Ординатура / Офтальмология / Английские материалы / Nutrition and the Eye A Practical Approach_Eperjesi, Beatty_2006

Table 5.2.1 Relationship between dietary intake of lutein and macular pigment optical density

be related to specific lesions of early ARM or late AMD, thus suggesting that self-selected dietary patterns of older women in the recent past do not appear to be strongly associated with prevalence of ARM. However, further work is needed to investigate whether dietary intakes over longer periods in an individual’s past are related to ARM.

In CAREDS, although total dietary intake of fat was not associated with early ARM, the type of dietary fat was related to risk for this condition with diets high in polyunsaturated fatty acids associated with increased risk of drusen, pigmentary abnormalities and retinal pigment abnormalities, whereas monounsaturated fats were protective against these lesions. Dietary intake of long-chain omega-3 fatty acid was not associated with early ARM in CAREDS.

BODY FAT LEVEL AND DISTRIBUTION AND ARM IN CAREDS5 , 6

BMI (kg/m2) and WHR at CAREDS baseline were used to determine body fat level and distribution, respectively. High BMI was positively related to pigmentary abnormalities at the macula, whereas high WHR was associated with retinal pigment epithelial abnormalities, suggesting that adiposity represents a risk for ARM.

SUPPLEMENT USE AND ARM IN CAREDS7

Eighty-eight per cent of women in CAREDS used vitamin and mineral supplements. Three types of supplement were identified, as follows: multivitamins; high-dose antioxidants (at least two of the following: >10 000 IU/day of b-carotene; >120 mg/day vitamin C; or >60 IU/day of vitamin E); and high-dose zinc (>15 mg/day). Interestingly, use of high-dose antioxidant supplements for a prolonged duration (>10 years) was associated with lower risk for early stages of ARM, whereas use of multivitamins or high-dose zinc supplements was unrelated to ARM.

Forty-eight per cent of subjects had consumed supplements containing L, although the median intake of supplemental L was only 250 mg. Preliminary analysis has revealed that supplement use is more common with higher dietary intake of L and Z, and may therefore confound relationships. Consequently, the investigators have emphasised that they will evaluate the relationships between supplement use over time and the ophthalmic end-points, and adjust for dietary intake.

MENOPAUSAL HORMONE THERAPY AND ARM8

The profile of the CAREDS sample provided an excellent opportunity to investigate previous reports indicating a reduced risk of ARM among women who used HRT. Past use of HRT was found, in CAREDS, to be associated with reduced risk of soft drusen, although the protective effect was not related to the duration of HRT use.

Current HRT use was marginally associated with increased risk of late ARM, suggesting that such therapy use may have a different impact on ARM pathogenesis or progression depending on the stage of the disease at the time of exposure to HRT.

CONCLUSION

CAREDS has the potential to investigate a number of other important relationships, including those between serum concentrations of L and Z and

MPOD. Also, factors contributing to a relative lack of MPOD and/or serum levels of the xanthophylls (in spite of adequate dietary intake of the macular carotenoids), if any, will be identified. Further, the relationship between MPOD and ARM will be investigated.

CAREDS is the largest cohort study of the relationships between dietary carotenoids and

References

the two major age-related eye diseases, ARM and cataract. It will help to determine whether intake of these carotenoids is essential to eye health in middle and older age, and, if so, will suggest a level of intake that is associated with a reduction in risk for such ocular morbidity, and will help to identify factors that may modify these relationships.

1.Carotenoids and Age-related Eye Disease Study Research Group. CAREDS manual. Madison, WI: University of Wisconsin, Madison.

2.Snodderly M, Mares JA, Wooten BR et al. Macular pigment density of women in the Carotenoids in AgeRelated Eye Disease Study (CAREDS). ARVO Abstract 2004; B605.

3.Mares-Perlman JA, Snodderly D, Gruber M et al. Determinants of macular pigment density in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women’s Health Initiative. ARVO Abstract 2004; B601.

