A Critical Appraisal of National and International Clinical Practice Guidelines Reporting Nutritional Recommendations for Age-Related Macular Degeneration: Are Recommendations Evidence-Based?

Eye care professionals should have access to high quality clinical practice guidelines that ideally are underpinned by evidence from robust systematic reviews of relevant research. The aim of this study was to identify clinical guidelines with recommendations pertaining to dietary modification and/or nutritional supplementation for age-related macular degeneration (AMD), and to evaluate the overall quality of the guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. We also mapped recommendations to existing systematic review evidence. A comprehensive search was undertaken using bibliographic databases and other electronic resources for eligible guidelines. Quality appraisal was undertaken to generate scores for each of the six AGREE II domains, and mapping of extracted nutritional recommendations was performed for systematic reviews published up to March 2017. We identified 13 national and international guidelines, developed or updated between 2004 and 2019. These varied substantially in quality. The lowest scoring AGREE II domains were for ‘Rigour of Development’, ‘Applicability’ (which measures implementation strategies to improve uptake of recommendations), and ‘Editorial Independence’. Only four guidelines used evidence from systematic reviews to support their nutritional recommendations. In conclusion, there is significant scope for improving current Clinical Practice Guidelines for AMD, and guideline developers should use evidence from existing high quality systematic reviews to inform clinical recommendations.


Introduction
Age-related macular degeneration (AMD) is an ocular disease affecting the central area of the retina (the macula), which is responsible for high-resolution daytime vision [1]. In the early stages of AMD, the macula shows characteristic sub-retinal lipoprotein deposits, known as drusen, and the monolayer of pigmented cells beneath the retina (retinal pigment epithelium) shows areas of hypo-and hyper-pigmentation. As the disease progresses, the retinal pigment epithelium can become atrophic, with secondary dysfunction and a loss of retinal photoreceptors [2]. Less commonly, new blood vessels grow beneath, or within, the retina; these vessels have a tendency to leak, causing disruption to the macular architecture and ultimately scar formation (neovascular AMD). Early AMD is typically asymptomatic; however, later stages of AMD can have a significant negative impact on visual function and quality of life [3]. AMD is currently the leading cause of severe vision impairment among people aged 50 and over in high-income countries [4]. With increasing life expectancy these numbers are projected to increase substantially in the future.
AMD is a complex disorder with several non-modifiable and modifiable risk factors [5]. The retina is particularly susceptible to oxidative stress, as a result of its high oxygen consumption and exposure to light; animal and cell culture studies have identified oxidative stress as a contributory factor for the development of AMD [6]. A large body of observational and experimental research in humans has investigated the association between dietary antioxidants and AMD, in particular whether an increased intake of antioxidant vitamin and minerals or specific carotenoids can prevent or slow the progression of the disease [7,8]. The role of particular essential fatty acids has also been investigated, including exploiting the anti-inflammatory properties of long-chain omega-3 fatty acids.
Based on accumulating research evidence, dietary modification and/or nutritional supplementation has been proposed as a simple and potentially cost-effective strategy for modifying the risk of AMD. Although there is a large body of research in this area, the quality of studies is highly variable and conflicting results have been reported. These factors pose challenges for clinicians, when attempting to provide evidence-based recommendations to patients about the relative risks and benefits of nutrition-based interventions. Clinical practice guidelines can be used to aid clinical decision-making in such circumstances. These documents should contain recommendations that are informed by a systematic review of the available research evidence, and a consideration of the benefits and harms of alternative interventions [9]. In the process of guideline development, developers either elect to perform their own systematic review of the literature, or to instead integrate the results from previously published reviews. Systematic reviews involve a process of systematically identifying, appraising and synthesising findings from all relevant research studies relating to a particular research question, with the intent of minimising the potential for bias. The objectives of the present study were to: (1) Identify clinical practice guidelines for AMD that contain nutritional recommendations, based upon a systematic literature search; (2) Evaluate the quality of these guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool; and (3) Map clinical practice guideline recommendations, as related to nutrition and AMD, to relevant systematic reviews.

Eligibility Criteria
We included national and international clinical practice guidelines for AMD that contained nutritional recommendations, including dietary modification or nutritional supplementation, as strategies to prevent or slow the progression of the disease.

