Advances in the management of dry AMD

The road from research to clinical care is a long one for various reasons and is not entirely unjustified. Amid the urging of progress and “new science,” one should remain vigilant in assuring that no harm is caused to the patients we serve.

To this accord, the AREDS trials¹ have been a game changer in the management of atrophic age-related macular degeneration (dry AMD). They have given us evidence-based guidance on when and how to manage and prevent progression of the disease.

This article will address 2 facets of dry AMD management—early diagnosis and early intervention—with a focus on color vision, macular pigment optical density (MPOD) measurement, and carotenoid vitamin therapy.

Like many other chronic diseases, dry AMD suffers from the issues related to early diagnosis. The drusen that are so hallmark to dry AMD are also seen in individuals that do not have, or at least do not yet have, dry AMD.

How does one go about determining when the changes in retina are “normal” age-related changes or the onset of early dry AMD?

The AREDS simplified grading scale² for AMD is a good start, and the Beckman classification system³ improves upon the AREDS simple classification system.

Related: What’s hot (and not) in retinal news

In early stages of the disease, AMD does not show overt changes in visual function like visual acuity changes. But if more challenging tasks are presented, such as visual function in dim illumination, one indeed shows decline.

When a patient presents with a challenge in diagnosis or if the eye care provider (ECP) would like to detect progression of the disease, the ECP could utilize extended color vision testing.

Functional testing and dry AMD

Doctors have used screening color vision tests such as red-cap tests, the Ishihara test, and the D-15 color blindness test very successfully, and they indeed have their place in our clinics.

However, when investigating early visual disfunction, one may need quantifying threshold strategies.

The cone-contrast threshold test is helpful as an early-detection strategy of various diseases. The use and benefits of color vision testing in early detection of disease and its progression is not a new concept.

Numerous diseases, such as diabetes, cause changes to color vision prior to the onset of retinopathy.⁴ Researchers from the Duke University School of Medicine have used a variety of visual function tests and structural measurements to identify progression in early AMD and intermediate-stage AMD.⁵ The overarching goal was to detect progression in AMD in a short period of time and to identify useful end points for future clinical trials.

The researchers utilized the Rabin Cone Contrast Test (Innova Systems) to isolate the 3 cone types and to determine cone-contrast thresholds.

Related: Case report: the “other” AMD


This device uses precise calibration as well as letter optotypes in red, blue, or green color that a patient is asked to recognize and report. This isolates and allows testing of the individual cone systems integrity while assuring that the other cone types are suppressed.

This longitudinal study of visual function in dry AMD showed that the Rabin Cone Contrast Test was able to detect changes in color vision due to progression of dry AMD within a 12-month period.⁵

These results highlight the fact that detection of progression in short duration allows the possibility for early intervention and prevention of progressive vision loss.

Measuring macular pigment may be key to appropriate care

One does not expect a general physician or endocrinologist to manage diabetes without blood glucose measurements or hemoglobin A_1c values. Yet ECPs often manage dry AMD without knowing baseline MPOD values.

It is true that low MPOD does not mean a patient has AMD, but a lower MPOD is a known alterable risk factor of AMD. It is postulated that early and intermediate stages of maculopathy are predominated by oxidative stress and low-grade inflammatory activation in aging retinae.^6,7

It is not surprising, then, that patients with dry AMD benefit from treatment using antioxidant therapy. The MPOD that is made up of carotenoids is known to vary among various ethnicities,⁸ and its level depends upon the dietary intake of carotenoids—as they cannot be synthesized in the human body.^9,10 The supplementation of carotenoid vitamin therapy has indeed shown benefits in dry AMD; however, these benefits are not universal.¹

There could be a number of reasons for the difference in benefits observed—for example, the amount of damage to the retina or bioavailability of these supplements.

Given that the eye is the end organ that needs to benefit from these supplements, the levels of MPOD at the fovea must increase with these therapies.

The current clinical gold standard in measuring MPOD is a heterochromatic flicker photometry, which is a psychophysical test.^9,11

Related: U of M Kellogg Eye Center receives $11.5 million for AMD research


The measurement of MPOD clinically as baseline and during clinical follow-up allows assessment of patient compliance with taking the nutritional supplements, assuring that the nutritional supplements are bioavailable and that carotenoids are indeed reaching end organs.

The AREDS trials¹ unfortunately did not measure MPOD. This may be due to the difficulty and inability to obtain reliable measurements in advanced stages of dry AMD, which is accompanied by less-than-optimal visual acuity.

