Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008
.pdf11 The Aging of the Choroid |
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48.Sarks SH, Arnold JJ, Killingsworth MC, Sarks JP (1999) Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study. Br J Ophthalmol 83:358-68
49.Loeffler KU, Lee WR (1986) Basal linear deposit in the human macula. Graefes Arch Clin Exp Ophthalmol 224:493-501
50.Curcio CA, Millican CL (1999) Basal linear deposit and large drusen are specific for early agerelated maculopathy. Arch Ophthalmol 117:329-39
51.Burns RP, Feeney-Burns L (1980) Clinico-morphologic correlations of drusen of Bruch’s membrane. Trans Am Ophthalmol Soc 78:206-25
52.Ishibashi T, Sorgente N, Patterson R, Ryan SJ (1986) Aging changes in Bruch’s membrane of monkeys: an electron microscopic study. Ophthalmologica 192:179-90
53.Young RW (1987) Pathophysiology of age-related macular degeneration. Surv Ophthalmol 31:291-306
54.El Baba F, Green WR, Fleischmann J, Finkelstein D, de la Cruz ZC (1986) Clinicopathologic correlation of lipidization and detachment of the retinal pigment epithelium. Am J Ophthalmol 101:576-83
55.Friedman E, Smith TR, Kuwabara T (1963) Senile choroidal vascular patterns and drusen. Arch Ophthalmol 69:220-30
56.Ruberti JW, Curcio CA, Millican CL, Menco BP, Huang JD, Johnson M (2003) Quick-freeze/ deep-etch visualization of age related lipid accumulation in Bruch’s membrane. Invest Ophthalmol Vis Sci 44:1753-9
57.Starita C, Hussain AA, Pagliarini S, Marshall J (1996) Hydrodynamics of ageing Bruch’s membrane: implications for macular disease. Exp Eye Res 62:565-72
58.Fisher RF (1987) The influence of age on some ocular basement membranes. Eye 1:184-9
59.Lakatta EG, Levy D (2003) Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a ‘set up’ for vascular disease. Circulation 107:139-46
60.Haimovici R, Gantz DL, Rumelt S, Freddo TF, Small DM (2001) The lipid composition of drusen, Bruch’s membrane, and sclera by hot stage polarizing light microscopy. Invest Ophthalmol Vis Sci 42:1592-9
61.Barnes MJ, Farndale RW (1999) Collagens and atherosclerosis. Exp Gerontol 34:513-25
62.Karwatowski WS, Jeffries TE, Duance VC, Albon J, Bailey AJ, Easty DL (1995) Preparation of Bruch’s membrane and analysis of the age-related changes in the structural collagens. Br J Ophthalmol 79:944-52
63.Grunwald JE, Hariprasad SM, DuPont J (1998) Effect of aging on foveolar choroidal circulation. Arch Ophthalmol 116:150-154
64.Raab MF, Gagliano DA, Teske MP (1988) Retinal arterial macroaneurysms. Surv Ophthalmol 33:73-96
65.Ring HG, Fujino T (1967) Observations on the anatomy and pathology of the choroidal vasculature. Arch Ophthalmol 78:431-444
66.Robertson DM (1973) Macroaneurysms of the retinal arteries. Trans Am Acad Ophthalmol Otolaryngol 77:55-67
67.Russell RWR (1963) Observations on intracerebral microaneurysms. J Pathol 93:393-398
68.Sarks SH (1973) Senile choroidal sclerosis.Br J Ophthalmol 57:98-109
69.Friedman E, Smith TR, Kuwabara T, Beyer C (1964) Choroidal vascular patterns in hypertension. Arch Ophthalmol 71:842-850
70.McLeod DS, Lutty GA (1994) Highresolution histologic analysis of the human choroidal vasculature. Invest Ophthalmol Vis Sci 35:3799-3811
71.Pauleikhoff D (1990) Aging of Bruch’ s membrane: histological, morphologic and clinical correlation. Proc int soc eye res VI 337:101
72.Ciulla TA, Harris A, Kagemann et al. (2002) Choroidal perfusion perturbations in nonneovascular age related macular degeneration. Br J Ophthalmol 86:209-13
73.Sarks SH (1978) Changes in the region of the choriocapillaris in aging and degeneration. XXIII Concilium Ophthalmologicum, Kyoto, 1978. Amsterdam: Excerpta Medica 228-38
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74.Sarks JP, Sarks SH, Killingsworth MC (1988) Evolution of geographic atrophy of the retinal pigment epithelium. Eye 2:552-77
75.Korenzweig AB (1977) Changes in the choriocapillaries associated with senile macular degeneration. Ann Ophthalmol 9:753-64
76.Grunwald JE, Metelitsina TI, Dupont JC, et al. (2005) Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci 46:1033-8
77.Loeffler KU, Hayreh SS, Tso MOM (1994) The effects of simultaneous occlusion of the posterior ciliary artery and vortex veins. Arch Ophthalmol. 112:674-682
78.Kishi S, Tso MOM, Hayreh SS (1985) Fundus lesions in malignant hypertension I. A pathologic study of experimental hypertensive choroidopathy. Arch Ophthalmol. 103:1189-1197
79.Hayreh SS, Servais GE, Virdi PS (1986) Fundus lesions in malignant hypertension VI. Hypertensive choroidopathy. Ophthalmology 93:1383-1400
80.Hayreh SS (1980) Acute choroidal ischaemia. Trans Ophthalmol Soc UK. 100:400-407
81.Hayreh SS (1975) Anterior Ischemic Optic Neuropathy. Springer-Verlag, Heidelberg, Germany
82.Hayreh SS (1983) Macular lesions secondary to choroidal vascular disorders. Int Ophthalmol 6:161-170
83.Foos RY, Trese MT (1982) Chorioretinal juncture. Arch Ophthalmol 100:1492-1503
Chapter 12
Age-Related Macular Degeneration I: Types
and Future Directions
Susanne Binder, MD and Christiane I. Falkner-Radler, MD