4.Moeller SM, Tinker LF, Blodi B et al. Relationship between dietary patterns and age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women’s Health Initiative. ARVO Abstract 2004; B729.

5.LaRowe TL, Mares JA, Wallace RB et al. Relationships of body fat level and distribution to age-related

maculopathy in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women’s Health Initiative. ARVO Abstract 2004; 2244.

6.Mehta NR, Blodi B, Ritenbaugh C et al. Relationship between dietary fat and age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women’s Health Initiative. ARVO Abstract 2004; B759.

7.Gruber MJ, LaRowe T, Moeller SM et al. Relationship of supplement use to age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study to the Women’s Health Initiative (WHI). ARVO Abstract 2004; B766.

8.Wallace RB. Association of menopausal hormone therapy to age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study (CAREDS), an ancillary study of the Women’s Health Initiative. ARVO Abstract 2004; B764.

via a questionnaire. These were measured at baseline, 4 months, 8 months and 12 months. The seven-increment Lens Opacity Cataract Scale was used to evaluate subjectively lens opacification at baseline and the final examination. Compliance was assessed by telephone. Fourteen subjects failed to complete the study, but 96% of subjects took nearly 92% of their assigned capsules.

At the end of the trial when the groups were unmasked, in groups 1 (L) and 2 (L/A), MPOD increased by approximately 0.09 log units from baseline, Snellen equivalent visual acuity improved by 5.4 letters for group 1 (L) and 3.5 letters for group 2 (L/A); contrast sensitivity also improved for groups 1 and 2. There was a net subjective improvement in Amsler grid for group 1

(L) only and there was a subjective improvement in glare recovery after 4 months of supplementation for group 2 (L/A); this finding is very likely to relate to the increase in MPOD. Subjects in group 3, who received the placebo, had no significant changes in any of the measured findings. Interestingly, there was no progression in AMD retinopathy or lens opacification for any subject, irrespective of their group, and there were no significant between-group differences in minor side-

effects among groups 1 (L) and 2 (L/A) and 3 (P). None of the subjects in group 2 (L/A) experienced a minor cardiovascular event or died during the trial, whereas 4 subjects in group 1 (L) and 3 subjects in group 3 (P) underwent cardiovascular surgery or died.

CONCLUSIONS

The investigators concluded that visual function improved with L alone or L together with other nutrients. However, they also noted that the results should be considered as preliminary given the small number of subjects, the short time period of observation and the lack of statistical significance among the three groups. Nevertheless, this is an important study, which showed that atrophic AMD is a nutrition-responsive disorder and that improvements in visual function can be obtained over a short period of time. The research team went on to suggest that further studies were needed with more patients, of both genders, and for longer periods of time to assess long-term effects of L or L together with a broad spectrum of antioxidants, vitamins and minerals in the treatment of atrophic AMD.

1.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 2004; 75:216–230.

CHAPTER CONTENTS

Purpose 218 Inclusion/exclusion criteria 218 Randomisation 218

Masking 218

Study formulation 218 Baseline data 218 Outcome measures 218 Fundus photography 218 Visual acuity 219 Contrast sensitivity 219 Colour vision 219 Follow-up 219 Discussion 219 References 220

Age-related macular disease is the leading cause of blind registration in the developed world. One aetiological hypothesis involves oxidation, and the intrinsic vulnerability of the retina to damage via this process. This has prompted interest in the role of antioxidants, particularly the carotenoids lutein and zeaxanthin, in the prevention and treatment of this eye disease.

Randomised controlled trials (RCTs) are considered to be the ‘gold standard’ in clinical research.1,2 They involve random assignment of participants into treatment and placebo groups. They have the ability to reduce, by masking, the influence of confounding variables by random assignment of the treatment (intervention), and the ability to reduce bias or the possibility that any observed effect is due to other factors. The term ‘double-masked’ or ‘double-blinded’ refers to the fact that neither participants nor investigators know who is in the treatment or placebo group. In RCTs designed to investigate the effect of nutritional supplements, this is usually achieved by coding the tablet containers. At the end of the trial period the code is broken and the gathered data analysed.

