Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Clinical background

Clinical manifestations of dry age-related macular degeneration (AMD) include drusen, retinal pigment epithelium (RPE) hyperplasia, RPE depigmentation, and geographic atrophy (GA) (Box 68.1). The prevalence of early AMD is 18% in the population aged 65–74 years and 30% in those older than 74 years.1 GA is the advanced atrophic form of dry AMD. Approximately 3.5% of people aged 75 and older have GA,2 and its prevalence is greater than 20% among persons aged 90 and older.3 In the 70s and 80s, choroidal new vessels (CNVs) are approximately twice as common as GA, but GA is more common in the oldest group.

In many patients, small areas of GA develop near the fovea, often in areas of resorbed drusen or mottled hypoand hyperpigmentation (Figure 68.1). Over time these areas enlarge, creating multifocal GA surrounding the fovea. The areas may then coalesce, first into a horseshoe-shaped area of atrophy and later into a ring of atrophy, still sparing the foveal center. Finally, the fovea becomes atrophic, and the patient must use eccentric vision for all visual tasks.4–7 When the fovea is surrounded by atrophy, the patient may be able to read single small letters on a visual acuity chart but may have great difficulty reading because the surrounding scotomata block off parts of words and sentences. Similarly, these patients may have difficulty recognizing faces, because parts of the face are obscured by the scotomata. In addition, these small spared areas pose a great challenge for low-vision rehabilitation, in that too much magnification will put more of the word in the blind area and may actually make reading more difficult. Patients often use two areas for fixation, a central one for small print and an eccentric one to see the larger picture.8,9 This pattern of disease progression can lead one to underestimate the severity of visual impairment associated with GA if one measures central visual acuity solely.

GA is an important cause of moderate and severe visual loss among AMD patients. In a large natural history study, 40% of the patients with GA and vision of 20/50 or better

worsened by 3 or more lines on an Early Treatment of Diabetic Retinopathy visual acuity chart over a 2-year follow-up period. A total of 27% of the patients with this good baseline visual acuity worsened to 20/200 or less by 4 years of followup.10 The degree of impairment in dim environments at baseline is predictive of subsequent visual acuity loss.11 Thus, there is very significant decline in visual acuity during a 2-year period among patients with GA.

The appearance and rate of enlargement of atrophy are very symmetric between eyes in patients with bilateral GA, who constitute the majority of GA patients. The enlargement rate appears to be characteristic of the individual, and this between-subjects factor is more significant than is the size of the GA in estimating the subsequent rate of GA enlargement.7

Choroidal neovascularization is relatively uncommon in patients with bilateral GA without CNVs in either eye at baseline. In contrast, patients with CNVs in one eye and GA without CNVs in the fellow eye have a much higher rate of developing CNVs in the eye with GA.12,13 It is not yet understood why some patients are more likely to develop CNVs, and others are more likely to develop GA.

The differential diagnosis of dry AMD includes Stargardt disease, central areolar choroidal atrophy, Doyne honeycomb dystrophy, drug toxicity, Best disease, adult vitelliform dystrophy, and some forms of retinitis pigmentosa (Box 68.2). Membranoproliferative glomerulonephritis type II (MPGN II) can be associated with drusen, GA, and CNVs.14–19

Pathology

The abnormal extracellular matrix (ECM) of AMD eyes includes basal laminar deposit, basal linear deposit, and their clinically evident manifestation, soft drusen. The RPE deposits cytoplasmic material into Bruch’s membrane throughout life, possibly to eliminate cytoplasmic debris or as a response to chronic inflammation (see Pathophysiology, below).20–23 Histologically, AMD eyes exhibit abnormal

extracellular material in two locations: (1) between the RPE plasmalemma and the RPE basement membrane (basal laminar deposit); and (2) external to the RPE basement membrane within the collagenous layers of Bruch’s membrane (basal linear deposit).24 Although basal laminar deposit persists in areas of GA, basal linear deposit disappears, which is consistent with the notion that basal linear deposit arises mostly from the RPE–photoreceptor complex.25 Basal linear deposit may be more specific to AMD than basal laminar deposit.26 Soft drusen can represent focal accentua-

