Stopping Dry-to-Wet AMD Conversion

This stepwise approach may help prevent and detect conversion to advanced-stage disease.

BY DANIEL F. KIERNAN, MD

One in 10 people over the age of 60 have some form of AMD. That ratio increases to one in four people over 70. As ophthalmologists surely know, AMD is the leading cause of legal blindness for people over age 55 in the Western world — more than 5 million new cases a year reported in Europe and North America alone.¹ While the statistics are depressing, the great news story of this past decade has been the advent of new treatments for advanced AMD, which can arrest the disease and restore sight, but — and it’s a major “but” —you need to catch the disease at the right time to initiate or refer for treatment in order to protect visual acuity. Here are my guidelines for recognizing and seizing that moment.

The Dry-to-Wet Progression

Drusen formation typifies AMD in its earliest stages (Figure 1). Drusen deposits may enlarge and physically impinge on the photoreceptors or RPE. A prevailing theory holds that larger drusen deposits may initiate a complement-mediated inflammatory component leading to progressive tissue hypoxia and release of factors including VEGF and PLGF, which in turn stimulate increased vascular permeability, macular edema, exudation and choroidal neovascularization (CNV). These vessels are initially fragile, so they can break, leading to subretinal hemorrhage and photoreceptor iron toxicity. As CNV matures, it can lead to disciform scar formation, also known as end-stage wet AMD. At this stage, drugs or surgery are usually of no benefit.

AMD Stages and Follow-Up Frequency

The main objectives in following dry AMD patients should include a frequent monitoring schedule to detect and treat advancing AMD at its earliest occurrence. Clinical trials have shown early treatment with the appropriate therapy saves vision in these patients.² Understanding how to grade AMD is the foundation for determining the frequency of monitoring. The AREDS classification, named for the Age-Related Eye Disease Study, is now the most widely used.³

A characteristic sign of early AMD is the presence of a few — 20 or fewer — medium-size drusen or retinal pigmentary abnormalities. In the intermediate stage, at least one large druse, numerous medium-size drusen, or geographic atrophy that does not extend to the center of the macula characterize AMD (Figure 2). Advanced or late AMD can be either non-neovascular (dry) or neovascular (wet). Drusen and geographic atrophy extending to the center of the macula is characteristic of advanced dry AMD.

In advanced wet AMD, CNV, subretinal exudates, hemorrhage or edema, or all, are characteristic.⁴ If only a few small drusen exist, monitoring the eye every one to two years is sufficient. The more advanced the disease, the more frequent the monitoring: annual examinations with more drusen and early dry AMD; two to three times a year with intermediate disease; and three to four times annually with advanced dry-stage disease. Obviously if CNV develops, monthly examinations may be in order.

Figure 1. Fundus photograph demonstrating extensive drusen with RPE changes in a patient with dry AMD.

Figure 2. Fundus photograph demonstrating progression of dry AMD to include extensive geographic atrophy.

Nutrition as a Weapon

In AREDS, which involved 3,640 patients with AMD, daily antioxidant supplementation consisting of vitamin C (500 mg), vitamin E (400 IU), beta carotene (15 mg), zinc oxide (80 mg), and cupric oxide (2 mg), reduced the rate of progression from intermediate to advanced AMD — by 25% over five years when compared to placebo — and resulted in a 19% reduction in the risk of moderate visual loss.⁵ If all Americans at risk for advanced AMD (e.g., patients with intermediate AMD in either eye or advanced AMD in one eye only) were to receive this supplementation, more than 300,000 people could avoid advanced disease over five years.⁶

The National Eye Institute (NEI) has completed enrollment and is currently analyzing results for AREDS2. The aim of this trial is to assess the roles of lutein, zeaxanthin and omega-3 long-chain polyunsaturated fatty acids in preventing or slowing AMD progression.⁷ Observational data have shown a decreased risk of advanced disease in AMD patients who consume higher amounts of fish or omega-3 fatty acids than others in the study. ⁸

AREDS2 will also evaluate the merit of eliminating beta-carotene from AMD patients’ diets because it has been associated with an increased risk of lung cancer in cigarette smokers.^9,10 The dose of zinc tested in AREDS was supported by a small clinical trial, although current data suggest that the body may maximally absorb only 25 mg.¹¹ This study followed all participants through five years.

