Article Date: 5/1/2012

Keeping the Flood Gates Closed

Keeping the Flood Gates Closed

How to manage dry age-related macular degeneration



We've all heard The Little Dutch Boy story: By identifying and then using his finger to seal a small leak in his village's dam, the boy ultimately prevented a disastrous outcome. When identifying dry age-related macular degeneration (AMD) suspects and patients, you, the optometrist, share an awful lot with this fictional hero.

Determining risk

Currently, AMD has no cure. You can, however, assess a patient's risk factors for the condition via patient history form, educate him about these risk factors and how he can decrease them to prevent dry AMD. These risk factors: aging, family history, obesity, race (whites are much more likely to incur AMD caused vision loss than blacks), gender (women are at a high risk), smoking, vascular disease (such as diabetes), long-term excessive exposure to ultraviolet radiation and short-wavelength visible light from sunlight, a diet lacking in antioxidant vitamins, minerals and carotenoids (such as lutein, zeaxanthin and mesozeaxanthin), and, most recently, a patient's macular pigment optical density (MPOD).

“We routinely measure patients' pigment levels,” says Pamela A. Lowe, O.D., of Chicago, Ill. “This is because many studies have shown that if their pigment levels are low — which may be due to poor nutrition or genetics — then they [patients] are at an even greater risk for the condition.”

Currently, QuantifEYE (Zeavision- and MacuScope (Marco measure MPOD.

To reduce the likelihood of Dry AMD — a prelude to disaster — you can educate at-risk patients to make these changes:

Change their diet to facilitate weight loss. Educate overweight patients that research has implicated excessive body-mass index as a risk factor for AMD progression, and explain, in layman's terms, the three theories regarding this finding: (1) Adipose tissue stores up to 80% of the carotenoids (lutein, zeaxanthin, etc.), consumed via diet. If one's body has too much adipose tissue, however, too much lutein and zeaxanthin, which protect the macula, do not get delivered to the eye.1 (2) Adipose tissue manufactures a lot of pro-inflammatory cytokines, and inflammatory markers in the blood have been noted to increase in parallel to growing body weight. In fact, growth in inflammatory markers has been linked with both intermediate and advanced AMD. (3) It is believed the diets of the overweight are lacking in the carotenoids due to low ingestion of fruits and vegetables.1
Advise smokers to quit. Inform your cigarette-smoking patients that nicotine increases the patient's risk of AMD-caused blindness by threefold, says Jerome Sherman, O.D., a professor at the State University of New York College of Optometry. Specifically, educate these patients, in layman's terms, that research has shown smoking may result in accumulated oxidative damage in the retina, decreased MPOD, reduced choroidal blood flow in the eye, and that it may promote ischaemia, hypoxia and micro-infarctions, all of which may increase the macula's susceptibility to degenerative changes.2 In addition, tell these patients that smoking has been shown to enhance the effect of genetic susceptibility to AMD.3

Diagnostic Tests for Dry AMD
ICD-9 Codes:
► Dry AMD. 362.50
► Drusen. 362.57

CPT Codes:
► OCT, Retina. 92134
► Amsler Grid (No CPT code: cannot be billed.)
► PHP. 92081
► Fundus Photos/or Auto-Fluorescence. 92250
► Eye Examination (E/M or EYE code).

Prescribe sun protection. Educate patients that research has revealed melanin, the body's natural sunscreen contained in the hair, skin and eyes, is lost as we age, and that by age 65 half of it is gone, making patients even more vulnerable to AMD. Also, inform them that recent studies reveal the sun's blue/violet light spectrum penetrates the eye's macular pigment and that given both these findings, it's essential the patient acquires UV-blocking sunglasses (up to 400nm).4 In those at increased risk (e.g. family history, outdoor occupation, etc.) consider selective short wavelength filters or absorbers, says Leo P. Semes, O.D., a professor of optometry at the University of Alabama at Birmingham School of Optometry. Also, encourage the use of wide-brimmed hats.
Promote a diet comprised of antioxidant vitamins, minerals and carotenoids. Explain that leafy, dark-green vegetables, such as kale and spinach, are said to be high in lutein and zeaxanthin, which, along with mesozeaxanthin, comprise much of the macula's protective pigment.
Recommend omega-3 fatty acid consumption. Inform patients that these exist in salmon, among other fish, as well as plant-based sources, such as flaxseed oil, almonds and walnuts, and that they contain anti-inflammatory properties, which have been shown to protect against oxidative-caused apoptosis in the retina. Further, explain that omega-3s tend to balance lipids in the blood stream, facilitating the transport of carotenoids to the retina.5

