AMD update

AMD: New Theories and New Treatments

In the first of a two-part series, we explore the pathophysiology and prevention of age-related macular degeneration.

BY ANDREW S. GURWOOD, O.D., F.A.A.O. AND JEFFRY GERSON, O.D.
Elkins Park, Pa.

Age-related macular degeneration (AMD) is the leading cause of acquired legal blindness in the United States for white persons older than age 65.^1–17 A total of 1.75 million individuals older than age 40 suffer from some form of the disease with another seven million having drusen, placing them at risk.¹⁷ AMD is present in approximately 10% to 18% of the population older than age 52 and in up to 30% to 33% of individuals older than age 75.^1,6

Further, researchers estimate that by the year 2020, some 2.95 million Americans will suffer from the visually impairing sequelae of AMD.¹⁷

AMD is an extension of abnormalities that begin and progress through Bruch's membrane, involving the retinal pigment epithelium (RPE) and photoreceptors.^1,2 The earliest clinical manifestation of AMD are drusen (focal thickening of Bruch's membrane — vitronectin, apolipoproteins B and E, (complement, lipid).⁶ RPE, neural retina and choroidal cells synthesize most of the molecular constituents of drusen. The process of drusen formation can be derived from extraocular sources, such as smoking. This may be the reason drusen share an apparent association with atherosclerotic and cardiovascular risk factors.^6,9 While the presence of drusen do not definitively indicate AMD, clinicians regard them as a potential precursor, warning of the possibility for pathological progression and visual loss.^1,2 AMD is bilateral in 55% of cases.¹

The visual symptoms associated with AMD depend on its severity and type.^1–6 In general, the "dry" form (no subretinal choroidal neovascularization, exudation or hemorrhage) is less severe, producing a gradual, painless distortion or loss of central vision.^1–6 The "wet" form (subretinal choriodal neovascularization, exudation and or hemorrhage) produces more acute, severe central visual loss (in many cases six lines or more) than the dry form, with lasting impairment. Wet AMD-induced visual losses are often rapid and may remain progressive despite treatment.^1–9

Some of the clinical retinal signs of dry AMD include drusen of the posterior pole, granular clumping and disorganization of the RPE in the macular area. (Other signs: Macular RPE hyperplasia and degeneration of the outer retinal layers with circumscribed areas of geographic atrophy of the RPE.^1,2

In addition to severe vision loss, some of the clinical retinal signs associated with wet AMD include the presence of hard and soft drusen, subretinal thickening secondary to classic or occult choroidal neovascularization — which produces a grayish-green subretinal hue when observed by the clinician — subretinal, intraretinal or vitreous hemorrhage, subretinal and intraretinal exudation with serosanguinous fluid accumulation and fibrovascular scar formation (disciform scarring).^{1–4,6,16, 17}

PATHOPHYSIOLOGY

Common changes

From a clinicopathologic perspective, all forms of AMD possess initial, common changes within the macular RPE. Some researchers postulate that isolated interruptions of homeostasis within regions of the RPE, Bruch's membrane and/or choriocapillaries initiate these changes.¹ They believe that these changes cause widespread failures resulting in eventual photoreceptor degradation and that through time, the accumulation of undigested extracellular debris alters the Bruch's membrane composition (i.e., increased lipid and protein content) and permeability (eg., decreased permeability to water-soluble constituents in plasma, decreased amino-acid transport and possibly decreased removal of extruded RPE-derived cytoplasmic debris across the Bruch's membrane).⁶ Researchers say that these changes complicate the diffusion of waste products, hormones and nutrients, including oxygen and vitamin A, to and from the RPE. In response to this metabolic distress, the RPE itself may produce substances that stimulate choroidal neovascular membrane's (CNV) growth.

All the while, the photoreceptors disintegrate, causing the inner nuclear layer to collapse and initialize the demise of the outer retinal layers.¹

Wet AMD results when new, weak and leaky blood vessels compromise the macular RPE/Bruch's barrier. Angiogenic factors, released within the damaged tissues secondary to the pathologic process, at least in part, stimulate the new vessel growth.⁶

The vessels grow upward into the retina from the choriocapillaris to form CNV, termed occult when poorly defined, or classic when easily defined. Sometimes, we refer to the membranes as subretinal choroidal neovascular membranes (SRNVM). These membranes are undesirable because their incompetent vasculature may leak serosanguinous fluid at the level or adjacent to the level in which they reside, causing RPE detachment, sensory retinal detachment, subretinal or intraretinal bleeding and fibrovascular, disciform scarring.^1–4,6

Five concepts

The five principle concepts relevant to the current cell biology of AMD:

1. AMD involves tissue changes associated with the break down of aging along with additional pathological changes (i.e., AMD isn't just an aging change).⁶

2. In both aging and AMD, oxidative stress causes retinal pigment epithelial (RPE) and choriocapillaris injury.⁶

3. The process of AMD (and perhaps more globally, the process of aging), RPE and choriocapillaris injury results secondary to what appears to be a chronic inflammatory response within Bruch's membrane and the choroid.