Search Strategy
We searched the Ovid MEDLINE and Embase bibliographic databases from January 1999 to January 2019 using search filters for identifying clinical guidelines that were developed by the Canadian Agency for Drugs and Technologies in Health (https://www.cadth.ca) (see Supplementary Materials). In addition to the bibliographic database searches, we also searched Guideline Central Summaries (https://www.guidelinecentral.com/summaries/) and the Turning Research into Practice (TRIP) database (https://www.tripdatabase.com/), and undertook a search of the webpages of national and international professional organisations for ophthalmology and optometry. The search was not limited by language and we used Google Translate to extract recommendations and appraise guidelines that were not written in English. Table 1. Clinical guideline quality domains used in the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool.

Domain Content
Scope and Purpose (3 items) Concerned with the overall aim of the guideline, the specific health questions, and the target population Stakeholder Involvement (3 items) Focuses on the extent to which the guideline was developed by the appropriate stakeholders and represents the views of its intended users Rigour of Development (8 items) Relates to the process used to gather and synthesize the evidence, the methods to formulate the recommendations, and to update them

Search Results
The searches identified 868 potentially relevant records. Following title and abstract screening, 838 were excluded. After a full-text review of 30 potentially eligible records, 17 were excluded as they did not contain recommendations for nutritional interventions. Thirteen guidelines were included in the final analysis. Figure 1 shows the flow diagram for guideline selection.  Table 2 summarises the characteristics of 13 national guidelines from the United Kingdom [24,25], United States [26][27][28], Canada [29,30], Australia [31], New Zealand [32], Spain [33], Germany  Table 2 summarises the characteristics of 13 national guidelines from the United Kingdom [24,25], United States [26][27][28], Canada [29,30], Australia [31], New Zealand [32], Spain [33], Germany [34], and the Philippines [35], and an international ophthalmology guideline [36], that were published between  25,32], while the remainder were developed by professional societies or associations for specific eye care professions.  [26][27][28][29]31,34,35] provided nutritional recommendations (either positive or negative) for reducing the risk of developing AMD (primary prevention) ( Table 3). Guidelines from Canada [29], Germany [34], and Australia [31] included recommendations on the value of dietary modification for primary prevention. With regard to supplements, a guideline produced by an expert panel of optometrists in the United States [28] recommended the use of xanthophil supplements (lutein, zeaxanthin, and mesozeaxanthin) in 'sub-clinical' AMD and another suggested that supplementation with antioxidants may be beneficial for those who are nutritionally deficient [26]. Five guidelines specifically stated that there was evidence that use of high-dose anti-oxidant vitamin and mineral supplements was not beneficial for primary prevention (Table 3) [24, 27,31,34,35].

Characteristics of Included Guidelines and Nutritional Recommendations
All of the included guidelines provided recommendations regarding nutritional strategies for secondary prevention (i.e., slowing the progression of AMD) ( Table 4). Five guidelines [24,28,30,31,33] included dietary advice, consisting of encouraging people with AMD to eat a healthy diet and, in particular, to increase consumption of foods rich in the macular carotenoids (lutein and zeaxanthin) and/or eat more oily fish as a source of omega-3 essential fatty acids. With regard to nutritional supplements, all guidelines addressed the topic of antioxidant vitamin and mineral supplements; the vast majority referred to supplements containing the combinations of antioxidant vitamins, zinc and carotenoids used in the Age-Related Eye Disease Studies (AREDS) or AREDS2 studies [7,8]. Only the U.K. National Institute for Health and Care Excellence (NICE) guideline [25] did not advocate the use high-dose antioxidant vitamin and mineral supplements for the secondary prevention of AMD. The NICE guideline committee concluded that "the current clinical evidence was not able to demonstrate a clear treatment benefit of antioxidant vitamin and mineral supplement for people with early AMD and was insufficient to make a strong recommendation on the use of these supplements". The majority of guidelines acknowledged the risks as well as the benefits of antioxidant vitamin and mineral supplementation. Although acknowledging the lack of evidence, two guidelines [28,34] stated that omega-3 fatty acid supplements could be considered. By contrast, the NICE committee [25] concluded that "omega-3 fatty acid supplementation had no meaningful effect on AMD progression and visual acuity, and that therefore no recommendations could be made on this topic".

