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Choroidal Neovascularization Figure 1: Structure of the human eye. The human eye is one of the most perfect and remarkable vision instruments that Nature has created in it's age long evolutionary quest for perfection. It allows us to observe both the wonders of this world and of the heavens above us. It allows us to distinguish colors, shapes and distances. Its basic structure is represented in Fig. 1. The incoming light travels through the Pupil, and the Lens behind it focus it in the Retina that coats the inner part of the globe that the Sclera constitutes and that gives the eye its familiar form. The retina is nourished by a layer of capillaries that constitute the Choroid and are located between the retina and the sclera. The light that shines upon the retina is detected by the cones and rods that are responsible by distinguishing color and allowing for low light vision respectively. The are of higher concentration of cones is called the fovea and is, also, the area of the human body with the highest consumption of oxygen. After the image has been processed by the cones and rods it's transformed into electric impulses that are propagated along the optic nerve toward the Brain where they will be used to reconstitute the image that the eye is observing. Given the perfection, ubiquity and usefulness of this natural machine it seems as a natural consequence that anything that poses a threat to it be the subject of great study, research and concern. Age Related Macular Degeneration (AMD) is one of those threats. It affects about 1.65 million Americans over $50$ years old and is one of the leading causes of loss of vision in elderly patients. The most common form of AMD is Choroidal Neovascularization (CNV) that is characterized by the abnormal growth of blood vessels originating from the choriocapillaries that provide nourishment to the lower layers of the retina. The wet form1 is responsible for $90\%$ if the loss of vision due to CNV, even though it only corresponds to about $10\%$ of the total number of cases diagnosed. The retina can be though of as having four principal layers, as represented in Fig. 2a). The choriocapillaries that form the choroid are responsible for carrying the nutrients required by the cellular layers above them. The Bruch membrane that lays between the choriocapillaries and the Retinal Pigment Epithelium acts as a filter between the RPE and the choriocapillaries, selecting which substances are allowed to move in either direction and keeping the choriocapillaries away from the RPE. On the other hand, the RPE is a layer of cells with multiple functions. The most noticeable of which are the secretion of angiogenic and anti-angiogenic factors such as Vascular Endothelial Growth Factor (VEGF) and Pigment Epithelium-Derived Factor (PEDF), respectively. These molecules are responsible, among many other things for the growth and recession of blood vessels. Type I Figure 2: Type I CNV. The new blood vessels are formed in the sub RPE region. Choroidal Neovascularization, depending on its location on the retina is classified in two different types and a third one that corresponds to the simultaneous presence of both other types. In Type I neovascularization, there occurs some sort of damage to the Bruch membrane that allows the VEGF growth factor to come in contact with the choriocapillaries located bellow it. This, in turn, will initiate the process of angiogenesis on these vessels that then grow through the membrane and form a new vascular surface between the Bruch membrane and the RPE layer, as we represent in Fig. 2. This type of growth is hard to detect trough the usual Fluorescein Angiogram that is commonly performed as a diagnosis tool, and is, therefore, sometimes refereed to as occult CNV. In Fig. 2b) we represent a microscope slide of a retina with Type I CNV from the murine model. In the figure it is easy to distinguish the small new blood vessels formed between the RPE layer (just bellow the white stripe half way through the image) and the Bruch's membrane, as well as the normal choriocapillaries. Type I CNV can later evolve into Type III2 if the new vessels manage to perforate the RPE similarly to what happens in Type II. Type II Figure 3: Type I CNV. The new blood vessels are formed in the sub retinal region and above the RPE. Sometimes the capillaries break through the RPE as well as the Bruch membrane and try to create a new vascular layer above the RPE. The human body tries to contain the development of the new and potentially harmful vessels by making the RPE cells divide and surround the new blood vessels. However, this tactic is not always effective and, when it fails, we find ourselves in the presence of Type II CNV. Since the medium above the RPE was not conceived for the presence of fragile blood vessels, they, most of the times, break or leak thus justifying the name of wet or exudative AMD that is sometimes used to describe this form of CNV, as represented in Fig. 3. In Fig. 3a) we have a schematic representation of the description we provided for this kind of neovascularization. In Fig. 3b) we have a