Assessing the “Concrete”
Once you determine the risk factors and clinical signs of early dry AMD, Dr. Sherman recommends you have these patients undergo prognostic genetic testing for a more definitive sense of the patient's risk of progression.
“At that point, the most important thing to know is, what's the patient's genetic risk of going on to develop serious loss of vision over the patient's lifetime? We do a genetic test [to determine this]. The test we use requires us to take a swab of the patient's inner cheek for a DNA sample and mail it to a lab,” he explains. “Within two weeks, we are notified by fax and by letter as to the patient's risk for progression to advanced AMD.”
Currently, MaculaRisk (Arctic Dx) and RetnaGene (SEQUENOM) classify the patient's risk for developing wet AMD. The MaculaRisk test results categorize the patient's risk from the lowest level, category one, which indicates a 3% risk of progression, to category five, which carries a 73% risk of developing serious vision loss in the patient's lifetime. The RetnaGene test also provides a comparative probability rating to indicate whether the patient has a low, moderate or high risk of developing wet AMD.
Dr. Sherman says he uses these classifications to determine a patient's follow-up schedule: once a year for those in category one and up to five times a year for those in category five. He says that those who choose not to utilize genetic testing (it can cost hundreds of dollars out of pocket) are scheduled for follow-up appointments based on lifestyle risk factor(s), familial history and clinical findings, such as autofluorescence, MPOD, ocular coherence tomography, preferential hyperacuity perimetry, etc.
“You want to know about the patient's possibility of conversion to Wet AMD as soon as possible, so you can do your best to prevent irreversible vision loss,” says Dr. Sherman.

Dr. Lowe adds she also encourages patients to have one or two glasses of red wine a meal per day for women and men, respectively, as the dark grape's skin contains resveratrol, which has been shown to ameliorate ocular oxidative stress.6,7,8 She says she also encourages the consumption of up to three Hershey's Kiss-size dark chocolates with 70% or higher cocoa, a day, as dark chocolate contains polyphenols, which have been shown to have some anti-vascular endothelial growth factor (VEGF) properties.

Spotting a “leak”

The dry AMD diagnosis hinges on two key factors: drusen presence, or lipid deposits in the perimacular region, which appear as yellow lesions; and pigment mottling in the retinal pigment epithelium. You can detect both via ophthalmoscopy. The three stages of Dry AMD:9

Early AMD. This is characterized by small drusen or a few medium-sized drusen. Patients are typically asymptomatic.
Intermediate AMD. This stage reveals many medium-sized drusen or one or more large drusen. Many patients will be asymptomatic, though some will report a blurred spot in their vision's center, and these patients often require more light to accomplish tasks, such as reading.
Advanced dry AMD. This is characterized by drusen and a breakdown of the retinal pigment epithelium — revealed by abnormal levels of lipofuscin — which supports tissue in the macula. This breakdown can result in geographic atrophy. To determine lipofuscin's level, you employ autofluorescence.

“… If [the lipofuscin level is] normal, you'll see a normal glow. If there's too much [lipofuscin], that means that the retinal pigment epithelium is metabolically active and actually sick,” Dr. Sherman explains. “If there's too little — hypoautofluorescence — it means that the retinal pigment epithelium has died, and there is no more lipofuscin present.” (See “Assessing the “Concrete,” page 53.)

Plugging the “leak”

If you diagnose intermediate or advanced dry AMD or the patient has a significant genetic risk to convert to wet AMD, as determined by DNA testing, you have an excellent chance of delaying wet AMD onset by having the patient use the Age-Related Eye Disease Study (AREDS 1) oral formulation. This formulation: 500mg/d vitamin C; 400IU/d vitamin E, 15mg/d beta-carotene, 80mg/d zinc oxide and 2mg/d cupric oxide (copper).

This combination of antioxidants and zinc was shown to reduce advanced AMD risk by 25% in patients who had extensive intermediate drusen, at least one large druse, noncentral geographic atrophy in one or both eyes, or advanced AMD or vision loss (<20/32) due to AMD in one eye.10 The study further revealed that moderate-to-advanced AMD patients decreased their moderate vision loss risk (a visual acuity score loss of at least 15 letters) by 19%. Contraindications: Smoking (beta-carotene — see below), hospitalizations for genitourinary issues (zinc — see below) and vascular disease, such as diabetes, can cause heart failure (vitamin E). Another potential contraindication: interactions with other medications the patient may already be taking. For this, reason, consult with the patient's primary care physician prior to prescribing the AREDS formulation.

