AMD UPDATE: What's new in Therapeutics
Emerging treatments for this widespread condition may prove useful for generations to come.
BY LEO SEMES, O.D., Birmingham, Ala.

ILLUSTRATION BY ERIC LINDLEY

Age-related macular degeneration (AMD) will be a major public health problem in the second half of this century. It is the leading cause of irreversible blindness in the U.S. among patients over 50 years of age. In fact, there are currently 1.75 million patients with AMD in this country. While these numbers and predictions may be sobering, be aware that they include both neovascular and non-neovascular AMD.

In this article, AMD refers to all types age-related macular degeneration, including age-related maculopathy (ARM). This will be the umbrella for both forms, the neovascular (NV, "wet" or "exudative") and non-neovascular (nNV "dry" or "atrophic").

An ounce of prevention

Preventative and prophylactic strategies should always be considered for our patients. As important as the anatomy and pathogenesis of AMD is a discussion of the risk factors. While it is well known that many risk factors are genetic, there are several major risk factors that are modifiable. These include cigarette smoking, lifetime blue-light exposure, high-lipid diet, and vitamin and mineral intake.

Another preventative measure you can stress is UV protection. While there is some controversy among epidemiological studies regarding the role of environmental light exposure in AMD, clinical and laboratory evidence strongly suggests that minimizing blue (and perhaps to a greater extent violet) light from reaching the retina may be very beneficial in reducing the incidence and severity of AMD. Be especially cognizant that sun exposure is cumulative over a lifetime, the majority of which is acquired by age 25.

The role of nutrition, vitamins, and other dietary supplements is poorly defined. The Cochrane database recently compiled a collection of evidence-based studies that both support and refute the benefits of anti-oxidant vitamins for AMD.

The arena of supplements is somewhat chaotic. There are issues of efficacy, competitive absorption and potentially dangerous interactions.

	1A. This eye shows a small area of RPE atrophy below the macula, but no CNVM.
	1B. The same eye four years later. Note the increased atrophic appearance.
	2A. Pigment disruption and drusen are present. Amsler grid shows a paracentral scotoma.
	2B. This macula shows some pigment disruption, but no drusen.
	Neovascular AMD with fresh blood; the center of the macula has been compromised by previous neovascularization.

The Age-Related Eye Disease Study (AREDS) also provides information and education to help guide your patients. (AREDS Report No. 8). This trial showed subjects who took vitamin (C, E, beta caro-tene) and mineral (zinc, copper) supplements reduced their risk of AMD by about 25% versus those in the placebo group. Further investigation into the study's results revealed that the greatest benefit accrued in those with more advanced atrophic AMD. The study design included a four-step classification scheme for drusen and pigmentary changes, as well as an advanced category that related to risk of progression. The photos can be viewed as part of the AREDS report No. 8. This scheme is useful for determining whether a patient is at risk for AMD. Follow-up publications indicate that there is, from both epidemiologic and clinical standpoints, an overall public-health benefit to selected vitamin and mineral supplementation.

Some have criticized AREDS because it did not include high doses of lutein or zeaxanthine. AMD is thought to cause oxidative damage to these naturally occurring macular pigments. Oral supplementation trials suggest that these items are absorbed into the blood stream and are deposited at the macula, offering a potential replacement for lost natural pigments. The National Eye Institute (NEI) will conduct a clinical trial, AREDS-lutein, to explore the potential benefits of a supplement containing lutein. Look for the results in about 10 years. Until then, the best guidance for patients regarding diet and dietary supplements seems to be the AREDS formulation, plus at least 4mg of lutein daily.

Finally, inflammation plays a role in many disorders from heart disease to dry eye; AMD is no exception. Histochemical evidence suggests an inflammatory component in drusen formation. A future direction for AMD treatment may be oral anti-inflammatories. However, recent evidence is conflicting and further study is necessary to answer this question definitively.

Treatment options

Neovascular AMD represents the more devastating form of the disease. About 15% of patients will evolve from the atrophic form to the neovascular form over a 5-year period. The presence of large drusen (> 125 u) often indicates a clinical risk for conversion. Fortunately, fewer than 15% of all AMD cases fall into this category.

Considerable attention is given to treatment options for NV AMD. The results of the macular photocoagulation study (MPS) show this option may provide a small benefit for patients with lesions outside the center of the macula. Patients with lesions under the center of the macula underwent laser photocoagulation and were compared with a control group. Those who received treatment had (on average) better vision two years following randomization/treatment than the control group. So, while there was some benefit for this subgroup, the effect was not immediate.

Also, note that subfoveal photocoagulation should be considered beneficial only in eyes with small, well-defined neovascular lesions and evidence of classic CNV membrane (CNVM). For this and other reasons (collateral damage being one), alternative treatments are being evaluated. These include surgical (submacular surgery, RPE transplantation, retinal translocation, to name a few), photochemical (verteporfin and some of the aptamers), as well as anti-inflammatory (angio- static steroids) options. Other trials include membrane differential filtration and medications such as aspirin and sildenafil (Viagra, Pfizer). The basis for both aspirin and sildenafil therapy is postulated to be from their potential blood-flow improving attributes.

