Age-Related Macular Degeneration

Because Avastin® is used off-label, and its makers do not plan to seek approval of the drug for AMD, it has not been as thoroughly investigated as either Lucentis® or Macugen® (Gillies 2006). However, many retina specialists believe that Avastin®’s efficacy parallels that of Lucentis® (Rosenfeld 2006).

Lucentis®, Macugen®, and Avastin® are all administered by intraocular injection - in other words, these medications are injected directly into the eye. The injections are given after the surface of the eye has been cleansed and sterilized. Some doctors will give antibiotic drops prior to the injection. Some form of anesthesia is usually administered. This can be given in the form of drops or as a very small injection of anesthetic around the eye. A very fine needle is used and the actual injection takes only a few seconds.

A fourth intraocular anti-VEGF treatment, the VEGF Trap-Eye, is in late-stage research and appears to require fewer injections compared to Lucentis®, while still offering the same improvements in eye sight over a one year period. In trials of more than 2,400 patients, VEGF Trap-Eye intraocular injections dosed every two months offered the same benefits as Lucentis® dosing once per month (Anon 2011). It is anticipated that this drug will receive approval for the treatment of AMD in late 2011 or early 2012.

Possible complications are a retinal detachment and the development of a cataract. High intraocular pressure usually follows the injection but generally resolves within the hour.

Possible adverse effects of intraocular injections occur at a rate of fewer than 1 per 100 injections (Rosenfeld 2006). When adverse effects occur, however, they can be very serious and sight-threatening. One possible adverse reaction is a serious eye infection known as endophthalmitis, an inflammation of the internal coats of the, which sometimes leads to loss of vision or server damage to the eye.

Photodynamic Therapy (PDT) is a systemic treatment used in oncology by a variety of specialists to eradicate premalignant and early-stage cancer and reduce the tumor size in end-stage cancers involving three key components: a photosensitizer, light, and tissue oxygen.

Photosensitizing agents are drugs that become active when light of a certain wavelength is directed onto the anatomical area where they are concentrated. It is an approved treatment for wet macular degeneration, and is a more widely preferred treatment that takes advantage of certain unique properties of subretinal neovascular vessels.

Compared with normal blood vessels, neovascular tissue appears to retain the light-sensitive medicine used in photodynamic therapy. After the medicine, verteporfin for example, has been injected into a peripheral vein. Verteporfin can detect abnormal blood vessels in the macula - it attaches itself to the proteins in the abnormal blood vessels. Laser light of specific wavelengths, which activates photosensitive drugs like verteporfin, is focused through the eye for about one minute. When verteporfin is activated by the laser, the abnormal blood vessels in the macula are destroyed. This happens without any damage to surrounding eye tissue, because normal retinal vessels retain very little verteprofin, the abnormal subretinal vessels are selectively destroyed. Blood or fluid cannot leak out and damage the macula any further (Wormald 2007).

While verteporfin photodynamic therapy (PDT) slowed wet AMD progression, newer anti-vascular epithelial growth factor (VEGF) therapies have shown vision improvement in many patients. Combination therapies (PDT + corticosteroid + anti-VEGF) have shown some promise, particularly in certain classes of disease (Miller 2010).

Laser Photocoagulation: Laser photocoagulation (LP) is effective to treat eyes with wet type AMD. However, LP is limited to the treatment of well-defined, or "classic," subretinal neovascularization, present in only 25% of those wet type AMD (Anon 2011). In eligible eyes, LP is effective at preventing future vision loss, but it cannot restore or improve vision. In addition, choroidal neovascularization can recur after treatment and cause further vision loss (Yanoff 2004). LP has not worked well on atrophic (dry) AMD.

Surgery: Subretinal surgery has been attempted for age-related macular degeneration. Some surgeries were geared toward the removal of blood and the subretinal neovascular membrane. Another type of surgery tried to physically displace the macula and move it onto a bed of healthier tissue. Overall, research studies show that the results of surgery are disappointing (Bressler 2004). Vision has generally not improved after surgery (Hawkins 2004). Additionally, the frequency and severity of surgical complications were generally thought to be unacceptably high.