Clinical Guideline Quality Scores
The overall inter-rater agreement on scoring of the individual items was excellent (correlation coefficient: 0.81 (95% confidence interval (CI) 0.76 to 0.84)).
The quality of each guideline, across each of the AGREE II domains, is shown in Table 5. The median percentage scores (%) for different domains ranged from 13% to 75%, with substantial heterogeneity in quality between guidelines. Only two of six domains had a median score over 50% ('Scope and Purpose' and 'Clarity of presentation'). The lowest scoring domains were 'Applicability' (median 13% (range 0 to 98%)), 'Editorial Dependence' (median 20.8% (range 0 to 100%)), and Rigour of Development (median 20.4% (range 9.2 to 95.9%)). For the 'Rigour of Development' domain, only four of the 13 guidelines achieved a score ≥50%; this was largely due to a failure to demonstrate that systematic methods had been used to search for relevant evidence, no description of the criteria used for selecting and/or evaluating the evidence, and no information on the methods used by the developers to formulate recommendations.

Mapping Clinical Guideline Recommendations to Systematic Review Evidence
We extracted individual recommendations relating to nutritional strategies for both preventing and slowing the progression of AMD (see Tables 3 and 4 for an overview). For some guidelines, no evidence was provided to support nutritional recommendations [33,36]. For other guidelines, individual studies (i.e., RCTs or prospective cohort studies) were cited. Only four guidelines [24,25,30,34] included evidence from systematic reviews despite the availability of reliable systematic reviews for all of the extracted nutritional recommendations [13][14][15][16][17][18][19][20][21][22][23].   3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements. Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.

None
ions: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet otenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Table 4. Nutritional recommendations for secondary prevention (i.e., slowing the progression) of age-related macular degeneration (AMD).

Systematic Review Cited with a Recommendation
ions: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet otenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements. mmendations for secondary prevention (i.e., slowing the progression) of age-related macular degeneration (AMD).

Systematic Review Cited with a Recommendation
included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet anthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Table 4. Nutritional recommendations for secondary prevention (i.e., slowing the progression) of age-related macular degeneration (AMD).

Systematic Review Cited with a Recommendation
ions: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet otenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.   3 Diet high in sume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean uraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ent may be beneficial, and should be discussed in conjunction with the patient's tweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Balanced diet; 2 A diet high in green, leafy vegetables (rich in antioxidants and carotenoids); 3 A diet high in macular carotenoids (zeaxanthin and lutein) and omega-3 fatty acids; 4 Antioxidant nutrient supplements (particularly for nutritionally deficient); 5 Evidence of no benefit for antioxidant vitamin and/or mineral supplements for primary prevention; 6 Supplement containing xanthophylls (lutein, zeaxanthin, meso-zeaxanthin) for 'sub-clinical' AMD. 7 Supplements not currently recommended for people with normal ageing changes.
ions: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet otenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.
Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements. Diet anthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements. Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements. Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Table 4. Nutritional recommendations for secondary prevention (i.e., slowing the progression) of age-related macular degeneration (AMD).

Clinical Guideline
Dietary Advice Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Table 4. Nutritional recommendations for secondary prevention (i.e., slowing the progression) of age-related macular degeneration (AMD).

Clinical Guideline
Dietary Advice Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Table 4. Nutritional recommendations for secondary prevention (i.e., slowing the progression) of age-related macular degeneration (AMD).

Clinical Guideline
Dietary Advice Abbreviations: , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean iet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's edical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements. Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in es (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean etables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ecommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's vidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence plements.  Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean et rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies r AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's dical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence of omega-3 fatty acid supplements.   3 Diet high in sume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean uraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies ent may be beneficial, and should be discussed in conjunction with the patient's tweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence , recommendation included; NICE, National Institute for Health and Care Excellence; NR, no recommendation. Guideline recommendations: 1 Diet rich in carotenoids (lutein and zeaxanthin) and omega-3 fatty acids; 2 Dietary intake of antioxidants, docosahexaenoic acid, and omega-3 fatty acids; 3 Diet high in fresh fruit and green, leafy vegetables (rich in antioxidants and carotenoids); 4 Consume oily fish rich in DHA and follow healthier eating styles e.g., Mediterranean diet; 5 A diet rich in green leafy vegetables, fish and antioxidants should be encouraged; 6 Antioxidant nutrient supplements; 7a Age-Related Eye Disease Studies (AREDS) or AREDS2 supplement recommended; 7b AREDS or AREDS2 supplement may be beneficial, and should be discussed in conjunction with the patient's general medical practitioner. 8 No evidence that benefit of AREDS supplement outweighs the risk; 9 Omega-3 fatty acid supplement recommended; 10 No evidence for benefit of omega-3 fatty acid supplements.