Box 68.1  Clinical findings in dry age-related

macular degeneration

•Drusen

•Retinal pigment epithelium (RPE) hyperplasia

•RPE depigmentation

•Geographic atrophy

tions of basal linear deposit in the presence or absence of diffuse basal linear deposit-associated thickening of the inner aspects of Bruch’s membrane.24,27 Soft drusen can also represent a localized accumulation of basal laminar deposit in an eye with diffuse basal laminar deposit.27

Drusen represent the earliest clinical finding in AMD (Box 68.3). Drusen composition and origin have been analyzed

Box 68.2  Conditions mimicking dry age-related

macular degeneration

•Stargardt disease

•Central areolar choroidal atrophy

•Doyne honeycomb dystrophy

•Drug toxicity

•Best disease

•Adult vitelliform dystrophy

•Membranoproliferative glomerulonephritis type II

•Some forms of retinitis pigmentosa

Box 68.3  Histopathology of age-related macular

degeneration

•Accumulation of abnormal extracellular material (basal laminar and basal linear deposit)

•Geographic atrophy (loss of photoreceptors and subjacent retinal pigment epithelium and choriocapillaris)

•Choroidal neovascularization

extensively.28–38 Small (i.e., 63- m-diameter) drusen generally do not signify the presence of AMD.1,24,39,40 Excessive numbers of small hard drusen, however, can predispose to RPE atrophy at a relatively young age.41 Soft drusen are usually pale yellow and large with poorly demarcated boundaries. Many different molecules have been identified in drusen, most of which seem to be the product of oxidative and inflammatory processes (Table 68.1). Many of the molecular constituents of drusen are synthesized by RPE, neural retina, or choroidal cells, but some are derived from extraocular sources.

Areas of GA have a loss of RPE cells as well as overlying photoreceptors and subjacent choriocapillaris atrophy.39,42 Choriocapillaris may be lost as a result of RPE loss,43,44 and assessment of the region immediately outside the area of GA indicates that the RPE cells are lost first.45 In many patients with GA, there is increased fundus autofluorescence in the area surrounding the GA, termed the junctional zone.46 This autofluorescence is a product of RPE cells laden with lipofuscin.47 Lipofuscin, particularly the N-retinylidene-N- retinylethanolamine component (A2E: see Pathophysiology, below), is harmful to RPE cells48 and may be partly responsible for GA progression. Using a scanning laser ophthalmoscope (such as the Heidelberg retinal analyzer, HRA) with argon blue light and a barrier filter and with image averaging techniques, one can obtain a high-resolution fundus autofluorescence image (Figure 68.1). Areas that are dark have lost autofluorescence because there is RPE atrophy or attenuation. Areas that are bright have increased lipofuscin deposition. The pattern of increased autofluorescence may be useful in predicting the rate of enlargement of areas of GA.49

Etiology

The prevalence of both CNVs and GA is much higher in white populations as compared with black populations.50–53 Smoking increases the risk of developing GA and may also increase its rate of progression.54,55 The presence of drusen measuring 250 m or greater and pigmentary abnormalities are risk factors for the development of GA.56 The way that inflammatory and immunologic factors relate to the development of AMD is not yet clear, but is an active area of investigation.

Pathophysiology

Aging–AMD overlap

Some of the biochemical and histopathological features of AMD seem to occur as a normal part of aging (e.g., lipofus-

Pathophysiology

Table 68.1  Some molecular constituents of drusen

α1-Antichymotrypsin

α1-Antitrypsin

Alzheimer’s amyloid β peptide

Advanced glycation end products

Amyloid P component

Apolipoprotein B and E

Carbohydrate moieties recognized by wheatgerm agglutinin, Limax flavus agglutinin, concanavalin A, Arachea hypogea agglutinin, and

Ricinis communis agglutinin

Cholesterol esters

Clusterin

Complement factors (C1q, C3c, C4, C5, C5b-9 complex)

Cluster differentiation antigen

Complement receptor 1

Factor X

Heparan sulfate proteoglycan

Human leukocyte antigen-DR

Immunoglobulin light chains

Major histocompatibility antigen class II

Membrane cofactor protein

Peroxidized lipids (derived from long-chain polyunsaturated fatty acids, i.e., linolenic acid and docosahexanoic acid, which are normally found in photoreceptor outer segments)

