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European Geriatric Medicine 6 (2015) 69–75

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Hot topic in geriatric medicine

Age related macular degeneration – challenge for future: Pathogenesis


and new perspectives for the treatment
K. Michalska-Małecka a,*, A. Kabiesz a, M. Nowak b, D. Śpiewak a
a
Department of Ophthalmology, University Centre of Ophthalmology and Oncology of Medical University of Silesia, Ceglana Street 35, 40-952 Katowice, Poland
b
Pathophysiology Division, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Traugutta Square 2, 41-800 Zabrze, Poland

A R T I C L E I N F O A B S T R A C T

Article history: The authors presents the review of the literature concerning the pathogenesis, classification, risk factors
Received 9 June 2014 as well as perspectives for the treatment of age-related macular degeneration (AMD). AMD is a
Accepted 4 September 2014 progressive illness, which is the most common cause of blindness in developed countries. The
Available online 7 October 2014
degenerative changes associated with both forms (dry and wet AMD) occur in the central part of retina,
the macula, but the exact aetiology is still not unclear. The pathogenesis of AMD includes: lipofuscine
Keywords: genesis, drusogenesis, and local inflammatory state, as well as neoangiogenesis. Multiple studies have
Age related macular degeneration
assessed the role of genetic variants on AMD development and progression, especially with complement
Angiogenesis
factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes, the two major susceptibility
Free oxygen radical
Genetic polymorphism genes for AMD. The disease has been associated with light-induced oxidative damage, accumulation of
cholesterol and other lipids, and has been linked to systemic factors such as smoking, hypertension and
atherosclerosis. Also female gender, and a high body-mass index (BMI > 30) have been reported as the
important demographic and environmental risk factors in AMD. The neovascular form of AMD is
characterized by the formation of subretinal choroidal neovascularization (CNV) and is the cause of most
cases of blindness in the elders. Currently, the only approved treatment for dry AMD is the use of AREDS
formulation. In the near future, it is likely that the treatment of dry AMD will be a combination of
different drugs that will target the different pathways involved in the pathogenesis and progression of
dry AMD. Exudative AMD is treated through injections of anti-VEGF A drugs as pegaptanib or
ranibizumab and bevacizumab, which are considered the standard drugs. Aflibercept, or VEGF Trap-eye,
is a novel compound derived from the native VEGF receptor (VEGFR) that binds to all VEGF and VEGF-B
isoforms as well as to PlGF. It may be considered an attractive alternative to other anti-VEGF agents.
ß 2014 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/3.0/).

1. Introduction progressive deterioration of the macula, AMD patients experience


a multitude of visual problems that significantly affect their mental
Age-related diseases such as age-related macular degeneration health and quality of life (QoL) [5]. Visual impairment leads to
(AMD) and cataract will assume increasing importance in the reduced QoL, poorer general health, and increased mortality
public health of the nation. AMD and cataract are both common [6]. The decrease of vision is a serious risk factor for loss of balance,
causes of visual acuity loss and reduced quality of life in the elderly. perhaps leading to falls and injury. Many risk factors for falling
Conditions may coexist that limit the final result after cataract among elder people have been identified in epidemiological
surgery [1,2]. studies, including poor vision [7].
AMD is a multi-faceted condition that affects the central retina,
which ultimately leads to blindness in millions of people world- 2. Epidemiology
wide. The pathophysiology and risk factors for AMD are complex,
and the symptoms manifest in multiple related but distinct forms There are around 20 million reported patients with all kinds of
[3]. Untreated AMD can result in blindness, especially in white AMD, but the total number is probably 100% higher. Data from
men or women over the age of sixty with blue irises [4]. With different research centers are alarming and confirm the high AMD
incidence rate [4]. The disease is more common in Caucasian
individuals than in pigmented races. In predominantly Caucasian
* Corresponding author. populations, the age-standardized prevalence of AMD in at least
E-mail address: k.michalska.malecka@gmail.com (K. Michalska-Małecka). one eye is 7760 cases per million. AMD is the most important single

http://dx.doi.org/10.1016/j.eurger.2014.09.007
1878-7649/ß 2014 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
70 K. Michalska-Małecka et al. / European Geriatric Medicine 6 (2015) 69–75