Discussion
Nutritional supplements for 'eye health' are marketed at the general population, and are also widely recommended by optometrists and ophthalmologists for people who have clinical signs of AMD [37,38]. Clinical practice guidelines are a useful method for presenting evidence-based recommendations to health care professionals, and are intended to be used to inform clinical decision-making and reduce potential variations in practice. The aims of the current study were to identify all clinical guidelines for AMD that include recommendations relating to diet and/or nutrition; to evaluate the methodological quality of these guidelines using the AGREE II tool (the most widely used instrument for appraising clinical practice guidelines); and to investigate whether specific nutritional recommendations were underpinned by evidence from systematic reviews.
We identified 13 clinical practice guidelines meeting our inclusion criteria. The overall quality of these guidelines was judged to be low to moderate, with the median percentage scores for four of the six AGREE II quality domains being below 50%. The lowest scoring domains were 'Rigour of Development', 'Applicability', and 'Editorial Independence'. Low scores in these domains are of major concern, as they relate to: the process by which relevant research evidence is gathered and synthesised; the methods used to formulate the recommendations; the likely barriers and facilitators to implementation of the guideline recommendations; and how conflicts of interest are managed. It is important that guideline users are able to identify the evidence underpinning each recommendation, however many of the guidelines failed to make an explicit link to the evidence used to formulate recommendations. Transparency with respect to the reporting of conflicts of interest amongst guideline development panels is also essential, to avoid the potential for biased recommendations. Patient engagement in the development of the clinical practice guidelines was also generally poor, despite standards (including those defined by the World Health Organisation) [39] recommending the inclusion of patients on guideline development panels. The intent of this engagement is to ensure a focus on patient-centred guidelines that can enhance the quality of care [40].
Only one guideline (the National Institute for Health and Care Excellence (NICE) guideline NG82) achieved high scores in all of the AGREE II assessment domains. This is perhaps unsurprising, since the NICE guideline development manual states that NICE guidelines "are based on internationally accepted criteria of quality as detailed in the Appraisal of Guidelines of Research and Evaluation II (AGREE II) instrument". The development and implementation of high quality clinical practice guidelines requires substantial time, expertise and resources. Less formal guideline development groups, such as those produced by 'expert panels' or professional organisations, may lack the resources and/or methodological expertise to produce guidelines of the highest quality. In such circumstances, adapting existing high quality guidelines to local contexts may be an alternative to de novo development. The AMD Preferred Practice Patterns (PPP) Philippines (2016) [35] is an example of where this strategy has been adopted. This guideline was prepared by a panel from the Vitreo-Retina Society of the Philippines for the Philippine Academy of Ophthalmology, by adapting recommendations from the American Academy of Ophthalmology (AAO) PPP for AMD (updated in 2015).
Many robust systematic reviews have considered the merit of a variety of dietary and nutritional recommendations for AMD. In the present study, we used the systematic evidence searches performed by Lindsley et al. [11] and Downie et al. [12] to identify relevant systematic reviews, up to March 2017. These studies identified 11 unique systematic reviews on nutritional interventions for AMD, published between 2007 and 2016. Four of these reviews were published in the Cochrane Library. Mapping of clinical practice guideline recommendations to systematic review evidence showed that four of the included guidelines [24, 25,30,34] made reference to systematic reviews to support their nutritional recommendations. Other guidelines included evidence from individual RCTs or non-randomised trials only. In some cases, recommendations were provided with no supporting citations. Although it is likely that a proportion of the systematic review evidence would not have been available to the panels developing the three earliest guidelines, published between 2004-2009 [26,33,36], this evidence would certainly have been available to later panels and could have been used to inform their recommendations. Inconsistent uptake of evidence from systematic reviews by decision-makers and guideline developers is known to be related to several factors, including lack of awareness, lack of access and lack of familiarity [41]. The outcome of failing to use the best-available research evidence (i.e., systematic reviews) to inform practice guidelines is that this time-intensive, rigorous research effort is wasted. Furthermore, the entire rationale for the guideline to support evidence-based practice, and optimise patient outcomes is potentially not achieved.
