be older and have additional medical comorbidities, many 

would be at risk for some of the potential harms associated with supplementation. Because of the 

very slow rate of disease progression in patients with mild AMD, the lack of evidence of benefit 

in these patients and the potential for harm – especially amongst those with baseline medical 

comorbidities – the current literature does not support widespread use of these supplements for 

mild AMD. The balance of benefits and harms in patients with Category 3 or 4 AMD and limited 

life expectancy is unclear. Because the benefits of nutritional supplements do take several years 

to accrue, it is unclear that their use in patients with limited life expectancy is indicated. 

Our findings concur with and add to the findings of similar reviews. A recent Cochrane 

collaborative review found evidence for modest benefit of antioxidant, vitamin and mineral 

supplementation reducing the progression of AMD in people with moderate to severe signs of the 

disease, and no evidence that subjects with early signs of the disease show a treatment benefit.18

Our findings add to prior reviews in that we looked at a broader group of studies to examine the 

potential harms of supplements because the potential risks are not limited to only those with 

AMD, making studies including all older adults relevant to the question of harms.

FUTURE STUDIES

Based on the progression observed in AREDS among subjects with Category 2 AMD, we 

estimate a study enrolling 17,000 subjects followed over five years would be needed to detect 

a clinically significant difference in visual loss between subjects treated with antioxidants + 

zinc versus a placebo. Such a study is unlikely to be funded and completed in the near future. 

The natural history of AMD is a very slow and lengthy progression from retinal evidence of 

disease to functional vision loss. Not all patients with evidence of retinal disease have vision 

impairment that interferes with functional status. In other words, subtle changes in retinal 

function due to AMD may cause visual disability that is not well reflected on the basis of visual 

acuity measurements alone. Well-validated intermediate markers of functional vision loss would 

be useful. Well-designed prospective cohort studies of patients with mild AMD could elucidate 

the types of intermediate findings that could accurately predict future clinically significant vision 

loss. In addition, studies would need to confirm that these findings are consistent when measured 

across large groups of patients. 

Given the relative lack of information about the effects of xanthophylls, carotenoids, and omega-3 

fatty acids, future trials should be considered to assess the effects of these supplements in AMD 

patients. The results of the ongoing AREDS II trial should help to address the current gaps in 

evidence about the effects of the xanthophyll and omega-3-fatty acids. In addition, the AREDS II 

trial interventions will include four variations of the original AREDS formula for randomization. 

However, smokers in the study will be randomized to only groups 2 or 3 since neither of these two 

groups’ supplements includes beta-carotene. The only variation between these two groups is the 

high or low Zinc content. This comprises a “smokers” subset of AREDS II.48
26

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Previous and current studies, including the ongoing AREDS II trial, have focused on functional 

vision loss and AMD progression as the principal outcomes of interest. The large majority 

of patients with AMD, however, may suffer from more subtle visual disabilities that may, 

nevertheless, profoundly alter their visual functioning, such as losing their ability to safely 

operate a motor vehicle. It is important to emphasize that these patients, while visually impaired, 

may still record less than clinically significant visual loss as measured by visual acuity. Evidence 

is lacking as to whether quality of life outcomes and activities of daily living benefit from 

treatment, and further study of these outcome measures is warranted. 

CONCLUSIONS

Evidence of benefit from supplementation with carotenoids and antioxidants on functional 

vision loss in patients with AMD is based mainly on the results of one large trial. The observed 

benefit occurred only among subjects with Category 3 or 4 AMD. There is evidence for a low 

risk of harm from some nutritional supplements at high doses. As with any clinical intervention, 

the balance of benefits and harms regarding supplementation in AMD patients depends upon 

the population being considered. Given that AMD patients are older and have additional 

medical comorbidities, many would be at risk for some of the potential harms associated with 

supplementation. The precautionary principle should be observed while further evidence evolves. 

Table 2 summarizes the evidence regarding the benefits and harms of oral supplements for AMD. 

While our report notes the uncertainty in the conclusions of many of the included studies, 

reasonable recommendations can be extended:

• Carotenoid and antioxidants supplements significantly decrease visual loss and can be 

recommended for patients with Categories 3 and 4 AMD.

• Current literature does not support the use of these supplements for patients with mild 

AMD.

• Certain nutritional supplements have significant potential harms:

◦ Increased mortality and congestive heart failure in high risk patients with vitamin E.