Phospholipids and neutral lipids

Tissue inhibitor of matrix metalloproteinases-3

Transthyretin (major carrier of vitamin A in the blood)

Ubiquitin

Vitronectin

Reproduced from Zarbin MA. Current concepts in the pathogenesis of agerelated macular degeneration. Arch Ophthalmol 2004;122:598–614. Copyright © 2004, American Medical Association. All Rights Reserved.

cin accumulation in RPE cells and oxidative damage).57 Up to 65% of the proteins identified in drusen are present in drusen derived from AMD as well as healthy age-matched donors.58 Approximately 33% of the drusen-derived proteins from AMD donors, however, are not observed in healthy donor drusen. Thus, despite the fact there is some degree of continuity between aging changes in the photoreceptor– RPE–Bruch’s membrane–choriocapillaris complex and aging changes associated with AMD, aging and AMD seem to be distinct conditions (Box 68.4).

It is hypothesized that the photoreceptor–RPE–Bruch’s membrane–choriocapillaris complex is a site of chronic oxidative damage, which is most pronounced in the macula (Figure 68.2). This damage incites inflammation, mediated via complement activation, at the level of RPE–Bruch’s membrane–choriocapillaris. Patients with mutations in components of the complement system are less able to modulate the inflammatory response, resulting in excessive cellular damage and accumulation of extracellular debris. These

changes, which involve modification of the ECM, cause additional inflammation and cell damage. This chronic inflammatory response involves cellular components of the immune system as well as the classical and alternate pathways of the complement system. Accumulation of abnormal extracellular material (including membranous debris, oxidized molecules, ECM molecules, and components of the complement system) is thus a sign of chronic inflammatory damage, is manifest in part as drusen and pigmentary abnormalities, and fosters the development of the late sequelae of AMD in susceptible individuals, i.e., GA and/or CNVs. Many treatments for AMD under investigation are based on concepts related to this hypothesis of pathogenesis. Evidence regarding this hypothesis is considered below.

increases the risk of oxidative damage to RPE cells, reduces RPE phagocytic capacity, and can cause RPE death.59–63

The reaction product of ethanolamine and two retinaldehyde molecules, A2E, is the major photosensitizing chromophore in lipofuscin that causes reactive oxygen species (ROS) production. A2E interferes with lysosomal enzyme activity, reduces lysosomal protein and glycosaminoglycan degradation, and inhibits RPE phagolysosomal degradation of photoreceptor phospholipid.64–66 RPE cells with excessive A2E exhibit membrane blebbing and extrusion of cytoplasmic material into Bruch’s membrane. Excessive RPE lipofuscin (and A2) accumulation may play a critical role in the pathogenesis of GA.49

ing the risk of developing AMD.73 This notion is consistent with the different clinical manifestations of AMD in different ethnic groups. In contrast to whites, for example, soft drusen are only a moderate risk indicator for developing CNVs among Japanese patients, and the 5-year risk of developing CNVs in the second eye is relatively low among Japanese patients.74

The Age-Related Eye Disease Study (AREDS)75 demonstrated that, among patients with extensive intermediate drusen, at least one large druse, noncentral GA in one or both eyes, advanced AMD in one eye, or vision loss in one eye due to AMD, supplementation with ascorbic acid, vitamin E, beta-carotene, zinc oxide, and cupric oxide reduced the risk of developing advanced AMD from 28% to 20% and the rate of at least moderate vision loss from 29% to 23%. The AREDS data may mean that oxidative damage plays a role in the progression of AMD in its clinically evident intermediate and late stages and that disease progression can be altered with antioxidant supplementation. However, zinc also affects the complement system (e.g., inhibits C3 convertase activity),76 and C3a des Arg (a cleavage product of C3a that reflects complement activation) levels are higher in patients with AMD versus controls.77

AMD histochemistry

Using biomarkers of oxidative damage in postmortem eyes from AMD patients, Shen and coworkers found that many eyes with advanced GA showed evidence of widespread oxidative retinal damage, primarily in the inner and outer nuclear layers.78 The authors posited that a subpopulation of patients with GA have a major deficiency in their oxidative defense system.

