Article Date: 1/1/2009

Assessing Dry Macular Degeneration
AMD

Assessing Dry Macular Degeneration

Three unanswered questions and new research shape our understanding of AMD.

STUART RICHER, O.D., PH.D., F.A.A.O. North Chicago, Ill.

Though not a medical emergency, dry macular degeneration, which is under the purview of optometrists, represents 90% of all potential cases of age-related macular degeneration (AMD). Left untreated, it leads to an inability to safely drive an automobile and read.

In this article, I review the open, unanswered questions concerning risk assessment, genetic testing and supplementation and then discuss high-impact emerging visual function research likely to continue to impact our profession in the near future.

Three unanswered questions

1. Secondary Prevention: Is it possible to prevent catastrophic vision loss in high risk AMD patients?

Based upon the original Age-Related-Eye-Disease Study (AREDS) 2001 Report no. 8 and the Cochrane Review in 2006, the answer is yes.1,2 Use of above recommended daily allowance doses of vitamins C, E and beta carotene and the mineral zinc, with doses specified in the original study formulation, resulted in a relative risk reduction from 28% to 20%. High-risk patients include those with a single large soft drusen, multiple intermediate soft drusen, RPE rarefaction/chorioretinal atrophy (especially parafoveal) or a sentinel AMD event in one eye, such as AMD neovascularization/geographic atrophy. Statistically speaking, 14 high-risk AMD patients will need to be placed on an AREDS formula to protect one of these patients against catastrophic vision loss (neovascularization or geographic atrophy), through a five-year period. AREDS post hoc analysis reports no. 20 and no. 22 suggest, but do not prove, that this relative risk can be improved further with inclusion of omega-3 fatty acids and the carotenoids lutein/zeaxanthin, respectively.3,4 A definitive answer concerning omega-3/carotenoids is the subject of the AREDS II study, in which prospective, randomized, double-masked, placebo controlled data are now being acquired in order to establish (or not establish) a causal, and not merely associative, relationship.5 Results are expected in 2012.

2. Primary Prevention: Can vitamins and minerals help the "worried well;" for example, the daughter or son who is concerned that they too may develop AMD?

The three major AMD risk factors are age, smoking and obesity. Inflammation and oxidative stress are no doubt involved with the pathogenesis. Association studies have identified DNA variants (single nucleotide polymorphisms or SNPs) strongly associated with disease susceptibility. The first "AMD gene" discovered was complement factor H (CFH) now known to be affected by five different SNPs. However, subsequent multiple additional genes have been identified in AMD, including secondary complement pathway activating gene CC3 on chromosome location 19p13 and two genes, which increase oxidative stress: the ARMS-2 gene (chromosome location 10q26) and a mitochondrial DNA (mtDNA) gene.6,7 A SNP comprehensive genetic–environmental clinical blood test and age-stratified and individualized risk analysis is now available from Arctic Dx (www.macularisk.com).8 Figure 1 shows a photo of the "Macula Risk" saliva–based sampling kit, and Figure 2 shows the percentage of risk of developing AMD with age by Risk Group Frequency.

Figure 1: The "Macula Risk" saliva collection kit.

Figure 2: The results of the Macula Risk test indicates levels of AMD risk from 1 through 5 (1 = low risk, 5 = very high risk), with each level corresponding to a specific lifetime and age-stratified percentage risk. The population frequency of each risk group varies.

The recent Cochrane Review of preventive AMD data suggests that intake of extra vitamins (minerals) aren't helpful in preventing the disease.2 However, the data are limited, as few studies were devoted to evaluating the primary prevention question. It appears likely that increased dark green leafy vegetable and fish consumption are helpful, in part because they also help reduce associated cardiovascular risk factors and improve vision (see below). It appears prudent to advise our "worried well" to maintain a proper body mass index (BMI) and avoid smoking, while keeping to a healthy diet devoid of any overt micronutrient and essential fatty acid deficiencies. A good quality moderately-dosed broad spectrum ocular multivitamin mineral formulation is probably a good idea for those who demonstrate genetic risk.