In late 2010, the FDA approved a device called the Implantable Miniature Telescope (IMT) to improve vision in some patients with end-stage AMD. The IMT replaces the natural lens through surgery in only one eye and provides two-time magnification. The other eye is used for peripheral vision. In the clinical trials on which FDA approval was based, at 1 and 2 years after surgery, 75 percent of patients had an improvement in their visual acuity of two lines of more, 60 percent of patients improved their vision by three lines, and 40 percent of patients had a four-line improvement on the eye chart (Hudson 2008 and www.accessdata.fda.gov).

Each person may respond differently to the various conventional treatments available for macular degeneration. From a patient’s perspective, it is very important to thoroughly understand wet macular degeneration and its treatment in order to be able to discuss a therapeutic plan with his or her doctor. A specific treatment plan should be tailored to each patient’s needs and disease activity.

The advent of anti-VEGF therapies, for example, has been seen as a significant advancement for patients with wet macular degeneration. It is important to speak with a specialist regarding the benefits and side effects of anti-VEGF drugs to determine if they are appropriate for your specific situation. It should be noted that there is some speculation, which is not supported by strong human data, that anti-VEGF macular degeneration treatments may exert systemic effects and negatively impact vascular health by “leaking” from the eye. It is, therefore, important to evaluate your cardiovascular health if you are receiving anti-VEGF treatment for macular degeneration. For instance, a person who has recently had a heart attack, or has extensive atherosclerosis may opt to avoid anti-VEGF treatments in favor of photodynamic therapy or laser photocoagulation. Individuals receiving anti-VEGF treatments should target an optimal cardiovascular health profile, which includes LDL levels below 100 mg/dL, fasting glucose between 70-85 mg/dL; etc. For more tips for supporting your cardiovascular health read our Atherosclerosis and Cardiovascular Disease Protocol.

AMD Nutritional Protocol

Emerging Options: Hormone Therapy

Research has shown that the hormone dehydroepiandrosterone, or DHEA, is abnormally low in patients with AMD (Bucolo 2005). DHEA also has been shown to protect the eyes against oxidative damage (Tamer 2007). Because the macula requires hormones to function, an emerging theory hypothesizes that low blood sex hormone levels cause the retinal macula to accumulate cholesterol in an attempt to produce its own hormones (Dzugan 2002). The accumulation of cholesterol in macula may lead to the production of pathologic drusen and subsequent macular degeneration. Inverse association of female hormone with neovascular AMD was observed with current and former use of hormone replacement therapy use among Caucasian and Latino women (Edwards 2010). Restoring optimal hormone balance with bioidentical hormones may be an effective new treatment for both men and women. Clinical studies are in process to test this hypothesis and possible hormonal treatment options.

Melatonin is a hormone and strong antioxidant that scavenges free radicals. Several studies have shown that many areas of the eye have melatonin receptors (Rastmanesh 2011, Lundmark 2006). Clinical study has shown that treatment with 3 mg of melatonin at bedtime in those with AMD prevented further vision loss (Yi 2005). In the study, 100 patients with dry or wet AMD received the nighttime dose. After six months, visual acuity had not diminished and the majority of patients had reduced pathologic macular changes upon examination.

Macular Pigments: Lutein, Zeaxanthin, and Meso-zeaxanthin.

The relation between the density of macular pigment and the onset of AMD is well established. The macular pigment is composed principally of three carotenoids: lutein, zeaxanthin, and meso-zeaxanthin. They represent roughly 36, 18, and 18% of the total carotenoid content of the retina. They are found within the macula and surrounding tissues, including blood vessels and capillaries which nourish the retina (Rapp 2000).