cause of blindness among Caucasian individuals in developed mild (20/20–20/40), moderate (20/50–20/100), severe (20/200 or
countries. Blindness resulting from AMD rarely occurs before age worse), very severe (20/800 or worse) [18].
70, and most cases occur after age 80. The age-standardized 1-year
incidence of legal blindness resulting from AMD is 212 cases per 4. Pathogenesis and risk factors of AMD
million [8]. In cross-sectional population-based studies La Cour
et al. found that about 45% of eyes with AMD have visual acuity The abnormalities of this disorder range from discrete drusen
reduced to 20/200 or worse [8]. In the US, the estimated prevalence deposits and pigmentary changes in early AMD to geographic
of AMD (neovascular and/or geographic atrophy) is 1.47%, affecting atrophy and/or choroidal neovascularization (CNV) in the
approximately 1.75 million individuals [9]. These numbers are advanced forms. Human retina undergoes changes as part of the
projected to increase by 50% by 2020 and data suggest that more natural course of aging. AMD is generally associated with
than 3 million people in the United States will be affected by the pathological changes in the retinal pigment epithelium (RPE)
disease by 2020 [9]. In Japan, which has the oldest and longest and Bruch’s membrane (a collagen-rich extracellular matrix
living population in the world, 1.64 million people are affected by between the RPE and choroidal vasculature) including appearance
visual impairment, of whom 61% are older than 65 years. Notably, of ophthalmoscopically visible focal yellow deposition of acellular,
early AMD is highly prevalent (12.7%) in those 50 years and older in polymorphous debris called drusen between the retinal pigment
the Japanese population, whereas late AMD is less prevalent epithelium and Bruch’s membrane [19]. Pathogenesis of AMD
(0.87%) [10]. In the newest study, Owen et al. report the prevalence includes: drusen genesis, lipofuscin genesis, local inflammatory
of late AMD standardized to the UK population aged 50 years or state genesis, as well as angiogenesis [20]. Druses are retinal
older was 2.4%, increasing to 4.8% in those aged 65 years or older, metabolites’ clusters gathered under RPE and the internal layer of
and 12.2% in those aged 80 years or older [11]. In another study, the choroid called Bruch’s membrane which handicap transport of
Jonasson et al. in Scandinavian population found a higher nutritive components and metabolites. Immune-chemical exam-
prevalence of AMD in the studied group [10]. The prevalence of inations have shown that druses contain plasma proteins,
early AMD was 12.4% for those aged 66–74 years and 36% for those lipoprotein (apolipoprotein E), cholesterol-rich lipids, polysac-
aged 85 years. The authors concluded that persons aged charides, glycoprotein and plasma amyloid P, responsible for
 85 years have a 10-fold higher prevalence of late AMD than complement inactivation and membrane attack complex (MAC)
those aged 70–74 years [12]. Over the last few years, life formation. The complement causes intensification of a local
expectancy in Poland has been increasing steadily and the inflammatory state and, as a consequence of this, degeneration
forecasts for the future are optimistic. For men, this rate is of photoreceptors and RPE [21]. Drusen are often classified as
predicted to grow from the current 70.4 years to 77.6 years in 2035, ‘‘hard’’ or ‘‘soft’’ (also called ‘‘large’’) and while the hard form is
while for women, from 78.8 to 83.3 years (compared with common in the aging human eye, soft drusen are more closely
respectively 56.0 and 61.6 years in 1950) [13]. In Poland, the associated with risk and progression of AMD [22]. Amorphous
estimated prevalence of AMD is 1.2 million people with 10–15% druses are heterogeneous. There are a few types of these colloid
prevalence of exudative form of disease and presently arrives bodies. The most common are:
about 100 thousand new patient yearly. About 40–50 thousand are
legally blind because of AMD.  hard, which are hyaline deposits the size of < 65 um;
 soft, the size of > 65 um, of irregular shape, with tendency to
3. Classification of AMD form bigger clusters;
 mixed, which appear when hard and soft druses occur
Clinically, there are two types of AMD dry (degenerative) and simultaneously.
wet (neovascular) form. The latter form of AMD includes
geographic atrophy and more severe disciform (neovascular) Yellow deposits which appear in RPE basement membrane are
variant first described in 1885 by Haab as senile macular called basement lamina druses. Each druse can turn into calcified
degeneration [14]. one. Drusen are also classified as small (<63 mm in diameter with
Dry AMD accounts for about 80% of cases affecting both eyes, discrete margins), medium (63–124 mm) or large (>125 mm with
but it typically causes only mild loss of vision [15]. Geographic indistinct edges) [23].
atrophy (GA), the advanced non-neovascular form of AMD, As the human organism ages, numerous metabolites appear in
accounts for 35% of all cases of late-stage AMD and 20% of legal the retina, which can make the process of druse formation and
blindness attributable to AMD [16]. Dry AMD, which is usually lipofuscin genesis accelerate. Lipofuscin (LF), called cell-aging
slowly progressing, for unknown reasons can become an aggres- factor, is a product of incomplete metabolism of external segments
sive–neovascular form of this disease. On account of the complex of photoreceptors by phagolysosomes. Due to loss of the protein-
character of AMD changes, there are many classifications of this lipid membrane tightness, liposome lipofuscin gets into cytoplasm
disease but the most general seems to be that shown by AREDS and then to extracellular areas, which finally results in forming
[17]. According to this examination there are 4 stages of AMD druses [20]. Molecule LF includes hybrid flurophor A2-E taking an
progression: active part in photoreceptors’ apoptosis, which suggests that LF is
involved in AMD pathogenesis [20]. When present in excessive
 initial (A), with small areas of hyperpigmentation and less than levels, lipofuscin and A2-E (a toxic vitamin A dimer) damage
20 middle-size druses; photoreceptors and choriocapillaris, leading to geographic atro-
 intermediate (B), with one or a few big druses, many middle- phy. Besides being toxic to the RPE, A2-E has also been shown to
size druses or geographical atrophy outside the retinal activate the complement cascade [24,25].
macula; Long-term epidemiological studies have identified valuable
 advanced (C and D), with the most progressive changes information on the prevalence, incidences, natural history and
characteristic of both dry and exudative AMD, which can occur associated risk factors of AMD [22]. The disease has been
with or without neovascularization. associated with light-induced oxidative damage [26], accumula-
tion of cholesterol and other lipids [27], and has been linked to
In clinical practice, the severity of AMD can be categorized systemic factors such as smoking [28], hypertension and
based on Snellen visual acuity (VA) testing of the better-seeing eye: atherosclerosis [29,30]. Cigarette smoking is associated with
K. Michalska-Małecka et al. / European Geriatric Medicine 6 (2015) 69–75 71