Of the nine guidelines that considered nutritional approaches for the primary prevention of AMD, most considered the potential merit of dietary modification, although some also made recommendations in relation to nutritional supplementation. Several epidemiological studies have investigated whether specific dietary patterns and/or foods are associated with a reduced risk of developing AMD. A meta-analysis of prospective cohort, case-control and cross-sectional studies concluded that consumption of two or more servings of oily fish per week was beneficial in the primary prevention of AMD [13]. Another recent systematic review reported that a high consumption of vegetables rich in carotenoids and oily fish containing omega-3 fatty acids was beneficial for those at risk of AMD [42]. However, emphasising the potential difference in nutritional benefit(s) derived from whole foods versus supplementation, consuming anti-oxidant supplements does not prevent the primary onset of AMD [16]. It is therefore concerning that a recent (2017) U.S. 'guideline' [28], produced by a panel of optometrists, recommended prescribing xanthophil supplements (i.e., lutein, zeaxanthin and mesozeaxanthin) to patients with 'sub-clinical' AMD, as "it is better to prescribe a supplement than not to prescribe a supplement". Although termed a 'guideline', this document achieved the poorest quality scoring of all those included, with characteristics of a 'clinical viewpoint' rather than a 'guideline' per se.
Nutritional strategies for secondary prevention of AMD (i.e., slowing progression of the disease) were included in all of the clinical guidelines. Five guidelines [24, 28,33,34] included dietary advice, consisting of recommendations for people with AMD to eat a healthy balanced diet and, specifically to increase the consumption of foods rich in the macular carotenoids and/or eat more fish (as a source of omega-3 fatty acids). A Mediterranean diet has been linked to a reduced risk of AMD progression [43]. Epidemiological studies suggest that a high dietary intake of omega-3 fatty acids is associated with a significant reduction in the risk of both intermediate [44,45] and late-stage AMD [46,47]. However, the best-available research evidence does not support long-chain omega-3 fatty acid supplementation for slowing disease progression [15]. Despite this, and acknowledging that there is a lack of evidence to substantiate such a position, two recent clinical guidelines [28,34] included a recommendation for clinicians to consider this approach.
With respect to high-dose anti-oxidant vitamin and mineral supplements for managing AMD, there were divergent recommendations. Notably, only the U.K. NICE guideline [25] did not advocate prescribing supplements containing the formulation of antioxidant vitamins, zinc and carotenoids investigated in the Age-Related Eye Disease Studies (AREDS [7] and AREDS2 [8]). This recommendation was based upon the committee's assessment of the limitations of the current, best-available evidence, and a need for "further research in this area". Indeed, there remain several key unanswered questions. For example, the minimum effective dose required for a given antioxidant to impart a potential retinoprotective effect remains unclear. Whether a single component, or a combination of components, represents the optimal formulation is also uncertain. The NICE guideline committee recommended "a well conducted randomised trial [ . . . ] to provide an evidence base for the benefits and risks of individual components of the antioxidant supplements, and provide the ability to establish the treatment effect of antioxidant supplementation (the AREDS2 formula) on AMD progression by comparing AREDS2 formula with no treatment (for instance normal diet)". Although many of the guidelines considered the potential contraindications and/or side effects of high-dose antioxidant vitamin and mineral supplements, four of the guidelines did not articulate these risks [28,31,32,36]. Given that the decision to prescribe an intervention should balance the potential risks versus benefits of treatment, lack of this key information to guide clinical decision-making is a major shortcoming.
A key strength of the current study was the comprehensive search to identify eligible clinical practice guidelines. Data extraction and quality appraisal were conducted independently by two reviewers, using a recognised assessment tool (AGREE II), which has established metrics of reliability and validity [48]. Overall, the reporting of methodological details for clinical guideline development was poor and therefore it was not possible to make a judgement as to whether the guidelines had used an appropriate evidence-based approach in their development.

Conclusions
Despite the availability of robust systematic reviews evaluating the efficacy and safety of nutritional interventions for AMD, this study found evidence that these resources are infrequently used to support recommendations in AMD clinical practice guidelines. Consequently, guidelines often present conflicting recommendations that could lead to variations in clinical care. The AGREE II quality evaluations of the included guidelines identified several key areas that require improvement, particularly the rigour of development, managing potential conflicts of interests, and presenting strategies for implementing guideline recommendations into daily practice.
Author Contributions: J.G.L., J.R.E. and L.E.D. were involved in all aspects of the study conception and design, data acquisition, analysis and interpretation. J.G.L. wrote the first draft of the manuscript and this was critically revised by J.R.E. and L.E.D. All authors approved the final version of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest in relation to this work.