Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

Histology

The choroid is composed of four layers (proceeding outermost to innermost):

●the suprachoroidal layer, or lamina fusca

●the choroidal stroma

●the choriocapillaris

●the lamina vitrea or Bruch’s membrane (BM)

The Suprachoroidal Layer or Lamina Fusca

This layer is composed of elastic fibers and branched, syncytial elements with flattened, oval-shaped nuclei, all immersed within in a network of thin collagen lamellae. The nerves and the long posterior ciliary arteries run through the lacunae situated between the lamellae. These structures, unlike the short posterior ciliary arteries and the vorticose veins, do not penetrate the lamina fusca. This layer also contains giant melanocytes whose cytoplasm is full of granules. Posteriorly, the lamellae insert perpendicularly into the sclera, producing rigid cohesion; anteriorly, adherence to the sclera is looser because the lamellae lie parallel to the sclera. This layer has a thickness of 10-15 microns, and it extends anteriorly to the scleral spur.

Choroidal Stroma

This layer is composed of collagen fibers (isolated or bundled); thin elastic fibers (0.3-0.4 microns); fibrocytes; large, star-shaped melanocytes filled with cytoplasmic pigment granules; macrophages; and blood vessels. The vessels are arranged in three layers: 1) the outermost, or Haller’s layer, which contains large-caliber vessels; 2) the middle layer, or Sattler’s layer, which contains medium-caliber vessels; and 3) the inner layer, or the choriocapillaris (also known as Ruysch’s membrane).

The Choriocapillaris

This layer is composed of a dense network of broad-lumened capillaries that are devoid of pericytes. The capillary endothelium is thin with relatively few nuclei. The cytoplasm of the cells contains pores closed by a thin membrane measuring 3 nanometers in the thickness in the part of the wall facing Bruch’s membrane, while the more external capillaries are characterized by endothelial cells whose cytoplasm is filled with vesicles. The thickness of the choriocapillary layer ranges from 10 to 30 microns. The capillaries of the choriocapillary layer are arranged to form lobules, each of which has its own terminal blood supply and is functionally

independent from the others. Each afferent arteriole reaches one unit and divides to form orderly, polygonal lobules at the posterior pole, and fan-shaped lobules in the peripheral regions.

The Lamina Vitrea or Bruch’s Membrane

This thin (2-4 microns), elastic mucoprotein membrane lies between the metabolically active tissue of the retinal pigment epithelium (RPE) and the choriocapillaris, which is the source of RPE’s blood supply. In young subjects, the three layers are tightly adhered. The portion facing the choroid is mesodermal in origin, while that part facing the RPE is derived from the ectoderm. Bruch’s membrane can be schematically divided into five layers:

●The external choroidal layer consisting of the endothelial cells of the choriocapillaries in the basement membrane, which is frequently interrupted by endothelial buds

●The outer collagenous zone (OCZ)

●A layer of fenestrated elastic fibers

●The inner collagenous zone (ICZ)

●The basement membrane of the RPE

The complex formed by the choriocapillaris, Bruch’s membrane, and the RPE represents an important connection system for exchanges with the retina. The thickness of Bruch’s membrane is greatest at the posterior pole.

Vascularization

The choroid receives its blood supply from the anterior ciliary arteries and from the long and short posterior ciliary arteries.

The Anterior Ciliary Arteries

These vessels arise from the muscular branches of the ophthalmic artery; and their numbers range from six to eight. They run alongside the tendons of the ocular muscles—generally two arteries per tendon. They give rise to conjunctival and episceral branches before perforating the sclera to reach the choroid at the level of the ciliary muscle, which they supply with a few branches. They continue on, anastomosing with the long posterior ciliary arteries to form the greater circle of the iris. This circle is composed of the anterior and posterior ciliary arteries and is located near the ciliary margin of the iris. It gives rise to branches that run posteriorly to supply the ciliary muscle and ciliary processes and others that run through the iris toward the pupillary margin, where they form anastomoses with one another and give rise to the small arterial circle of the iris.

