**2. Methods**

This is a narrative or traditional review intended to summarize the literature about health promotion for AMD and the role of nutrition. We used several databases and searches, primarily PubMed and the Cochrane Library. The principal purpose of this review is to give a comprehensive overview of the topic and to highlight significant areas of research. In addition, we seek to identify gaps in the clinical literature on health promotion for AMD and the role of nutrition and to offer information that is particularly relevant to the primary health care providers and eye care providers not specializing in the field.

## **3. Background**

AMD affects the macular region in the retina, which is responsible for our central vision. Numerous activities such as driving, reading, cooking, operating a smart phone, and watching television depend on having a healthy macula that can be severely affected in the later stages of this condition [12, 13].

AMD can be broadly classified into two categories, as either dry AMD or wet AMD, each with their own characteristic signs and symptoms [13, 14]. AMD is graded depending on severity as early, moderate or late stage. Dry AMD's clinical features can vary depending on severity. Mild dry AMD includes few hard drusen with or without pigmentary changes in the retinal pigment epithelium (RPE) in the macular region with patients typically not complaining of any visual symptoms. The drusen (yellow deposits) are early fundoscopic signs of the disease in the macula [15, 16]. Moderate dry AMD includes one or more large drusen with or without hyperpigmentation typically associated with patients reporting visual

#### *Health Promotion for AMD and the Role of Nutrition DOI: http://dx.doi.org/10.5772/intechopen.103835*

symptoms such as persistent central blur [6]. Severe dry AMD presents with GA with significant visual symptoms and signs including reduced visual acuity, visual distortion, central visual field defects, and reduced contrast sensitivity.

AMD has a wide range of clinical presentations which correlate to the current state of the individual's visual function. Early AMD patients typically have good vision and are primarily asymptomatic or with only mild symptoms. Visual symptoms may include difficulty in dark-adapting; for example, adapting to driving at night or reading in a dimly lit room. Dark adaptation is an important biomarker of early disease [15, 17]. Moderate AMD presents with one or more large drusen the size of >125 μm in width, which is approximately the size of a branch retinal artery. This finding indicates more extensive involvement of the outer retina, the RPE, and its basement membrane [6]. Advanced AMD is associated with symptoms of reduced vision, visual distortion and central visual field defects [18].

Advanced AMD presents with clinical features of geographic atrophy (GA) and/or choroidal neovascularization (CNV). GA is a damaging clinical feature of advanced dry AMD with associated moderate to the severe reduction in vision. It presents as an area of atrophy with demarcated borders affecting the neurosensory retina which contains the photoreceptors, as well as the RPE and underlying Bruch's membrane and choriocapillaris. Presentation and size of the atrophy vary. The fovea, the central zone with in the macula, provides us with fine detail in our central vision. The foveal center is typically spared until the late stages of GA progression [19]. Approximately 20% of eyes with AMD that have progressed to legal blindness have GA as the cause. GA results from a progression of the clinical features seen in the early and moderate stages of AMD [19].

An eye with dry AMD may convert to wet AMD, where new weak blood vessels (CNV) form. CNV typically develops in the choroid and extends towards the retina causing, fluid leakage or hemorrhaging in the macular region from these new blood vessels. The natural course of untreated CNV is fibrovascular scarring, an indication of severe macular damage and profound central vision loss [18]. Patients that convert to wet AMD typically experience sudden decrease in vision along with visual distortions. Wet AMD encompasses only 10–15% of the population of patients with AMD. However, it is responsible for 80% of severe vision loss or blindness in AMD. If wet AMD is present in one eye, the fellow eye has a 48% chance of converting from dry to wet disease within 5 years. Significant risk factors for the conversion from dry AMD to wet AMD include soft confluent drusen, pigmentary irregularities and a current or past history of smoking [10].

Eyes with CNV are said to have wet AMD. GA represents large areas of cellular death. CNV represents new blood vessel growth and is associated with intraretinal, subretinal, and/or sub-RPE fluid, hemorrhage, and or scarring in the macular region. Treatment with intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is the mainstay of treatment for active, wet AMD. This type of pharmacotherapy aims to suppress the growth of the CNV, as well as reduce the amount of associated fluid, and potentially improve vision.