Fish oil and omega-3 supplements have gained in both popularity and notoriety through a variety of studies. An important issue we should bear in mind when considering the future applications of omega-3 products for AMD patients is the purity and formulation of the product. The triglyceride formulations have a much higher bioabsorption than ester formulations.¹²

Genetic Testing

For years physicians and patients have known that AMD runs in families. Although the general population has a 10% chance of developing advanced AMD regardless of family history, first-degree relatives of individuals with AMD are four times more likely to develop advanced AMD if they live to be 80. Since investigators discovered genes that predispose carriers for advanced AMD, the role genetics play in AMD-related vision loss has been evident. Seddon et al. found that both environmental and genetic factors were independently related to advanced AMD, and modifiable factors can alter genetic susceptibility.¹³ Several recent studies also clearly indicate that the AMD risk score identifies a highly susceptible population.^14-16

Macula Risk (Arctic Dx, Bonita Springs, Fla.) is a simple DNA test physicians collect in the office with a buccal cheek swab. It is indicated for patients with early to intermediate AMD. The swab obtains a sample that is sent to a DNA testing laboratory for analysis. The risk analysis takes into account a combination of AMD genes and smoking history to identify those most likely to progress to advanced AMD with vision loss.

Results are available within four weeks. The test may help tailor a disease management strategy specific to a patient’s risk, such as increasing the frequency of appointments or referral to a retinal specialist for monitoring. For example, a patient at an elevated risk (Macula Risk Level 3, 4 or 5) may benefit from an increased frequency of eye examinations (Figure 3).

Risk of Progression from Early/Intermediate AMD

Figure 3. The results of the Macula Risk genetic test and lifestyle analysis are returned within 3-4 weeks, and indicate a patient’s lifetime risk of developing advanced disease. A patient at an elevated risk (Macula Risk Level 3, 4 or 5), may benefit from an increased frequency of eye examinations and/or lifestyle changes.

Based on a patient’s Macula Risk test result, you may also recommend lifestyle changes including smoking cessation, increased dietary antioxidant consumption, micronutrient supplementation, control of blood pressure and cholesterol, etc. Most insurance providers, including Medicare, reimburse for Macula Risk testing. Patients must have had an eye examination and have a diagnosis of AMD. Otherwise, the test costs $750 out of pocket.

Home Monitoring

Before the AREDS trials or modern pharmacologic treatments for wet AMD, patient education was one of the few ways we could intervene in a potentially blinding condition. Instructing patients on how to use at-home devices such as an Amsler grid helped them become part of the disease management process and, potentially, earlier detection of conversion to wet disease.

Although the actual predictive value of allowing a patient to detect early visual changes is not as good as testing during a formal examination, it can be done with greater frequency and at less cost. So it was and is still a valuable tool. An additional consideration: Not including it in the exam or noting it as discussed in the patient record may have implications for medical liability; the Amsler grid is still considered standard of care for these patients.

Amsler Grid

The subjective symptoms of AMD may vary between acquired metamorphopsia, scotoma, and blurred vision or, in many cases, nothing at all. The Amsler grid has been the “gold standard” for giving patients something to help monitor their central vision between appointments. It is critical that you properly educate patients about its correct use: Examine each eye carefully, with the fellow eye closed or covered, and while wearing near correction, and then check for subtle distortions on the Amsler grid. The patient may perceive scotomas and visual distortions as breaks, waves or missing portions of grid lines.¹⁷

Despite frequent at-home testing with an Amsler grid, its sensitivity and specificity for detecting CNV may be as low as 70% and 85.5% respectively, compared to 90% and 81.8%, respectively, with preferential hyperacuity perimetry testing.¹⁸ This technology is emerging as a novel, more standardized and monitored way for patients to assess macular changes between appointments.

Foresee Home

Using technology based on preferential hyperacuity perimetry, Notal Vision (St. Louis) introduced the ForeseeHome AMD monitor through a large, randomized NEI study and also through a limited market research study. This technology is based on the theory of Vernier acuity, the ability to perceive minute differences in the relative spatial localization of two objects. Patients are advised to use the ForeseeHome device each day; the test takes three minutes per eye. The patient is shown a dotted line with some dots deviating from the line; he or she will identify observed distortion by clicking a connected mouse.

When the elevation that CNV causes is larger than the artificial distortion, the patient will preferentially pick the spot of true distortion, thus indicating a change from baseline and potential early wet AMD. The device automatically sends test results to the Notal Vision Data Monitoring Center through an embedded cellular or phone modem. Test results are compared to the patient’s baseline and a normative database. In the event of a statistically significant change, Notal Vision contacts both the practice and the patient to schedule an exam. If the monitoring center does not receive test results for seven consecutive days, the company contacts the patient.

NEI is conducting an ancillary study to AREDS2 investigating home-based telemonitoring with the ForeseeHome vs. standard monitoring of AMD. This is a post-FDA-approval, multicenter, randomized clinical trial for which results should be announced in late 2013 or early 2014. The telemonitoring system requires a prescription from an eye doctor. The prescription confirms that the patient has been diagnosed with dry AMD, has visual acuity of 20/60 or better, has no previous advanced AMD or other pathology that could compromise test results, and has an ability to use the ForeseeHome device. The practice sends the prescription form to Notal Vision, which ships the device directly to the patient.