The Posterior Ciliary Arteries

The posterior ciliary arteries (PCA) are the main source of blood supplying the head of the optic nerve. They also supply the pre-equatorial portion of the choroid (the RPE), 130 of the outer retina (or, when the cilioretinal artery is present, the full thickness of the retina in this zone), and the lateral and medial aspects of both the ciliary bodies and iris. The PCA circulation is therefore the most important component of the ocular vasculature and that of the optic nerve. Disturbances in the PCA circulation can lead to a variety of disorders involving the ocular vasculature and the head of the optic nerve, which can produce different degrees of visual impairment. The ophthalmic artery gives rise to one to five posterior ciliary arteries that are distinguished as short and long PCAs.

Short Posterior Ciliary Arteries (SPCA)

Subdivision of the PCAs gives rise to 10-20 short ciliary arteries—the paraoptic branches, which penetrate the sclera near the optic nerve, and the distal branches, which penetrate the sclera a short distance from the optic nerve and run radially toward the equator. The distal SPCAs that penetrate the sclera temporally to the optic nerve supply blood to the macular region.

Long Posterior Ciliary Arteries (LPCA)

There are generally two LPCAs—one medial and one lateral. They penetrate the bulb on the horizontal plane, not far from the distal branches of the SPCAs—one on the lateral side, and the other on the medial aspect—and run radially on the horizontal meridian forward to the iris.2,3,4,5,6,7

Vascular Patterns of the Posterior Ciliary Arteries and their Branches

The earliest structural descriptions of the choroid plexus were based on postmortem studies in which material injected into the plexus solidified, providing a three-dimensional reconstruction of the tributary complex of the vessel being examined.

Professor Carella has conducted numerous studies on the anatomy of the choroid using chromopolymer injections. The scheme below summarizes the method used to study the choroid in cadavers:

1.Cross-section craniotomy (360° frontal-parietal-occipital)

2.Exposure and removal of the brain

lobules.21,23,24 Each lobule is supplied by a terminal arteriole located at its center. Drainage is provided by a network of venules located at the periphery of the lobule. There are no anastomoses between adjacent lobules. The lobules are arranged in a mosaic-like pattern. The shape and size of the various lobules varies depending on their location within the choroid (polygonal at the posterior pole, fan-shaped in the peripheral regions). The choriocapillaris is much thicker at the posterior pole and becomes progressively thinner toward the periphery. In conclusion, all these studies clearly demonstrate that there are no anastomoses between adjacent segments, and the PCAs and their branches thus behave as terminal arteries in vivo. The discrepancies between data from in vivo and postmortem studies could be due to the fact that the vascular bed of the choroid is richly innervated by autonomic fibers in vivo. The influence of these nerves on blood flow and circulation is naturally absent in postmortem studies. The true physiological behavior of this vascular bed can be evaluated only by in vivo fluorescent angiography. In contrast, when the material is injected under pressure in postmortem studies, it fills the entire vascular bed without any neuronal control. These studies can therefore provide information only on the morphology of the choroid plexus and not on the physiology of choroidal blood flow. In vivo studies are thus able to explain the localized nature of inflammatory, ischemic, and metastatic lesions of the choroid.

Areas Supplied by the Anterior Ciliary Arteries

The anterior ciliary arteries run along the four rectus muscles in a posteroanterior direction and then, at the level of the bulbar tendon insertion, they provide blood to the bulbar conjunctiva before penetrating the sclera. During their intrascleral course, they give rise to small branches that interweave to form the intrascleral arterial plexus. After crossing the sclera, they anastomose with branches of the long PCAs to form the greater arterious circle of the iris. The vessels that branch off from this arterial circle extend to the iris, the ciliary body, and the ciliary muscle. In addition, some recurrent branches of the circle run to the anterior portion of the choroid.