Iron is an essential element for enzymes involved in the phototransduction cascade, in outer-segment disc membrane synthesis, and in the conversion of all-trans-retinyl ester to 11-cis-retinol in the RPE (see He et al79 for references). Free Fe2+ catalyzes the conversion of hydrogen peroxide to hydroxyl radical, which causes oxidative damage (e.g., lipid peroxidation, DNA strand breaks). Iron accumulation in the RPE and Bruch’s membrane is greater in AMD eyes than in controls, including cases with early AMD, GA, and/or CNVs.80 Some of this iron is chelatable.80 One patient with GA also had iron accumulation in the photoreceptors and internal limiting membrane as well as increased ferritin (which sequesters intracellular iron) and ferroportin (an iron export protein that transports unutilized/unstored intracellular iron).81 Increased intracellular iron causes oxidative photoreceptor damage.82 Although iron overload is a feature of AMD pathobiology, it is not clear that iron overload is a cause of AMD.79

Drusen biochemistry

Advanced glycation end products occur in soft drusen, in basal laminar and basal linear deposits, and in the cytoplasm of RPE cells associated with CNVs.30,58 Advanced glycation end products induce increased expression of cytokines known to occur in CNVs.30 Carboxymethyl lysine, a product of lipoprotein peroxidation or sequential oxidation and glycation, is present in drusen and CNVs.58,83 One study of drusen protein composition reported oxidative protein modifications in tissue inhibitor of matrix

Pathophysiology

metalloproteinases-3 and vitronectin.58 Also, carboxyethyl pyrrole (CEP) protein adducts, which are uniquely generated from the oxidation of docosahexaenoate-containing lipids, were present and were much more abundant in drusen from AMD versus age-matched control donors.58 (Docosahexaenoic acid is abundant in the outer retina, where it is readily susceptible to oxidation.84) Gu and coworkers85 found that the mean level of anti-CEP immunoreactivity in AMD human plasma was 1.5-fold higher than in age-matched controls. Sera from AMD patients demonstrated mean titers of anti-CEP autoantibody 2.3-fold higher than controls.85 In addition to being consistent with the notions that AMD is associated with oxidative damage and that CEP immunoreactivity and autoantibody titer may predict AMD susceptibility, these results indicate that the immune system may play a role in AMD pathogenesis.

AMD is associated with chronic inflammation

Anatomic studies provided initial evidence for the role of inflammation in the early and late stages of AMD (see Zarbin57 for references). In addition to membranous debris that is probably derived from RPE cells,42,57,86 drusen contain complement components C3 and C5, components of the membrane attack complex (C5b-9), complement factor H (CFH), and C-reactive protein (CRP) (Table 68.1).32,33,35,87,88 Bioactive fragments of C3 (C3a) and C5 (C5a) are present in drusen and induce vascular endothelial growth factor expression in RPE cells.89 These findings provide a mechanistic explanation for the fact that confluent soft drusen are a risk factor for CNVs in AMD eyes. In fact, CNVs cannot be induced by laser photocoagulation in C3-deficient mice.90 Thus, the presence of proinflammatory molecules in drusen creates a stimulus for chronic inflammation in the RPE– Bruch’s membrane–choriocapillaris complex that can result in some features of late AMD.

Drusen, GA, and CNVs are associated with mutations in components of the complement pathway, which is part of the innate   immune system92

Three enzyme cascades comprise the complement system (Figure 68.3): the classical pathway (activated by antigen– antibody complexes and surface-bound CRP), the alternative pathway (activated by surface-bound C3b, microbial pathogens, or cellular debris), and the lectin pathway (activated by mannose, a typical component of microbial cell walls, and oxidative stress).

Mutations in the CFH gene (CFH), as well as in the closely related genes CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5, are strongly associated with both increased and decreased risk for AMD.88,93–97 The CFH Y402H variant (in which tyrosine is replaced with histidine at amino acid 402) is located within a binding site for CRP and is associated with increased risk for drusen, GA, and CNVs.98–101 Individuals homozygous for the CFH Y402H variant have a 48% risk of developing GA or CNVs by age 95 years versus a risk of 22% in noncarriers.101 Nonetheless, one study reported that no single polymorphism (including Y402H) could account for the contribution of the CFH locus to disease susceptibility.102