3. Stabilization and improvement of vision function: Is this possible for AMD patients?

The PHOTOTROP Study (2003) suggests the use of mitochondrial support (mitotrophic) nutrients might improve vision as well as retinopathy.9 The LAST study (2004), conducted at our laboratory, suggested that vision in AMD can be improved with intake of 10mg of the carotenoid lutein with or without other antioxidants. The LUXEA (2006/7), LUNA (2007) TOZAL (2007) and CARMIS (2008) recent clinical trial data substantiate our findings of either an improvement in macular pigment optical density or improvement in vision in most AMD patients with intake of lutein/zeaxanthin.10-14 Our LAST II data further suggests that the AMD patients who benefit most, in terms of enhancing macula pigment, are those who have the lowest macular pigment readings — i.e. the lowest habitual intake of carotenoids.15

Baseline pre-intervention data from The zeaxanthin and Vision Function (ZVF) Study of patients with mild and moderate AMD, presented earlier this year, suggests that macular pigment is central to global AMD visual function and positively correlated with visual acuity, low luminance vision, contrast sensitivity, glare recovery, tritan vision and even self-assessed NEI VFQ subscale-driving ability.16 Because of the small time frame (one year) and limited number of patients (n=60) in study, there isn't enough statistical power to determine whether zeaxanthin actually affects disease progression. (See "Early Results from the ZVF Study," below.)

Early Results from the ZVF Study
The ZVF (Zeaxanthin and Vision Function) Study (FDA protocol #78793 Chrysantis, Inc, West Chicago, Ill.), which is being conducted at the Department of Veteran Affairs Hospital in North Chicago, began in December 2007. ZVF is a randomized, double-blind, lutein-controlled study of the predominant foveal carotenoid, Z, on MPOD, visual function, retinal blood flow and neuro-cognitive status in atrophic AMD. The sample population includes 60 AMD patients (approx 120 eyes) randomly assigned to one of two dietary supplement treatment carotenoid pigment arms (8mg Z; n=25 and 8mg Z/9mg L; n=25), or to a traditional 9mg lutein supplement intervention control group (n=10).
Baseline demographic, visual function, ocular and neurocognitive assessment profiles post-randomization have been presented at the ARVO 2008 poster section in Ft Lauderdale, Fla.17 All 60 subjects have completed their baseline examinations, and we are preparing this baseline data for peer review. Although, the power and time frame of this study are probably insufficient to assess clinical AMD disease progression, our comprehensive data set should provide further unique insights about AMD visual function and response to supplemental nutritional carotenoids.

The emerging centrality of macula pigment (MP)

Some 600 carotenoids exist in nature with 50 carotenoids in the food chain, 13 in human plasma and six of these of high concentration in the plasma. Within this group of six, there is growing interest concerning the two macula oxy-carotenoid pigments lutein (L) and zeaxanthin (Z). These MPs are not synthesized from the body and therefore must be taken in from the diet. L predominates in the para-foveal macula, while Z predominates in the central fovea. A third carotenoid: mesozeaxanthin (MZ), of which we know very little, but which may help to stabilize outer segment photoreceptors can only be synthesized from L:

► lutein (36% and peri-foveal-peripheral)

► zeaxanthin (18% and central)

► mesozeaxanthin (18% and central-posterior retina)

These anatomic considerations alone suggest that if doctors prescribe supplements, they should always attempt to supplement with L and Z together, and not Z alone. A key question remains, however about these carotenoids affects on MP, as delineated in the excellent recent summary article by Beatty et al.18

The in vivo measurements of MP are mostly indirect and do not reflect absolute retinal levels because:

► selecting a method of measuring MP and assessing the validity of MP measurements presents difficult choices.

► correlations between MP and dietary and serum L and Z are poor.

To measure MP, the authors point to heterochromic flicker photometry (HFF), which is not influenced by the optical properties of the pre-retinal media and does not require pupil dilation. However, HFF requires 20 minutes per eye, which may present difficulties for older patients who can become fatigued. Two simplified, fovea–only HFF instruments, which require five minutes per eye, are now available in the United States: They are: The Macu-Check, from Marco Instruments, and the QuantifEye, from ZeaVision. Neither instrument however, provides a distribution graph or 3D image of MP.