4. In AMD, RPE and choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix (ECM), which induces altered diffusion of nutrients to the retina and RPE, precipitating further RPE and retinal damage.⁶

5. The abnormal ECM alters the behavior of the RPE-choriocapillaris, ultimately leading to an atrophy of the retina, RPE, and choriocapillaris. This atrophy creates conditions favorable to new vessel growth (neovascularization).⁶

Using this model, it is conceivable that both the environment and multiple genes can alter a patient's susceptibility to the disease. Implicit in this characterization of the pathogenesis is a linear progression from one stage of the disease to the next.⁶

Hypoxia also appears to play a role in CNV formation, although researchers have not specifically proven this.³ Some theorize that initial oxidative damage leads to excessive formation of abnormal ECM. Thickened Bruch's membrane, combined with factors, such as smoking, may then create a relatively hypoxic retinal environment. Relatively minor changes in the diffusion properties of the Bruch's membrane or in choroidal blood flow could then impart disproportionate effects on the RPE and photoreceptors. Because the photoreceptors consume 90% to 100% of the oxygen delivered by the choriocapillaris, a relative state of hypoxia could then result in RPE death and geographic atrophy with stimulation of CNV growth.³

Idiopathic polypoidal choroidal vasculopathy (ICPV) is a relatively new and distinct clinical entity with many of the subretinal features of AMD.^14–16 It has a predilection for individuals of pigmented races but is also documented in the literature as having a prevalence in the Irish, French, German and Italian populations. ¹⁶ It demonstrates an inner choroidal vascular network of vessels with an aneurysmal protrusion that is visible clinically as a reddish orange, spheroidal, polyp-like structure. We should differentiate ICPV from typical choroidal neovascularization and other known choroidal degenerative, inflammatory and ischemic disorders because of differences in clinical course and treatment.^14–16 The natural course of the disease often follows a remitting-relapsing course. Clinically, it's associated with chronic, multiple, recurrent serosanguineous detachments of the retinal pigment epithelium and neurosensory retina, ironically, with long-term visual preservation. Photodynamic treatment appears to be a promising alternative to conventional laser therapy.^15,16

New investigations have uncovered information supporting some "out–of–the–box" thinking that characterizes AMD as a dystrophic inflammation rather than a degeneration.^6,9

Researchers have recently identified the C-reactive protein (CRP), a systemic inflammatory marker associated with an increased risk for cardiovascular disease (CVD), as a potential marker for AMD.⁹ Interestingly and almost simultaneously, the Age-Related Eye Disease Study (AREDS) team was working on a report potentially linking an increased risk of mortality in AMD patients by way of CVD.¹⁰ In this study, fundus photographs assessed the AMD status of 930 AREDS patients. Researchers took fasting blood specimens between January 1996 and April 1997 to determine high-sensitivity CRP levels.⁹ Results revealed that CRP levels were significantly higher among participants who had advanced AMD (case patients) than among those with no AMD. After adjustment for age, sex and other variables, including smoking and body mass index, CRP levels were significantly associated with the presence of intermediate and advanced stages of AMD. These results may implicate the role of inflammation in the pathogenesis of AMD, producing a new road for investigators.⁹

Investigators have implicated other systemic factors in AMD as well. For instance, when researchers test choroidal neovascular membranes with polymerase chain reaction, these CNVM's show evidence of Chlamydia pneumonia that aren't seen in CNVMs from different causes.¹⁸ We also know that genetics play a factor, as Complement Factor H is the first major AMD risk gene found and may particularly increase the risk of geographic atrophy.^19,20 Another more recent finding is the association of increased levels of homocysteine in AMD patients, as well as a higher risk of stroke, as found in the Atherosclerosis Risk in Communities Study.^21,22