In summary, any RCT will involve the following steps:3

1.sample selection from the population

2.baseline variables measured

3.participants randomised

4.interventions applied (one will be a placebo)

5.follow-up of the cohort

6.outcome variables measured

7.results analysed.

PURPOSE

The purpose of the Aston RCT is to determine the effect of 18 months of daily lutein and antioxidant supplementation on measures of visual function in subjects with and without age-related macular disease. At the time of writing the study is ongoing.

INCLUSION/EXCLUSION CRITERIA

For inclusion participants have to present with no ocular pathology in one eye, or no ocular pathology other than dry age-related macular degeneration in one eye. A cataract-grading system consisting of grades 1, 2 and 3 for each of cortical, nuclear and posterior subcapsular cataracts has been developed. Participants presenting with lens opacities precluding fundus photography are excluded. Throughout the trial period, progression of any type of cataract to the successive grade will require the participant to withdraw. Participants also have to provide written informed consent, and have to be available for three visits to Aston University, Birmingham.

Exclusion criteria include type 1 and 2 diabetes because vitamin E has been shown to affect glucose tolerance4–8 and diabetic retinopathy may confound the results. Those taking warfarin medication are excluded as zinc may decrease the absorption and activity of warfarin,9 as are those who use nutritional supplements that potentially raise vitamin and mineral intake above safe limits. The most recent guidelines for upper limits of nutritional supplementation are set out in the UK Food Standards Agency report.10 Neovascular agerelated macular degeneration and other ocular disease that could potentially interfere with the results are excluded.

Park, Birmingham B7 4AP, and are identical in external and internal appearance, and taste. The tablets are packaged in identical, sealed, white containers; the only difference is the symbol on the label. The manufacturer has allocated distinguishing symbols, μ and l. Investigators and participants do not know which symbol represents the placebo tablets, and which represents the active formulation.

STUDY FORMULATION

The study formulation contains the following nutrients in each tablet:

Participants in both groups are instructed to take one tablet, at the same time every day, with food.

BASELINE DATA

On application, participants complete a food frequency questionnaire, a food diary and a health questionnaire. The food questionnaire and diary ask for information about diet for analysis using Foodbase 2000 software (Institute of Brain Chemistry and Human Nutrition, London N7 8DB).

The health questionnaire provides information about general health, ocular health, nutritional supplementation, medication, smoking history and time spent living abroad.

RANDOMISATION

The random number-generator function in Microsoft Excel is being used to allocate participants to μ and l groups. Even numbers are allocated to the l group.

OUTCOME MEASURES

The investigation of several measures of visual function is required, as age-related macular disease can produce varying signs and symptoms.

The study formulation and placebo tablets have been produced by Quest Vitamins, Aston Science

Fundus photographs of the macula will be assessed using colour and edge analysis software.

Macular Mapping Test

The Macular Mapping (MM) test (SmithKettlewell Research Institute, 2318 Fillmore Street, San Francisco, CA 94115, USA) was developed to map visual defects caused by macular disease. It was developed by MacKeben and Colenbrander11 and differs from conventional field analysis in that the stimuli are single letters rather than spots of light. This is a novel piece of equipment and each participant is given a practice run to eliminate learning effects. At the end of the test a single figure score is presented.

Glare recovery

Eger Macular Stressometer (EMS) (Gulden Ophthalmics, Elkins Park, PA 19027, USA) is used to assess photostress recovery time (PSRT). This is the time taken for the regeneration of photopigments in bleached photoreceptors. Resynthesis of the photopigments is dependent upon the integrity of the photoreceptors and retinal pigment epithelium;12 it follows that the PSRT may be extended in those with diseases affecting these structures.

VISUAL ACUITY

Distance and near visual acuity are measured using Bailey–Lovie logMAR charts. LogMAR charts have five letters and 0.1 logMAR progression per line. The advantage of using these charts is that they provide an equal-interval scale, and there are five letters per line. Standard Snellen charts do not provide a linear scale and have a decreasing number of letters per line as the letter size increases.