Lutein, zeaxanthin and meso-zeaxanthin ensure proper functioning of the macula by filtering out harmful ultraviolet light and by acting as antioxidants (Beatty 2000, Kaya 2010). During the aging process, there is a decrease in levels of lutein and zeaxanthin; low levels of macular pigments are linked to AMD (Johnson 2010). An autopsy study on donated eyes found that levels of all three carotenoids (lutein, zeaxanthin, and meso-zeaxanthin) were reduced in those with macular degeneration compared to control subjects. The most significant finding, however, was the sharp decrease in meso-zeaxanthin in the macula of macular degeneration subjects (Bone 2000). This postmortem study helped confirm other studies indicating the importance of all three carotenoids in maintaining the structural integrity of the macula (Krinsky 2003). These carotenoids protect the macula and the photoreceptor cells beneath via their antioxidant properties and light-filtering capabilities (Landrum 2001).

Intake of lutein and zeaxanthin is an important preventative measure, but may also reverse the degeneration process when it is ongoing (Richer 2004). Because lutein and zeaxanthin have the tissue-specific characteristic of all carotenoids, their natural tendency is to concentrate in the macula and retina. Consumption of foods rich in these substances is especially important, as they have a direct effect on macular pigment density: The denser the pigment, the less likely a retinal tear or degeneration will occur (Stahl 2005). Fruits with a yellow or orange color, like mangoes, kiwis or oranges, and vegetables of the dark green leafy variety and orange and yellow types are food sources of lutein and zeaxanthin (Bone 2000).

Unlike lutein and zeaxanthin, meso-zeaxanthin is not found in the diet, but it is needed to maintain youthful macular density (Bone 2007). Patients with macular degeneration have been shown to have 30% less meso-zeaxanthin in their macula compared to healthy eyes (Quantum Nutritionals, unpublished data). When taken as a supplement, meso-zeaxanthin is absorbed into the blood stream and effectively increases macular pigment levels (Bone 2007).

Other Recommend Foods

Soy contains the phytonutrient genistein, which has documented antiangiogenesis properties postulated to be the result of inhibiting VEGF (Yu 2010). This property of inhibiting blood vessel growth is important in limiting abnormal ingrowth of choroidal blood vessels. In mice, genistein inhibited retinal neovascularization and expression of VEGF (Wang 2005).

Food rich in Omega-3 fatty acids: Oily fish like salmon, tuna, mackerel and flax seeds are important sources of omega-3 fatty acids, essential for protection against macular degeneration and other diseases (Landrum 2001). A meta-analysis published in Archives of Ophthalmology found that patients with a high dietary intake of omega-3 fatty acids had a 38% lower risk of late (more advanced) AMD. Additionally, an association was observed between eating fish two times a week and having a reduced risk of both early and late AMD (Chong 2008).

Dietary Supplements

Anthocyanidins and Cyanidin-3-Glucoside (C3G) are critical components of bilberry and powerful antioxidants (Amorini 2001, Zafra-Stone 2007). Positive results have been noted in many animal studies and some human studies using bilberry for macular degeneration, and other eye disorders, including, diabetic retinopathy, retinitis pigmentosa, glaucoma, and cataracts (Fursova 2005, Milbury 2007). C3G has been shown to improve night vision in humans by enabling the rods in the eye responsible for night vision to resume functioning faster (Nakaishi 2000). In animal cells, C3G regenerated rhodopsin, the retinal complex that absorbs light (Amorini 2001). The anthocyanidins in bilberry decrease vascular permeability by interacting with blood vessel collagen so as to slow down enzymatic attack on the blood vessel wall. This may prevent leakage from capillaries, prevalent in neovascular AMD. Studies also show that bilberry increases oxidative stress defense mechanisms in the eyes (Milbury 2007). There may be additional benefits by adding vitamin E (Roberts 2007).

Interestingly, C3G, which is highly bioavailable, enhances other functions in the body (Miyazawa 1999; Tsuda 1999; Matsumoto 2001). Its potent antioxidant properties protect tissues against DNA damage, often the first step in cancer formation and aging of tissues (Acquaviva 2003; Riso 2005).