MANAGEMENT

Prevention

Primary-care practitioners should begin managing patients who have potential or diagnosed AMD by recognizing the associated risk factors and educating their patients on these risk factors. The disease is more common in individuals who have a family history of AMD, have a light complexion, in those who have a cardiovascular history, history of previous lung infection, hyperopia and decreased grip strength.^9,10,11 The disease is typically more progressive in males. Also, smoking is a significant risk factor.^1,5 The most important risk factors for AMD (i.e. those associated with at least a two-fold increased risk) appear to be age, smoking and race.⁶ In general, the risk to patients with dry AMD for progression to wet AMD, for any given five-year period is approximately 14% to 20%.^5,6 In patients who have already lost vision in one eye to wet-stage disease, the risk through the course of five years for developing wet-stage disease in the fellow eye is 10% for patients whose fellow eye has neither large drusen nor pigment clumps, 30% for fellow eyes containing either large drusen or pigment clumps and 50% for fellow eyes with both pigment clumps and large drusen, according to classic research.⁸

The management for dry-AMD patients begins with biannual, thorough, eye examinations with detailed, dilated fundoscopy. Home therapy, aimed at early detection and prevention, using a home Amsler grid, particularly a black grid with white lines, may work to monitor the stability of suspicious or involved maculae.² The elimination of potentially harmful ultraviolet (UV) light using UV coatings on spectacles and sunglasses may also reduce the risk of photochemical/oxidative damage to the retina for all patients.¹ Researchers have indicated that oral antioxidants, such as vitamins C and E and oral zinc, may play a role in reducing retinal damage by terminating the chemical reactions initiated by free radicals, created by retinal metabolism.^6,7,10–12 Research has also shown that multiple vitamins, oral zinc or products specifically designed for this purpose are useful in slowing the progression of AMD.^{1,2,5–7,10–12}

Several studies have demonstrated the link between good health, good diet and low-dose aspirin/statin drugs with reduced AMD development or progression.^23–28 One prospective cohort four-plus year study of 261 patients older than age 60 who had non-exudative disease revealed that total and specific types of fat intake, as well as consumption of fat-containing food groups (baked goods), modified (increased) the risk of and or progression of the disease. Fish intake and nuts reduced the risk of disease and progression, according to the study.^25,26 In a study of twins, the same researchers who conducted the non-exudative disease study reported on the negative effects of cigarette smoking and the positive effects of omega-3 fatty acid intake in AMD development.²⁹ There has been much discussion recently on the potential positive effects of omega-3 fatty acids, but there seems to be conflicting and nonconclusive information thus far.³⁰ This is one reason for the importance of the AREDS 2 trial. One study examined 326 dry-AMD patients older than age 60 during a three-year period and concluded that therapy with statin drugs or aspirin decreased the rate of CNV formation.²⁷

AREDS findings

Researchers conducted AREDS, which involved more than 3,600 patients, to determine whether high-dose supplementation could influence the natural progression of eye disease in older Americans.^6,13,28 AREDS found that prospective administration of purified vitamin C (500 mg/d), vitamin E (400 IU/d), beta-carotene (15 mg/d), zinc (80 mg/d) and copper (2 mg/d) reduced the risk of developing advanced AMD from 28% to 20% and the rate of at least moderate vision loss from 29% to 23%, while providing virtually no impact on the progression of cataracts.^6,13 The AREDS clinical trial has provided concrete evidence in support of supplement usage. Researchers have applied their data to an estimated eight-million Americans at least age 55 at risk for advanced AMD in whom practitioners should consider the AREDS formulation. Of these people, projections calculate that 1.3 million would develop advanced AMD if they received no treatment. If all these people at risk received supplements, such as those used in AREDS, more than 300,000 could avoid advanced AMD and any associated vision loss during a five-year period.¹³

The Retinal and Choroidal Diseases Panel of the National Advisory Eye Council has also recognized the benefits of prevention, given the hypothesis that beta-carotene levels are inversely related to AMD in experimental studies and amidst increasing evidence that visible and ultraviolet light can damage the retina through production of superoxide radicals. Because antioxidants (including beta-carotene, zeaxanthin, vitamins A, E and C and selenium) seem to protect against oxidative damage by acting as scavengers for the superoxide radicals, the National Eye Institute (NEI) is currently sponsoring The Randomized Trial of Beta–Carotene in Macular Degeneration Study.³¹ The goal of the study: to determine whether one 50-mg beta-carotene capsule taken on alternate days protects against the development of AMD and whether additional risk factors emerge after simultaneous controlling for other potential confounding factors.³¹