CONTRAST SENSITIVITY

Contrast sensitivity is measured using a Pelli–Robson chart (Clement Clarke International, Edinburgh Way, Harlow, Essex CM20 2TT, UK) and provides additional information about vision. The Pelli–Robson chart determines the contrast required to read large letters and is designed to test mid to low spatial frequencies.

COLOUR VISION

Colour vision measured using the PV-16 quantitative colour vision test (Precision Vision, 944 First Street, La Salle, IL 61301, USA). Macular disease can cause a deficiency in blue-yellow colour vision as the short-wavelength photoreceptors are concentrated around the fovea.

FOLLOW-UP

Data collection will take place at baseline and 9 and 18 months. Data collection takes place in a standard consulting room at Aston University. Enrolment, randomisation and data collection are carried out by HB. HB and FE are masked to group assignment.

DISCUSSION

There is evidence for selective deposition of lutein in the retina, increase of retinal and serum levels of lutein with supplementation, and an increased risk of age-related macular disease with reduced retinal lutein levels. This RCT will provide further information regarding the effect of lutein and antioxidant supplementation on specific measures of visual function in people with and without agerelated macular disease.

Randomised masked trials differ from observational studies in that they have the ability to demonstrate causality. Masking reduces the influence of investigator bias, and the influence of confounding variables is reduced by random assignment of participants to intervention groups. The current paucity of treatment modalities for this condition has prompted research into the development of prevention strategies. A positive effect of the supplementation on normals may be indicative of its potential role in preventing or delaying the onset of age-related macular disease. This may be particularly important for those with a positive family history, or exposure to other risk factors. A positive effect in age-related macular disease-affected eyes may suggest a role of nutritional supplementation in prevention of progression of the disease, or even in reversal of symptoms.

1.Muir Gray J. Appraising the quality of research. In: Richardson P, ed. Evidence-based healthcare. How to make health policy and management decisions. London: Churchill Livingstone; 1997:117–168.

2.Huwiler-Muntener K, Juni P, Junker C, Egger M. Quality of reporting randomized trials as a measure of methodologic quality. J Am Med Soc 2002; 287:2801– 2804.

3.Cummings S, Grady D, Hulley S. Designing an experiment: clinical trials I. In: Hulley S, Cummings S, Browner W et al., eds. Designing clinical research. Philadelphia: Lippincott/Williams & Wilkins; 2001: 143–155.

4.Bierenbaum M, Noonan F, Machlin L. The effect of supplemental vitamin E on serum parameters in diabetics, post coronary and normal subjects. Nutr Rep Int 1985; 31:1171–1180.

5.Paolisso G, D’Amore A, Giugliano D. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin dependent diabetic patients. Am J Clin Nutr 1993; 57:650–656.

6.Paolisso G, D’Amore A, Galzerano D. Daily vitamin E supplements improve metabolic control but not insulin

secretion in elderly type II diabetic patients. Diabetes Care 1993; 16:1433–1437.

7.Tütüncü N, Bayraktar M, Varli K. Reversal of defective nerve condition with vitamin E supplementation in type 2 diabetes. Diabetes Care 1998; 21:1915–1918.

8.Skrha J, Sindelka G, Kvasnicka J, Hilgertova J. Insulin action and fibrinolysis influenced by vitamin E in obese type 2 diabetes mellitus. Diabetes Res Clin Pract 1999; 44:27–33.

9.Pinto J. The pharmacokinetic and pharmacodynamic interactions of foods and drugs. Top Clin Nutr 1991; 6:14–33.

10.Expert Group on Vitamins and Minerals. Safe upper limits for vitamins and minerals. Food Standard Agency 2003. Available online at: www.foodstandards.gov.uk/ multimedia/pdfs/vitamins2003.pdf (accessed 2003).