increased oxidative stress, lipid peroxidation, fibrinogen levels, presence of age related diseases. The pathogenesis of dry AMD is
and platelet aggregation. It is also associated with reduced plasma not completely understood and it is suggested that oxidation and
high-density lipoprotein and antioxidant levels [31]. Cigarette inflammation play important roles in the pathogenesis of the
smoking can damage choroidal vessels and diminish choroidal diseases. Apart from adrenal glands, the retinal tissue is one of the
blood flow through atherosclerosis. Nicotine promotes angiogen- tissues with the biggest oxygen needs due to the complexity of its
esis through nicotine-induced up-regulation of VEGF, a proangio- metabolism processes. Processes of cellular respiration occurring
genic factor involved in the pathogenesis of neovascular AMD in mitochondria are a source of reactive oxygen forms (ROF) which
[32]. Authors found that cigarette smoking also causes inflamma- can damage both retinal cones and rods, especially when reductive
tion by activating complement C3 and other inflammatory mechanisms are failing [49]. The human antioxidative system
mediators and reducing serum levels of complement factor H consists of two parts, enzymatic and nonenzymatic part. Enzy-
[33]. Lee et al. found that current cigarette smoking in exudative matic part of the system includes: catalase, glutathione peroxidase
AMD patients is associated with a poor visual acuity improvement and reductase and superoxide dismutase [50]. Correct activity of
following intravitreal ranibizumab therapy [34]. Cigarette smoking these systems is controlled by zinc, selenium, copper and
increases the risk of developing AMD, with heavier smokers manganese ions. The non-enzymatic part of this system includes
showing an increasingly greater risk of advanced forms of AMD vitamins E and C, glutathione as well as carotenoids, and especially
[35]. Patients diagnosed with early AMD exhibit signs of systemic lutein and mezoxantine, which are natural components of the
and retinal vascular alterations that correlated with known risk macula [51]. Nowak et al. have raised a point that oxidative could
markers for future cardiovascular morbidity [36]. Significant be one of the factors involved in the pathogenesis of AMD and
choroidal vascular alterations, such as changes in choriocapillaris suggested the possible protective effect of antioxidants supple-
density and volume and choroidal vessel diameter, have been mentation [52]. Although the rods and cones are replaced every
reported both in ageing and AMD [37]. Choroidal ischaemia is well 10 days their outer segments may be at particular risk of the
accepted as a causative factor, but its severity and prevalence have oxidative damage because of high concentration of the poly-
not been well documented because of the difficulty in imaging the unsaturated fatty acids in the photoreceptor outer segment
choroid due to light absorption by the overlying retinal pigment membrane. Docosahexaenoic acid (DHA) is an omega-3 fatty acid
epithelium (RPE) [38]. Coleman et al. based on results of their study that is a primary structural component of the human retina,
found ultrasonographic evidence of choroidal ishcaemia in AMD comprising 60% of the polyunsaturated fatty acids in the retina. It is
[38] which is consistent with the results presented by others the most oxidizable fatty acid in the body and is found in the
authors [39]. Other authors concluded that pharmacological membrane of the outer segment of the photoreceptors. The human
agents such as sildenafil, tadalafil, niacin or other agents that macula has a lifelong exposure to light and very high oxygen
increase choroidal perfusion could have a beneficial effect on consumption. The antioxidant index of the body, that includes the
delaying or interdicting AMD [40]. Cardiovascular risk factors, such measurement of the antioxidative enzymes activity and plasma
as hypertension and hyperlipidemia have been inconsistently nonenzymatic components concentration, has been studied in
associated with AMD risk as well. Elevated serum triglycerides AMD patients by several researchers but the results were
were associated with increasing intermediate AMD in one series contradictory [52–56]. Uruglu et al. found that there is a significant
while another population found no association with serum lipids increase in oxidative stress in AMD patients and significant
[41]. Apolipoprotein E (apo E) is unique among lipoproteins, decrease in antioxidant defense measured by the total thiol level
because of its special connections with nervous tissue. In the and in PON1 activity [54]. Similar results were presented by other
retina, the analogue of the astrocyte, the Muller cells seem to be the authors who found that superoxide dismutase (SOD), gluthatione
site of apo E production. Apo E mobilizes and redistributes lipids, in reductase (GR) and gluthatione peroxidase (GPx) activity are
maintenance and repair of neuronal cell membranes in central significantly higher and serum vitamin C and total antioxidant
nervous system (CNS) injury and neurodegenerative disorders capacity significantly decreased in control group than compared
[42]. Apart from homeostasis of cholesterol and triglicerides, Apo E with patients with AMD [55–57]. There is more and more evidence
has also other functions, e.g. immunoregulation, nerve regenera- that vitamins with antioxidative potential (e.g, vit. A, C and E) are
tion or activation of lipolic enzymes [43]. Some prior studies have one of the protective factors for vascular endothelium. They
suggested a possible role of apo E polymorphism in development of decrease inflammation, inhibit platelet aggregation and progres-
AMD. It is interesting, that authors have found a reduced risk of sion of the atherosclerosis. The results of case-control studies
AMD in peoples carrying e4 allele, whereas for other neurode- concerning supplementation with antioxidative vitamins are often
generative disorders and cardiovascular diseases authors have ambiguous but they generally indicate a decrease in the risk of
found increased risk for these subjects [44,45]. Apo E may have a degenerations and cardiovascular diseases, especially if they are
significant role in retinal membrane renewal, and cell membrane given early [17,58]. In conclusion the finding of the various studies
remodeling in macular area is probably the most important for suggests that the patients with both forms of AMD are an altered
normal physiology and functions of the retina. Failure of this metabolic state of oxidation-reduction and that it is convenient to
process may be a risk for development of degenerative disorders of give therapeutic interventions with antioxidants supplementation.
the central retinal area. In other study female gender, and a high Inflammation has been hypothesized to have a role in the
body-mass index (BMI > 30) have been reported as the important pathogenesis of age-related macular degeneration (AMD)
demographic and environmental risk factors in AMD [46,47]. There [59]. Medzhitov first introduced the idea of para-inflammation
are similarities between the drusen formation in AMD and in as a tissue adaptive response to noxious stress or malfunction that
formation of plaques in Alzheimer’s disease (AD). Drusen contain has characteristics intermediate between basal and inflammatory
similar protein components to the plaques found in AD. ApoE and states [60]. Para-inflammation has characteristics that are inter-
amyloid beta (Ab) are found both in AMD drusen as well in AD mediate between basal and inflammatory states. In the aging
plaques. The Ab found in drusen is thought to be locally derived retina, oxidized lipoproteins and free radicals are major causes of
from the RPE cells. In the AMD inflammatory process, there is an tissue stress and serve as local triggers for retinal para-inflamma-
associated rise in expression of both Ab protein and acute-proteins tion. Para-inflammatory responses in the retina may be reflected in
such as C-reactive protein (CRP) [48]. In the last decade much microglial activation and subretinal migration, and breakdown of
interest has been focused on the connection between the function blood-retinal barrier. Drusen have been shown to contain proteins
of the antioxidative system, concentration of antioxidants and the associated with immune-mediated processes and inflammation,
72 K. Michalska-Małecka et al. / European Geriatric Medicine 6 (2015) 69–75