Abstract Age-related macular degeneration is the leading cause of severe visual impairment in industrialized countries in patients over 50 years of age. In its natural course, AMD leads to progressive loss of central vision, leaving the patients with only orienting vision and the peripheral visual field at its final stage.
This chapter deals with the description of future trends in therapy. In fact, combination therapies will become more tailored to the stage and severity of the disease. To provide long-term effects, long-acting delivery systems for drug combinations need to be developed. In addition, combinations with surgical therapies, laser, or photodynamic treatment (PDT) might be reasonable to decrease dosage and treatment intervals. For non-responders or advanced cases of AMD, cell-derived therapies will be necessary—like retinal transplantation or gene therapies— for better restoration of a more normal foveal condition to restore the vision in an aging patient.
Keywords AMD, PTD, Therapy, human eye future directions, retinal transplantation.
Introduction
Age-related macular degeneration (AMD) is currently the leading cause of severe visual impairment in industrialized countries in patients over 50 years of age.1 Although prevalence varies, the two largest studies show that AMD occurs between 2.8 and 20.9 percent in patients over 55, and 15.5 - 41.7 percent over the age of 75.2,3 In its natural course, AMD leads to progressive loss of central vision, leaving the patients with only orienting vision and the peripheral visual field in its final stage. Within two years, a loss of six lines (30 letters) will occur in more than 60 percent of patients.4 AMD represents a major medical and social problem, with 2025 million people affected worldwide. This number is expected to triple in the next 30 years because of the increase in aging populations.5 In addition, higher expectations of better quality of life (including the ability to read and drive) are being demanded by elderly patients, which makes AMD an even more significant
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problem. Furthermore, numbers of cases in developing countries do increase with better screening of patients, although AMD might manifest itself in various forms according to environmental and nutritional circumstances on different continents.6
Etiology and Pathogenesis
The etiology of AMD is not fully understood. Genetic factors, oxidative stress, ischemia, and aging of the retinal pigment epithelium are proposed etiologic factors.7 Most likely, genetic and environmental factors determine whether the onset of the disease is earlier or later in life.8 AMD is believed to be caused by progressive deterioration of the retinal pigment epithelium (RPE), Bruchs’membrane (BM), and the choriocapillaris choroidal complex that consequently leads to subsequent damage of the photoreceptor (PR) cells.9 The RPE plays a central role in maintaining retinal function by assuming a strategic position as the metabolic gatekeeper between PRs and the choriocapillaris that suffer cumulative damage over lifetime and—in susceptible individuals—induce AMD.10
RPE
RPE is a cuboidal hexagonal monolayer comprising the outermost layer of the retina. Its apical portion faces the outer segments of the PRs and its basolateral surface interacts with the choriocapillaris.11 The RPE is a post-mitotic cell that does not proliferate under normal conditions, and its tight junctions represent the outer blood retinal barrier. Besides its function as a metabolic coordinator for PR cells, including the digestion of PR outer segments, it participates in vitamin A metabolism (visual circle), melanin synthesis, extracellular matrix synthesis, and molecule transport, and secretes and responds to numerous growth factors and other cytokines. Among them, RPE expresses several fibroblast growth factors (bFGF, acidic FGF, and FGF5), as well as ciliary neurotrophic factor (CNTF)12. In addition, vascular endothelial growth factor (VEGF-A)—a very potent angiogenic growth factor—is secreted to act as a paracrine trophic factor for the epithelium of the choriocapillaris, and to maintain its fenestrations.13,14 In hypoxia, hyperglycemia, advanced glycation end products (AGE), and other pathologic stimuli, VEGF expression is up-regulated, thus playing a central role in ocular neovascularisation.15,16 Insulin-like growth factor (IGF-1) and its binding protein (IGF-BP) are synthesized also by the RPE and were found to be up-regulated in various ischemic retinal conditions.17 Most important, however, is the secretion of pigment epithelial derived factor (PEDF), which acts as the key coordinator of retinal neuronal and vascular function, and is a potent inhibitor of angiogenesis.18,19 An equilibrium shift in VEGF and PEDF secretion ratios might be a possible cause of development of choriodal neovascularization (CNV) in AMD.20 With age, the number and density of RPE decreases, and accumulation of lipofuscin—a yellowishbrownish autofluorescent lipofuscin granula with lipid membranes that contain toxic biomolecules that interact with normal function—occurs.
