new in Therapeutics
for this widespread condition may prove useful for generations to come.
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
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.
This macula shows some pigment disruption, but no drusen.
AMD with fresh blood; the center of the macula has been compromised by previous
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
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.
have criticized AREDS because it did not include high doses of lutein or
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.
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.
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 <
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.
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
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.
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
Others favor combination therapy
with intravitreal steroid injections before PDT, which is an emerging trend.
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
Dr. Semes is associate professor and
director of continuing education at UABSO. He has received the UAB President's award
for teaching excellence. Dr. Semes has published over 60 articles and has been named
to 2000 Outstanding Intellectuals of the 21st Century.
Optometric Management, Issue: July 2005