Age-related macular degeneration (AMD) is a severe disease among elderly leading to loss of vision. This article describes the existing concepts about the both dry and wet AMD, existing therapeutic strategies, and upcoming treatments in near future.
We can perceive the beauty of this world through eyes. Defects in eyes can lead to impaired vision and sometimes blindness also. Among several others the age-related macular degeneration (AMD) is a visual disorder in which the macula degenerates due to aging and as such elderly individuals suffer from this disease. The AMD is the leading cause of irreversible blindness in the elderly. Due to increased aging population, the number of people suffering from the AMD is expected to rise as shown in Figure 1. Understanding AMD in detail requires an understanding of the structure and function of the eye.
The human eyes aretwo ball-shaped organs situated in the bony orbit of the skull. The eye is an outward extension of the central nervous system (CNS). Each eye is composed of thecornea, pupil, lens, retina, optic disc, extraocular muscles, and nerves and blood vessels of the orbit. The cornea is the transparent anterior component of the outer layer. The pupil is the central aperture of iris
with adjustable diameter by intrinsic smooth muscles. The lens is a transparent,biconvex disc that is flattened from tension exerted by theciliary body and suspensory ligament and rounds slightly when tension is released by the ciliary muscle. The retina is the inner layer of the eyeball situated adjacent to thevitreous body. The retina consists of the posterior optic part and the anterior nonvisual part. The optic retina is formed by the inner nervous layer and the outer pigmented layer separated by an inter-retinal space. The macula is a small yellowish area of the nervous retina located lateral to the optic disc, which contains the highest concentration of photoreceptor cells. The fovea centralis is a central depression of macula lutea.
The retina is composed of several layers of cells. These are photoreceptor cells, including rods and cones, retinal
pigment epithelium (RPE), choroid, and Bruch’s membrane. The photoreceptor cells contain pigment molecules known as rhodopsin and cone opsin, which absorb photons of light. The RPE is composed of epithelial cells behind photoreceptor cells. The choroid is a layer of blood vessels which penetrate the eye and is located behind the RPE. In between the RPE and choroid is a membrane called the Bruch’s membrane, which separates the RPE from the choroid [4, 5].
The optic disc contains ganglion cell axons which converge to form the optic nerve. The optic disc is also the site where the central retinal artery enters the eyeball. There are seven extraocular muscles that provide support to each eyeball: superior rectus, inferior rectus, medial rectus, lateral rectus, superior oblique, inferior oblique, and levator palpebrae superioris. Several nerves penetrate the orbit: ophthalmic nerve (V1), optic nerve (CNII), trochlear nerve (CNIV), abducens nerve (CNVI), and oculomotor nerve (CNIII). The blood vessels that penetrate the orbit are the ophthalmic artery, central vein of theretina, and ophthalmic veins[6, 7].
Physiological Aspects of Human Eye:
The cornea is the first structure to refract light that enters the eye. The pupil allows passage for the aqueous humor flow from theposterior chamber to anterior chamber. Decreased drainage of aqueous humor from the anterior chamber results in increased intraocular pressure, causing glaucoma. The sphincter papillae of iris decreases aperture size, whereas dilator pupillae increases aperture size.In the retina, rods are primarily responsible for vision in dim light, whereas cones are primarily responsible for color vision. The macula is responsible for central high-resolution visual acuity and enables one to see fine detail, read, and recognize faces.Light is converted by photoreceptor cells into electrical signals through various chemical processes. A crucial molecule that aids in the production of rhodopsin molecules is vitamin A. Vitamin A is brought into the eye by blood vessels present in the choroid and sent to the RPE where it gets metabolized and is transferred to photoreceptor cells to form pigment molecules. Once photons are converted into electrical signals, the signals are transferred to neurons connected to photoreceptor cells and sent to the visual cortex in the occipital region of the brain for visual processing. The RPE provides structural and functional support to photoreceptor cells. It nourishes photoreceptor cells by providing nutrients, and is also involved in photoreceptor phagocytosis and cytokine secretion. The choroid provides oxygen and other nutrients to the retina.
