Age-Related Macular Degeneration 2015

US Pharm. 2015;40(6):22-26.

ABSTRACT: Age-related macular degeneration (ARMD) is the most common cause of severe vision loss in elderly persons in developed countries and accounts for one-third of cases of untreatable vision loss. ARMD is a painless, irreversible, degenerative eye condition associated with the damage and ultimate death of photoreceptors. There are two types of ARMD, dry and wet; dry ARMD is far more common, but wet ARMD is usually a more advanced disease state and is associated with rapid distortion and sudden loss of central vision. Various agents are used for treatment, and lifestyle changes and dietary constituents are important for preventing ARMD and halting its progression. As new therapies become available, early identification of patients with risk factors for ARMD will be increasingly important.

Age-related macular degeneration (ARMD) is the leading cause of irreversible visual impairment in the elderly.¹ ARMD is a degenerative disease of the central part of the retina—known as the macula—that results in a loss of central vision, which is essential for most daily activities.² It is characterized by a loss of visual acuity caused by degeneration of the choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors, usually beginning with drusen and pigmentary changes in Bruch’s membrane.^1,3

The condition, which affects 30 million to 50 million people worldwide, is the leading cause of irreversible blindness in developed countries in people aged 50 years and older.^1,2 More than 1.75 million persons in the United States were reported to have ARMD in the year 2000, and it is thought that the incidence will increase to almost 3 million by 2020.²

The prevalence of ARMD increases exponentially every decade after age 50.⁴ In many Western countries, the prevalence of ARMD in individuals older than 55 years is 1.6% and increases to about 13% in persons older than 84 years.² The loss of central visual acuity leads to a reduction in activities of daily living, as well as to mobility problems and an increased risk of falls, fractures, and depression in the elderly.⁵

Stages of ARMD

Early stages of ARMD are characterized by a macula that has yellowish subretinal deposits (drusen) and/or increased pigment. Patients with early ARMD have stable visual acuity for many years, and loss of vision is gradual.⁵ Although there are various classification systems for ARMD, the Age-Related Eye Disease Study (AREDS) classification (TABLE 1) is most commonly used.⁶

Advanced ARMD causes a significant loss of vision. There are two types of ARMD: dry and wet.

Dry ARMD: The dry form of ARMD is also known as nonexudative, nonneovascular, or atrophic ARMD. This is the more common form of ARMD, seen in about 90% of cases.⁷ Vision loss in dry ARMD is gradual and usually is associated with moderate visual impairment, as well as functional limitations including fluctuating vision, difficulty reading, and limited vision at night or under conditions of reduced illumination. Upon examination, the macula shows areas of depigmentation.⁵

Wet ARMD: Wet ARMD, which is also referred to as exudative or neovascular ARMD, accounts for about 10% of cases.⁷ However, its presence usually indicates a more advanced disease state, and it is associated with rapid distortion and a sudden loss of central vision over a period of weeks to months.² A number of studies have demonstrated that, in patients with wet ARMD, the eyes have two times the expected prevalence of vitreomacular adhesion and are less likely to have a posterior vitreous detachment.⁸ Fluid and exudate may accumulate underneath the retina in patients with neovascular ARMD, resulting in severe macular edema.^5,7 If left untreated, the neovascular membrane forms a big scar in the macular area, resulting in a sudden decrease in central vision.⁷ Choroidal neovascularization (CNV) is an advanced stage of wet ARMD that can lead to the development of polypoidal choroidal vasculopathy. The condition progresses from drusen to the development of CNV, whereby the choriocapillaries cross Bruch’s membrane and spread laterally within the planes of these lesions.⁹

Etiology and Risk Factors

The etiology of ARMD is multifactorial and involves an interplay of genetic, environmental, metabolic, and functional factors, including aging, family history, smoking, high blood pressure, obesity, hypercholesterolemia, and arteriosclerosis.^4,8 The deterioration of the macula results in the loss of central vision only; peripheral vision remains intact.⁵ Central vision is needed for identifying letters, numbers, facial features, border surfaces, angles, and colors; reading; driving; watching television; and many other activities requiring “high-definition” vision.^5,10 Since peripheral vision is not affected, patients with ARMD typically do not require canes or guide dogs.