C3G protects endothelial cells against peroxynitrite-induced endothelial dysfunction and vascular failure (Serraino 2003). In addition, C3G fights inflammation by inhibiting inducible nitric oxide synthase (iNOS), reducing vascular inflammation (Pergola 2006). At the same time C3G upregulates activity of endothelial nitric oxide synthase (eNOS), which helps maintain normal vascular function (Xu 2004). These effects on blood vessels are especially important in the retina, where delicate nerve cells depend on the single ophthalmic artery for their sustenance.

In animal models, C3G prevents obesity and ameliorates blood sugar elevations (Tsuda 2003). One way it does this is by increasing gene expression of the beneficial fat-related cytokine adiponectin (Tsuda 2004). As we well know, diabetics are predisposed to severe eye problems including blindness from elevated blood sugar levels.

C3G helps to induce apoptosis (programmed cell death) in a number of human cancer lines, an important step in cancer prevention (Fimognari 2004; Chen 2005). In a similar fashion (but via a different mechanism), C3G stimulates rapidly proliferating human cancer cells to differentiate so that they more closely resemble normal tissue (Serafino 2004).

Finally, in early 2010, it was discovered that C3G is neuroprotective in experimental cellular models of brain function, helping to prevent the disastrous effects of the Alzheimer’s-related protein amyloid beta on brain cells (Tarozzi 2010).

Grape Seed Extract is a potent antioxidant, classified as a bioflavonoid. Bioflavonoids derived from plants are readily assimilated into our body when consumed. Bioflavonoids appear to protect retinal ganglion cells (Majumdar 2010). Studies conducted in fruit flies have revealed that grape seed extract attenuates the aggregation of pathologic proteins, which suggests a protective effect against macular degeneration and neurodegenerative disorders. Accordingly, fruit flies administered grape seed extract exhibited improved eye health (Pfleger 2010). Similar experiments in diabetic animals indicate that grape seed extract limits the ocular blood vessel damage seen in diabetic retinopathy, a diabetes induced degradation of the retina, which shares some pathological characteristics with AMD (Li 2008).

Compelling laboratory evidence demonstrates that grape extracts can inhibit angiogenesis in human cells (Liu 2010). This suggests that grape seed extract may suppress the aberrant blood vessel growth observed in wet AMD.

Resveratrol is a potent polyphenolic antioxidant compound produced by grapes and other plants for protection against pathogens. In humans, it exerts a broad range of physiologic effects when ingested orally. Several studies have demonstrated cardioprotective properties of resveratrol, including endothelial protection and attenuation of oxidized-LDL-induced vascular damage (Rakici 2005; Lin 2010). In addition, emerging evidence indicates that resveratrol may combat macular degeneration and promote eye health via several mechanisms.
           
In an animal model, resveratrol was able to stave off diabetes-induced vascular lesions (Kim 2011). Moreover, this same study showed that resveratrol was able to dampen VEGF signaling in mouse retinas, a key pathologic feature of AMD. Another study corroborated these results by showing that resveratrol inhibited angiogenesis and suppressed retinal neovascularization in mice prone to develop macular degeneration due to a genetic mutation (Hua 2011).
           
Also, several laboratory experiments have suggested additional protective mechanisms of resveratrol in macular degeneration, including protecting retinal pigment epithelial cells from hydrogen peroxide-induced oxidative stress, and light damage (Kubota 2010; Pintea 2011).

Given these exciting initial findings regarding resveratrol and macular degeneration, and its stellar track record in a variety of other conditions, Life Extension believes that individuals with AMD (especially the “wet” variety) may benefit from supplementation with resveratrol.

Ginkgo Biloba improves microcapillary circulation in the eye and slows deterioration of the macula (Thiagarajan 2002). It increases blood flow by inhibiting platelet aggregation and regulating blood vessel elasticity, improving blood flow through major blood vessels and capillaries. Ginkgo is also a powerful antioxidant (Mahadevan 2008).