Altered interactions of CRP and CFH may lead to changes in C3b activation. Homozygotes with the 402HH genotype have a 2.5-fold increase in CRP in the RPE and choroid compared with 402YY controls, independent of AMD disease status.103 CFH and FHL-1 with the Y402H mutation display reduced binding to CRP, heparin, and RPE cells, which can cause inefficient complement regulation at the cell surface, particularly when CRP is recruited to sites of injury.97

Mutations in factor B (BF) and complement component 2 (C2) alter the risk of AMD.104 Both risk and protective BF and C2 haplotypes exist. These effects may be independent of CFH mutations.105 C2 is involved in C3 cleavage via the classical pathway, and BF is involved in C3 cleavage via the alternative pathway (Figure 68.3).92

532

A single nucleotide polymorphism in the C3 gene (R80G) was strongly associated with AMD in both an English and a Scottish group of patients.106 The estimated populationattributable risk was 22%.

Oxidative damage can activate   the complement system

Cultured immortalized RPE cells that have accumulated A2E and are irradiated to induce A2E photo-oxidation form C3 split products in overlying serum.107 Thus, products of the photo-oxidation of bis-retinoid lipofuscin pigments in RPE cells may serve as a trigger for the complement system.107

Given the relative abundance of lipofuscin in the submacular RPE, this trigger could predispose the macula to chronic inflammation and AMD. These experiments link RPE lipofuscin, oxidative damage, drusen, and inflammation, all of which have been implicated in AMD pathogenesis.57,92,107

Oxidative stress reduces the ability of interferon-γ to increase CFH expression in RPE cells.108 Interferon-γ-induced increase in CFH is mediated by transcriptional activation by STAT1, and its suppression by oxidative stress is mediated by acetylation of FOXO3, which enhances FOXO3 binding to the CFH promoter and inhibits STAT1 interaction with the CFH promoter.

Hollyfield and coworkers described an animal model that links oxidative damage and complement activation to AMD.109 Mice were immunized with mouse serum albumin adducted with CEP, a unique oxidation fragment of docosahexaenoic acid that is present in drusen of AMD eyes.58 Immunized mice developed antibodies to the hapten, fixed C3 in Bruch’s membrane, accumulated drusen, and developed lesions resembling GA. Choroidal neovascularization was not observed. An intact immune system is required for these events, which may mean that both the adaptive and innate components of the immune system are required for the development of GA.

Among patients with defective complement regulation and MPGN II, drusen tend to occur in the macular region (as do GA and CNVs).14,17 One may speculate that oxidative damage is more pronounced in the macular region, and, as a result, chronic inflammatory damage is more concentrated in the macula.

AMD risk-enhancing mutations not directly involving the complement pathway are also linked to inflammation and/or oxidative damage (Table 68.2)

An AMD susceptibility locus on chromosome 10 (10q26) seems to play a major role in AMD pathogenesis.110–115 The protein encoded by the hypothetical gene LOC387715 (with an alanine-serine polymorphism as the likely disease-

Table 68.2  Some age-related macular degeneration risk-enhancing mutations not directly involving the complement pathway

Pathophysiology

causing variant) in 10q26 may be involved in AMD pathogenesis and is flanked by PLEKHA1 and high-temperature requirement factor A1 (HTRA1). Although two groups found that mutations in HTRA1 are associated with increased risk of AMD (Table 68.2), another group found that this gene was only indirectly associated with AMD.116 Mutations in CFH, BF, C2, and HTRA1 seem to confer risk in an independent, log-additive fashion.111,114,117

Mitochondrial haplogroup H is associated with a reduced prevalence of any AMD.118 Haplogroup J is associated with a higher prevalence of large, soft distinct drusen, and haplogroup U is associated with an increased prevalence of RPE abnormalities.

