Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008
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Fig. 11.2 Early phase ICG in a young subject: watershed zone between the long posterior ciliary arteries can be easily seen passing just temporally of the optic disk
Fig. 11.3 ICG image in an old normal subject: watershed zone is hardly defined and the choroidal arterioles are thinner and more torturous. The veins appear dilated
●morphology of the tissues based on conventional B-mode sonography
●color-coded visualization of the vessels
●vessel hemodynamics based on pulsed Doppler analysis
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Color Doppler is noninvasive and does not require the use of contrast agents—it is also easy to perform, can be repeated as needed, and is well-tolerated by patients. It provides specific topographic information and data-characterizing blood flow. Color Doppler furnishes morphological information as well as quantitative data on ocular blood flow, including peak systolic velocity, telediastolic velocity, mean velocity, and the resistance index. Atrophy and depigmentation in the peripheral
a.
b.
Fig. 11.4 Color Doppler imaging of the choroidal vasculature. In (a), the ophthalmic artery presents a low resistance index in a young subject. At the opposite, in an elderly patient (b), the opthalmic artery shows a high resistance index. In (c), we report the color Doppler image of the normal choroid
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c.
Fig. 11.4 (continued)
choroid are common findings in senescence. Similar atrophic changes are frequently seen in the peripapillary region, as well. In both settings, the lesions are associated with (and perhaps caused by) fibrosis, hyalinization, and occlusion of the choroidal vessels—especially those of the choriocapillaris.
ICG angiography can detect aneurysms of the choroidal arteries, which appear as focal sac-like dilatations. Various mechanisms have been implicated in their pathogenesis. Aneurysms of the retinal artery are associated with hypertension, arteriosclerosis, and aging.64,65,66 Similar aneurysms can develop in cerebral vessels as a result of hypertension.67 In a study conducted by Schneider et al., ICG angiography was performed on patients with geographic atrophic lesions caused by AMD. The studies revealed68,48 aneurysms of the choroidal vessels that are typically observed in areas of geographic atrophy with reduced choroidal
perfusion.69,70,68,71,48
Age-related Diseases that Preferentially Target the Choroid
This category includes age-related macular degeneration (AMD)—vascular changes associated with systemic diseases such as hypertension, diabetes, and atherosclerosis that are typically found in elderly subjects.
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Age-related Macular Degeneration (AMD)
AMD is one of the main causes of blindness in industrialized countries. There are exudative and nonexudative forms. The latter is clinically defined by the presence of Drusen and pigmentation changes in the RPE, including geographic atrophy. The exudative form has the same characteristics, plus signs of choroidal neovascularization (CNV) (choriocapillaris vessels that perforate Bruch’s membrane and grow into the subretinal spaces and under the RPE), hemorrhages, hard exudates, and serous detachment of the neuroepithelium or of the RPE caused by CNV.
AMD is a multifactorial, degenerative disease that affects the RPE, Bruch’s membrane, the photoreceptors, and the choroid. The pathophysiological mechanisms underlying its development are clearly related to aging. The anatomical structures mainly affected by the disease are the complex consisting of the choriocapillaris, the RPE, and Bruch’s membrane.71 Bruch’s membrane is a semipermeable complex that allows intense metabolic exchange between the choroidal and retinal sides. It contributes to the creation of a barrier between the blood and the external retina since the negative electrical charge of the membrane proteoglycans acts as a filter for macromolecules coming from the choroidal circulation. Some of the most important histopathological and pathogenetic changes of AMD occur in this membrane.
The outer retina receives oxygen and metabolites that diffuse across Bruch’s membrane and the RPE from the choroidal vessels. For the inner retinal layers, the supply comes from the capillary layers of the retinal circulation. The photoreceptor cells located in the foveal zone are characterized by oxidative metabolism that is four times higher than that of central nervous system cells. The high flow through the choriocapillaris ensures an adequate supply of metabolic products and effective clearance of the catabolites produced. With time, lipid and protein substances and catabolites can accumulate in Bruch’s membrane. Increases in the thickness of the membrane diminish its permeability and elasticity, which reduces supplies of oxygen and metabolites. The substances that accumulate originate in the vessels of the choriocapillaris and in the cells of the RPE, which is the main site of phagocytosis and elimination of the outer segment and of photoreceptor catabolites. From a functional point of view, these morphologic changes reduce the passage of nutrients and the elimination of catabolic products and ultimately lead to the formation of Drusen.
The next step involves progressive decreases in the production of pigment epi- thelium-derived growth factor (PEDF). Compared with healthy subjects, AMD patients have significantly lower levels of this growth factor in cells of the RPE, Bruch’s membrane, and the choroidal stroma. As a result of these changes, the resistance and integrity of the membrane are threatened. Breats can form that are an important stimulus for subretinal neovascularization.