11.MacKeben M, Colenbrander A. The assessment of residual vision in patients with maculopathies. Noninvasive assessment of the visual system. Tech Dig 1993; 3:274–277.

12.Brindley G. Physiology of the retina and visual pathways. Baltimore, MD: Williams & Wilkins, 1970.

Clinical examinations/procedures to be

The CARMA study is a multicentre study investigating the potential beneficial effects of antioxidant supplements, including lutein (L) and zeaxanthin (Z), on the course of age-related maculopathy (ARM). Recruitment started in July 2004, and preliminary results will be available in 2007. The following is a description of the CARMA protocol.

INTRODUCTION

There is general consensus that cumulative blue light damage and/or oxidative stress play important roles in the pathogenesis of ARM and its late stage, AMD. Macular pigment, composed of the carotenoids L and Z, is a blue light filter and powerful antioxidant and is thought to protect against AMD. A recent randomised placebo-controlled trial of 4757 subjects, the AREDS,1 demonstrated a reduction in the risk of progression to AMD in eyes with ARM after long-term supplementation with high doses of naturally occurring antioxidants (vitamin C, vitamin E, b-carotene and zinc). AREDS was not designed to detect subtle differences in visual function in the short term between the various intervention groups as its principal aim was to identify a protective role in the prevention of progression to advanced AMD. AREDS also did not use L and Z which were unavailable at the time of inception of that study.

The CARMA investigators therefore designed a pilot randomised controlled clinical trial of parallel-group design, where patients at high risk of developing advanced AMD are invited to par-

ticipate. Subjects are randomised to receive an antioxidant cocktail containing vitamins, minerals and L + Z or placebo, and undergo tests of macular function at baseline and at 6-monthly intervals. Differences between groups in the rate of deterioration of visual function in response to antioxidant supplements, if observed, will strengthen the argument for screening for ARM and the use of dietary modification with or without supplementation. This study will also provide insight into the potential role that antioxidants play in maintaining macular health.

The primary hypothesis is that progression from early ARM to late AMD may be delayed or prevented through supplementation with key antioxidants (vitamins, minerals and carotenoids) which are either known to be present in high concentrations in healthy neural retina–retinal pigment epithelium–choroidal interface, or are free radical scavengers and thus have potential protective roles in minimising oxidative stress.

OBJECTIVES

●To study the effect of supplemental antioxidants on macular psychophysical function in eyes at very high risk of AMD within the context of a randomised controlled clinical trial.

●To measure macular pigment in vivo by resonance Raman spectroscopy and to assess serum levels of the biochemical constituents of macular pigment in subjects participating in the above trial.

1.protocol number

2.production lot number of the test articles

3.investigator number

4.patient number

5.expiry date of the test and placebo articles

6.storage conditions

7.caution.

ROUTE OF ADMINISTRATION

Patients will be randomised to receive by mouth two tablets of Carmavite daily, or two tablets of the placebo during the 12-month study period. Masking of the patient, study coordinator, visual acuity examiner, photographer and examining ophthalmologist is maintained throughout the 12-month study period.

PATIENTS

Number and source

Approximately 500 patients who meet the inclusion/exclusion criteria will be enrolled in this study.

Inclusion criteria

●Patients must be willing to give written informed consent, make the required study visits and follow instructions.

●Patients must be at least 50 years of age.

●Patients may be of any race and either sex.

●Two categories of ARM patients may be included: category 1 and category 2.

TEST AND CONTROL ARTICLES

Study medications

●test article: L + Z+ vitamins C, E and zinc: 2 tablets per day (to be known as Carmavite)

●the test article and placebo will be supplied in sealed containers.

Category 1

●If there is choroidal neovascularisation or geographic atrophy in one eye, any level of ARM is permissible in the fellow eye provided that visual acuity is equal to or better than logMAR 0.3.

Category 2

LABELLING

The container labelling will consist of the following particulars:

●clinical diagnosis of severe ARM in at least one eye

●≥20 soft distinct or soft indistinct drusen