In contrast to mutations affecting the complement system, mutations in Fibulin5,119 Fibulin6,120,121, apolipoprotein E (APOE),122–125 and possibly ABCA4126–131 may cause AMD but only in a relatively small number of patients. Some of these (or related) mutations seem to enhance complement activation either through alterations in the ECM or through increased lipofuscin accumulation.132

Mutations causing nonexudative versus exudative complications of AMD

The TLR3 412Phe variant of the Toll-like receptor 3 gene (TLR3) seems to confer protection against GA among Americans of European descent with AMD, possibly by suppressing RPE apoptosis.133 This association was only evident if controls were limited to patients with fewer than five small drusen. Since TLR3 encodes a viral sensor that supports innate immunity, these results may mean that viral doublestranded DNA plays a role in the development of GA.134

Currently identified AMD-associated mutations in CFH,

TLR4, LCO387715/HTRA1, C2-BF, and C3 do not predispose to the development of GA versus CNVs to any significant degree.99,101,106,111,135,136 These observations are consistent with the notion that GA and CNVs have a common pathogenesis at least with regard to the involvement of the complement system. Perhaps these genes play a critical role in the relatively early stages of AMD pathogenesis. Even among whites, for example, only a minority of patients with soft drusen progress to advanced AMD, which may mean that the main risk loci identified so far (1q32 and 10q26) are associated with development of the early manifestations of AMD and that the late manifestations are under the control of different genes and/or are a consequence of processes that are initiated relatively early in the disease. One study demonstrated that loci on chromosomes 5 (5p13) and 6 (6q21-23) seem to influence the rate of pigmentary abnormalities and GA progression.137 These findings may indicate that separate genes modulate the risk of developing soft drusen versus pigmentary abnormalities and GA.138 Other investigators have not reported identical results, but different methodologies were used.139,140

Data on gene–environment interactions seem to be inconclusive.101,111,113,114,141–145 Nonetheless, it is interesting to note that cigarette smoking decreases plasma CHF levels,146 and smoke-modified C3 has diminished binding to CFH.147 Decreased levels or activity of CFH may result in uncontrolled complement-mediated tissue damage to the RPE– Bruch’s membrane–choriocapillaris complex.

Box 68.5  Treatment strategies for age-related

macular degeneration

•Reduce lipofuscin formation

•Manage abnormalities of the complement system

•Inhibit oxidative chemical reactions

•Neuroprotection

•Cell-based therapy

Treatment strategies

Antioxidants do not seem to be effective in the prevention of early AMD (i.e., drusen, retinal pigmentary changes: Box 68.5).148 AREDS75 did not show a statistically significant benefit of the AREDS formulation for either the development of new GA or for involvement of the fovea in eyes with pre-existing GA. In part, this result may be due to the paucity of GA patients in the study. The AREDS 2 study (http://www.clinicaltrials.gov/ct2/show/NCT00345176? term=AREDS&rank=1) will likely include more GA patients and provide more information about GA and its progression, and whether the proposed treatment benefits eyes with GA. Some additional strategies for dry AMD treatment are considered below.

Reduce lipofuscin formation

The fenretinide study aims at reducing lipofuscin accumulation, using an oral agent. Fenretinide binds serum retinol binding protein, displaces all-trans-retinol from RBP, and thus induces a loss of complex formation with transthyretin.149 The result is impaired RPE uptake of all-trans-retinol, slowing of the visual cycle, and reduced lipofuscin deposition in a mouse model of Stargardt disease.150 This molecule may reduce lipofuscin accumulation in GA and may slow the enlargement rate of GA (http://www.clinicaltrials.gov/ ct2/show/NCT00429936?term=fenretinide&rank=28). Another approach is to inhibit the conversion of all-trans- retinyl ester to 11-cis-retinol by blocking RPE65 using nontoxic small molecules.151

Manage abnormalities of the   complement system

Rheopheresis is under study for the treatment of dry AMD (http://www.clinicaltrials.gov/ct2/show/NCT00078221? cond=%22Dry+AMD%22&rank=4).152 Perhapsthisapproach could remove chelatable pro-oxidants (e.g., iron) from Bruch’s membrane or remove inhibitors of the regulators of the complement system. (The renal abnormalities in patients with MPGN and complement deregulation have been managed with plasma infusion and/or exchange,153 and plasma exchange has been effective in treating neuroimmunological disorders.154 However, chronic plasma infusion may not be a successful long-term therapy.155)

In a preclinical model, Nozaki and coworkers89 have shown that genetic ablation of receptors for C3a or C5a reduces CNV formation after laser injury and that antibody-

mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV formation. It is not clear whether this approach would also be helpful in the prevention of GA, but there is an animal model in which the approach may be tested.109