The changes observed during the course of AMD may therefore represent an extreme variant of the normal aging process. Disturbances of the ocular circulation in patients with AMD have been documented by various studies.72 Comparative studies of ICG angiograms of AMD patients and healthy, age-matched controls
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have revealed that arterial filling is slowed in the former group. Arteriolar fluorescence is characterized by asymmetric distribution with focal filling deficits at the foveal level. The arterial watershed zones are poorly defined. In general, they appear larger and have darker margins than those of the controls. The choroidal arterioles are thinner and more tortuous, and the number of collateral vessels is reduced. The veins appear dilated. The number of macular arterioles is reduced, and fluorescence is diminished in the arterial filling phases. These changes, however, are also noted in healthy elderly subjects. At least part of the diminished arterial perfusion observed in the choroids of AMD patients might be attributed to choroidal aging.
Data from histo-pathological studies suggest that choroidal circulation is reduced in these patients, which supports the view that AMD is associated with hemodynamic anomalies.73,74,46,75 Laser Doppler flowmetry is a noninvasive method for measuring choroidal blood flow, blood volume, and flow velocity with a diode laser. In a study conducted by Grunwald, these three parameters were investigated with laser Doppler flowmetry in normotensive and hypertensive AMD patients. Compared with the patients who had no history of hypertension, those in the hypertensive subgroup had significantly diminished choroidal blood flow. Several studies have demonstrated reductions in choroidal blood flow in patients with AMD and Drusen.75 The decreases observed in the parameters of choroidal blood flow are inversely proportional to the severity of the AMD, and they are also associated with an increased risk for choroidal neovascularization.76
The findings of Ross et al.36 show that choroidal neovascularization develops more frequently at the borders of the watershed zones, which is consistent with the view that ischemic areas can play a role in its development. These watershed zones, which are the last areas labeled during the early phases of ICG angiography, are the areas most likely to develop ischemia and hypoxia if choroidal flow decreases. The association between diminished choroidal blood flow, AMD, and arterial hypertension may reflect an abnormal autoregulatory response caused by those histopathological changes that are now known to be typical of AMD, such as the reduced density and calibers of the capillaries in the macular region of the choroid.46
Disorders Affecting the PCAs Circulation
These changes can occur during the course of several systemic diseases (hypertension, arteriosclerosis, and diabetes). They have been reproduced in primates by occlusion of the PCAs or experimental induction of malignant hypertension.12,14,
77,78,79
When there is an occlusion in a branch of the PCAs, which supply the peripheral regions of the choroid, fluorescein angiography reveals a triangular defect in the zone of the obstruction. The location and extension of the damage depends on the site of the occlusion itself. Triangular syndromes can also develop after laser photocoagulation or diathermy. The long posterior ciliary arteries originate temporally and laterally to the macula; diathermy or photocoagulation in this region produce a
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typical peripheral triangular syndrome. Triangular syndromes caused by obstruction of the short ciliary arteries are smaller and more irregular. When they are confluent, they can lead to the atrophy of an entire quadrant.
Acute Ischemic Lesions of the Choroid
The appearance of these lesions depends on their stage of evolution, the size of the artery or arteriole involved, and the severity of the ischemia.12,14,82-80
Evolutionary Stage of the Lesions
Recently developed lesions are white—the RPE and retina are no longer perfused.12,14,82 About a week after onset, their appearance begins to change. After one to two weeks, they are grayish-white and granular, and they gradually take on the appearance of a nonspecific pigmented chorioretinal lesion. Initially, histopathology reveals coagulative necrosis of the RPE and outer retina associated with disruption of the blood-retinal barrier secondary to RPE damage. Even in eyes with severe ischemic damage, the bloodretinal barrier resumes its activity after about three months.82 In the acute stage, fluoroangiography reveals initial hypofluorescence due to a filling defect and late hyperfluorescence related to stain uptake. Advanced chorioretinal lesions are associated with hyperfluorescence (window effect) with no staining.
Size of the Artery or Arteriole Involved in the Occlusion
Occlusion of the long PCAs produce large choroidal infarcts.12,14,82 The lesions are often triangular and located in the periphery of the ocular fundus with the base facing the equator and the apex pointing toward the posterior pole.12,14-16,81 Focal occlusions of the terminal arterioles of the choroid result in small, roundish, localized lesions that represent infarcts of the lobules of the choriocapillaris. Elschnig’s spots, which are seen in advanced hypertensive choroidopathy, are a typical example of these focal ischemic lesions.84
Severity of the Ischemia
Severe forms of ischemia cause true infarcts of the choroid, RPE, and outer retina. Moderate or mild ischemia causes ischemic dysfunction of the RPE, with or without overt RPE infarction. The barrier function of the RPE is lost, and liquid passing from the choroid to the retina causes serous detachment of the retina, similar to that seen in hypertensive choroidopathy and in eclampsia84 (see Fig. 11.5).