photograph of the retina of a patient with Type II CNV, were we can see the new blood vessels above the RPE layer. Without the Bruch membrane and the RPE to act as a filter between the capillaries and the Photoreceptor Cell Layer (PCL) and also due to the leakage that is characteristic of this type of neovascularization, the cones and rods that form the PCL start to die causing partial or, in extreme cases, complete loss of vision. Fig. 4 illustrates the characteristic loss of vision that is associated with Type II CNV. The Amsler grid represented on the left side of Fig. 4 is commonly used as a home diagnosis tool for people with AMD. When AMD has caused damage to the photoreceptors on the retina the person will see the Amsler grid in a way similar to what is represented on the right hand side of Fig. 4. Figure 4: Perception of the Amsler grid for someone with normal vision (left) and for someone with AMD (right). Type III Figure 5: Type III CNV. The new blood vessels are formed both in the sub RPE and in the sub PCL region. This type of CNV represents an hybrid between the two previous types, and is, for this reason, usually referred to as combined type. It usually starts simply as a Type I neovascularization but something happens that causes the new blood vessels to break the RPE layer and start developing in a way similar to the one described for Type II, causing the same type of reaction from the RPE layer and potentially causing the same degree of vision loss as would a case of Type II. In Fig. 5a) we have a schematical representation that illustrates the similarities between this type an and a superposition of the two types referred previously. In the photograph of Fig. 5b) we can clearly see well developed blood vessels both between the Bruch membrane and the RPE as above the RPE. Time evolution In the previous sections we discussed and illustrated the main characteristics and consequences of the three types of Choroidal neovascularization. In this section we will discuss the time evolution of the radius affected by the growth of the new blood vessels as they develop. The angiogenic process goes thought three important stages, the initiation, active and involution stages, represented in Fig. 6 by the three red boxes. Figure 6: Time evolution of the radius of the neovascularization for the murine. The initiation stage corresponds to the first onset of neovascularization dominated by the action of the Vascular Endothelial Growth Factor (VEGF) secreted by the RPE and present in large concentrations in the area between the RPE and Bruch's membrane. This molecule is responsible, among other things, for stimulating the growth of the blood vessels3. In the active stage, the area covered by the new capillaries achieves its maximum radius when the concentration of VEGF starts to decrease and its role starts to become secondary. As shown in the second red square of Fig. 6, in the murine model, the maximum radius is usually attained sometime around the fifth or sixth day. By this time the containment attempts made by the RPE and described above have already failed and the damage to the retina and the loss of vision has already begun. Finally, in the involution stage, another molecule secreted by the RPE, the Pigment Epithelium Derived Factor (PEDF), initiates its anti-angiogenic action causing the area occupied by the blood vessels to decrease. This corresponds to the final stages of the process when the damage caused to the retina is already done and beyond repair. As represented in the third red box of Fig. 6, this stage can prolong itself for a longer time than both of the previous stages combined because the regression of the vessels takes longer that their growth. The description that we provided of the three different stages is very superficial and mentions only the main characteristics and the most important angiogenic and anti-angiogenic factor that are present in the process. There are, however, many other factors that besides playing a role of their own also interact with the VEGF and PEDF in order to influence theirs. The role of these other factors is not nearly as well known as the role of the ones mentioned and are, for this reason, overlooked. For a more complete description of the factors involved and of their respective roles we refer the reader to the specialized medical bibliography listed in the end of this text. Two particularly good reviews of the processes that we described thus far are available in [1,2]. Bibliography 1 J. Ambati et al. Age-related macular degeneration: Etiology, pathogenesis, and therapeutic stratagies. Survey of Ophtalmology, (48):257-293, 2003. 2 H. Grossniklaus. Choroidal neovascularization. American Journal of Ophthalmology, (137):496-503, 2004. Footnotes ... form1 The wet form is distinguishable from the more common dry form by the leakage in the new capillaries that are formed. ... III2 Type III CNV is sometimes referred to as mixed type CNV. ... vessels3 Since the growth of the vessels is related to the absorption of a molecule in solution we can say, in physical terms, that it is diffusion limited.   © Copyright 2004 Bruno Goncalves - All rights reserved