Glutathione and Vitamin C are antioxidants found in high concentrations in the healthy eye and in diminished quantities in AMD patients. Vitamin C aids glutathione synthesis in the eye. When combined with cysteine, an amino acid antioxidant, cysteine remains stable in aqueous solutions and is a precursor to glutathione synthesis. Vitamin C is important because it absorbs ultraviolet radiation and prevents cataracts (Tan 2008). And topical Vitamin C inhibited angiogenesis in an animal model of inflammatory neovascularization (Peyman 2007).

L-Carnosine is a naturally occurring antioxidant and anti-glycation agent. Studies have shown that carnosine inhibits lipid peroxidation and free radical-induced cellular damage (Guiotto 2005). Topically applied N-acetyl-carnosine prevented light-induced DNA strand breaks and repaired damaged DNA strands (Specht 2000), and has improved visual acuity, glare and lens opacification in animals and humans with advanced cataracts (Williams 2006, Babizhayez 2009).

Selenium, an essential trace mineral, is a component of the antioxidant enzyme glutathione peroxidase, important in slowing the progression of AMD and other eye disorders including cataracts and glaucoma (Head 2001, King 208). In mice, increased expression of glutathione peroxidase protected against oxidative-induced retinal degeneration (Lu 2008).

Coenzyme Q10 (CoQ10) is an important antioxidant that may protect against free radical damage within the eye (Blasi 2001). Mitochondrial DNA (mtDNA) instability is an important factor in mitochondrial impairment culminating in age-related changes and pathology, and in all regions of the eye, mtDNA damage is increased as a consequence of aging and age-related disease (Jarratt 2010). In one study, a combination of antioxidants including CoQ10, acetyl-L-carnitine, and omega-3 fatty acids improved the function of mitochondria in retinal pigment epithelium and subsequently stabilize visual functions in patients affected by early AMD (Feher 2005).

Riboflavin, Taurine, and Lipoic Acid: Other antioxidants to prevent AMD are riboflavin, taurine, and R- lipoic acid. Riboflavin is a B complex vitamin that reduces oxidized glutathione and helps prevent light sensitivity, loss of visual acuity, and burning and itching in the eyes (Lopez 1993). Taurine is an amino acid found in high concentrations in the retina. A deficiency of this amino acid alters the structure and function of the retina (Hussain 2008). R- lipoic acid is considered a “universal antioxidant” because it is fat and water soluble. It also reduces choroidal neovascularization in mice (Dong 2009).

B Vitamins: Recent advances in knowledge surrounding the causes of AMD have unearthed shared risk factors with cardiovascular disease (CVD) and similar underlying mechanisms, particularly elevated biomarkers of inflammation and CVD including C-reactive protein (CRP) and homocysteine (Vine 2005). Researchers have identified that elevated levels of homocysteine, and low levels of certain B vitamins (critical to the metabolism of homocysteine), are associated with an increased risk of AMD and vision loss in older adults (Rochtchina 2007). A strong study from Harvard University found that supplementing with folic acid, B6, and B12 can significantly reduce the risk of AMD in adults with cardiovascular risk factors (Christen 2009). The data, along with additional confirmatory studies have convinced physicians to recommend B vitamin supplementation in patients with AMD. The most compelling research indicates that including folic acid (2.5 mg/day), B6 (50 mg/day) and B12 (1 mg/day) in the diet may prevent and reduce the risk of AMD, according to a study in more than 5,000 women (Christen 2009).

Summary

There has been limited success within conventional medical treatment protocols to restore lost eyesight from either form of AMD. Leading researchers are documenting the benefits of more holistic approaches to AMD. Patients are encouraged to increase physical fitness, improve nutrition (including a reduction in saturated fats), abstain from smoking, and to protect their eyes from excessive light. Dietary supplementation with trace elements, carotenoids, antioxidants, and vitamins is recommended for improving overall metabolic and vascular functioning. Early screening and patient education offer the most hope for reducing the debilitating effects of the disease.