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Treat your AMD patients as you would a family member with AMD.

Optometrists *

Therapeutic opticians **

Dispensing opticians ***

This article considers the management of patients with AMD based upon the lead author's approach with his immediate family. Genetic testing, imaging techniques and the role of carotenoids will be discussed.

1 CET POINT

Introduction

Age-related macular degeneration (AMD) is still the leading cause of severe irreversible vision loss in Western Europe as well as in the US, in spite of the availability of anti-vascular endothelial growth factor (anti-VEGF) injections which have improved outcomes in patients with wet AMD. (1) Most clinicians would opine that although wet AMD can be treated quite effectively if the conversion of dry to wet can be detected in a timely fashion, dry AMD remains an untreatable disorder. Geographic atrophy of the retinal pigment epithelium (RPE), the advanced form of dry AMD, which is nearly as common as neovascular AMD, remains an untreatable disorder at present. (1) As with myriad disorders in the human body, if you cannot treat it, try harder to prevent it.

As a leading retinal researcher once said: 'AMD begins in the uterus.' Due to the slow progression of the condition, drusen and RPE changes prior to age 50 years are uncommon, and vision loss typically occurs after the of age 60 years. But, a patient's genetic profile, already determined in utero, accounts for approximately 60% of the attributable risk of AMD and cannot yet be modified. (2) The remaining 40% is due to epigenetics and environment, which can be manipulated. (2)

Improvements in nutrition and lifestyle make sense and go well beyond AMD considerations. Nutritional supplementation with carotenoids, especially lutein, zeaxanthin, and meso-zeaxanthin which compose the macular pigment, is crucial; levels of macular pigment optical density (MPOD) can be measured in the consulting room using established techniques. But carotenoids do go well beyond the eye. Measuring systemic carotenoid levels can now be accomplished objectively with a non-invasive hand scanner in 30 seconds. The carotenoid level in the palm correlates with the macular carotenoid level. (3) A change in lifestyle and appropriate supplementation will increase both the skin carotenoid score and the macular pigment optical density (MPOD) which can be easily measured in practice. (4-6)

Ophthalmic technologies play an important role in the detection and monitoring of patients with AMD. Optical coherence tomography (OCT) and fundus autofluorescence (FAP) are key additions over the last decade. Optical coherence tomography angiography (OCT-A) is now available to detect early choroidal neovascularisation. The conversion of dry to wet AMD can now also be detected earlier with devices designed for in-home testing which are yet to penetrate the UK market. Patients capable of completing a visual field assessment can generally undertake these tests in their homes several times a week. Anecdotally, patients' conversion can be detected and then treatment initiated within days, enabling vision to be retained.

This article covers genetic testing lifestyle improvements, measurements of carotenoid levels, nutraceutical considerations, in-practice and home evaluations, and novel treatment approaches. As clinicians, this comprehensive approach is what the authors recommend for family members and arguably should be utilised for all patients.

Genetic considerations

Perhaps the most hotly contested and clinically important controversy in eye care over the past several years has centred on the role of genetics to determine which nutraceutical should be prescribed for which patients with intermediate AMD. In the US, the prestigious National Eye Institute (NEI) contends that all patients with intermediate AMD, regardless of their genetics, should take the AREDS 2 formulation which contains 80mg of zinc in addition to select vitamins, carotenoids, and copper. (7) The often-quoted result of AREDS is that the risk of progression can be reduced by about 25% with the recommended nutraceutical combination regardless of the patients' genetic profile. This has been challenged, primarily by Awh et al, in several publications dating back to 2013. (8) This group obtained genetic profiles of patients in the original AREDS database and discovered that patients with two high risk CFH alleles and no high risk ARMS2 alleles have an increased rate of progression if taking the AREDS formulation when compared to those taking a placebo. It appears that 13-19% of the white population in the US have a zinc sensitivity and are harmed by the AREDS containing zinc formula when compared to those not taking AREDS.

A recent study by Vawas et al revisited this controversy by using a novel, rigorous, and powerful statistical tool termed bootstrapping on a group of subjects never tested before. (9) An analysis of this study and others concludes that based upon their specific genetic profile, the AREDS formula may reduce the risk of progression to choroidal neovascularisation (CNV) by as much as 85%, but also increase the risk to nearly 300% in those with the genetic profile previously identified by Awh et al. (8) Interestingly, there is no identified link between nutraceuticals and genetics in geographic atrophy.