Areas Supplied by the Short Posterior Ciliary Arteries

The paraoptic branches of the PCAs supply blood to the optic nerve, the peripapillary region of the choroid, and the circle of Zinn-Haller. Each of the distal short ciliary arteries supplies a sector of the choroid that generally extends from the posterior pole to the equator. The sectors vary considerably in shape, size, and location. Their margins are irregular, and they fit together like the pieces of a jigsaw puzzle. Further subdivisions of the short PCAs correspond to smaller segments, irregular in shape and size, so that the blood supply from the various choroidal arteries has a geographic distribution—the smaller the artery, the smaller the area it supplies.

Areas Supplied by the Long Posterior Ciliary Arteries

Each artery runs radially within the horizontal meridian—one on the medial side, one on the lateral side. On the temporal side, the long PCA supplies a sector that is temporal to the macula and whose apex is oriented posteriorly. Each artery also supplies small sectors of the ciliary body and the iris, on both the medial and lateral sides.

The Watershed Zone in the Vascular Bed of the PCAs

The watershed zone marks the divide between the distribution territories of two terminal arteries. This zone is the most vulnerable to ischemic damage when there is a drop in the perfusion pressure of the vascular bed of one or more of the terminal arteries. There are watershed zones between the areas supplied by the various ciliary arteries—those supplied by the short PCAs, and those supplied by the anterior and posterior ciliary arteries.17,21,23 In the presence of two long PCAs (medial and lateral), the watershed zone between these two vessels consists of a vertical band whose location is highly variable—it can be situated temporally to the peripapillary choroid; it may cross the temporal peripapillary choroid or a segment of the optic nerve; it may surround the entire optic disk; or it may cross the nasal peripapillary choroid. Various combinations of the previous pictures are also possible. In the presence of three or more long PCAs, the watershed zones between various PCAs play an important role in ischemic optic neuropathies because the optic nerve lies in a watershed zone, which renders it highly vulnerable to ischemic damage. It is important to recall that the temporal branches of the distal short PCAs enter the bulb and supply blood to the macular region, where their watershed zones are located.

The studies of Hayreh have shown that there are no anastomoses between the long and short PCAs. Therefore, the long and short PCAs are separated by a watershed zone.

Watershed Zones Between the Territories Supplied by the PCAs and the Anterior Ciliary Arteries

Experimental and clinical studies involving the occlusion of the posterior ciliary artery 11-20,25 or the anterior ciliary artery have clearly demonstrated that there are no in vivo anastomoses between the anterior and posterior ciliary arteries. Using ICG, Takanashi et al.26 also showed that there are no functional anastomoses between the terminal branches of the PCAs and those of the anterior ciliary arteries. Therefore, there is a watershed zone between the PCAs and the anterior ciliary artery, and this zone is located in the equatorial region of the choroid.23,29

From a clinical point of view, it is well-known that the watershed zones play a fundamental role in the development of ischemic lesions. Therefore, it is clear that portions of the optic nerve and choroid lying in a watershed zone are more subject to ischemic damage. These data are supported by various studies.29,27,28,29,30,31,32,33,34,35,36

Age-related Changes in the Choroid

The most important data come from cadaver studies and in vivo imaging studies (ICG angiography, Doppler, and laser Doppler flow studies).

Histological Studies of Age-related Changes in the Choroid

The choroids of young subjects are characterized by a higher number of cell nuclei, which is thought to reflect the presence of inflammatory infiltrates that are especially common in newborns (term and preterm alike). With advancing age, small, homogeneous, focal deposits of anomalous material appear in Bruch’s membrane. These deposits, known as Drusen, are surrounded by degenerated pigment epithelium and are sometimes calcified.