The measurement of MPOD in poor test takers and individuals with suboptimal visual acuity may be addressed by objective techniques of measurement of MPOD, which do not depend on or require too much subjective input.

Various objective measures used in research laboratories could provide a quick and reliable measure of MPOD. These include dual-wavelength autofluorescence techniques,¹² resonance Raman imaging,¹³ and macular pigment reflectometry (MPR).^11,14 MPR not only can provide a repeatable MPOD, but also lutein and zeaxanthin optical density values.^11,14

MPOD values measured using the MPR technique closely match heterochromatic flicker photometry.¹¹ Measurement of a patient’s lutein and zeaxanthin optical density in vivo in a 30-second period offers significant clinical advantages when applied to individualized or personalized medicine.

Related: Alcoholism treatment may play key role in restoring vision for AMD, RP patients


This could help answer various fundamental questions and enhance our understanding of both physiological and pathological states.

When personalized medicine becomes reality, we may find that supplementing with carotenoid vitamin therapies that are needed by a patient—rather than the “one size fits all” approach—may lead to better clinical outcomes.

Does carotenoid vitamin therapy only help intermediate-stage AMD?

The AREDS trials showed that supplementation with carotenoid vitamin therapy prevented progression from intermediate to advanced stages of AMD.

Further, the AREDS2 trial¹ (NCT00345176) showed that carotenoid supplementation with lutein and zeaxanthin indeed favored this treatment, particularly in those who had low serum levels at baseline.

It’s fair to ask if carotenoid vitamin therapy also benefits other stages of AMD, and it is equally important to ask what other benefits of carotenoid vitamin therapy can be seen in patients with dry AMD.

It would be ideal if additional large-scale trials like AREDS provide all the answers for early diagnosis, prognostics, and new treatments when they become available.

This aspiration may be impractical for all scientific questions, however. When such large trials are not available, doctors will need to evaluate all tiers of evidence available to derive clinical guidelines for disease states.

Numerous reports have shown clinical benefits by raising the levels of xanthophylls in the retina through dietary supplementation. Thus, adjunctive carotenoid vitamin therapy may offer enhanced neuroprotection by augmenting MPOD and subsequently preventing further injury.^15,16

Related: ODs are ignoring macular degeneration


Higher levels of MPOD are thought to preserve retinal tissue, specifically the layers containing photoreceptors in the fovea, through 2 primary mechanisms: by serving as an innate optical filter against blue light and as a protective antioxidant by neutralizing free radicals and reducing consequent oxidative injury.^15,16

A recent systematic review of carotenoids in the management of AMD showed that at least 20 epidemiological studies and 35 randomized controlled trials (RCTs) have evaluated this topic.¹⁶

These studies evaluated various facets of the topic: supplementation and increase in serum carotenoids, MPOD, and changes in visual function. Whereas improvements in best-corrected visual acuity were seen in 6 out of 18 trials, remarkable benefits in contrast sensitivity were demonstrated in 10 out of 15 RCTS.¹⁶

Improvements were also seen in glare disability, photostress recovery time, and multifocal electroretinogram results.¹⁶

Thus, it was concluded that consistent evidence from large-scale epidemiology studies and several RCTs substantiate the synergic neuroprotective benefits afforded by carotenoid vitamin therapy in eyes with any stage of AMD.¹⁶

It is important to note that these visual benefits may be decreased in late-stage AMD compared with early- or intermediate-stage AMD.^16,17

A dose-response relationship with a stronger effect, greater serum carotenoids, and MPOD levels is seen with supplementation of a higher dose of carotenoids.¹⁸

In a recent RCT,¹⁹ 6-month supplementation of carotenoid vitamin therapy with a greater amount of ocular carotenoids (28 mg) and omega-3 fatty acids (675 docosahexaenoic acid and 230 eicosapentaenoic acid) provided superior performance when compared with AREDS2 formulation softgels (12 mg).

This not only provided greater serum carotenoid levels, but also led to significant improvements in measured contrast sensitivity in patients at risk for AMD. Such results indicate that quicker and greater visual benefits can be seen if patients supplement with a larger dose of ocular xanthophylls.

Related: Viewpoints: Remote monitoring centers for dry AMD

Conclusions

Roughly 1 in 8 individuals 60 years or older is suffering from AMD, so it is fair to say that AMD deserves our special attention.