Ischemic Lesions of the Macular Choroid
The temporal branches of the distal short PCAs supply blood to the macular choroid. These arteries subdivide to form numerous terminal branches. The result
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Fig. 11.5 Chromopolymer casting studies of the choroidal vasculature in a diabetic patient. Ischemic damage zones are identified as areas of absence of the choriocapillaries
is a high number of watershed zones, which render the macular choroid one of the zones at highest risk for ischemic injury.82 It is important to recall that, when there is a drop in the perfusion pressure in the vascular bed of one or more of these terminal arteries, the watershed zone (which is poorly perfused) is the area most vulnerable to ischemic damage.
These findings are confirmed by fluorescein angiographic studies in monkeys with malignant hypertension, which reveal delayed filling in the macular region of the choroid where lesions associated with hypertensive choroidopathy are most commonly found.84 When the perfusion pressure is experimentally reduced in the same studies, fluorescein angiography reveals a marked delay in filling that involves the watershed zones of the macular region of the choroid.27,87 The watershed zones represent the most common site of ischemic damage. Therefore, it is reasonable to expect that lesions will frequently be found in the macular region.
For similar reasons, patients with atherosclerosis frequently present with reticular pigmented degeneration in the equatorial region, which represents the watershed zone between territories supplied by the anterior and posterior ciliary circulations.27,87,83
Hypertensive Choroidopathy
The characteristics of the vascular bed of the choroid explain the pathophysiology of the damage that occurs during the course of malignant hypertension. The choroidal bed is not equipped with a blood-eye barrier because the walls of the choriocapillaries contain large fenestrations. The vascular bed of the choroid has no autoregulatory
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system. It tends to respond passively, like a sponge, to changes in IOP (like those that occur during open-bulb surgery) or arterial blood pressure.
The following scheme has been proposed to explain the pathogenesis of the choroid damage caused by hypertension—in the absence of a barrier in the vessels of the choriocapillaris, hypertension causes seepage of plasma containing angiotensin II and other vasoconstrictors into the choroidal space. These substances cause vasoconstriction, which leads to ischemia—first in the choroid and then in the RPE. Damage to the RPE disrupts the barrier between the blood and the outer retina and leads to serous detachment of the neuroretina. This hypothesis is confirmed by the fact that the following changes are observed in hypertensive choroidopathy.
Anomalies Involving the Choroidal Vascular Bed
In the initial stages, fluorescein angiography reveals a delayed choroidal filling that is particularly marked in the macular region.84 Histo-pathologic studies have revealed true occlusion of the choroidal arteries.83
Lesions of the RPE
Focal ischemic lesions are found. For simplicity’s sake, these lesions can be classified as acute or degenerative. Those of the acute phase are pale white, pin-point lesions located predominantly in the macular region of the RPE, and less frequently in other areas of the RPE. They are associated with focal serous detachments of the retina and produce late staining on fluorescein angiography.84 Within two to three weeks, these lesions are inevitably transformed into degenerative focal lesions. As time passes, they tend to become confluent, producing progressively larger areas of RPE atrophy or diffuse pigmented alterations. The vessels of the choroid become sclerotic.84 Fluorescein angiography reveals hyperfluorescence (window defects), but there is no staining because the blood-retina barrier is intact.
Serous Detachment of the Neuroretina
Detachments may be focal, flat, bullous, or total. They can be located in the macular and/or peripapillary region and/or in the periphery. The subretinal fluid is initially clear, but it becomes increasingly turbid and occasionally proteinaceous. Subretinal fibrosis may develop. In the macular region, the detachment sometimes has a pseudocystic appearance.84
Conclusion
The choroid is a complex system that receives its blood supply from the anterior and posterior ciliary arteries and serves as transport for nutrients to high metabolic tissues and dissipation of the heat produced by the retina during photochemical and
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metabolic reactions. We reported choroid alterations that are part of the physiologic aging process, and the physiopatology of age-related pathologies such as hypertension, diabetes, atherosclerosis, and age-related macular degeneration. In all cases, the choroid seems to be a major target of the aging process, and may be due to its high metabolic activity.
Acknowledgment We are happy to acknowledge Prof Fernando Galassi (Clinica Oculistica, Università di Firenze) for his contribution to the color Doppler imaging section of this chapter.
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