Gene therapy to silence genes by preventing mRNA expression is under clinical study for treatment of CNVs. This approach may be useful for prevention of nonexudative manifestations of AMD since deletion of genes closely related to CFH (i.e., CFHR1 and CFHR3) seems to be strongly protective against AMD.96 However, since the Leu-Leu genotype of TLR3 is associated with increased apoptosis in RPE compared to the Leu-Phe genotype and since the TLR3 412Leu variant is associated with a relative increased risk of GA, short-interfering RNA therapies in the eye may be toxic.134

Inhibit oxidative chemical reactions

The OMEGA study uses an eyedrop with a prodrug, OT 551, to treat GA.156 This prodrug penetrates the eye well and is converted in the eye to the active drug, which has an antioxidant effect and may reduce angiogenesis (http://www. clinicaltrials.gov/ct2/show/NCT00485394?term=Othera& rank=1).

Elucidation of the mechanism of suppression of interferon- γ-induced expression of CFH by oxidative stress provides targets for therapeutic intervention. Wu and coworkers suggested that local administration of acetylase inhibitors could help to blunt the oxidative stress-induced suppression of CFH expression in RPE cells.108 Sustained increased expression of SIRT1 by gene transfer would accomplish the same goal. Ultimately, one could envision combination therapy in patients at risk for, or who show early signs of, AMD aimed at direct reduction of oxidative stress with antioxidants, suppression of acetylation of FOXO3, and use of other inhibitors of complement activation.

Cell-based therapy

Transplanted cells can secrete numerous molecules that may exert a beneficial effect on the host retina (i.e., neuroprotection), choroid, or both, even if they do not cure the underlying disease.157 In the case of nonexudative AMD, cell transplants may prevent progression of GA (through replacement of dysfunctional or dead RPE) and may even bring about some visual improvement in selected patients (through rescue of photoreceptors that are dying but not dead).158,159 The Ciliary Neurotrophic Factor (CNTF) study capitalizes on the ability of CNTF to slow degeneration and protect photoreceptors.160 Encapsulated cells are implanted into the eye. These cells are genetically engineered to produce CNTF. The capsule allows CNTF to diffuse into the eye but does not allow the cells to migrate out of the capsule (http://www. clinicaltrials.gov/ct2/show/NCT00277134?term=CNTF& rank=2).

Conclusion

Dry AMD is a major cause of visual loss in industrialized societies. Pathological features include the accumulation of

an abnormal ECM and photoreceptor, RPE, and choriocapillaris atrophy. One hypothesis of AMD pathophysiology is that oxidative damage incites inflammation at the level of RPE–Bruch’s membrane–choriocapillaris, which is mediated via complement activation. Some patients with mutations in the complement system are less able to modulate the inflammatory response, resulting in excessive cellular damage and accumulation of extracellular debris. This chronic inflammatory response involves cellular components of the immune system as well as the classical and alternate pathways of the

Key references

complement system. Accumulation of abnormal extracellular material, manifest in part as drusen and pigmentary abnormalities, fosters the development of the late sequelae of AMD in susceptible individuals. Many treatments for dry AMD are under investigation (e.g., antioxidant therapy, reduction of lipofuscin formation, management of complement system abnormalities, cell-based therapy) and are based on concepts related to this hypothesis of pathogenesis.

5.Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988;2:552–577.

7.Sunness JS, Margalit E, Srikumaran D, et al. The long-term natural history of geographic atrophy from age-related macular degeneration: enlargement of atrophy and implications for interventional clinical trials. Ophthalmology 2007;114:271–277.

32.Anderson DH, Mullins RF, Hageman GS, et al. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411– 431.

44.Korte GE, Burns MS, Bellhorn RW. Epithelium–capillary interactions in the eye: the retinal pigment epithelium and the choriocapillaris. Int Rev Cytol 1989;114:221–248.

49.Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol 2007;143:463–472.

57.Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004;122:598–614.

78.Shen JK, Dong A, Hackett SF, et al. Oxidative damage in age-related macular degeneration. Histol Histopathol 2007;22:1301–1308.

88.Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005;102:7227– 7232.

89.Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA 2006;103:2328–2333.

92.Donoso LA, Kim D, Frost A, et al. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2006;51:137–152.

93.Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in

age-related macular degeneration. Science 2005;308:385–389.