◦ Increased risk of prostate cancer with vitamin E.

◦ Increased risk of lung cancer among smokers with beta-carotene.
27

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Table 2. Summary of the evidence on the effects of nutritional supplements for age-related 

macular degeneration

Outcome Treatment Population Effect* GRADE 

Classification† Comment

Functional 

vision loss

Carotenoids Early AMD (~) Low Single study (N=90) found a small increase 

in visual acuity after 12 months, but the 

improvement was not clinically significant 

(i.e. <15 letters).12

Antioxidants‡ Categories 

3-4 AMD

(+) Moderate Evidence of benefit from 1 large multicenter 

trial10 and one smaller trial.11 4 small trials 

found neutral effects on functional vision 

loss.12-15

Antioxidants Category 2 

AMD

(~) Low No evidence of benefit after 7 years of 

treatment in 1 large multicenter trial that 

included 1,063 Category 2 subjects.10

Omega-3 fatty acids Early AMD 

(94% in 

Categories 

1- 2)

(~) Very Low One study found evidence of slowed visual 

acuity loss but not to a clinically significant 

degree. Very few subjects in this study 

(6.4%) had Categories 3-4 AMD.16

Quality of life Carotenoids AMD (~) Low No significant findings on night driving in 

one study (N=90).12

Antioxidants N/A (0) N/A No evidence.

Omega-3 fatty acids N/A (0) N/A No evidence.

Mortality Beta-carotene Smokers (–) Moderate High-dose beta-carotene (20 to 30 mg/

day) was linked with increased mortality 

in 2 large trials in smokers and asbestos 

workers.25, 26

Vitamin E General 

population

(–) High High-dose vitamin E (>=400 IU/day) was 

associated with a slight increase in mortality 

in a meta-analysis of 11 trials.19

Lung cancer Beta-carotene Smokers (–) Moderate High-dose beta-carotene (20 to 30 mg/

day) was linked with increased lung cancer 

incidence among smokers in a metaanalysis of 4 large trials.21 No increase in 

lung cancer was observed among former 

and non-smokers.

Prostate 

cancer

Vitamin E General 

population

(–) Low High-dose vitamin E (400 IU/day) was 

associated with an increase in prostate 

cancer in one study.31

Gastrointestinal 

cancers

Antioxidants General 

population

(~) High Supplements had no effect on incidence of 

gastrointestinal cancers in a meta-analysis 

of 12 good-quality trials.23

Congestive 

heart failure

Vitamin E DM, CVD, or 

post-infarction

(–) Low Vitamin E (300-400 IU/day) was linked with 

increased CHF hospitalization in 2 trials of 

high-risk patients.34, 35

Urinary tract 

infections 

(UTIs)

Zinc AMD (–) Low Zinc (80 mg/day) was associated with 

more UTIs and hospital admissions due to 

genitourinary causes compared with nonzinc treated subjects in one large study.42
28

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

Outcome Treatment Population Effect* GRADE 

Classification† Comment

Yellowing of 

the skin

Beta-carotene 

Lutein

AMD and 

general 

population

(–) High Transient yellowing of the skin was 

frequently reported in trials of betacarotene24 and in two trials of lutein44

Gastrointestinal (GI) 

symptoms

Antioxidants AMD (–) High GI symptoms were the most common 

adverse effect that led to withdrawal from 

studies, according to a systematic review 

of 10 RCTs of antioxidant supplements for 

AMD.18

GRADE = Grades of Recommendation, Assessment, Development, and Evaluation; ICU = intensive care unit; RCT = 

randomized controlled trial; AMD = age-related macular degeneration; CHF = congestive heart failure.

* Effect: (+) benefit; (–) harm; (~) mixed findings/no effect; (0) no evidence.

† GRADE classification: high = further research is very unlikely to change our confidence on the estimate of effect; moderate = 

further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; 

low = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change 

the estimate; very low = any estimate of effect is very uncertain.

‡ Trials of antioxidants included treatment with antioxidants alone or combined with carotenoids or other supplements.
29

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

REFERENCES

1. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Archives of Ophthalmology. Apr 2004;122(4):564-572.

2. Augood C, Chakravarthy U, Young I, et al. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. American Journal of Clinical Nutrition. Aug 

2008;88(2):398-406.

