Update: A 76-Year-Old Man With Macular Degeneration

In a Clinical Crossroads article published in May 2006,¹ Jorge Arroyo, MD, discussed the epidemiology and pathophysiology of age-related macular degeneration (AMD). The discussion centered on Dr G, a 76-year-old semiretired surgeon devastated by the loss of depth perception in his right eye because it prevented him from continuing to practice surgery. Three years prior to the conference, Dr G noticed subtle vision changes, which progressed, resulting in a diagnosis of AMD. After the diagnosis, Dr G received photodynamic therapy to the right eye 5 times, twice with the experimental addition of intraocular triamcinolone. Despite these treatments, Dr G lost vision in his right eye. At the time of the conference, Dr G was primarily concerned with protecting the vision in his left eye, allowing him to maintain autonomy and function with general ease. Dr Arroyo suggested that Dr G meet with a visual rehabilitation specialist to discuss strategies to help him overcome the functional limitations of his vision loss. Dr Arroyo also advised Dr G to adhere to a diet high in fruits, vegetables, fish, and nuts and to take a daily Age-Related Eye Disease Study (AREDS)–recommended antioxidant and zinc formulation. Finally, Dr Arroyo recommended that Dr G's depressive symptoms be addressed and treatment provided if necessary.

My vision is much worse. The best corrected vision in my left eye is 20/50 and I need a +5 lens for reading. I can't use standard bifocals because the lower half of the lens is a +5-diopter lens and if I look down I will trip, since I have no depth perception. I have arranged for my optician to make me a special lens using an 8-mm strip of corrected glass with +5-diopter correction in the mid portion of the left lens transversely, and that would give me an 8-mm-wide corrected lens for reading.

I’ve tried not to let the macular degeneration interfere with my quality of life. I’m pretty much the same except I get upset and I get angry. Reading was always a very important part of my life, and now I get very frustrated because I read slowly, and I can't scan. I have tried books on tape, but I fall asleep.

Music has always been a major part of my life as well. One of the real deprivations is that I can't play the piano because I can't read the music at the same time that I see the keyboard. But I can still simply listen to music, which is a great form of enjoyment for me.

I take all the supplements that people say will prevent macular degeneration: gluten, zinc, and, now, I am adding copper because that is what is in the study medication.

I am still working as the director of a small plastic surgery residency training program, and I take that very seriously. The residents are very supportive; they read the charts to me outside the patient's room, and then I go in the room with them and the patient is never the wiser of my inability to read or to write notes. I can't write notes in the charts because I can't follow the lines and I usually write the second line over the first line. It's not a happy situation.

I’m more depressed than ever. My internist has recommended that I go talk to a psychiatrist about it. Talk is not going to solve my problems. And even though I have a great deal of respect for psychiatrists, you can't talk yourself into seeing.

Although our ability to treat AMD has made steady progress over the past 2 years, it is clear from the frustration expressed by patients like Dr G and their treating physicians that the road ahead will be both long and challenging. I hope that as our understanding of the underlying pathophysiology of AMD improves, we will continue to make significant inroads into both the prevention and treatment of this disease.

The vision in Dr G's better eye with dry AMD has dropped from 20/30 2 years ago to 20/50 despite best correction. Unfortunately, simple visual acuity is a relatively poor measure of overall visual function in patients with AMD like Dr G, given the common loss of pericentral vision due to parafoveal chorioretinal atrophy.

We know from the results of the AREDS randomized controlled trial that patients with moderate and advanced AMD who took 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta carotene, 80 mg of zinc oxide, and 2 mg of cupric oxide per day had an approximate 25% reduction in their risk of progression to advanced AMD and visual acuity loss.² The follow-up AREDS II chemoprevention trial is currently enrolling patients to evaluate whether the antioxidants lutein and zeaxanthin, with or without 1 g/d of omega-3 long-chain polyunsaturated fatty acids, also reduces the risk of progression to advanced AMD and visual acuity loss.^{3 - 5}

There are at least 3 other clinical trials currently under way targeting dry AMD that may be of interest to Dr G. One of these trials is testing the efficacy of topical antioxidant eye drops (OT-551) in patients with geographic atrophy⁶ ; the second trial is testing the efficacy of surgically implanted encapsulated human NTC-201 cells that release ciliary neurotrophic factor⁷ ; and the third trial is studying fetal cell transplantation in patients with dry AMD.⁸ Ongoing trials in patients with neovascular AMD are studying the efficacy of topical eye drops of the angiogenesis inhibitor pazopanib,⁹ subconjunctival injection of the antiproliferative polyamine analog CGC-11047,¹⁰ and various combination treatment protocols that combine intravitreal anti–vascular endothelial growth factor agents with photodynamic therapy.^{11 - 12}

In more than 50% of cases of macular degeneration, genetic defects can be found in various loci in the complement factor H (CFH) gene. Patients who have some of these mutations and have other modifiable risk factors such as smoking have been found to have a multiplicative relationship between risk factors.¹³ In another study that demonstrated a gene-environment interaction, patients with the Y402H CFH variant who also had significantly elevated antibodies to Chlamydia pneumoniae had a 12-fold increase in the risk of AMD.^{14 - 15}

Various companies are currently gearing up to provide rapid and affordable genetic screening of some of these mutations to allow physicians to determine individual risk more accurately, advise patients regarding modifiable risk factors, and better target specific experimental treatments. Some of these mutations are thought to result in increased complement activation and inflammation that is associated with AMD. Various research studies are examining the effects of anti-inflammatory drugs or vaccines on the progression of AMD. Some of these include an intravitreal complement inhibitor (POT-4), vaccination with the immunomodulatory substance Copaxone (glatiramer acetate), and treatment with the anti-inflammatory agents infliximab, sirolimus, and daclizumab (see http://www.clinicaltrials.gov).

Recent studies have also demonstrated that the pathophysiology of AMD is systemic in nature, rather than simply ocular. The presence of AMD is in effect a biomarker of generalized systemic disease and is associated with a significantly higher risk of myocardial infarction and stroke.^{16 - 17} Given these findings, patients diagnosed as having AMD (especially the neovascular form) should consider aggressively controlling cardiovascular risk factors.

In summary, I recommend that Dr G, given his moderate AMD, continue to take the AREDS-recommended vitamins to reduce the risk of progression to advanced AMD by 25%. If he is unable or unwilling to participate in the follow-up AREDS II trial, I would recommend that he add foods or supplements (eg, fish oil or cod liver oil) that are high in omega-3 fatty acids to his diet. Dr G may wish to consider being screened for CFH mutations (once these become readily available) that may more specifically quantify individual risk of AMD progression. He is already highly motivated to do what he can to modify his risk, but his family members may find the information important. Although significant progress in the understanding and treatment of AMD has been made over the past 10 years, clearly much more work lies ahead.