and inflammatory cells have been found on the outer surface of [74]. CFH, ARMS2 these two allelic variants contribute to late AMD
Bruch’s membrane in AMD eyes [61]. It has been hypothesized that in more than 80% of cases [74,75]. Other genes that harbor
infectious agent activation of an aberrantly regulated alternative established risk variants for AMD include the complement factor B
complement pathway might contribute to the development of (CFB), complement component 2 (C2), complement component 3
AMD [62]. Earlier data from a sample of a cohort study showed an (C3), complement factor I (CFI), and the apolipoprotein E (APOE)
association of Chlamydia pneumoniae antibody titers with the 7- genes [76]. The last stage of the complement inactivation
year progression of AMD [53]. Data from two small case control (classical and lectyne) is the occurrence of the membrane attack
studies also showed an association with Chlamydia pneumoniae, complex (MAC) [77]. Convertase C3 is crucial here, and nine
but not other pathogens with AMD [63,64]. In a previous study mutations of the single nucleotide, including R102G by its
authors reported racial/ethnic differences in the frequency of early influence on cellular disintegration, are closely connected with
AMD with decreasing overall frequencies found in whites (5.4%), exudative AMD [77].
Chinese (4.6%), Hispanics (4.2%), and blacks (2.4%) in the Multi The neovascular form of age-related macular degeneration
Ethnic Study of Atherosclerosis [65]. The reasons for these racial/ (AMD), also known as wet AMD, is characterized by the formation
ethnic differences, especially between whites and blacks, were not of subretinal choroidal neovascularization (CNV) and is the cause
explained by known risk factors such as cigarette smoking, history of most cases of blindness in the elders. Wet AMD is the major
of alcohol drinking, BMI, hypertension, diabetes status, and cause of severe vision loss in developed nations and is estimated to
markers of subclinical cardiovascular disease [65]. Van de Ven affect > 2.5 million people worldwide [78,79]. The patients
et al. showed that a history of inflammatory diseases or use of anti- affected by exudative AMD often experience rapid loss of fine
inflammatory agents, or biomarkers of inflammation and related resolution central vision over several months, and early visual
processes also did not explain racial/ethnic differences in stabilization is a key issue in preserving visual acuity [80]. Angio-
prevalence of early AMD among the different racial/ethnic groups genesis is the development of new blood vessels from pre-existing
[66]. Authors found that whites, blacks, and Hispanics who were all vessels and whilst being a crucial process in normal physiology, it
homozygous for the complement factor H (CFH) Y402H CC variant is an important pathogenic process in both benign and malignant
genotype had the highest frequencies of early AMD compared with disease [81]. A lot of markers, both stimulating and inhibiting can
those with the CFH Y402H TT wild genotype. The CFH Y402H CC influence on this process. Activators of angiogenesis include: VEGF,
variant genotype distributions varied among the racial/ethnic nitric oxide (NO), integrins: a5b1, avb3 and avb5, transforming
groups and did explain some of the difference in early AMD growth factor beta 1 (TGFb1) and its receptors, growth factors:
prevalence for Chinese and for Hispanics but did not explain the acidic fibroblast growth factor (aFGF), basic fibroblast growth
difference in AMD prevalence between whites and blacks factor (bFGF), hepatocyte growth factor (HGF), insulin-like growth
[66]. Genetic studies have implicated roles for the immune factor I (IGF-I), platelet-derived growth factor (PDGF), epidermal
system, particularly abnormalities in the complement system in growth factor (EGF), hypoxia-inducible factor 1 alpha (HIF-1a), IL-
pathogenesis and severity of AMD. Although patients with AMD do 8, IL-1, prostaglandin (PGE 1, PGE 2, PGF), erythropoietin,
not have signs of overt ocular inflammation, histologic studies histamine, bradykinin, tumour necrosis factor alpha (TNFa)
have shown the presence of macrophages, lymphocytes, and mast [82,83]. Abnormal angiogenesis is a hallmark of diseases such as
cells, as well as fibroblasts, associated with both atrophic lesions cancer, chronic inflammation and also the neovascular form of
and with neovascularization of the retina [67]. Over the past AMD [84,85]. Choroidal neovascularization (CNV) represents the
decade, studies has found that inflammation play a large role in the growth of new blood vessels from the choroid into the subretinal
pathogenesis of age-related macular degeneration (AMD). In fact, pigment epithelium. Several proangiogenic factors are consistently
the main genetic changes (polymorphism) associated upregulated during CNV formation, particularly two members of
with AMD were found to be genes that regulate inflammation, the vascular endothelial growth factor (VEGF) family, VEGF-A and
most notably CFH [68]. Complement factor H is a circulating placental growth factor (PlGF) [84,86]. These factors activate
protein that inhibits directly or indirectly the three complement quiescent endothelial cells and promote cell proliferation, migra-
activation pathways. In patients with early and late AMD, many tion and vascular permeability [84].
CFH polymorphisms have been described [69]. With abnormal
CFH, complement system downregulation is defective and excess 5. Treatment of AMD
inflammation may result. Additionally, histological analysis of
drusen revealed the presence of complement factors and the While a treatment for geographical atrophy (GA) remains to be
terminal membrane attack complex [70]. It is still unknown established, treatments for neovascular AMD using photodynamic
whether those complement factors are systemically or locally therapy and antivascular endothelial growth factors exist.
produced in the retina [71]. Chronic subclinical local inflammation Currently, the only approved treatment for dry AMD is the use
of the retina in AMD patients may trigger and/or sustain the of AREDS formulation [17,58,87]. In the near future, it is likely that
damaging process [59,60]. Despriet et al. found that markers of the treatment of dry AMD will be a combination of different drugs
inflammation, such as serum C-reactive protein (CRP) are related that will target the different pathways involved in the pathogen-
to AMD only in carriers of CFH Y402H variants [72]. Multiple esis and progression of dry AMD [88]. Firstly pharmacological
studies have assessed the role of genetic variants on AMD targeting of components involved in dry AMD pathogenesis is
development and progression, especially with CFH and age-related prevention of photoreceptors and RPE cells loss. Ciliary neuro-
maculopathy susceptibility 2 (ARMS2) genes, the two major trophic factor (CNTF) is a potent neurotrophic factor that slows
susceptibility genes for AMD. CFH Y402H heterozygotes allele down loss of photoreceptors in various animal models of retinal
conferred 4.6-fold increased risk for AMD and the homozygotes a degeneration [89], and there are evidences of its efficacy in human
7.4-fold increased risk, as compared with the homozygous non- retinitis pigmentosa [90]. Alpha-2 adrenergic receptor is present in
risk genotype [73]. Individuals heterozygotous for ARMS2 A69S the mammalian retina and brimonidine tartrate (Allergan Inc.,
allele conferred 2.7-fold increased risk of AMD compared with USA, an alpha-2 adrenergic receptor agonist has been shown to
wild-type homozygous allele, whereas a 8.2-fold increased risk is protect retinal ganglion cells, bipolar cells, and photoreceptors in
associated with the homozygous risk allele. An additive effect numerous models of experimental nerve injury, including retina
of CFH Y402H and LOC387715 A69S is seen with 50-fold increase in ischemia, ocular hypertension, retinal phototoxicity, and partial
the risk of AMD in subjects homozygous for both risk alleles optic nerve crush [91]. Other authors in an animal model found
K. Michalska-Małecka et al. / European Geriatric Medicine 6 (2015) 69–75 73