Current treatments

Photodynamic therapy (PDT) with verteporfin (Visudyne, CIBA-Novartis) is an alternative to standard laser photocoagulation. Verteporfin therapy is borrowed from cancer treatment and targets CNVM by selectively collapsing new vessels while sparing central vision. PDT is a two-stage process. First, the drug (a photosensitive dye) is injected into the antecubital vein, much like the process for fluorescein angiography. The lesion is then visualized at the slit lamp through a pre-corneal lens. A laser light (690nm) delivered over a specified time (83 sec) activates the drug.

The Treatment of AMD with Photodynamic Therapy (TAP) report presented two favorable double-blind, placebo-controlled, randomized, multi-center, phase III clinical trials. The treatment benefit was sustained at two years, with fewer verteporfin-treated patients (47%) having moderate vision loss than those given a placebo (62%). Treatment benefit was most apparent in patients with predominantly classic subfoveal lesions (i.e., those in whom classic CNVM accounted for >50% of the area of the entire lesion). Severe vision loss (loss of >30 letters, comparable to about six lines of visual acuity) was limited in vertepor-fin-treated patients when compared with the placebo group (15% vs. 36%, respectively, P < 0.001).

The Verteporfin in Photodynamic Therapy trial (VIP), investigated the efficacy of verteporfin therapy in a different group of patients. Most of these patients had either occult, but not classic CNVM, with presumed recent disease progression, or classic CNVM with visual acuity better than Snellen equivalent of 20/40. At 24 months, the risk of both moderate and severe vision loss was reduced significantly in patients who received verteporfin compared with patients given placebo. The results of these and other investigations of vertep-orfin suggest that it may be an option for patients with AMD and occult subfoveal CNVM and presumed recent disease progression, as well as those patients with predominantly classic subfoveal CNVM, especially with poorer levels of visual acuity. Retreatment may be necessary, though treatment paradigms and retreatment recommendations continue to evolve.

Modern methodology

Transpupillary thermotherapy (TTT), also borrowed from intraocular tumor treatment, is another alternative being consider- ed for CNVM. TTT, like PDT, uses a relatively large spot size, low irradiance, and long exposure time to infrared laser radiation, which, in theory, should cause involution of the CNVM. Time will tell if this alternative strategy has promise.

Removal of CNVM by submacular surgery through a temporal retinotomy site may minimize photoreceptor damage. The major limitation of this procedure is loss of RPE and atrophy of the choriocapillaris.

Macular translocation aims to improve CNVM-impaired central vision by rotating the retina so that viable photoreceptors are now aligned with the visual axis. Efficacy studies so far show disappointing results and significant complications.

On the horizon

Newer treatment strategies include intraocular steroids (triamcinolone acetate) or sub-Tenon's steroid injection (RETAANE, Anecortave acetate suspension; Alcon.). This method achieved approvable status from the FDA in May. Preliminary results of injections given every three months appear promising. Intravitreal injection of triamcinolone acetate has also been reported to produce positive outcomes (e.g., inhibition of neovascularization) in animal models as well as a small group of humans. The future domain of NV AMD treatment may include combinations of steroids with PDT or one of the aptamers (anti-VEGF agents).

Anti-VEGF (vascular endothelial growth factor) agents have been pursued for many years. The leading contemporary candidates are rhu-FAB (Lucentis, Genentech) and pegaptanib sodium (Macugen, Eyetech Pharmaceuticals; Pfizer), which received FDA approval in December 2004. Each of these inhibits the proliferative proteins responsible for choroidal neovascularization.

Other approaches

Co-managing optometrists should appreciate that retinal specialists may embrace various treatment strategies based on their interpretation of the literature, clinical experience and evolving combinations. Those favoring photodynamic therapy (PDT), for example, may follow patients very frequently post-op (2-3 weeks) using imaging studies (Optical Coherence Tomography (OCT) Carl Zeiss Meditec; HRT Macula Module, Heidelberg Engineering) to determine treatment response.

Others favor combination therapy with intravitreal steroid injections before PDT, which is an emerging trend.

Another approach is intravitreal steroid injection alone (4-20mg triamcinolone acetate). This treatment strategy is repeated at six-month intervals.

Still another treatment strategy for neovascular AMD is posterior juxtascleral depot (PJD) injection of anecortave acetate (15mg, Retaane, Alcon). This angiostatic steroid appears to have a six-month duration and would be repeated semi-annually.

As many as three million people may be affected by AMD by the year 2020. Understanding the genetic factors and pharmacologic interactions will ultimately lead to more effective treatment options for these patients.