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Bruch’s Membrane
Bruch’s membrane (BM) is a 1-4 mm thick structure wwere the basal RPE rests. Its five different layers are: 1) the basal membrane of the RPE, 2) the inner collagenous layer, 3) the elastine layer, 4) the outer collagenous layer, and 5) the basal membrane of the choriocapillaris endothelial cells. BM increases in thickness with age for some time and becomes distorted.
Basal Lamina Deposits
Basal lamina deposits (BlamD, BlinD) consist of amorphous material located between the basement membrane of the RPE and its cytoplasm. They are considered the earliest changes of AMD found in histopathologic examinations,21 and clinically they are almost invisible.
Drusen
Drusen represent the first clinically visible changes in the ocular fundus. They appear as yellowish-white dots that can occur in the macula, the paramacular area, and in the retinal periphery as signs of senescence or early AMD. In relation to size and margin, they are divided into hard Drusen—consisting of hyaline material— and soft Drusen—consisting of a granular, amorphous vesicular structure—with indistinct margins and a size larger than 63 m (see Fig. 12.1).
In some Drusen, neutral lipids prevail while others are predominately composed of phospholipids.22 If Drusen are numerous (more than five), they become an independent
Fig. 12.1 Diffuse soft and hard Drusen in the macular (a) and and perimacular area (b)
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risk factor for AMD.23 If soft Drusen coalesce, they form a serous pigment epithelial detachment (PED) or RPE atrophy. Patients with Drusen and good vision in both eyes will experience new atrophic or exudative lesions annually in 8 percent over three years.24 The reason for the foveal location of AMD might be explained by topographical differences in the structure and composition of BM in the macula,25 higher oxidative stress of the central area related to light overload, and stress and other factors.
Recent access to the human genomic sequence has made more powerful analytical methods possible, including haplotype mapping and single nucleotide polymorphism (SNP) analysis.26,27,28,29 It was reported that a variation of the factor H gene (HF1/CFH) dramatically increases the likelihood of developing AMD. In an earlier report of the same group, the formation of Drusen with deposits of inflammatory proteins was implicated with the complement cascade—a pathway associated with the innate immune system,30,31 indicating that a low grade chronic inflammation is an important factor in the pathogenesis of AMD. Because AMD is a complex disease that occurs in different forms and stages, it would seem likely that multiple genes are involved with varying penetration for the different forms of AMD.
Risk Factors for AMD
Age
Age is associated with an increased incidence, prevalence, and progression of AMD.32
Family History
Family history has become the second largest risk factor during the last few years. First-degree relatives of involved patients have, for example, a 3-fold increased risk of developing exudative AMD.33 An overall inheritability of early AMD of 45 percent was demonstrated in a twin study, showing an 81 percent inheritability with the presence of 20 or more hard Drusen, 57 percent for large soft Drusen, and 46 percent for pigment changes.34
Gender
According to a report from the Blue Mountain Eye Study, the female sex shows twice the incidence of CNV as men,35 although there is no gender significance for AMD in general.