that a selective serotonin 1A agonist (Tandospirone, Alcon that binds to all VEGF and VEGF-B isoforms as well as to PlGF [99].
Laboratories Inc., USA) protects photoreceptors and RPE cells from It may be considered an attractive alternative to other anti-VEGF
photo-oxidative stress by decreasing microglia activation/recruit- agents because it appears to offer visual outcomes similar to
ment and complement deposition in the outer retinax [92]. The ranibizumab and bevacizumab with a longer duration of action. For
analysis of the drusen in patients with Alzheimer disease treated the first time, an anti-VEGF drug can be given at 2-month intervals
with glatiramer acetate (an immunomodulatory drug currently with results comparable to ranibizumab given every 4 weeks
used to treat multiple sclerosis) showed that the drug reduces [100]. The data demonstrate that VEGF trap binds human VEGF-A
drusen area. Specifically in patients with dry AMD, glatiramer with higher affinity and a significantly faster association rate, thus
acetate shrank or eliminate more drusen than did sham treatment neutralizing VEGF-A with greater potency than ranibizumab or
[93]. bevacizumab [99].
Secondly pharmacological targeting of components involved in Projections over the next decade suggest that the number of
dry AMD pathogenesis is suppression of inflammation. It is likely prevalent cases of late AMD will increase steadily by a third by
that if inflammation will be reduced, development or progression 2020 due to population ageing. These evidence-based estimates
of AMD will also be reduced. Inflammatory elements are present in can be used to help plan social and healthcare provision for the
drusen, such as components of the complement system, acute- present and the future.
phase proteins, proteins that modulate the immune response,
lipofuscin, and dendritic cells [71]. In an animal model study Disclosure of interest
authors found that fluocinolone acetonide is a potent corticoster-
oid that presented a neuroprotective effect by dampening retinal The authors declare that they have no conflicts of interest
neuroinflammation [94,95]. Several therapeutic agents involved in concerning this article.
the complement cascade are under investigation [88]. POT-4
(Potentia Pharmaceuticals, USA) is a synthetic peptide that References
reversibly binds complement factor C3 and inhibits activation
of the complement cascade (ClinicalTrials.gov number, [1] Evans JR, Fletcher AE, Wormald RP. Causes of visual impairment in people
NCT00473928). Eculizumab (Alexion Pharmaceuticals, USA) is a aged 75 years and older in Britain: an add-on study to the MRC Trial of
Assessment and Management of Older People in the Community. Br J
humanized IgG antibody that selectively inhibits the cleavage of C5 Ophthalmol 2004;88(3):365–70.
factor into C5a and 5b (ClinicalTrials.gov number, NCT00935883). [2] Michalska-Małecka K, Nowak M, Gościniewicz P, Karpe J, Słowińska-Łożyńska
ARC1905 (Ophthotech Corp., USA) is an aptamer that is a potent L, Łypaczewska A, et al. Results of cataract surgery in the very elderly
population. Clin Interv Aging 2013;8:1041–6.
and selective inhibitor of factor C5 of the complement cascade
[3] van Lookeren Campagne, Lecouter J, Yaspan BL, Ye W. Mechanisms of age
(ClinicalTrials.gov number, NCT 00950638). FCFD4514S (Genen- related macular degeneration and therapeutic opportunities. J Pathol
tech Inc., USA) is a human monoclonal antibody that inhibits 2014;232(2):151–64.
complement factor D, a protein involved in the alternative [4] McConnell V, Silvestri G. Age-related macular degeneration. Ulster Med J
2005;74(2):82–92.
complement pathway (ClinicalTrials.gov numbers, NCT [5] Yuzawa M, Fujita K, Tanaka E, Wang EC. Assessing quality of life in the
00973011) [88]. Treatment of dry AMD still remains a challenge. treatment of patients with age-related macular degeneration: clinical re-
Currently, the only approved treatment for dry AMD is the use of search findings and recommendations for clinical practice. Clin Ophthalmol
2013;7:1325–32.
Age-Related Eye Disease Study (AREDS)-based vitamin supple- [6] Finger RP, Kupitz DG, Holz FG, et al. The impact of the severity of vision loss on
ments, which does not halt the vision loss but lowers the risk of vision-related quality of life in India: an evaluation of the IND-VFQ-33. Invest
developing advanced stages of AMD (either geographic atrophy or Ophthalmol Vis Sci 2011;52(9):6081–8.
[7] Harwood RH. Visual problems and falls. Age Ageing 2001;30(Suppl. 4):13–8.
neovascular AMD) and reduces visual loss in people at risk for the [8] la Cour M, Kiilgaard JF, Nissen MH. Age-related macular degeneration:
disease [17,87]. The AREDS established that antioxidant vitamin epidemiology and optimal treatment. Drugs Aging 2002;19(2):101–33.
and mineral supplementation (AREDS formulation) consisting of [9] Friedman DS, O’Colmain BJ, Muñoz B, et al. Eye Disease Prevalence Research
Group Prevalence of age-related macular degeneration in the United States.
b-carotene (15 mg), vitamins C (500 mg) and E (400 IU), and zinc Arch Ophthalmol 2004;122(4):564–72.
(as zinc oxide 80 mg), along with copper (as cupric oxide 2 mg) [10] Oshima Y, Ishibashi T, Murata T, Tahara Y, Kiyohara Y, Kubota T. Prevalence of
slowed progression of AMD in individuals at high risk of age related maculopathy in a representative Japanese population: the
Hisayama study. Br J Ophthalmol 2001;85(10):1153–7.
developing advanced AMD [87]. Recent analyses demonstrate
[11] Owen CG, Jarrar Z, Wormald R, Cook DG, Fletcher AE, Rudnicka AR. The
that the beneficial effects are restricted mostly to preventing the estimated prevalence and incidence of late stage age related macular degen-
progression to neovascular AMD [69]. eration in the UK. Br J Ophthalmol 2012;96(5):752–6.
The arsenal of VEGF blockers has evolved over time, with newer [12] Jonasson F, Arnarsson A, Eriksdottir G, et al. Prevalence of age-related
macular degeneration in old persons: Age, Gene/environment Susceptibility
generations offering potentially improved anti-angiogenic activity Reykjavik Study. Ophthalmology 2011;118(5):825–30.
by increasing their affinity for VEGF-A, and/or the number of VEGF- [13] Glówny Urza˛d Statystyczny. Life expectancy tables of Poland Central Statis-
isoforms and family members that they inhibit. Pegaptanib tical Office;[webpage on the Internet] 2011, Available from: http://
www.stat.gov.pl/cps/rde/xbcr/gus/POP_life_expectancy_in_2011.pdf.
(MacugenTM, Eyetech, Inc.) is an aptamer that selectively binds [14] Haab O. Erkrankungen der Macula lutea. Centralblat fur practische. Augen-
to and neutralizes VEGF-A165, but not VEGF-A121, and was the first heilkunde 1885;9:383–4.
anti-VEGF therapy approved for the treatment of wet AMD [15] Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J
Med 2008;358(24):2606–17.
[96]. The development of new agents for wet AMD has focused [16] Klein R, Klein BE, Knudtson MD, Meuer SM, Swift M, Gangnon RE. Fifteen-year
on both improving efficacy and extending the duration of action in cumulative incidence of age-related macular degeneration: the Beaver Dam
comparison with the commonly used anti-VEGF drugs ranibizu- Eye Study. Ophthalmology 2007;114(2):253–62.
[17] AREDS Report no. 8. A randomized, placebo-controlled, clinical trial of high-
mab and bevacizumab, which are considered the standard drugs.
dose supplementation with vitamins C and E, beta carotene and zinic for age-
Ranibizumab is a monoclonal humanized antibody fragment and related macular degeneration and vision loss. Arch Ophthalmol 2001;119:
bevacizumab is a whole monoclonal antibody, and both show a 1417–36.
[18] Brown GC, Brown MM, Sharma S, et al. The burden of age-related macular
high binding affinity for all isoforms of VEGF. These agents appear
degeneration: a value-based medicine analysis. Trans Am Ophthalmol Soc
to have similar efficacy profiles and mechanisms of action, i.e., they 2005;103:173–84.
block the extracellular availability of VEGF which can arrest [19] Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflam-
choroidal angiogenesis and reduce vascular permeability for a mation in the formation of drusen in the aging eye. Am J Ophthalmol
2002;134:411–31.
limited period of time [97,98]. Aflibercept, or VEGF Trap-eye, is a [20] Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and ther-
novel compound derived from the native VEGF receptor (VEGFR) apy. Pharmacol Rep 2006;58:353–63.
74 K. Michalska-Małecka et al. / European Geriatric Medicine 6 (2015) 69–75