The bottomline question is will the AREDS formulation help or harm your patient with intermediate AMD? The answer is in their genetics, and such testing is readily available to all clinicians in the US, although not commonplace within the UK. In addition to determining if zinc is potentially dangerous, the genetic test classifies a patient into five 'macula risk' (MR) categories. Patients in MR 3-5 should be counselled about the risks, and followed more carefully. If genetic testing is not performed, the authors would advise that high dose zinc combinations such as AREDS 2, should be avoided.

Eye carotenoids

The results from AREDS set specific guidelines for patients with intermediate AMD but not for patients with very early or no AMD. About 10-15% of the population has AMD at age 60 and about 15-20% at age 75; it is intuitive that early treatment at a younger age may protect millions of people from ever developing AMD. (10-12) But long-term scientific evidence for this approach is lacking at present.

The AREDS 2 trial recommends incorporation of lutein and zeaxanthin and eliminating beta-carotene which was the only carotenoid in the original AREDS formulation. Of the 600+ carotenoids in nature, three are known to be concentrated in the macula--lutein, zeaxanthin, and meso-zeaxanthin, the latter being the only carotenoid documented to selectively concentrate in the fovea. The Meso-Zeaxanthin Ocular Supplementation Trial (MOST) study by John Nolan et al recommends taking all three in a product such as MacuHealth. (13) Recent evidence reveals that these carotenoids actually improve visual function via increased contrast sensitivity and reduce glare. The MOST study revealed that these three carotenoid isomers in combination improve contrast sensitivity and glare reduction not only in patients with AMD but also in normals. John Nolan et al have widened their research and their most recent study published in Journal of Alzheimer's Disease reveals that the macular carotenoids when combined with omega 3 is beneficial in this disease. (14)

MPOD testing, consisting of the triplet carotenoids, has been commercially available for decades, but has not found great favour with eye care practitioners due to less than ideal reproducibility. (15) Nevertheless multiple studies have suggested that patients with lower MPOD levels may be at a higher risk of developing AMD. (16-18) A study found that premature infants had undetectable MPOD and unusually low serum lutein/zeaxanthin and skin carotenoid concentrations, suggesting that these infants are either deficient in carotenoids or suffering severe oxidative stress; (19) these studies continue to add to the body of work showing the importance of MPOD levels in relation to ocular health.

Heterochromatic flicker photometry (HFP) is a psychophysical method to test MPOD that most clinicians are familiar with. Due to its psychophysical nature, significant patient concentration, training, and time are necessary to perform the test accurately. As with any test that relies on patients' subjective responses, HFP results are prone to variability. For these reasons, an objective test of MPOD, such as the dual wavelength autofluorescence technique based on the Heidelberg Spectralis, is preferable in both research and clinical settings. Unlike HFP, the autofluorescence technique to measure MPOD is more an imaging procedure and does not require patient feedback. This objective test has been found to have less inter-examiner and test-retest variability in head to head trials with HFP systems. (20) Though they provide more accurate information, an autofluorescence based measurement of MPOD requires dilation, which may reduce penetration of this technology into a clinical setting. MPOD measurements have been found to correlate with serum and skin carotenoid measurements and carotenoid consumption. (3)

Carotenoids elsewhere

But carotenoids go well beyond the eye. Antioxidants neutralise the myriad free radicals in our environment that can wreak havoc to cell membranes and nuclear DNA in billions of our cells. Carotenoids are the antioxidant first line of defence. A Harvard study has revealed an association between high carotenoid levels and low risk of breast cancer. (21) In a major Yale summary article, the authors conclude that carotenoids are a biomarker for good health. (22) The supplementation of carotenoids to delay the onset of Alzheimer's disease (AD) in addition to AMD is perhaps not surprising since the eye and brain are so closely related. Although beyond the scope of this article, there is evidence that the biomarker of AD, beta amyloid, can be detected far simpler with imaging of the eye than with imaging of the brain. (23)

Carotenoid numbers

Eye care practitioners and many patients are preoccupied, perhaps correctly, with numbers. A typical physical exam will reveal a slew of numbers: weight, blood pressure, cholesterol level, HbA1c but virtually never our carotenoid number. Traditional blood tests to measure serum carotenoids are obviously impractical in an optometry clinic setting. However, carotenoid levels can be assessed by placing a palm on a small instrument (see Figure 1). Sir C V Raman, a physicist from India, won the Noble prize for discovering that carotenoids, specifically, can convert blue light to green light (nothing else in the human body can do this). Using this phenomenon, the instrument gives a skin carotenoid score (SCS) proportional to the number of carotenoid molecules in the stratum corneum of the palm. This number, ranging from under 10,000 to over 80,000, is highly correlated with serum carotenoid levels and is also correlated to the macular carotenoids. (24-26) As race and age do not affect measurement, there is no need for multiple databases.

