• Macular Degeneration: When Standard Therapies Fail

    By Annie Stuart, Contributing Writer

    This article is from January 2008 and may contain outdated material.

    Hope can be a precious commodity—especially when people have a serious disease such as macular degeneration. “In the past, we mostly patted people on the back and said, ‘Let’s hope it doesn’t happen in the other eye,’” said Nancy M. Holekamp, MD, associate clinical professor of ophthalmology at Washington University in St. Louis.

    Today, more options are available, at least for wet AMD. But what is the ethical responsibility of the ophthalmologist when standard treatments fail? How does a physician balance the need to use evidence-based medicine with the desire to explore emerging technologies for patients in drastic need? And how best to work with those patients who come demanding alternative therapies?

    “We need to be careful about recommending alternative medicine for macular degeneration patients—people will spend their last dime on something they think will be of benefit,” said Deepinder K. Dhaliwal, MD, chief of cornea and refractive surgery and associate professor of ophthalmology at the University of Pittsburgh. At the same time, she added, “Eastern medicine is rich in what it can provide—we need to understand it better and apply some of the techniques that have proven efficacy.”

    However, many patients aren’t waiting for bedrock science or their physician’s approval. More than one-third of all Americans seek some form of complementary and alternative medicine (CAM) each year—care that costs billions.1 When combined with forays into other types of investigative, experimental or speculative treatments, these pursuits reflect the public’s pervasive interest in exploring their options, said Charles M. Zacks, MD, chairman of the Academy’s Ethics Committee.

    An Evolving Arsenal

    Standard treatments for exudative AMD have grown in number over the past several years. Photodynamic therapy with verteporfin and anti-VEGF agent pegaptanib were considered significant advances. Off-label use of bevacizumab, another anti-VEGF agent, entered the mix as well. And, most recently, ranibizumab became available.

    But one now-accepted treatment might have been dismissed as merely “alternative medicine” had it not been for a rigorous study: The AREDS trial, involving more than 4,700 participants, demonstrated that supplementation with certain antioxidants and zinc reduced the risk for developing advanced AMD by more than 25 percent—vindicating the claim that photoreceptors might be preserved with antioxidant agents.

    “The AREDS study was a wonderful but rare example of applying the scientific method to what would otherwise be considered alternative therapy,” said Dr. Holekamp. Unfortunately, she added, many patients follow the maxim, “If a little is good, more is better,” and very high doses of vitamins can have side effects.

    Recruitment for a second AREDS study of lutein, zeaxanthin and fish oil is now under way. Lutein and zeaxanthin—carotenoids found in yellow and dark green, leafy vegetables—may work by filtering short-wavelength light that is damaging to the retina.

    Introducing the Alternatives

    For the millions of patients with AMD—particularly dry AMD—who cannot benefit from the established therapies, various CAMs may look enticing.

    Apheresis. Used for 30 years to treat certain systemic disorders such as myasthenia gravis, therapeutic sequential apheresis involves pumping venous blood through a filter that separates plasma from cells. A second filter selectively removes high molecular-weight proteins and lipids from plasma, which is then remixed with cells and returned to the patient. Removal of proteins, it is thought, might improve AMD by enhancing microcirculation and perfusion of the macula.2

    Started by trauma physicians operating clinics in Florida, apheresis for AMD was “like a hammer looking for a nail,” said Dr. Holekamp. According to anecdotal reports, said Dr. Zacks, people were charged exorbitant fees for multiple sessions “and were literally mortgaging their houses to raise money for this.”

    Although initial trial results from small studies suggested benefit, apheresis “fell off the map” in early 2007, said Dr. Holekamp, after OccuLogix announced that the phase 3 trial of its apheresis device did not show an effect in the intent-to-treat group.3

    Enthusiasts now must await a new study, called Rheo-AMD—a multicenter, randomized, double-masked, placebo-controlled trial to evaluate safety and efficacy of the procedure in patients with intermediate to late-stage dry AMD.

    Microcurrent stimulation (MCS). A technique that applies electrical stimulation to nerve fibers using cutaneous electrodes, MCS is another approach whose mode of action and efficacy require further research. When applied to the macula for AMD, MCS may work by improving membrane permeability, nerve conduction velocity, protein synthesis or ATP levels. Although adverse effects are low, evidence of its effectiveness is not sufficient to support its use, according to an Academy Complementary Therapy Assessment.2 However, the Macular Degeneration Foundation has created the Macular Electrophysiology Initiative to secure funding for future studies.

    Acupuncture. In 1996, the FDA approved the use of acupuncture by licensed practitioners. This technique penetrates the skin with thin, solid, metallic needles, which are manipulated by hand or electrical stimulation. “Acupuncture studies have demonstrated a change in neurotransmitters and neurohormones, as well as alterations in blood flow and immune function,” said Dr. Dhaliwal.4

    Two small case studies indicate positive results in using acupuncture for AMD. In the second, more extensive of these, 108 patients in a single practice showed 69 percent improvement in both near and distance vision, with both wet and dry types benefiting. A third of participants gained more than two lines on ETDRS charts.5

    These are exciting results, said Dr. Dhaliwahl, but she added that there is still a paucity of controlled data on acupuncture in the peer-reviewed ophthalmic literature.

    Dr. Dhaliwal hopes to change that. She’s launched the Center for Integrative Eye Care at the University of Pittsburgh, where a central goal will be to conduct further studies.

    Surgical Solutions for AMD?

    Surgical solutions largely remain a last resort for patients who fail to respond to other less invasive therapies.