The company is introducing the ForeseeHome with a patient-pay model through select practice sites. The practice incurs no costs. Notal Vision provides a demonstration device, patient education brochures, and other support materials. Participating practices receive compensation for performing patient training in the office as well as alert monitoring and report interpretation.

Role of SD-OCT

If CNV does occur despite the previously mentioned ways for stratifying risk and slowing progression of the disease, the time from diagnosis of wet AMD to treatment matters. Delays can result in significant vision loss. Muether et al. reported that a subset of six patients among 69 diagnosed with new wet AMD experienced rapid loss of one or more lines within 21 days, although overall the average visual acuity decline was slow (an average of one logMAR line over 110 days). They advised expediting treatment to maximize vision preservation so that delays do not exceed two weeks.¹⁹

OCT technology has refined our ability to observe sub-retinal and intraretinal macular edema, potentially hastening the detection of conversion of dry to wet AMD. In the last several years, nine different posterior segment spectral-domain (SD) OCT systems have become commercially available, with typical resolutions in the 5-10 μm range, and many more data points analyzed per scan. The advent of this technology has provided us with extensive amounts of new anatomical, physiological and pathological data. The current literature shows a rapidly growing amount of data for SD-OCT technology, and it is clear that large amounts of in vivo information can be acquired without invasive intervention, effectively allowing a “virtual biopsy” of the retina.²⁰

Figure 4. Time-domain OCT correctly scans (bottom left) but the software erroneously flattens (top left) a pigmented epithelial detachment in a patient at risk for wet AMD. In the same patient, spectraldomain OCT correctly scans and reports the PED (right images).

Growing evidence indicates that SD-OCT may be superior to time-domain (TD) OCT for diagnosing wet AMD. Erikkson et al. demonstrated differences in repeatability and reproducibility comparing the Stratus TD system with the Cirrus SD-OCT (Carl Zeiss Meditec, Dublin, Calif.) in eyes affected by wet AMD. However, when the software for manual correction of fovea position was used (essentially meaning, when the scan was centered using a single click on the analysis screen), the SD-OCT variability decreased markedly, and the repeatability was close to what had been reported in normal eyes, demonstrating a significant advantage of SD over TD-OCT.²¹

Similarly, the increased image resolution of Spectralis SD-OCT (Heidelberg Engineering, Carlsbad, Calif.) improved the inter-observer agreement for grading intra-retinal cysts and epiretinal membranes in patients with wet AMD compared to TD-OCT.²² OTI Spectral SLO/OCT (Optos Health Inc., Marlboro, Mass.) was also found to be superior to TD-OCT for detecting the alterations typically related to CNV, such as intra-retina edema, pigmented epithelial detachments, internal limiting membrane thickening and hard exudates. Consequently the authors concluded that physicians should strongly consider SD-OCT over TD-OCT for patients with AMD. ²³

Interestingly, another study also showed that Cirrus and Spectralis SD-OCT showed a greater ability to evaluate qualitative features indicating disease activity and fewer errors in automated segmentation compared to Stratus TD-OCT. However after treatment and during subsequent follow-up, the study observed few differences in central macular thickness changes between the systems.²⁴

In a study using three separate graders who were retinal specialists, pair-wise comparison of Cirrus SD-OCT with Stratus TD-OCT systems revealed that Cirrus-based grading more frequently reported the presence of sub- and intra-retinal fluid and detected overall neovascular activity at a higher rate than Stratus-based grading. Thus the choice of TD- versus SD-OCT systems has a measurable impact on clinical decision-making in wet AMD.²⁵ One example illustrates a potential error Stratus TD-OCT has made in detecting a pigment epithelial detachment but Cirrus SD-OCT has not (Figure 4). Although the hefty price may play a role in the decision to purchase an SD-OCT device, it seems this technology is superior in detecting conversion to wet AMD.

When in Doubt, Collaborate

You can maximize your edge in preventing and detecting conversion to wet AMD with several emerging and established technologies and practices. However, many times the diagnosis may still remain in question without further testing — for example, with fluorescein or indocyanine green angiography, to which the generalist may not have access. In these circumstances it may be in the patient’s best interest to refer to a retinal specialist for further evaluation. While frequently active CNV may not be present, missing just one patient and inadvertently allowing vision loss to occur is something we all want to avoid, especially since very effective treatments for wet AMD are readily available. OM

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Dr. Kiernan is a vitreoretinal surgeon at Ophthalmic Consultants of Long Island, Rockville Centre, N.Y. He disclosed he has no financial interest in any of the products mentioned in this article.