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Race
Caucasians seem to have a higher prevalence of AMD.36 However, recent studies suggest that colored people develop early signs of AMD quite frequently, but seem to have a low incidence of advanced AMD at all ages.37,38
Smoking
Cigarette smoking became the third highest risk factor, and both current and prior smokers are at increased risk for AMD.39 This might be related to effects on the antioxidant metabolism as well as the blood flow.40 Interestingly, female smokers seem to be at higher risk for progression to advanced AMD, while male smokers may be of higher risk for non-exudative AMD.35
Hypertension
Hypertension turns out to be even more important than arteriosclerosis, although similar compositions of Drusen and arteriosclerotic deposits are present.41 It was found that Angiotensin,2 a main risk factor for systemic hypertension, induces VEGF and angiopoetin expression, which both play an important factor in angiogenesis.42
Nutrition
Diet and body mass index (BMI) have been carefully studied because they could be influenced through nutrition and lifestyle. For example, the intake of high linolenic acid is associated with a 49 percent increased risk of AMD, and high docosahexaenoic acid is associated with a 30 percent lower risk of AMD.43 The analysis of the BMI found that obese individuals are at higher risk for both dry and neovascular AMD, while very lean individuals are at higher risk for dry AMD.44
Comorbidity
Comorbidity of AMD with other age-related diseases was examined in few studies. In the Beaver Dam Population,45 a significant correlation between hearing loss and late AMD was documented. In the Rotterdam Study,46 a striking correlation was
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found in patients with late AMD who developed Alzheimer’s disease. Cardiovascular diseases, which have smoking and hypertension as common risk factors with AMD, are also discussed today.
AMD Types
AMD is divided into two main subtypes—the primary neovascular (exudative, wet) NV-AMD, and the non-neovascular (non-exudative, atrophic, dry) NNV-AMD.
Neovascular AMD
NV-AMD occurs only in about 20 percent of all AMD forms, but is responsible for rapid and severe visual loss in the majority of patients. The hallmark of NV-AMD is choriodal neovascularization (CNV), which can either grow directly from the choriocapillaries into the sub-RPE or subretinal space, or be preceded by a serious PED after soft Drusen coalesce and become vascular. If the CNV connects with retinal neovascularization, it can form a retinal choriodal anastomosis termed as retinal angiomatous proliferation (RAPs).47,48 The main stimulus for neovascularization is imbalance of the angiogenic vascular endothelial growth factor (VEGF) versus the angioinhibitours pigment epithelial derived factor (PEDF) secretion from trans-differentiated RPE cells. The route of new vessels seem to go through areas of lesser resistance—for example, defects in Bruch’s membrane and RPE irregularities.49 Clinically, these CNVs are seen as elevated grey-green or pinkishyellow lesions, sometimes with pigment, exudates, and blood (see Fig. 12.2).
In the later stage, chronic leakage and bleeding leads to the formation of a central fibrovascular scar with further loss of RPE and photoreceptors. In this terminal form of AMD, only irreversible, orientating vision remains.
Besides visual acuity testing and biomicroscopic examination, the two most important additional examination methods are the angiography and optical coherence tomography of the retina.
Flouresceine Angiography
With fluoresceine angiography, 5mg of natrium-fluorescein are injected into the cubital vein of the patient, and series photographs are taken after the pupil is dilated. CNVs can be detected and categorized either as classic or occult, or a combination of the two, depending on the leakage patterns they present at various time points on the angiogram. This differentiation was imperative for laser treatments where well defined margins for treatment decision were necessary. Today the differentiation is still important to evaluate disease activity and to decide on drug selection in the area of intravitreal applications of antiinflammatory and anti-VEGF medication (see Fig. 12.3).
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Fig. 12.2 Neovascular AMD shows yellow-greyish cental area (arrow ) and small hemorrharges on the edges
Fig. 12.3 Fluoresceine angiography of classic and occult CNV. Early (a) and late face (b) angiogram of a classic CNV, showing immediate hyperfluorescence in the early phase. Early (c) and late face (d) angiogram of occult CNV, showing hyperfluorescence of dye only in the late phase
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Because fluorescein is a hydrophilic molecule, only Drusen rich in phospholipids will stain with this dye, while Drusen composed mainly of neural lipids will not stain.50
Optical Coherence Tomography
Optical coherence tomography (OCT) has brought additional insights in the diagnosis and follow-up of AMD. It provides precise information about the retinal layers in the macular region—intra-, subretinal, and subpigment and the epithelial fluid dynamics—showing PR-atrophy as well as RPEbehavior and scarring. In close proximity to the retina, the posterior hyaloid behavior, and the underlying choriocapillary-choroid condition can be examined, too. Compared to fluoresceine angiography, it is a noninvasive examination technique that can be repeated without additional stress on the patient (see Fig. 12.4).
Fig. 12.4 Optical Coherence Tomography (OCT). (a) OCT shows Drusen as irregularities in the area of the retinal pigment epithithelium—Bruch’s membrane (arrows)—and the foeveal contour is normal (red arrow). (b) Choroidal neovascularisation (arrows) with massive subretinal edema (red arrow) and loss of foveal contour