[21] Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, et al. Drusen proteome [50] Vertuani S, Angusti A, Manfredini S. The antioxidants and pro-antioxidants
analysis: an approach to the etiology of age-related macular degeneration. network:an overview. Curr Pharm Des 2004;14:1677–94.
Proc Natl Acad Sci U S 2002;A99:14682–7. [51] Wiśniewska-Becker A, Nawrocki G, Duda M, Subczyński WK. Structural
[22] Klein R, Peto T, Bird A, Vannewkirk MR. The epidemiology of age-related aspects of the antioxidant activity of lutein in a model of photoreceptor
macular degeneration. Am J Ophthalmol 2004;137:486–95. membranes. Acta Biochim Pol 2012;59(1):119–23.
[23] Ratnapriya R, Chew EY. Age-related macular degeneration–clinical review [52] Nowak M, Świe˛tochowska E, Wielkoszyński T, Marek B, Karpe J, et al. Changes
and genetics update. Clin Genet 2013;84(2):160–6. in blood antioxidants and several lipid peroxidation products in women with
[24] Zhou J, Jang YP, Kim SR, Sparrow JR. Complement activation by photooxida- age-related macular degeneration. Eur J Ophthalmol 2003;13(3):281–6.
tion products of A2E, a lipofuscin constituent of the retinal pigment epithe- [53] Danulescu R, Costi D. Use of blood markers in early diagnosis of oxidative
lium. Proc Natl Acad Sci U S A 2006;103(44):16182–7. stress in age related macular degeneration. Rev Med Chir Soc Med Nat Iasi
[25] Radu RA, Hu J, Yuan Q, Welch DL, Makshanoff J, Lloyd M, et al. Complement 2012;116(4):1136–42.
system dysregulation and inflammation in the retinal pigment epithelium of [54] Ugurlu N, Asik MD, Yulek F, Neselioglu S, Cagli N. Oxidative stress and anti-
a mouse model for Stargardt macular degeneration. J Biol Chem 2011;286(21): oxidative defence in patients with age-related macular degeneration. Cuee
18593–601. Eye Res 2013;38(4):497–502.
[26] Jarrett SG, Boulton ME. Consequences of oxidative stress in age-related [55] Zafrilla P, Losada M, Perez A, Caravaca G, Mulero J. Biomarkers of oxidative
macular degeneration. Mol Aspects Med 2012;33:399–417. stress in patients with wet age related macular degeneration. J Nutr Health
[27] Curcio CA, Johnson M, Rudolf M, Huang JD. The oil spill in ageing Bruch Aging 2013;17(3):219–22.
membrane. Br J Ophthalmol 2011;95:1638–45. [56] Shen XL, Jia JH, Zhao P, Fan R, Pan XY, Yang HM, et al. Changes in blood oxidative
[28] Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP. Smoking and antioxidant parameters in a group of Chinese patients with age-related
and age-related macular degeneration: a review of association. Eye (Lond) macular degeneration. J Nutr Health Aging 2012;16(3):201–4.
2005;19:935–44. [57] Colak E, Majkic-Singh N, Zoric L, Radosavljevic A, Kosanovic-Jakovic N. The
[29] Klein R. Overview of progress in the epidemiology of age-related macular impact of inflammation to the antioxidant defense parameters in AMD
degeneration. Ophthalmic Epidemiol 2007;14:184–7. patients. Aging Clin Exp Res 2012;24(6):588–94.
[30] Friedman E. The role of the atherosclerotic process in the pathogenesis of age- [58] Chew EY, Clemons TE, Agron E, et al. Long-term effects of vitamins C and E,
related macular degeneration. Am J Ophthalmol 2000;130:658–63. beta-carotene, and zinc on age-related macular degeneration: AREDS Report
[31] Seddon JM, George S, Rosner B. Cigarette smoking, fish consumption, omega- No. 35. Ophthalmology 2013;120(8):1604–11.
3 fatty acid intake, and associations with age-related macular degeneration: [59] Donoso LA, Kim D, Frost A, et al. The role of inflammation in the pathogenesis
the US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol of age-related macular degeneration. Surv Ophthalmol 2006;51:137–52.
2006;124:995–1001. [60] Medzhitov R. Origin and physiological roles of inflammation. Nature
[32] Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, et al. Nicotine stimulates 2008;454(7203):428–35.
angiogenesis and promotes tumor growth and atherosclerosis. Nat Med [61] Hageman GS, Luthert PJ, Victor Chong NH, et al. An integrated hypothesis that
2001;7:833–9. considers drusen as biomarkers of immune-mediated processes at the RPE-
[33] Ni Dhubhghaill SS, Cahill MT, Campbell M, Cassidy L, Humphries MM, Bruch’s membrane interface in aging and age-related macular degeneration.
Humphries P. The pathophysiology of cigarette smoking and age-related Prog Retin Eye Res 2001;20:705–32.
macular degeneration. Adv Exp Med Biol 2010;664:437–46. [62] Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the
[34] Lee S, Song SJ, Yu HG. Current smoking is associated with a poor visual acuity complement regulatory gene factor H (HF1/CFH) predisposes individuals to
improvement after intravitreal ranibizumab therapy in patients with exuda- age-related macular degeneration. Proc Natl Acad Sci U S A 2005;
tive age-related macular degeneration. J Korean Med Sci 2013;28(5):769–74. 102:7227–32.
[35] Khan JC, Thurlby DA, Shahid H, Clayton DG, Yates JR, Bradley M, et al. Genetic [63] Kalayoglu MV, Galvan C, Mahdi OS, et al. Serological association between
Factors in AMD Study. Smoking and age related macular degeneration: the Chlamydia pneumoniae infection and age-related macular degeneration. Arch
number of pack years of cigarette smoking is a major determinant of risk for Ophthalmol 2003;121:478–82.
both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol [64] Ishida O, Oku H, Ikeda T, et al. Is Chlamydia pneumoniae infection a risk factor
2006;90:75–80. for age related macular degeneration? Br J Ophthalmol 2003;87:523–4.