On the Horizon
Dry AMD is the focus of a great deal of research efforts both in the laboratory and clinic. Here's a brief rundown:
Acetyl-L-carnitine, n-3 fatty acids and coenzyme Q10. One study involving 106 patients randomized to receive this combination treatment or a placebo revealed that this treatment brought about improved visual function and reduced drusen in patients who had early dry AMD.12
ACU-4429. Overseen by Otsuka Pharmaceuticals and Acuela, Inc., this oral agent is designed to slow the rod cycle. Phase I trials have been completed, and the agent has been granted the FDA Fast Track designation.
Anti-Factor D. Developed by Genentech and currently in Phase I and II clinical trials, this molecule is designed to inhibit complement activation and chronic inflammation in geographic atrophy associated with dry AMD.
ARC-1905. In development by Ophthotech, this complement factor 5 inhibitor is intended to reduce geographic atrophy and drusen.
ECGC (epigallocatechin gallate). Emerging evidence from the laboratory suggests that ECGC, an anti-oxidant, may attenuate oxidative-induced retinal degeneration and provide protection against UVA-induced damage to retinal cells.
MC-1101. Due to positive feedback during its end-of-Phase II meeting with the FDA, Macu-Clear, Inc. announced it will start Phase III studies on this eye drop created to prevent AMD progression by increasing ocular blood flow in the choroidal vessels. MC-1101 has been granted Fast Track designation by the FDA.
NT-501. In the area of neuroprotection, Neurotech is developing an implant designed for sustained release of ciliary neurotrophic factor to halt or reduce photoreceptor cell death in patients who have geographic atrophy. Neurotech has received FDA Fast Track designation for NT-501 for the treatment of visual loss associated with dry AMD.
POT-4. Currently in clinical trials jointly sponsored by Potentia and Alcon Laboratories, this complement factor 3 inhibitor is believed to reduce the rate of drusen formation.
RT-101 (fenretinide). ReVision Therapeutics has developed this oral cytotoxic retinoid, which has been shown to slow the binding of retinol to the retinol-binding protein in the bloodstream and, thereby, block its passage to the retinal pigment epithelium.

AREDS 2, which completed enrollment in June 2008 and is scheduled for completion in 2013 and 2014, seeks to:

Assess the effects of high supplemental doses of dietary lutein and zeaxanthin and the Omega-3 long-chain poly unsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid) on advanced AMD development. (Large levels of DHA and EPA were found linked with a reduced risk of AMD progression from bilateral drusen to central geographic atrophy in wet AMD patients.11
Determine the effects of eliminating beta-carotene as part of the AREDS formula on the development and progression of AMD. (Beta-carotene has been associated with an increased risk of lung cancer and death in smokers.)
Study the effects of decreasing zinc on AMD development and progression. (Those in the zinc-only AREDS arm had an excess of self-reported anemia and a frequency of genitourinary hospitalizations related to stress incontinence in women, prostatic hyperplasia in men and unspecified urinary tract infection.)10

“I think with all the antioxidants available, we're going to see a lot of focus on this in the future… ” says Dr. Semes. (See “On the Horizon,” page 54.)

When the “Dam” breaks

Should wet AMD conversion occur, you have a chance of preventing further vision loss by immediately referring the patient to a retinal specialist for anti-VEGF (vascular endothelial growth factor) injections, says Dr. Sherman.

In the meantime, regular follow-up visits — commensurate with the condition's severity — should include visual acuities, ophthalmoscopy, spectral domain optical coherence tomography, fundus photography, autofluorescence, perhaps central visual fields (although this is subjective testing) and preferential hyperacuity perimetry (PHP), which detects early conversion to wet AMD. The two PHP devices: the Foresee PHP (Reichert) and the ForeSee Home (Notal Vision), the latter of which enables daily monitoring by the patient at home.

Through acting fast and perseverance, the little Dutch boy saved his bucolic village from a torrent of water. Similarly, through acting fast to identify dry AMD suspects and patients and persevering through the management of the condition, you have an excellent chance of preventing the disaster of wet AMD — irreversible vision loss. OM

References are available in the online version of this article at www.optometric

Mr. Murphy is a freelance editor/writer based in the Philadelphia area. Send comments to

Optometric Management, Volume: 47 , Issue: May 2012, page(s): 50 - 55