Although numerous risk factors for ARMD have been identified, their association is variable, and the evidence for some of them is poor. As new and relatively effective treatments become available, the early identification of patients with risk factors becomes even more important. Risk factors associated with ARMD include old age, smoking, family history, female gender, obesity, sun exposure, atherosclerosis, hypertension, diabetes, polypharmacy, alcohol, ethnicity, hypothyroidism, and C-reactive protein.^2,5,8,11-22

Drusen

Drusen are focal deposits of extracellular debris that typically form between the basal lamina of the RPE and the inner collagenous layer of Bruch’s membrane. They are generally round and yellowish in color. These lesions, which are considered the hallmark of ARMD and are characteristic of the aging eye and age-related maculopathy, can be detected through various assays.²³

Drusen are classified as hard or soft, depending upon their borders and the level of risk they confer on progression of ARMD.⁹ Soft drusen are more commonly found in the macula and pose a higher risk of ARMD development.^9,23 They are slightly larger than hard drusen and do not have well-defined margins.⁷ Hard drusen tend to be smaller and well defined. The distinct features of the druse may give an indication of the stage of ARMD.²³ Furthermore, the content of drusen is important in understanding the formation process of the lesions that are specific to ARMD. Drusen are known to contain lipids, carbohydrates, zinc, and at least 129 different proteins, including extracellular matrix.²³ The molecules trapped in drusen have varying roles, including the processing of extracellular enzymes, the stigmata of formative processes (e.g., extrusion or secretion of cellular materials), and cellular invasion.²³

Diagnosis

In its early stages, ARMD is usually asymptomatic, but in some cases, patients may complain of acute vision loss, metamorphopsia, blurred vision, scotomas, or chronic visual distortion.^5,24 Since the onset of ARMD is gradual and often goes unnoticed for a long time, routine dilated eye examinations are recommended.¹³ It is useful for primary care physicians to know their patients’ profiles and be able to identify high-risk patients. The diagnosis is usually made by an ophthalmologist.

About 13% of patients with ARMD present with Charles Bonnet syndrome, in which mentally healthy patients experience loss of vision and complex visual hallucinations. The hallucinations are clear, well-defined, organized images over which the subject has little or no control.²⁵ Charles Bonnet syndrome is benign and frequently regresses as the visual cortex adapts to the loss of vision.²⁶

Various screening tests may be used by an ophthalmologist to establish a diagnosis. These include visual acuity tests, dilated funduscopic examination, optical coherence tomography, fluorescein angiography, indocyanine green angiography, fundus autofluorescence, and ultrasonography. In advanced cases, referral to a retinal specialist may be required.

The Amsler grid is a 4x4-inch checkerboard chart that has proven to be an effective tool for monitoring the progression of ARMD at home.⁵ Recently, novel computing systems using mobile handheld devices have been tested to monitor the retinal visual function of patients with ARMD.²⁷

Prevention

Given the aging of the population, the impact of macular degeneration will become even greater in the future. This gives rise to a need for preventive strategies and effective treatment options. The approach used in the management of ARMD is to identify and attack the disease in its early stages, slowing progression and vision loss.³ Various lifestyle changes and dietary constituents have been established as having a beneficial effect on preventing the disease and halting progression.³ The foods, minerals, and supplements that can assist with sight preservation are listed in TABLE 2.^13,28,29

Treatment

Thermal laser photocoagulation was the treatment of choice for many years in the management of patients with wet ARMD. In this procedure, the laser is directed toward the CNV to destroy it. This procedure, however, has been associated with a high rate of recurrence.³⁰

Various strategies for managing ARMD have been used or proposed, including laser photocoagulation for neovascular ARMD, submacular surgery, external beam irradiation, proton beam irradiation, focal radiation, intravitreal steroids (for their antiangiogenic properties), and transpupillary thermotherapy. These modalities demonstrated no efficacy, were associated with severe adverse effects, or were surpassed by more recent therapies.