Pathophysiology of Human Eye in Age-related Macular Degeneration
Understanding the basic anatomy and physiology of the eye and specifically the retina can help us in understanding the basis of AMD. The AMD is caused by degeneration of retinal cells present in the macula due to aging. As the retina ages, it does not eliminate waste products properly. With the passage of time, waste products accumulate between the RPE and Bruch’s membrane and appear as yellow spotsknown as drusens. The Drusens vary in size ranging from<63um to >124 um; they can be soft or hard depending on the appearance of their margins. Presence of Drusens is considered as the hallmark of AMD[9, 10]. The AMD is divided into two types: dry AMD and wet AMD. About 85% of cases of AMD are dry AMD. The other 15% of cases are wet AMD and represent the most advanced stage of the disease. Dry AMD is
characterized by presence of drusens.The accumulation of drusens leads to damage of the RPE and the resulting chronic aberrant inflammatory response can lead to large areas of retinal atrophy, known as geographic atrophy. Wet AMD, on the other hand, occurs when new abnormal blood vessels form under the retina in a process called choroidal neovascularization. Choroidal neovascularization is accompanied by increased vascular permeability and fragility, and may extend through the Bruch’s membrane. Wet AMD leads to localized macular edema, hemorrhage, and detachment of the RPE. If left untreated, wet AMD can leave a scar under the macula (Figure 2).
Etiology of AMD
A variety of risk factors can increase the likelihood of developing AMD. These are advanced aging, family history, genetic variants, smoking, obesity, hypertension, cardiovascular disease, sun exposure, and a diet low in omega-3 fatty acids and dark green leafy vegetables[8, 13, 14].
Symptoms of AMD
The symptoms of AMD vary depending on whether a patient is suffering with dry AMD or wet AMD. In dry AMD, the presence of drusens is the hallmark symptom with loss of central vision. The accumulation of drusens damages the RPE, which leads to geographic atrophy. Central blind spots known as scotomas may also be present. In dry AMD, there is no macular scar, edema, hemorrhage, or exudation. The wet AMD, on the other hand, presents with macular edema, hemorrhage, exudates, and possibly a scar. There is very rapid visual loss; scotomas may also appear in wet AMD. Both dry and wet AMD can lead to irreversible blindness if left untreated[11, 15].
Differential Diagnosis of Wet and Dry AMD
The diagnosis of both dry and wet AMD is conducted by a series of examinations. For dry AMD, fundoscopic exam is used to observe for presence of drusens in the eyes. Fundoscopic exam is also used to identify wet AMD[16, 17]. For wet AMD, additional exams including fluorescein angiography and color fundus photography are conducted which detect choroidal neovascularization, subretinal fluid, lipid deposition, hemorrhage, RPE detachment, and/or a fibrotic scar. The Amsler grid test is also often used both for dry and wet AMD to detect for visual changes.
Management of Age Related Macular Degeneration
There is no treatment available for reversing the AMD. However, certain medications can slow down progression of the disease. Dry AMD and wet AMD are managed differently. In dry AMD, the emphasis is to reduce risk of further exacerbation of the disease. This is accomplished by providing antioxidants which have long been thought to limit oxidative stress in the macula. Specific dietary supplements include zinc oxide, copper, vitamin C, vitamin E, beta carotene and/or lutein/zeaxanthin. In previous studies, patients who took these supplements reduced progression of intermediate dry AMD to advanced stage by 25% over a period of 5 years and resulted in a 19% reduction in the risk of moderate visual loss. Beta carotene should be substituted with lutein/zeaxanthin in current and former smokers as it can increase the risk of lung cancer in this population. Also, smokers should be advised to quit smoking as smoking has been associated with AMD[19, 20]. Dietary supplements should also be recommended for patients with wet AMD to reduce exacerbation of the disease. Neovascularization in wet AMD is managed primarily with antiangiogenic agents given by an intravitreal injection. The most common antiangiogenic agents currently used to treat neovascularization are ranibizumab and bevacizumab. Both ranibizumab and bevacizumab are vascular endothelial growth factor (VEGF) inhibitors. Another method of antiangiogenic treatment is ocular photodynamic therapy, in which an intravenously administered light-sensitive dye concentrates in new blood vessels and is activated with a laser beam over the macula, resulting in choroidal neovascular thrombosis. Photodynamic therapy limits visual loss in patients with wet AMD and has been shown to be safe. Several clinical trials are underway to study additional ways to manage both dry and wet AMD.
Besides the above described conventional treatments there are several investigational drugs for ADM in various stages of clinical trials. Among these for dry age-related macular degeneration is Lampalixumab, a humanized IgG Fab fragment having inhibitory effect on complement factor D; stem cell transplantation; CD59 gene therapy protocol photobiomodulation and brimonidine an alpha-2 receptor adrenergic agonist .
For wet age-related macular degeneration a new anti-vascular endothelial growth factor, anti-platelet derived growth factor, smaller molecule having anti-VEGF effect, anti-angiopoietin agents and gene therapeutic approaches are on the horizon .
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