Beta-carotene use must be undertaken with caution. The published analyses of two major lung cancer prevention trials, Beta-carotene and Retinol Efficacy Trial (CARET) and Alpha-Tocopherol Beta-Carotene (ATBC) study, have found an increased incidence of lung cancer in individuals receiving beta-carotene supplementation (in either vitamin form or by dietary intake).^32–35 In both trials, heavy smokers were adversely affected.^32–34 In the last decade, research proved that beta-carotene acts as an antioxidant, which supports human immune function.³⁵ Recent experiments demonstrate the higher intake, resulting in higher serum levels of beta-carotene, are associated with improvements in some physiological functions, such as pulmonary function.^33,35 The unexpected findings of increased lung cancer in beta-carotene supplemented smokers in the ATBC and CARET intervention studies have resulted in the need for continuing research efforts to define the mechanism(s) of action of beta-carotene.^32–35 Recent survey data, as well as laboratory animal studies, continue to find an inverse association between beta-carotene and cancer risk in non-smoking subjects.³⁵ Because beta-carotene is the major source of vitamin A for the majority of the world's population, it's critical to define the safe levels of intake.³²

Further, researchers from the AREDS trial have recently completed work comparing individuals using high doses of antioxidants or zinc with mortality.^10,13,28 Researchers randomly assigned participants to receive oral supplements of high-dose antioxidants, zinc, high-dose antioxidants plus zinc or a placebo. Researchers assessed risk of allcause and cause-specific mortality. During median follow-up of 6.5 years, 534 (11%) of 4,753 AREDS participants died. Participants with advanced AMD — compared with participants with few, if any, drusen — had increased mortality. Advanced AMD was associated with cardiovascular deaths. Patients with nuclear lenticular opacities who underwent cataract surgery were also associated with increased all-cause mortality and with cancer deaths.¹⁰ In this study, participants randomly assigned to receive zinc had lower mortality than those not taking zinc. The decreased overall survival of AREDS participants with AMD and cataract suggests that these conditions may reflect some systemic commonality rather than a strictly local process.¹⁰ Note that the level of zinc, nearly 70mg, although not problematic in the AREDS study, has the potential to have toxic affects.

The AREDS 2 study began recently. It assesses whether the AREDS formula is sufficient, or whether the addition of omega-3 fatty acids and/or lutein with zeaxanthin are beneficial. A secondary endpoint will determine if the levels of zinc in the original formulation are excessive and if doctors can remove beta carotene, in order to make it a formula more appropriate for smokers. Researchers hope to enroll 4,000 patients who they will follow through the course of five years at one of the many U.S. sites.

Researchers designed the lutein antioxidant supplementation trial (LAST) to determine whether nutritional supplementation with lutein or lutein together with antioxidants, vitamins and minerals improved visual function and symptoms in atrophic AMD.³⁶ Lutein is a naturally occurring yellow–orange pigmented substance classified as a carotenoid. It's a naturally occurring substance found in carrots, potatoes, green leaves and animal tissues. It (and its molecular relative zeaxanthin) are capable of absorbing energy from light. One study randomized 90 patients who had atrophic AMD into three groups. In all patients taking lutein, mean eye macular pigment optical density increased approximately 0.09 log units from baseline. Snellen equivalent visual acuity improved 5.4 letters in those taking 10mg of lutein and 3.5 letters for those taking lutein and antioxidants. Contrast sensitivity improved in both these groups as well. The lutein group experienced a net subjective improvement in the Amsler grid measurement. Questionnaires concerning subjective glare recovery were significant at four months for the group taking lutein and antioxidants. Patients who received the placebo had no significant changes. The data has led the researchers to conclude that lutein alone or together with other nutrients can improve visual function in these patients.³⁶

The idea of using laser photocoagulation to disrupt or reverse drusen formation has been under investigation since the1970s.^37–43 Researchers designed the Choroidal Neovascularization Prevention Trial (CNVPT) and the National Eye Institute's Complications of Age-related Macular Degeneration Prevention Trial (CAPT) to study the effect of laser photocoagulation when applied to drusen for the purpose of preventing vision loss by halting CNV formation and retarding the progression of AMD to its advanced, vision impairing forms.^{30,37–43,40} These studies showed a decrease in numbers of drusen at 12 months, but did not show a correlative decrease in CNVM development. As studies to this treatment haven't shown consistent improvement, doctors don't use this treatment today.

Rheopheresis

Another treatment aimed at stopping the progression of dry AMD and the possible development of CNVM is rheopheresis.

The goal of rheopheresis is to filter the blood to remove large proteins at AMD's earliest stages to try to reduce the risk of blindness and improve improve microcirculation in the macula.⁴⁴

The RHEO-AMD study was supposed to confirm efficacy of this treatment modality as previously seen in the The Multicenter Investigation of Rheopheresis for AMD (MIRA)-1 trial. Funding issues, however, have prompted the sponsor company to halt trails at this time.⁴⁵

Next month, we will look at treatments for wet AMD, surgical modalities, antiangiogenesis and low vision.

A full list of references will be available in the next installment. These references are also available upon request.