Although statins were proposed to have a beneficial effect on ARMD, there is insufficient evidence to support the use of statins in the management of ARMD, whether for preventing or delaying onset.³

The prognosis for patients with neovascular ARMD has improved significantly with the development of verteporfin photodynamic therapy (PDT) and antiangiogenic therapy (i.e., intravitreal pegaptanib sodium, intravitreal bevacizumab, and intravitreal ranibizumab).³¹

PDT: This therapeutic modality takes advantage of certain unique properties of subretinal neovascular vessels and is based on the fact that neovascular tissue differs from normal blood vessels in terms of retaining dye. In PDT, which uses a combination of drugs and laser therapy, a verteporfin photosensitive compound that localizes to the target tissue is injected into a peripheral vein and excited with laser light of a specific wavelength.³ Activated verteporfin forms free radicals, which coagulate the leaky subretinal vessel responsible for cellular injury.^3,5

For administration, verteporfin (Visudyne, Bausch and Lomb) must be reconstituted with 7 mL of Sterile Water for Injection to provide 7.5 mL containing 2 mg/mL. The reconstituted solution is an opaque dark green in color and must be protected from light. Reconstituted Visudyne should be used within 4 hours and should be inspected visually for particulate matter and discoloration prior to administration. Reconstituted Visudyne should be diluted with 5% Dextrose for Injection. Since it precipitates in normal saline, it should not be diluted with normal saline or another parenteral solution. Visudyne should not be mixed in the same solution used for other drugs.³²

Patients receiving PDT should be advised to avoid exposure to the sun and other sources of bright light. Some patients may complain of injection-site problems, photosensitivity, and infusion-related back pain during the first year of therapy.⁵ Severe chest pain and vasovagal and hypersensitivity reactions have been reported in some patients following verteporfin administration.³² The use of verteporfin is contraindicated in patients with porphyria or known hypersensitivity to any component of the preparation.³²

VEGF Inhibition: Based on the angiogenic role of vascular endothelial growth factor (VEGF) in neovascularization, VEGF inhibition has become one of the targets of successful therapies for neovascular ARMD. It has been shown that visual improvements of +6.9 letters to +11.3 letters can be achieved by using bevacizumab (Avastin, Genentech/Roche), ranibizumab (Lucentis, Genentech), and aflibercept (Eylea, Regeneron) intravitreally in patients with CNV.³³

Pegaptanib, an RNA-binding anti-VEGF₁₆₅ aptamer, was the first antiangiogenic agent tested.³⁴ Its use has declined since the development of the more potent agents ranibizumab and bevacizumab, which are derived from the same monoclonal antibody precursor.^35,36 Bevacizumab has quickly become more popular than ranibizumab, and its wide off-label use is due to its low cost.³⁷ A single dose of ranibizumab costs 40 times more than a dose of bevacizumab.³⁸

Role of the Pharmacist

Pharmacists are ideally placed to assist patients at risk for ARMD and those undergoing diagnosis or already diagnosed with ARMD. In addition to helping patients identify risk factors, pharmacists can advise patients on how to avoid ARMD. Additionally, pharmacists can suggest supplements that may slow the progression of the condition in patients who have been diagnosed.

Conclusion

ARMD is the primary cause of irreversible blindness in the Western world. The etiology of this condition is largely unknown and is thought to involve interplay of a number of modifiable and nonmodifiable risk factors. As the underlying pathologic mechanisms of the degenerative retinal disorder are discovered, therapies targeted to the involved pathways are being developed. The management of neovascular ARMD is promising, given the availability of antiangiogenic therapies (both established and upcoming). Despite the therapeutic modalities available, ARMD continues to have a high incidence, and there is a great need for more efficacious, more potent, and safer therapies.

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