    One example is macular translocation, which involves moving the macula so the fovea lies over a healthier part of the choroid layer. Two options include a 360-degree retinotomy with macular translocation or scleral imbrication with more limited macular translocation.1

    A recent review of patients with exudative AMD who had macular translocations with 360-degree retinotomies showed mixed results. Half of 90 patients had stabilization or improvement with follow-up of 14 to 79 months. Progressive atrophy of the pigment epithelium was a major limiting factor.2

    “As we get more success with the injectable anti-VEGF agents and hopefully other biologics that may come down the road,” said Dr. Holekamp, “fewer people are candidates for macular translocations. Surgical solutions for AMD appear to be making up an increasingly smaller piece of the treatment pie.”


    1 www.clevelandclinic.org/eye-patient-info-macular-translocation.asp

    2 Aisenbrey, S. et al. Arch Ophthalmol 2007;125:1367–1372.

    When Accepted Practice Fails

    As more options for treating AMD become available to the practitioner, said Dr. Holekamp, many physicians don’t wait for clinical trial data, which can take years to obtain. “But you can’t practice medicine based on a belief system,” she said. Dr. Dhaliwal agreed. “Go with proven therapies first. If you have no response or a poor response from standard treatment, then consider other modalities with at least some peer-reviewed evidence in the literature,” she said.

    To a certain extent, said Dr. Zacks, you must resolve these issues on a case-by-case basis, but make sure patients don’t disregard things that work. “If a patient is getting apheresis but can’t make their appointment for a Lucentis injection,” he said, “it’s time to clarify the scientific evidence or lack thereof.”

    It may not be possible to keep up with all emerging technologies, but you can learn about and assess the more common ones. The Academy’s Task Force for Complementary Therapies is a good place to begin, said Dr. Zacks, especially since much of the footwork is done (www.aao.org/guidelines-browse?filter=complementarytherapyassessment).

    Dr. Zacks also encourages his colleagues to stay open-minded. “Science progresses, and today’s fringe idea might become tomorrow’s standard therapy.” Dr. Dhaliwal also suggests not lumping all alternatives into one basket. “Take each and think about it separately,” she said, pointing to acupuncture as an example of a technique with thousands of years of patient use.

    Speak plainly of the options. The way Dr. Zacks conceptualizes this with patients is by explaining where a particular therapy belongs on the spectrum of choices. “At one end of the spectrum you have outdated things,” he said. “We expect that ophthalmologists will use current established therapies while carefully integrating cutting-edge treatments into clinical practice.” Following those, he said, are investigative and experimentally promising techniques. And shadowing those are speculative or unproven therapies, which include many alternative and complementary modalities.

    Patients deserve objective information about these, no matter where they fall on the spectrum and no matter how many choices are available, said Dr. Zacks. “You can give patients an intuitive feel for whether something is established or cutting-edge, experimental or unproven.” Avoiding ambiguity helps prevent people from being exploited, he added. “Problems clearly arise when people are spending lots of money on something that doesn’t work or is dangerous.”

    The issue of informed consent becomes increasingly important yet complex when dealing with unvalidated therapies, said Dr. Holekamp. “We must clearly communicate—and document—a number of caveats about any new therapy,” she said, including lack of FDA approval or rigorous research, as well as potential side effects and costs.

    Don’t drop the dialog. This is especially important if the physician has a patient who wishes to pursue unvalidated therapies, said Dr. Zacks. “Don’t create barriers to conventional therapy by disparaging unconventional ones.” He used the example of a patient with a chlamydia infection who was convinced that carrying crystals in her pocket would solve the problem. Dr. Zacks didn’t stop her, but said, “Do come back because we need to see if they’re working.” When the patient returned without improvement, he convinced her to try doxycycline to achieve “additional effect.”

    Likewise, when counseling a patient with end-stage macular degeneration with bilateral scars, Dr. Zacks works to maintain a collaborative relationship. “If you say, ‘There’s nothing I can do for you,’ the relationship is essentially over, which will encourage people to try alternatives on their own,” he said. “But if you say, ‘Let’s keep in touch,’ you keep the door open and they may come to you with the next thing, asking you if it might work.”

    Best for you, or your patient? A physician who is personally enthusiastic about a potential option should be clear with his or her patients about where it resides on the spectrum of choices and how likely it is to work, said Dr. Zacks. It’s important to ask questions like these: Am I recommending this therapy for myself or is it really in the patient’s best interest? Do claims of efficacy reflect reality? Is the price fair and reasonable?

    When in doubt, pull out the Academy’s Code of Ethics and related Advisory Opinions found at www.aao.org, said Dr. Zacks. These will serve both physicians and patients well as they navigate the plethora of choices that are in the news, on the Web, in development or just over the horizon. The goal shared by everyone is not establishing a treatment dogma, but controlling and preventing macular degeneration.


    Dr. Holekamp is a consultant and speaker for Genentech and a consultant for Alcon. Drs. Zacks and Dhaliwal report no related financial interests.


    EyeNet would like to thank Dave Yates and Dr. Holekamp’s photography staff for their skill and assistance.


    1 www.nccam.nih.gov/news/camstats.htm

    2 Academy Complementary Therapy Assessment. www.aao.org/education/guidelines/cta

    3 Pulido, J. S. et al. Trans Am Ophthalmol Soc 2006;104:221–231.

    4 wwww.nccam.nih.gov/health/acupuncture

    5 Lundgren, A. C. Medical Acupuncture 2005;16:33–35.