3. Flood V, Smith W, Wang JJ, Manzi F, Webb K, Mitchell P. Dietary antioxidant intake and 

incidence of early age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology. Dec 2002;109(12):2272-2278.

4. Mares JA, Voland RP, Sondel SA, et al. Healthy lifestyles related to subsequent 

prevalence of age-related macular degeneration. Archives of Ophthalmology. Apr 

2011;129(4):470-480.

5. Mares-Perlman JA, Klein R, Klein BE, et al. Association of zinc and antioxidant nutrients 

with age-related maculopathy. Archives of Ophthalmology. Aug 1996;114(8):991-997.

6. Moeller SM, Parekh N, Tinker L, et al. Associations between intermediate age-related 

macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-related Eye 

Disease Study (CAREDS): ancillary study of the Women’s Health Initiative. Archives of 

Ophthalmology. Aug 2006;124(8):1151-1162.

7. 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 agerelated maculopathy in the Beaver Dam Eye Study. American Journal of Epidemiology. 

Jul 15 1998;148(2):204-214.

8. Higgins JPT, Altman DG, editors. Chapter 8: Assessing risk of bias in included studies. 

In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. 2008;Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 

2008. Available from www.cochrane-handbook.org.

9. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology. Apr 

2011;64(4):383-394.

10. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, 

clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc 

for age-related macular degeneration and vision loss: AREDS report no. 8. Archives of 

Ophthalmology. Oct 2001;119(10):1417-1436.

11. Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular degeneration. Archives of Ophthalmology. Feb 1988;106(2):192-198.
30

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

12. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized 

trial of lutein and antioxidant supplementation in the intervention of atrophic age-related 

macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation 

Trial). Optometry. Apr 2004;75(4):216-230.

13. Stur M, Tittl M, Reitner A, Meisinger V. Oral zinc and the second eye in age-related macular 

degeneration. Investigative Ophthalmology & Visual Science. Jun 1996;37(7):1225-1235.

14. Newsome DA. A randomized, prospective, placebo-controlled clinical trial of a novel 

zinc-monocysteine compound in age-related macular degeneration. Current Eye Research. Jul 2008;33(7):591-598.

15. Richer S. Multicenter ophthalmic and nutritional age-related macular degeneration study-

-part 2: antioxidant intervention and conclusions. Journal of the American Optometric 

Association. Jan 1996;67(1):30-49.

16. Feher J, Kovacs B, Kovacs I, Schveoller M, Papale A, Balacco Gabrieli C. Improvement of visual functions and fundus alterations in early age-related macular degeneration 

treated with a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10. 

Ophthalmologica. May-Jun 2005;219(3):154-166.

17. Age-Related Eye Disease Study 2 Investigators. Age-Related Eye Disease Study 2 

(AREDS2): A Multi-Center, Randomized Trial of Lutein, Zeaxanthin and Omega-3 

Long-Chain Polyunsaturated Fatty Acids (Docosahexaenoic Acid [DHA] and Eicosapentaenoic Acid [EPA]) in Age-Related Macular Degeneration ClinicalTrials.gov identifier: 

NCT00345176 (Ongoing study).

18. Evans J. Antioxidant supplements to prevent or slow down the progression of AMD: a 

systematic review and meta-analysis. Eye. Jun 2008;22(6):751-760.

19. Miller ER, 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin 

E supplementation may increase all-cause mortality. Annals of Internal Medicine. Jan 4 

2005;142(1):37-46.

20. Gallicchio L, Boyd K, Matanoski G, et al. Carotenoids and the risk of developing lung cancer: a systematic review. American Journal of Clinical Nutrition. Aug 

2008;88(2):372-383.

21. Tanvetyanon T, Bepler G. Beta-carotene in multivitamins and the possible risk of lung 

cancer among smokers versus former smokers: a meta-analysis and evaluation of national 

brands. Cancer. Jul 1 2008;113(1):150-157.

22. Bjelakovic G, Nagorni A, Nikolova D, Simonetti RG, Bjelakovic M, Gluud C. Metaanalysis: antioxidant supplements for primary and secondary prevention of colorectal 

adenoma. Alimentary Pharmacology & Therapeutics. Jul 15 2006;24(2):281-291.

23. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Systematic review: primary and secondary prevention of gastrointestinal cancers with antioxidant supplements. Alimentary 

Pharmacology & Therapeutics. Sep 15 2008;28(6):689-703.
31

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

24. Jiang L, Yang K-h, Tian J-h, et al. Efficacy of antioxidant vitamins and selenium supplement in prostate cancer prevention: a meta-analysis of randomized controlled trials. 