It is yet to be determined which imaging modality (i.e. Raman spectroscopy, SLO fundus reflectometry or lipofuscin autofluorescence) will yield the most accurate and reliable distribution (and foveal value) of MP, especially in the presence of media opacities, such as cataract. In the ZVF study, of which I am principal investigator, we have found "crown-like" distributions of MP in many patients when examined using an autofluorescence instrument. (See figure 3.)

Figure 3: Fourteen-degree autofluorescent MP distribution maps of the population typically appear as illustrated on the left. However, a number of subjects have crown-like distributions (with a central depression) as illustrated on the right.

The poor correlation between serum levels and MP may be due to adipose tissue, a major storage depot for carotenoids and fat, which competes with retinal tissue for the ocular carotenoids. To account for the effects of adipose tissue, assessing BMI (body mass index) and percentage of body fat (via for example, bioelectric impedance) may very well become crucial in the future. Indeed, we are measuring both in our current research project. MP appears to be central to visual function in AMD patients. (See figure 4.)

Figure 4: This indicates the potential centrality of MP to human vision in disease-free and AMD patients.

The carotenoids L and Z may well be important in stabilizing or perfecting vision in disease–free patients. This is most important for patients with poor diets, who are obese and who also smoke. Often these factors occur in combination. Work from our laboratory has determined that supplemental intake of 10mg L is associated with improved visual function — namely better visual acuity, contrast sensitivity (CSF), glare recovery and even resolution of scotomas/metamorphopsias in AMD patients.10 More recently, we have shown that the baseline value of MP is crucial because the greatest rate of change in MP occurs in those patients with the lowest MP values15 (see figure 5).

Figure 5: Change in MPOD from Baseline to 12 Months, Controlling for Baseline Density. Note the greater change in MPOD for lower du values of baseline pigmentation.15

Supporting research

Several studies support the conclusions from our laboratory. The LUXEA (Lutein Xanthophyll Eye Accumulation) Study recently demonstrated that blue light sensitivity (mesoptic threshold) could be increased with 10mg L/2 mg Z.11 The LUNA (Lutein Nutrition effects measured by Autofluorescence) Study demonstrated that "Saturable mechanisms must play a role in the retinal capture and/or stabilization of the macular carotenoids."12 As with our results, there were several individuals who did not respond to carotenoid supplementation. Recently the results of an ancillary study of the CARMIS (Carotenoids and Antioxidant in Age Related Maculopathy Italian Study) have been published in Ophthalmology14: The study evaluated the multifocal ERG responses in AMD patients taking 10mg lutein, 1mg zeaxanthin, 4mg astaxanthin, 180mg of vitamin C; 30mg of vitamin E; 22.5mg of zinc and 1mg of copper. The authors state "In non-advanced AMD eyes, a selective dysfunction in the central retina occurs (0° to 5°) that can be improved by supplementation with carotenoids and antioxidants." No functional changes were present in the more peripheral (5° to 20°) retinal areas. Finally, in the TOZAL (Taurine – Omega III – Zinc – Antioxidants – Lutein) Study, an open case control study of an oral antioxidant and omega-3 supplement for dry AMD, the authors stated "The results of the TOZAL study agree with the LAST, LUXEA and CARMIS studies and are predictive for positive visual acuity outcomes in the AREDS II trial.13 However, patients will likely require supplementation for longer than six months to effect changes in additional visual parameters."

In terms of disease, it was recently demonstrated that low MP levels are associated with risk factors for vision loss from AMD such as 1) increasing age; 2) obesity; 3) smoking and 4) family history in otherwise healthy subjects ages 20 to 60.16 There is new evidence from AREDS that these carotenoids may protect the eye from advanced catastrophic vision loss as a result of AMD. Demographic, lifestyle and medical characteristics were ascertained on 4,519 AREDS participants aged 60 to 80 at enrollment. The highest vs. lowest quintiles of carotenoid intake after adjustment for total energy intake and non-nutrient-based covariates were determined.4 Dietary lutein/zeaxanthin intake was inversely associated with:

► Large or extensive intermediate drusen (odds ratio [OR] 0.73; 95% confidence interval [CI], 0.56-0.96).