It was long believed that in the chronic disease of dry AMD, not much occurs or is needed until much later in the disease state. We can now confidently say that is not true.

With advancements in clinical testing, such as the Rabin Cone Contrast Test, we can detect this disease easily. With devices that can measure MPOD, we can better manage the disease and monitor its progression.

The objective technology of MPR is to measure MPOD, and individual carotenoid optical density shows promise in personalized medicine.

Additionally, there are sufficient data from various RCTs to recommend carotenoid vitamin supplementation at all stages of AMD, which may prevent its progression and definitely provides improvement in vision. And who does not like improved vision?

References

1. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-2015. doi:10.1001/jama.2013.4997

2. Ferris FL, Davis MD, Clemons TE, et al; Age-Related Eye Disease Study (AREDS) Research Group. A simplified severity scale for age-related macular degeneration: AREDS report no. 18. Arch Ophthalmol. 2005;123(11):1570-1574. doi:10.1001/archopht.123.11.1570

3. Ferris FL 3rd, Wilkinson CP, Bird A, et al; Beckman Initiative for Macular Research Classification Committee. Clinical classification of age-related macular degeneration. Ophthalmology. 2013;120(4):844-851. doi:10.1016/j.ophtha.2012.10.036

4. Chen XD, Gardner TW. A critical review: psychophysical assessments of diabetic retinopathy. Surv Ophthalmol. 2021;66(2):213-230. doi:10.1016/j.survophthal.2020.08.003

5. Hsu ST, Thompson AC, Stinnett SS, et al. Longitudinal study of visual function in dry age-related macular degeneration at 12 months. Ophthalmol Retina. 2019;3(8):637-648. doi:10.1016/j.oret.2019.03.010

6. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2000;45(2):115-134. doi:10.1016/s0039-6257(00)00140-5

7. Xu H, Chen M, Forrester JV. Para-inflammation in the aging retina. Prog Retin Eye Res. 2009;28(5):348-368. doi:10.1016/j.preteyeres.2009.06.001

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9. Bernstein PS, Delori FC, Richer S, van Kuijk FJ, Wenzel AJ. The value of measurement of macular carotenoid pigment optical densities and distributions in age-related macular degeneration and other retinal disorders. Vision Res. 2010;50(7):716-728. doi:10.1016/j.visres.2009.10.014

10. Arunkumar R, Calvo CM, Conrady CD, Bernstein PS. What do we know about the macular pigment in AMD: the past, the present, and the future. Eye (Lond). 2018;32(5):992-1004. doi:10.1038/s41433-018-0044-0

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12. Green-Gomez M, Bernstein PS, Curcio CA, Moran R, Roche W, Nolan JM. Standardizing the assessment of macular pigment using a dual-wavelength autofluorescence technique. Transl Vis Sci Technol. 2019;8(6):41. doi:10.1167/tvst.8.6.41

13. Sharifzadeh M, Zhao DY, Bernstein PS, Gellermann W. Resonance Raman imaging of macular pigment distributions in the human retina. J Opt Soc Am A Opt Image Sci Vis. 2008;25(4):947-957. doi:10.1364/josaa.25.000947

14. Sanabria JC, Bass J, Spors F, Gierhart DL, Davey PG. Measurement of carotenoids in perifovea using the macular pigment reflectometer. J Vis Exp. 2020;(155). doi:10.3791/60429

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16. Lem DW, Davey PG, Gierhart DL, Rosen RB. A systematic review of carotenoids in the management of age-related macular degeneration. Antioxidants (Basel). 2021;10(8):1255. doi:10.3390/antiox10081255

17. Liu R, Wang T, Zhang B, et al. Lutein and zeaxanthin supplementation and association with visual function in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2014;56(1):252-258. doi:10.1167/iovs.14-15553

18. Ma L, Liu R, Du JH, Liu T, Wu SS, Liu XH. Lutein, zeaxanthin and meso-zeaxanthin supplementation associated with macular pigment optical density. Nutrients. 2016;8(7):426. doi:10.3390/nu8070426

19. Davey PG, Henderson T, Lem DW, Weis R, Amonoo-Monney S, Evans DW. Visual function and macular carotenoid changes in eyes with retinal drusen-an open label randomized controlled trial to compare a micronized lipid-based carotenoid liquid supplementation and AREDS-2 formula. Nutrients. 2020;12(11):3271. doi:10.3390/nu12113271