#### **3.1 Risk factors for AMD**

AMD is a complex, multifactorial disease with plethora of known modifiable and non-modifiable risk factors. Modifiable risk factors include smoking, high body mass index, history of hypertension, cardiovascular disease and high alcohol consumption [20]. Smoking has consistently been proven to be a major risk factor of early AMD and late AMD in many studies [21–23]. The duration of smoking also influences the incidence of AMD, showing 14% of all AMD cases may be due to patients who smoked for 40 years [20]. Smokers have a 2 to 4-fold increase

in developing AMD compared to people who do not have a history of smoking. Interestingly, former smokers who have not smoked in the last 20 years are not at a higher risk of developing AMD [20].

The literature has conflicting data from multiple studies on whether the amount of smoking or only duration increases the risk of AMD. The EUREYE study was a cross-sectional study that evaluated patients across Europe and saw a 27% correlation between smoking and the incidence of AMD [5]. Along with the increased risk of duration of smoking, the amount of cigarettes consumed and the associated increased risk of developing AMD was investigated. The Physicians' Health Study and the Nurses' Health Study determined a 2-fold increase in people who smoked 25 cigarettes per day. They also reported that males who smoked 20 or more cigarettes per day were 2.5 times more likely to develop AMD at the 12 years follow up opposed to those who did not smoke at the baseline. The Beaver Dam Study showed no association between the amount of smoking and the incidence of late AMD [24]. A meta-analysis was conducted on multiple studies that revealed a risk ratio of 2.75 for incidence of AMD when comparing current smokers versus "never smokers". When comparing former smokers versus never smokers, the risk ratio for AMD was 1.21 [5]. Smoking has also been shown to increase the incidence of the development of soft drusen and retinal pigmentary changes. Biological alterations associated with smoking increase the risk of developing AMD. For example, smoking reduces serum antioxidants, perfusion to the choroid, RPE drug detoxification pathways, and macular pigments such as lutein and zeaxanthin, further making the eye vulnerable to the development or progression of AMD [24]. Although, there is a debate if the amount of smoking during the person's smoking period is a separate risk factor, it is undeniable that a recent history of smoking does increase the risk of developing AMD.

Obesity and a sedentary lifestyle correlate with the development and progression of AMD. AMD and cardiovascular disease (CVD) have similar risk factors such as age, obesity, and smoking. Drusen in AMD and atherosclerotic plaque in CVD are relatively similar in their composition [4]. Systemic adverse effects caused by obesity include an increase in inflammatory markers, oxidative stress and blood lipid levels. These adverse effects are also factors that increase the risk for the development of AMD. This further supports the association between obesity and AMD [4]. There is also evidence for an association between obesity and low levels of the macular carotenoids lutein and zeaxanthin.

Carotenoids are fat-soluble xanthophyll pigments found throughout the retinal layers and most concentrated in the macula and are seen as a yellow spot during funduscopic evaluation. The amount and optical density of the macular pigment can be measured using clinical devices [25–31]. The macular pigment is composed of three carotenoids lutein zeaxanthin and meso-zeaxanthin an isomer of zeaxanthin. Zeaxanthin and its isomer are more concentrated than lutein within in the fovea, implying an important role for zeaxanthin in central macular integrity and the perception of fine detail [4]. Lutein's highest concentration is found in the peripheral macula. Being fat-soluble these carotenoids are also stored in adipose tissue. However, with the increase in adipose tissue in obese individuals, macular carotenoids are more readily stored in adipose tissue and are less readily available for the central retina [4, 32, 33].

A meta-analysis conducted by Zhang et al. showed a small positive association between excess body weight and risk for AMD. A low association was also found between being overweight or obese and increased risk of early AMD. This risk (for early AMD) is difficult to accurately assess because these patients are typically asymptomatic. Therefore, the association for early AMD with being overweight or obese may be underestimated in the study. Obesity was associated with an increased

#### *Health Promotion for AMD and the Role of Nutrition DOI: http://dx.doi.org/10.5772/intechopen.103835*

risk in the development of late AMD [4]. There was a linear relationship between increased body mass index and risk of AMD [4]. Therefore, the research supports a role for weight control in reducing the likelihood of developing AMD.