[36] Qin L, Mroczkowska SA, Ekart A, Patel SR, Gibson JM, Gherghel D. Patients [65] Klein R, Klein BE, Knudtson MD, et al. Subclinical atherosclerotic cardiovas-
with early age-related macular degeneration exhibit signs of macro- and cular disease and early age-related macular degeneration in a multiracial
micro-vascular disease and abnormal blood glutathione levels. Graefes Arch cohort: the MultiEthnic Study of Atherosclerosis. Arch Ophthalmol
Clin Exp Ophthalmol 2014;252(1):23–30. 2007;125:534–43.
[37] Spraul CW, Lang GE, Grossniklaus HE. Morphometric analysis of the choroid, [66] van de Ven JP, Smailhodzic D, Boon CJ, Fauser S, Groenewoud JM, Chong NV,
Bruch’s membrane, and retinal pigment epithelium in eyes with age-related et al. Association analysis of genetic and environmental risk factors in the
macular degeneration. Invest Ophthalmol Vis Sci 1996;37:2724–35. cuticular drusen subtype of age-related macular degeneration. Mol Vis
[38] Coleman DJ, Silverman RH, Rondeau MJ, Lloyd HO, Khanifar AA, Chan RV. Age- 2012;18:2271–8.
related macular degeneration: choroidal ischaemia? Br J Ophthalmol [67] Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiological
2013;97(8):1020–3. aspects of macular degeneration. Prog Retin Eye Res 2001;20(3):385–414.
[39] Berenberg TL, Metelitsina TI, Madow B, et al. The association between drusen [68] Telander DG. Inflammation and age-related macular degeneration (AMD).
extent and foveolar choroidal blood flow in age-related macular degenera- Semin Ophthalmol 2011;26(3):192–7.
tion. Retina 2012;32:25–31. [69] Haddad S, Chen CA, Santangelo SL, Seddon JM. The genetics of age-related
[40] Kim DY, Silverman RH, Chan RVP, et al. Measurement of choroidal perfusion macular degeneration: a review of progress to date. Surv Ophthalmol
and thickness following systemic sildenafil (Viagra1). Acta Ophthalmologica 2006;51(4):316–63.
2012;10:1111. [70] Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH. A potential role
[41] Munch IC, Linneberg A, Larsen M. Precursors of age-related macular degen- for immune complex pathogenesis in drusen formation. Exp Eye Res
eration: associations with physical activity, obesity and serum lipids in the 2000;70(4):441–9.
Inter99 Eye Study. Invest Ophthalmol Vis Sci 2013;54(6):3932–40. [71] Buschini E, Piras A, Nuzzi R, Vercelli A. Age related macular degeneration and
[42] Boyles JK, Zoellner CD, Anderson LJ, et al. A role for apolipoprotein E, drusen: neuroinflammation in the retina. Prog Neurobiol 2011;95(1):14–25.
apolipoprotein A-I, and low density lipoprotein receptors in cholesterol [72] Despriet DD, Klaver CC, Witteman JC, et al. Complement factor H polymor-
transport during regeneration and remyelination of the rat aciatic nerve. J phism, complement activators, and risk of age-related macular degeneration.
Clin Invest 1989;83:1015–31. JAMA 2006;296:301–9.
[43] Cardian AD, Bowlin TL, Krstenansky JL. Inhibition of lymphocyte proliferation [73] Schaumberg DA, Hankinson SE, Guo Q, et al. A prospective study of 2 major
by synthetic peptides homologous yo human plasma apolipoproteins B and E. age-related macular degeneration susceptibility alleles and interactions with
Biochem Biophys Res Commun 1988;154:741–5. modifiable risk factors. Arch Ophthalmol 2007;125:55–62.
[44] Shimano H, Ishibashi S, Murase T, et al. Plasma apolipoproteins in patients [74] Francis PJ, Zhang H, Dewan A, Hoh J, Klein ML. Joint effects of polymorphisms
with multiinfarct dementia. Atherosclerosis 1989;79:257–60. in the HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian
[45] Siest G, Pillot T, Regis-Billy A, et al. Apolipoprotein E: an important gene and population. Mol Vis 2008;14:1395–400.
protein to follow in laboratory medicine. Clin Chem 1995;41:1068–86. [75] Kaur I, Katta S, Hussain A, Hussain N, Mathai A, Narayanan R, et al. Variants in
[46] Klein BE, Klein R, Lee KE, Jensen SC. Measures of obesity and age-related eye the 10q26 gene cluster (LOC387715 and HTRA1) exhibit enhanced risk of age-
diseases. Ophthalmic Epidemiol 2001;8:251–62. related macular degeneration along with CFH in Indian patients. Invest
[47] Rudnicka AR, Jarrar Z, Wormald R, Cook DG, Fletcher A, Owen CG. Age and Ophthalmol Vis Sci 2008;49:1771–6.
gender variations in age-related macular degeneration prevalence in popula- [76] Baird PN, Guida E, Chu DT, Vu HT, Guymer RH. The epsilon2 and epsilon4
tions of European ancestry: a metaanalysis. Ophthalmology 2012;119: alleles of the apolipoprotein gene are associated with age-related macular
571–80. degeneration. Invest Ophthalmol Vis Sci 2004;45:1311–5.
[48] Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, et al. The Alzhei- [77] Dzik JM. The ancestry and cumulative evolution of immune reactions. Acta
mer’s Abeta peptide is deposited at sites of complement activation in Biochim Pol 2010;57(4):452–6.
pathologic deposits associated with aging and age-related macular degener- [78] Chappelow AV, Kaiser PK. Neovascular age-related macular degeneration:
ation. Proc Natl Acad Sci U S 2002;A 99:11830–5. potential therapies. Drugs 2008;68(8):1029–36.
[49] Bone RA, Gibert JC, Mukherjee A. Light distributions on the retina: relevance [79] La Cour M, Kiilgaard JF, Nissen MH. Age-related macular degeneration:
to macular pigment photoprotection. Acta Biochim Pol 2012;59(1):91–6. epidemiology and optimal treatment. Drugs Aging 2002;19(2):101–33.
K. Michalska-Małecka et al. / European Geriatric Medicine 6 (2015) 69–75 75