► Neovascular AMD (OR 0.65; 95% CI 0.45-0.93).

► Geographic atrophy (OR 0.45; 95% CI, 0.24-0.86)

Conclusion

This is an exciting time to be an optometrist, as we can now more fully address function as well as structure of the visual system and eye. You, the optometrist, now have the ability to enhance visual function with nutrition (diet and supplementation) as well as refractive intervention. OM

1. 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, Arch Ophthalmol. 2001 Oct; 119(10):1417-36.

2. Evans JR, Henshaw K. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration, Cochrane Database Syst Rev. 2008 Jan 23;(1).

3. SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007 May;125(5):671-9.

4. SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22, Arch Ophthalmol. 2007 Sep;125(9):1225-32).

5. Age-Related Eye Disease Study 2. The Lutein/Zeaxanthin and Omega-3 Supplementation trial. www.areds2.org. Accessed Dec. 29, 2008

6. Haines JL, Spencer KM, Pericak-Vance MA. Bringing the genetics of macular degeneration into focus. Proc Natl Acad Sci USA 2007 Oct 23;104(43): 16725-6.

7. Haines JL, Pericak-Vance MA. Rapid dissection of the genetic risk of age-related macular degeneration: achieving the promise of the genomic era. JAMA 2007 Jan24; 297(4): 401-2.

8. Save Your Sight. Macula Risk: A genetic test for age-related macular degeneration (AMD). www.macularisk.com. Accessed Dec. 29, 2008.

9. Feher J, Kovacs B, Kovacs I, et al. 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. 2005 May-Jun;219(3):154-66.

10. Richer SP, 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: Veterans LAST study (Lutein Antioxidant Supplementation Trial. Optometry 2004 Apr; 75(4):216-30.

11. Schalch W. et al Arch Biochem Biophy 2007 458(2); 128-135 & Wenzel AJ et al. Optom Physio Optics 2007 27(4), 329-35.

12. Trieschmann M, Beatty S, Nolan JM, et al. Changes in macular pigment optical density and serum concentrations of its constituent carotenoids following supplemental lutein and zeaxanthin: the LUNA study, Exp Eye Res. 2007 Apr; 84(4):718-28.

13. Cangemi FE. TOZAL Study: an open case control study of an oral antioxidant and omega-3 supplement for dry AMD, BMC Ophthalmol. 2007 Feb 26; 7:3.

14. Parisi V, Tedeschi M, Gallinaro G, et al. CARMIS Study Group, Carotenoids and antioxidants in age-related maculopathy Italian study: multifocal electroretinogram modifications after 1 year, Ophthalmology. 2008 Feb;115(2): 324-33.

15. S Richer, J Devenport and J Lang. LAST II: Differential temporal responses of macular pigment optical density (MPOD) in patients with atrophic ARMD to dietary supplementation with xanthophylls. Optometry 2007 May;78 (5):213-9.

16. Nolan JM, Stack J, O' Donovan O, et al. Risk factors for age-related maculopathy are associated with a relative lack of macular pigment. Exp Eye Res. 2007 Jan;84(1):61-74.

17. Richer SP, Stiles W, Graham K, Thomas C. The zeaxanthin and Atrophic AMD Visual Function Study (ZVF)-Investigator Initiated FDA IND #78,973 (Baseline Data), ARVO Poster #4973, Ft Lauderdale, Fl. 30 Apr 2008.

18. S Beatty et al, 2008, IOVS 49(3) 843-844.

Dr. Richer is chief of Optometry at the Department of Veterans' Affairs Medical Center and is associate professor of Family & Preventive Medicine at Rosalind Franklin University of Medicine & Science. He is an associate professor of Optometry at the Illinois College of Optometry and at the University of Missouri-St. Louis College of Optometry.


Optometric Management, Issue: January 2009