In the choroid of an elderly subject, granular deposits can also be seen on Bruch’s membrane. They have proved to be the result of lipid-degeneration phenomena. The intima of the vessel wall and Bruch’s membrane are targets of many age-related changes. These changes affect the endothelial surface of the vascular wall, and both the endothelial and epithelial surfaces of Bruch’s membrane. In both cases, the main effect of aging is an increase in thickness. The thickness of Bruch’s membrane increases by approximately 135 percent over ten decades.42,43 The thickening occurs mainly in the outer collagen zone.44 Age-related anatomical changes in Bruch’s membrane include the progressive accumulation of debris, lipid deposits, and alterations involving the extracellular matrix.

Accumulation of Debris

There are three types of deposits beneath the pigment epithelium: Drusen, basal linear deposits, and basal laminar deposits.45,46,47 Drusen can be seen on ophthalmoscopy. They are extracellular deposits situated between the basement membrane of the pigment epithelium and the inner collagen zone of Bruch’s membrane. Their composition is very similar to that of atherosclerotic deposits.

The second type of deposit has been defined by Green and Enger as the basal linear deposit. They form a thin membranous layer beneath the RPE.50 Sharks et al. maintain that they are made of a material released from the basement membrane of the RPE and are incapable of passing into the inner collagen

zone.50,48,49

The third type is the basal laminar deposit, which is found within the basement membrane of the RPE and is primarily composed of collagen.50 With age, this debris accumulates and eventually involves all collagen layers of the basement membrane.47 All of these deposits can represent waste products produced by an altered RPE51,52,53,54 or the sequelae of endothelial dysfunction at the level of the choriocapillaris.55

Lipid Deposits

Aging is accompanied by an exponential increase in lipid deposits within Bruch’s membrane. In the eyes of a patient under 60, these deposits contain small, round, solid particles that are scattered throughout the various layers of collagen. In elderly subjects, lipid droplets occupy over one third of the inner collagen zone, and they form a thin lipid layer external to the basement membrane of the RPE.56 These deposits lead to an exponential decrease with age in the hydraulic conductivity of Bruch’s membrane.57,58 The lipid deposits in Bruch’s membrane are composed of esterified and nonesterified cholesterol, and for this reason they have been compared to the atherosclerotic deposits found in blood vessels.59,59,60

Changes in the Extracellular Matrix

Collagen synthesis increases with age in both the choroid and in the arteries, and the excess collagen is also less soluble than normal.61,62 The fibers of the elastic membrane increase in number, and pin-point crystals are deposited between the fibers.45 Bruch’s membrane undergoes calcification and fragmentation, which reduces its elasticity.

Age-related Changes in ICG-angiographic Findings in Normal Subjects

ICG angiography allows dynamic studies of the choroidal circulation. Comparison of the angiograms of subjects from different age groups has revealed certain differences between young and elderly subjects. In young persons, arteriolar filling begins in the subfoveal region and extends radially toward the periphery of the ocular fundus. In the macular area, the choroidal system appears fine, tortuous, and multibranching. The vertical watershed zone that passes through the optic nerve is clearly visualized (see Fig. 11.2).

With age, small areas of hypofluorescence appear at the posterior pole, and arteriolar fluorescence becomes less intense. The choroidal arterioles become thinner and more tortuous, and there is a decrease in the number of collateral vessels. The vertical watershed zone becomes harder to detect (see Fig. 11.3).

These changes could be related to reduced blood flow through the macular choroid and to delayed arterial filling.46

These findings have been confirmed by laser Doppler flow studies, which also demonstrated age-related decreases in the choroidal blood volume.63 Ocular blood flow can be studied with various methods, including fluorescein angiography, scanning laser ophthalmoscopy, scanning laser Doppler flowmetry, Heidelberg retinal flowmetry, magnetic resonance imaging, transcranial Doppler, and color Doppler ultrasound. The latter method can provide precise information on certain hemodynamic parameters for each case studied. Color Doppler provides three types of information—simultaneously and in real time (see Fig. 11.4):