The authors' first experience with measuring systemic carotenoid levels using the palm-based biophotonic carotenoid scanner was among the staff in a typical Manhattan Optometrie office. The lowest score (from a former student who appeared healthy) was explained by her diet: very high in greasy cheese fries and low in fruits and vegetables. Within a day of seeing her score, her eating habits changed: vegetable juice in place of cola and vegetable soup instead of pepperoni pizza.

A 55-year-old male ophthalmologist amazingly scored 29,000 four times in the span of three months, attributed to his lack of lifestyle changes. The authors would generally recommend that patients with scores below 40,000 consider lifestyle changes and perhaps nutraceuticals. On the other hand, a 22-year-old optometry student changed her score from 38,000 to 58,000 in six weeks. Her household conscientiously h replaced processed snacks with fruits and doubled intake of greens. Several friends of the family who were also tested had very low scores; all were smokers. These low scores can likely be attributed to the increased production of free radicals in smokers. The greater the number of free radicals, the more antioxidants required to neutralise the free radicals.

The authors' recommendation to those patients with less than admirable SCS, that is to say lower than 40,000, is to reduce free radicals, improve diet, reduce weight and stress, and increase exercise and sleep when indicated. For some, the preferred approach is to choose and consume nutraceuticals. The majority of patients attempt lifestyle changes with some success and then may decide to 'supplement with supplements.'

In-practice procedures

The use of auxiliary testing such as FAF and OCT is quickly becoming the gold standard in many ocular diseases. OCT is generally considered the most important advancement in eye care in this century. Drusen and pigmentary changes (see Figures 2 and 3), the two hallmarks of AMD can be detected with OCT, often before they are visible ophthalmoscopically.

Recently, OCT-A has become available. Angiography without injection is ideal for optometrists worldwide. OCT-A identifies retinal circulation using the intrinsic motion of blood cells in the blood vessels. Whereas OCT acquires structural data, OCT-A acquires functional (and arguably structural) information, usually viewed in en face projections (see Figure 4). One such system, the Avanti with Angio Vue (Optovue) acquires four en face images in seconds. The four images are usually termed the superficial capillary plexus, the deep capillary plexus, the outer retina and RPE, and the choriocapillaris. In normal eyes, only the outer retina with the RPE slab fails to image blood vessels because the photoreceptors and RPE are devoid of blood vessels. In eyes with choroidal neovascularisation that has broken through Bruch's membrane, the new and abnormal web of blood vessels is easily observed. This technology may potentially improve the timely detection of CNV, which has much more favorable outcomes when treated earlier in the disease process.

Home monitoring

The discovery of retinal argon laser therapy and its potential to reduce visual burden in wet AMD shifted care from mere observation, to early detection and prompt treatment. Management protocols were adapted to educate patients on the importance of home screenings with Amsler grids and frequent follow up for high risk patients. Newer therapies, namely anti-VEGF medications, have been developed further, reducing the visual burden of wet AMD. All treatments for wet AMD are significantly more effective when initiated in the early stages. For this reason, it is crucial to identify patients as soon as possible during their conversion from dry AMD to wet AMD to preserve their vision. Though the longtime standard in at-home screening Amsler grid testing has been shown to have poor sensitivity and reproducibility in the identification of visual changes, it still remains the most common form of home monitoring. (27)

Technology now exists to allow simple home screening for macular disease, which is gaining popularity in the US. Systems, such as ForeseeHome utilise preferential hyperacuity or vernier acuity to detect macular visual changes, which are then reported to a reading centre. If these changes are statistically significant, the reading centre will contact the prescribing clinician so that a prompt evaluation of the patient can be scheduled. The AREDS 2 clinical trial included an investigational arm which established that patients using home-screening technology retained better visual acuity when converting to wet AMD as compared to patients receiving standard care. (28)

Conclusion

Patients with AMD, or a family history of such, deserve genetic testing for both the classification of a MR category and risk of 80 mg of zinc consumption. The MR category 1-5 can be used to approximate the number of visits per year. Those in category 5 are generally evaluated five times a year, primarily in an attempt to detect and treat CNV in a timely manner.