Nutrition & Cancer. Aug 2010;62(6):719-727.

25. Virtamo J, Pietinen P, Huttunen JK, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. 

JAMA. Jul 23 2003;290(4):476-485.

26. 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 followup after stopping Î2-carotene and retinol supplements. Journal of the National Cancer 

Institute. 2004;96(23):1743-1750.

27. The effect of vitamin E and beta carotene on the incidence of lung cancer and other 

cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study 

Group. New England Journal of Medicine. Apr 14 1994;330(15):1029-1035.

28. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New England Journal of 

Medicine. May 2 1996;334(18):1150-1155.

29. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation 

with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. 

New England Journal of Medicine. May 2 1996;334(18):1145-1149.

30. Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s Health Study. 

Journal of the National Cancer Institute. Dec 15 1999;91(24):2102-2106.

31. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of 

prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial 

(SELECT). JAMA. Jan 7 2009;301(1):39-51.

32. Klein EA, Thompson IM, Jr., Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. Oct 12 

2011;306(14):1549-1556.

33. Leppala JM, Virtamo J, Fogelholm R, et al. Controlled trial of alpha-tocopherol and betacarotene supplements on stroke incidence and mortality in male smokers. Arteriosclerosis, Thrombosis & Vascular Biology. Jan 2000;20(1):230-235.

34. Marchioli R, Levantesi G, Macchia A, et al. Vitamin E increases the risk of developing 

heart failure after myocardial infarction: Results from the GISSI-Prevenzione trial. Journal of Cardiovascular Medicine. May 2006;7(5):347-350.

35. 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. Mar 16 

2005;293(11):1338-1347.
32

Nutritional Supplements for Age-related Macular Degeneration: 

A Systematic Review Evidence-based Synthesis Program

36. Burr ML, Ashfield-Watt PAL, Dunstan FDJ, et al. Lack of benefit of dietary advice to 

men with angina: results of a controlled trial. European Journal of Clinical Nutrition. Feb 

2003;57(2):193-200.

37. Bairati I, Roy L, Meyer F. Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty. Circulation. Mar 

1992;85(3):950-956.

38. Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation. Nov 1994;90(5):2248-2257.

39. Kaul U, Sanghvi S, Bahl VK, Dev V, Wasir HS. Fish oil supplements for prevention of restenosis after coronary angioplasty. International Journal of Cardiology. Apr 

1992;35(1):87-93.

40. Kowey PR, Reiffel JA, Ellenbogen KA, Naccarelli GV, Pratt CM. Efficacy and safety of 

prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. Dec 1 2010;304(21):2363-2372.

41. Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and multivitamin-mineral 

supplementation on acute respiratory tract infections in elderly persons: a randomized 

controlled trial. JAMA. Aug 14 2002;288(6):715-721.

42. Johnson AR, Munoz A, Gottlieb JL, Jarrard DF. High dose zinc increases hospital admissions due to genitourinary complications. Journal of Urology. Vol 1772007:639-643.

43. Tardif JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of 

restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. New 

England Journal of Medicine. Aug 7 1997;337(6):365-372.

44. Shao A, Hathcock JN. Risk assessment for the carotenoids lutein and lycopene. Regulatory Toxicology & Pharmacology. Aug 2006;45(3):289-298.

45. Granado F, Olmedilla B, Gil-Martinez E, Blanco I. Lutein ester in serum after lutein 

supplementation in human subjects. British Journal of Nutrition. Nov 1998;80(5):445-

449.

46. Olmedilla B, Granado F, Southon S, et al. A European multicentre, placebo-controlled 

supplementation study with alpha-tocopherol, carotene-rich palm oil, lutein or lycopene: 

analysis of serum responses. Clinical Science. Apr 2002;102(4):447-456.

47. Leng GC, Lee AJ, Fowkes FG, et al. Randomized controlled trial of gamma-linolenic 

acid and eicosapentaenoic acid in peripheral arterial disease. Clinical Nutrition. Dec 

1998;17(6):265-271.

48. Edited by Holz FG, Spaide RF. Medical Retina - Essentials in Ophthalmology. Berlin 

Heidelberg New York: Springer; 2007.