[80] Bloch SB, Larsen M, Munch IC. Incidence of legal blindness from age-related [91] Lai RK, Chun T, Hasson D, Lee S, Mehrbod F, Wheeler L. Alpha-2 adrenoceptor
macular degeneration in Denmark: year 2000-2010. Am J Ophthalmol agonist protects retinal function after acute retinal ischemic injury in the rat.
2012;153(2):209–13. Vis Neurosci 2002;19(2):175–85.
[81] Risau W. Mechanisms of angiogenesis. Nature 1997;386:671–4. [92] Collier RJ, Wang Y, Smith SS, Martin E, Ornberg R, Rhoades K, et al. Comple-
[82] Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kudła B. Vascular endothelial ment deposition and microglial activation in the outer retina in light-induced
growth factor (VEGF) – part 1: in physiology and pathophysiology. Endok- retinopathy: inhibition by a 5-HT1A agonist. Invest Ophthalmol Vis Sci
rynol Pol 2011;62(5):444–55. 2011;52(11):8108–16.
[83] Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kudła B. Transforming growth [93] Landa G, Rosen RB, Patel A, Lima VC, Tai KW, Perez VR, et al. Qualitative
factor B1 (TGF B1) in physiology and pathophysiology. Endokrynol Pol spectral OCT/SLO analysis of drusen change in dry age-related macular
2013;64(5):384–96. degeneration patients treated with copaxone. J Ocul Pharmacol Ther
[84] Bressler SB. Introduction: understanding the role of angiogenesis and anti- 2011;27(1):77–82.
angiogenic agents in age-related macular degeneration. Ophthalmology [94] Glybina IV, Kennedy A, Ashton P, Abrams GW, Iezzi R. Photoreceptor neu-
2009;116:1–7. roprotection in RCS rats via low-dose intravitreal sustained-delivery of
[85] CarmelietF P., Jain RK. Angiogenesis in cancer and other diseases. Nature fluocinolone acetonide. Invest Ophthalmol Vis Sci 2009;50(10):4847–57.
2000;407:249–57. [95] Glybina IV, Kennedy A, Ashton P, Abrams GW, Iezzi R. Intravitreous delivery
[86] Crawford Y, Ferrara N. VEGF inhibition: insights from preclinical and clinical of the corticosteroid fluocinolone acetonide attenuates retinal degeneration
studies. Cell Tissue Res 2009;335:261–9. in S334ter-4 rats. Invest Ophthalmol Vis Sci 2010;51(8):4243–52.
[87] Age-Related Eye Disease Study Research Group. A randomized, placebo- [96] Gragoudas ES, Adamis AP, Cunningham Jr ET, Feinsod M, Guyer DR. Pegap-
controlled, clinical trial of high-dose supplementation with vitamins C and tanib for neovascular age-related macular degeneration. N Engl J Med
E and beta carotene for age-related cataract and vision loss: AREDS report 2004;351:2805–16.
no 9. Arch Ophthalmol 2001;119(10):1439–52. [97] Comparison of Age-related Macular Degeneration Treatments Trials (CATT)
[88] Damico FM, Gasparin F, Scolari MR, Pedral LS, Takahashi BS. New approaches Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizu-
and potential treatments for dry age-related macular degeneration. Arq Bras mab for treatment of neovascular age-related macular degeneration: two-
Oftalmol 2012;75(1):71–6. year results. Ophthalmology 2012;119(7):1388–98.
[89] Tao W, Wen R, Goddard MB, Sherman SD, O’Rourke PJ, Stabila PF, et al. [98] Ahfat FG, Zaidi FH. Bevacizumab vs ranibizumab-an appraisal of the evidence
Encapsulated cell-based delivery of CNTF reduces photoreceptor degenera- from CATT and IVAN. Eye (Lond) 2013;27(3):289–90.
tion in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci [99] Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of
2002;43(10):3292–8. vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap,
[90] Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, et al. ranibizumab and bevacizumab. Angiogenesis 2012;15(2):171–85.
Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I [100] Semeraro F, Morescalchi F, Duse S, Parmeggiani F, Gambicorti E, Costagliola C.
trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Aflibercept in wet AMD: specific role and optimal use. Drug Des Devel Ther
Acad Sci U S A 2006;103(10):3896–901. 2013;7:711–22.

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