Many clinicians recommend nutraceuticals with at least two (though often three) eye carotenoids. In patients with or without AMD, a sub-optimal SCS leads to recommendations of lifestyle changes and possibly nutritional supplements.

Patients deserve to know the importance of the carotenoids to good health and disease prevention. The benefits include a lower risk of blindness from AMD for some patients, improved vision by increasing contrast sensitivity and reducing glare, lower risk of various cancers, diabetes, cardiovascular disorders, and even AD. The same genetic profile (high risk CFH alleles and low ARMS2 alleles) linked to both AMD and a higher risk of progression for those on high dose zinc- is known to also increase the risk of AD. (29)

So, carotenoids: the eye and beyond--are you convinced of their importance for your family members with and without AMD as well as for your patients? If not, at least pause to ponder--hopefully, while munching on veggies.

Exam questions

Under the enhanced CET rules of the GOC, MCQs for this exam appear online at www.optometry.co.uk. Please complete online by midnight on 7 December 2018. You will be unable to submit exams after this date. Please note that when taking an exam, the MCQs may require practitioners to apply additional knowledge that has not been covered in the related CET article.

CET points will be uploaded to the GOC within 10 working days. You will then need to log into your CET portfolio by clicking on 'MyGOC' on the GOC website (www.optical.org) to confirm your points.

Course code: C-60805 Deadline: 7 December 2018

Learning objectives

* Be able to advise patients on AMD risk factors (Group 1.2.4)

* Be able to identify patients at risk of AMD and manage accordingly (Group 6.1.9)

* Be able to explain the management options for AMD to patients (Group 3.1.7)

* Be able to advise patients on AMD risk factors (Group 1.2.4)

* Understand the management of patients at risk of AMD (Group 8.1.2)

References

Visit www.optometry.co.uk, and click on the 'Related CET article' title to view the article and accompanying 'references' in full.

Dr Jerome Sherman OD and Dr Daniel Epshtein OD Mitt

Dr Jerome Sherman is a graduate of Pennsylvania College of Optometry and currently holds the position of Distinguished Teaching Professor at the State University of New York and Schnurmacher Institute of Vision Research. He continues to practice in the private sector at Omni Eye Surgery in Manhattan and is actively researching in the area of clinical ocular disease and special testing, which involves using the latest high tech advanced diagnostic techniques and instruments. His publications include over 750 clinical articles, research manuscripts, book chapters, two CDs and four books. His website retinarevealed.com has hundreds of cases and nearly 3,000 images. This website, through the Review of Optometry, is free to all. Jerry is also a founding member of both the Optometrie Retina Society and the International Foundation for Optic Nerve Disease.

Dr Daniel Epshtein currently practices in a hospital based ophthalmology practice at Mount Sinai St Luke's in New York City. Previously, he held a position in a high volume multispecialty practice where he supervised fourth year optometry students as an adjunct assistant clinical professor of the SUNY College of Optometry. Dr Epshtein's research focuses on using the latest ophthalmic imaging technologies to elucidate ocular disease processes and to help simplify equivocal clinical diagnoses. He has presented at multiple conferences including the American Academy of Optometry and the annual American Optometrie Association meeting. He lectures on numerous topics including multimodal imaging, ocular surface disease, glaucoma, and perioperative care.

Caption: Figure 1 Evaluating skin carotenoid levels using a palm scanner. Measuring systemic carotenoid levels makes sense in virtually every health profession

Caption: Figure 2 OCT and corresponding fundus photo reveal numerous soft drusen

Caption: Figure 3 OCT and corresponding fundus photo reveal pigmentary atrophy and migration

Caption: Figure 4 OCT-A en face imaging contrasting a normal patient and a patient with wet AMD
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Title Annotation:AMD; Age-related macular degeneration
Author:Sherman, Jerome; Epshtein, Daniel
Publication:Optometry Today
Geographic Code:4EUUK
Date:Nov 1, 2018
Words:3177
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