Obesity is a considerable public health challenge and multisystem disease. In 2009 and 2010, the prevalence of obesity was 35.5% and 35.8% in men and women in the USA, respectively [4]. The Beaver Dam Study which showed a 3.1% 15-year cumulative incidence of late AMD in adults aged 43–86 years old, so there is ultimately the potential of 110,000 cases of late AMD per year [4]. This finding is significant because obesity is a modifiable risk factor that, if addressed, can positively impact the number of AMD cases that can be avoided per year. Simply put, if the older population maintained a healthy body mass index and waist circumference, they would be giving themselves a better chance to avoid irreversible vision loss [4]. This is an example where health promotion can be effective in giving patients a strategy to avoid the development of AMD or slow its progression.

Beaver Dam Study showed the consumption of 4 or more alcoholic drinks per day was shown to increase the risk of the incidence of late AMD, specifically the wet form. It is important to note the study could not conclude heavy alcohol consumption's role in early AMD [24]. It is believed heavy alcohol consumption causes a reduction in serum antioxidants in tissues such as the retina, ultimately causing them to be susceptible to oxidative damage. Alcohol reduces the blood serum carotene, vitamin C and zinc which mirror the nutrients deficient in AMD [24].

There are risk factors for AMD that are not modifiable including age, genetics, race and sex [20]. With age the retinal layers most affected in early AMD—the RPE and underlying Bruch's membrane—begin to undergo structural and metabolic changes leading to an accumulation of metabolic waste products. Perfusion is reduced directly affecting the choroid layer that supplies nutrients to the RPE and photoreceptors (rods and cones) [5]. It is important to note that these age-related changes will not necessarily result in cellular death and functional vision loss. Environmental and genetic factors may make a person more susceptible to developing the AMD phenotype [20]. The complex integrated system of the choroid, RPE and photoreceptors contribute in maintaining the integrity of central vision. With age, this system can be altered and dysfunctional causing degenerative complications in the macula [34].

Although genetics is a known risk factor, AMD is a condition that does not follow the typical Mendelian inheritance patterns where we can predict if a relative or offspring will acquire the condition. To determine the susceptibility of a patient, the clinician has to consider the modifiable risk factors present along with the patient's age and heredity. Currently, the loci that are most associated with AMD are 1q32 (CFH) and 10q26 (PLEKHA1/ARMS2/HTRA1) [35]. Studies have shown that AMD can be present within families and show a higher incidence if a first-degree relative has been diagnosed with the disease. The Rotterdam Study showed that individuals who have a first-degree relative with AMD have a 4-fold higher risk of developing AMD [35].

#### **3.2 Clinical diagnosis and evaluation**

AMD can be diagnosed when a patient undergoes a comprehensive eye examination including dilated funduscopy by an eye care professional. The optometrist or ophthalmologist evaluates all aspects of the posterior segment of the eye, including the macula. Clinical findings associated with AMD are hard or soft drusen, retinal hypo or hyperpigmentation, macular edema, hemorrhaging and or other signs of CNV. If these findings are present, special testing can be performed to further investigate the extent of the maculopathy. Special testing includes retinal

photography, autofluoresence imaging, optical coherence tomography (OCT) and fluorescein angiography. Retinal photography is used to document the appearance of the macula. Autofluoresence imaging takes advantage of the natural ability of the RPEs lipofuscin to fluoresce when stimulated with the light of a particular wavelength. It is an assessment of metabolic activity [18].

OCT is a non-invasive imaging method that uses coherent light rays to produce a cross-sectional image of the retina. OCT of the macula produces an image that shows the distinct layers of the retina and can highlight abnormalities such as macular edema, CVN, GA, and hard or soft drusen. OCT of the macula is used to further investigate any suspicious macular abnormalities in a dilated fundus exam and document the findings as a baseline reading. An OCT of the macula will then be taken at subsequent follow-ups to monitor for progression [36].