94.Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421–424.

95.Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419– 421.

109.Hollyfield JG, Bonilha VL, Rayborn ME, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 2008;14:194–198.

150.Radu RA, Han Y, Bui TV, et al. Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. Invest Ophthalmol Vis Sci 2005;46:4393–4401.

Age-related macular degeneration (AMD) is a disease associated with a deterioration of central vision. As AMD is the leading cause of blindness in persons aged 75 and older in the USA and other countries worldwide, its importance cannot be underestimated.1,2

AMD is a spectrum of disease that is diagnosed based on clinical examination. It can be divided into nonneovascular, also known as dry or nonexudative disease, and neovascular, also known as wet or exudative disease. Advanced AMD is a term used to describe the most severe forms of AMD, namely geographic atrophy involving the center of macula, the fovea, or features of choroidal neovascularization (CNV). CNV is the growth of new blood vessels from the choroid toward the retina. They breach Bruch’s membrane and proliferate under the retinal pigment epithelium (RPE) and/or the retina.

Treatment of CNV has blossomed recently with the advent of anti-vascular endothelial growth factor (VEGF) therapy, yet a cure still remains elusive. A thorough understanding of the pathogenesis of neovascular AMD is important both for treating patients with AMD and for exploring new modes of therapy.

Clinical background

AMD involves the photoreceptors responsible for central vision, thus explaining the most common clinical presentation. Patients with neovascular AMD will typically note decreased or distorted vision. However other typical complaints include scotomas, micropsia or, occasionally, the patient may be asymptomatic.3 Symptoms are secondary to fluid and/or blood within or under the retina that results in disruption of the retinal architecture. Clinical examination combined with ancillary testing will confirm the presence of CNV, the hallmark of neovascular AMD (see diagnostic workup, below). As the disease progresses, complications such as RPE tears, breakthrough vitreous hemorrhage, or disciform scarring may result.

Historical development

Natural history data of neovascular AMD have been evaluated in a meta-analysis providing a sound basis for treatment. Using 53 trials a comprehensive study concluded that

vision loss of 0–3 lines occurred in 76% of untreated patients at 3 months. Severe visual loss (> 6 lines) was seen in 10% of untreated patients at 3 months, 28% at 1 year, and 43% at 3 years.4

Interestingly, while AMD was described as early as 1885, most of the current concepts of neovascular disease are attributed to J Donald M Gass and his work starting as early as the late 1960s. However, it was not until the early 1990s and the publication of the Macular Photocoagulation Study (MPS) that a documented effective treatment was achieved from a randomized controlled clinical trial (Figure 69.1). Yet, the MPS only demonstrated a favorable treatment benefit for patients with extraor juxtafoveal CNV due to the immediate visual loss associated with thermal laser performed to the foveal center.5,6 The next major breakthrough came in the late 1990s with the advent of photodynamic therapy (PDT). This opened the door to treating more patients using angiographic-based categories. Major clinical trials demonstrated a beneficial effect in treating subfoveal CNV in the reduction of moderate (3 or more lines) and severe (6 or more lines) visual loss in patients treated with PDT therapy versus placebo at 1 and 2 years. However, even the most efficacious subgroup analysis still demonstrated a 23% chance of moderate visual loss by 1 year despite treatment.7,8

Basic research into understanding the pathophysiology of neovascular AMD identified angiogenic growth factors as key regulators of CNV. This, in turn, led to the development of pharmacotherapy aimed at inhibiting angiogenic factors. In 2004 pegaptanib (Macugen) emerged as the first drug selectively to block the angiogenic factor VEGF-A, specifically targeting the 165 isoform. Treatment of CNV regardless of angiographic characteristics was proven in the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial. It was ascertained that 71% of treated patients lost less than 3 lines of vision versus 55% for the control groups.9 In 2005, off-label bevacizumab (Avastin) began to be used to treat patients with neovascular AMD, with anecdotal reports indicating excellent results. In particular, some patients noted an improvement in visual acuity.10,11

Stabilization and improvement of visual acuity were further categorized in the clinical trials surrounding ranibizumab (Lucentis) therapy. Ranibizumab is an intravitreal injectable medication approved by the Food and Drug Administration that, like bevacizumab, binds all isoforms of