Fluorescein angiography is an invasive test involving the intravenous injection of sodium fluorescein. The dye travels to the choroidal circulation in the eye within 10–15 s, then a camera can capture images of the highlighted retinal blood circulation. Fluorescein angiography is extremely helpful in monitoring wet AMD where it can detect areas of macular edema and or active CNV [37]. It is still considered the gold standard in the detection of new CNV.

#### **3.3 Treatment**

There is currently no cure for AMD, but there are several treatments. The goal of treatment and management is to slow the progression of the disease and, in the case of wet AMD, to reduce the adverse effects of CNV. Intravitreal anti-VEGF (vascular endothelial growth factors) injections are the mainstay of contemporary therapy for active wet AMD. Lifestyle modification and nutritional supplementation have been shown to benefit patient with moderate to late dry AMD. A randomized, doublemasked, placebo-controlled trial showed that people who at baseline had a lower level of macular pigment optical density (MPOD) showed benefits from taking supplements containing the dietary macular carotenoids lutein and zeaxanthin [25, 38–43]. The investigators also found an improvement in visual function associated with increased MPOD, which included visual acuity and contrast sensitivity [38, 40–43]. Increasing the macular pigment in patients appears to improve visual function and slow the progression of early AMD [38, 40–42]. However, prophylactic supplementation to prevent the onset of AMD continues to be inconclusive in the literature [40, 44].

Current management of early AMD should include health promotion with an emphasis on a healthier lifestyle involving diet, exercise and smoking cessation or avoidance. Nutrition education of patients should support the consumption of foods containing dietary macular carotenoids, which can further assist in increasing the MPOD. These foods include egg yolk, spinach, kale, collards, and brightly colored vegetables such as peppers [45]. For early AMD there is currently no treatment that can regress hard drusen or retinal pigmentary changes. A person with early AMD can continue with yearly follow-ups with their optometrist with education about lifestyle and diet/nutrition. At the initial visit, patients should be given an Amsler grid that tests the integrity of the macula. It is recommended the patient self-test each eye individually every day using their reading prescription with proper illumination to monitor their condition. The grid must be held at 33 centimeters to properly span a 20-degree field [46]. The Amsler grid test is checking for any structural changes in the macula such as new macular edema or CNV. The patient is to report whenever they notice metamorphopsia, which means the lines on the grid appear in a wavy or distorted fashion. Patients are also to report if they notice a scotoma, or missing area within the grid, and to make a timely appointment with their eye doctor.

In terms of nutritional supplementation, AREDS determined supplements may be recommended to prevent the progression of moderate AMD into late AMD [47]. These supplements contain antioxidants and micronutrients which help replenish the lack of those nutrients in the retina and consequently the properties and functions of the macula. Patients with moderate or advanced AMD need to be seen more frequently by an eye care professional than patients with early AMD. Along with the recommendation of taking the supplements listed above, reinforcing a healthier lifestyle is vital in maximizing patient outcomes.

CNV is a consequence of increased levels of VEGF in the eye. VEGF has many functions in the body including angiogenesis, bone formation, hematopoiesis, wound healing, neuroprotection and development [48]. VEGF is a potent signal protein which, when up-regulated, causes pathological angiogenesis and increased vascular permeability. For example, VEGF can give rise to new blood vessels that feed tumor growth, such as in breast cancer [48]. In AMD, the upregulation of VEGF causes the growth of new blood vessels to manifest under the RPE and/or the sensory retina. This new blood vessel growth causes devastating effects to the integrity of the macula ultimately causing a decrease in vision. Anti-VEGF therapy was initially used as cancer treatment and further investigation proved suspected beneficial ocular affects when it was noted patients' vision would also improve concurrently with cancer treatment [49].

Anti-VEGF agents are now used as a therapy for many ocular vascular diseases. The most common of these conditions are wet AMD and diabetic retinopathy. Common anti-VEGF drugs used in ophthalmic practice include bevacizumab (Avastin), ranibizumab (Lucentis) and aflibercept (Eyelea) [49]. Bevacizumab is considered an off-label therapy in retinal disease, whereas the other two drugs have an FDA indication for these purposes. Once treatment is initiated, the patient will need frequent injections to stabilize the condition along with monitoring of the macula with dilated funduscopy, OCT and fluorescein angiography [50].
