Pathophysiologic and Histopathologic Bases for Interpretation of Fluorescein Angiography
The anatomy and physiology of the choroid and retina and their relationship to the normal fluorescein angiographic findings were presented in Chapter 1 and are fundamental to understanding the principles of interpretation of fluorescein angiography in patients with ocular fundus abnormalities. In this regard the following facts are most important:
- 1.
The choroidal vasculature and its extracellular compartment are similar to that of the body outside the central nervous system in that ultrastructurally the capillary endothelial cells have a pore size that permits escape of relatively large molecules, including sodium fluorescein and some smaller proteins, into the choroidal extracellular compartment, which is normally partly expanded by extracellular fluid.
- 2.
The retinal vasculature and its greatly contracted extracellular compartment are similar to that of the brain in that the capillary endothelial cells are separated by tight junctions (blood–inner retinal barrier) that do not permit escape of large molecules, including sodium fluorescein and protein, into the retinal extracellular compartment, which is normally maintained in a state of relative deturgescence.
- 3.
The choroidal circulation and its expanded extracellular compartment, which are normally stained with fluorescein, are separated from the subretinal space and retinal extracellular compartment, which are not stained with fluorescein, by the retinal pigment epithelium (RPE; blood–outer retinal barrier). The RPE is a monocellular layer of cells connected by tight junctions that prevent escape of large molecules, including fluorescein and protein, from the choriocapillaris into the subretinal space, which is maintained in a state of relative deturgescence. To assist in the regulation of the extracellular environment, the choroidal and retinal vascular endothelia, as well as the RPE, probably have intracellular physiologic mechanisms that permit movement of molecules and water against an osmotic gradient. In addition to these functions, the RPE acts as an optical filter of irregular density to obscure the choroid partly from view.
This chapter briefly describes some of the basic pathophysiologic and histopathologic changes occurring in the posterior ocular fundus and illustrates how fluorescein angiography can assist in the detection and definition of these changes. Additional details concerning specific diseases are given in subsequent chapters.
In general, fluorescein angiography is useful in detecting (1) abnormalities of blood flow to or within the choroid, optic nerve head, and retina and (2) lesions that alter the normal pattern of fundus fluorescence.
Abnormalities of Blood Flow
With severe obstruction of either the carotid or the ophthalmic artery, there is usually evidence of delay in appearance of fluorescein in both the choroidal and the retinal circulation ( Figure 2.01A ). Because of the end-artery arrangement of the retinal circulation and its high visibility angiographically, severe obstruction of its circulation at any level from the central retinal artery to the central retinal vein is readily detected angiographically ( Figure 2.01B–D ).
Because of multiple posterior short ciliary arteries supplying the choroidal circulation and the rich arterial anastomosis within the choroid, angiographic demonstration of obstruction of one or more of the major choroidal arteries is infrequently demonstrated. Even when obstruction occurs, collateral circulation is usually sufficient to prevent infarction of the overlying retina, as illustrated in Figure 2.01E in a patient with ciliary artery obstruction caused by krypton red laser. Rapid-sequence angiography used in normal eyes often shows patchy areas of delayed choroidal perfusion in the posterior pole caused by minor variations in the length and diameter of the short ciliary arteries ( Figure 2.01F ). It may be difficult to differentiate these changes from those caused by pathologic obstruction of the posterior ciliary arteries. Peripherally, fewer pathways for anastomosis are available and occlusion of a major choroidal artery may cause a wedge-shaped area of ischemic infarction of the RPE and outer retina (Amalric’s triangle). After the disappearance of the white ischemic retina, angiography usually demonstrates evidence of arterial obstruction as the cause of the wedge-shaped area of RPE atrophy (see Figures 3.64K and L, and 9.15E and F). Acute obstruction of the precapillary arterioles and choriocapillaris is usually accompanied by ischemic whitening of the RPE and outer retina and a corresponding area of patchy loss of choroidal fluorescence (Figure 9.15C–F). It is difficult to differentiate these lesions biomicroscopically and angiographically from similar changes that are unrelated to choroidal vascular obstruction (such as blocked fluorescence due to opacification of the RPE (see discussion of acute posterior multifocal placoid pigment epitheliopathy, chapter 11).
Angiography is helpful in detecting a focal area of chronic obstruction of the choriocapillaris that is accompanied by atrophy of the overlying RPE and retina. Fluorescein leakage in the normal choroid occurs primarily from the choriocapillaris. If the choriocapillaris is obstructed, angiography may demonstrate perfusion of the large choroidal vessels but will show a delay in choriocapillaris perfusion and late choroidal and scleral staining within the area of overlying RPE atrophy ( Figure 2.02E–H ). Early staining along the periphery of such lesions occurs from leakage of fluorescein from the intact surrounding choriocapillaris. Angiography is helpful in differentiating these focal areas of RPE, retinal, and choriocapillaris atrophy from focal or geographic areas of depigmentation of the RPE that biomicroscopically may appear similar ( Figure 2.02A–D ). In these latter instances angiography may show that the choriocapillaris is relatively intact (see discussion of chloroquine maculopathy, chapter 9).
“Window” defects (transmission hyperfluorescence) in the retinal pigment epithelium causing focal hyperfluorescence
Focal areas of hypopigmentation, or thinning of the RPE, when associated with minimal or no alterations in the underlying choriocapillaris, will appear hyperfluorescent during the early phases of angiography because of the greater amount of inciting blue light reaching the choroid and the greater visibility of the choroidal fluorescence ( Figure 2.02A–D ). Stereoscopically, the area of the hyperfluorescence appears flat or depressed and remains relatively constant in size throughout the study. The changes in intensity of the fluorescence parallel that of the normal choroidal fluorescence ( Figure 2.02A–D ). Areas of focal atrophy or loss of the RPE and choriocapillaris will cause a delay in the early development of hyperfluorescence ( Figure 2.02E–H ).
Exudation and Fluorescein Staining
Water and electrolytes are free to move back and forth across the capillary endothelium. Large molecules, particularly protein and lipids, are not, however, because of the small capillary pore size. The amount of water that is present in the extracellular space is determined osmotically primarily by the pore size of the capillary endothelium and the amount of protein within the extracellular space. The amount of protein normally present there represents a balance between that escaping from the vascular compartment and that returning to the circulation by way of the lymphatic system. When either elevation of the intracapillary pressure or pathologic alteration in the capillary endothelium occurs, protein and in some cases larger lipoproteins and lipids escape into the extracellular space and bring water with them (exudation).
Intrachoroidal Exudation
Since fluorescein escapes normally from the choriocapillaris, angiography is of little value in detecting changes in capillary permeability in the choroid unless these changes are associated with either loss of adherence of the RPE to Bruch’s membrane or damage to the RPE blood–outer retinal barrier.
Choroidal Exudation Causing Localized (Disciform) Retinal Detachment
Localized detachment of the retina, often referred to as disciform detachment, that is caused by exudate derived from the choroidal circulation occurs primarily by three mechanisms: (1) detachment of the RPE; (2) choroidal neovascularization; and (3) devitalization of the RPE.
Detachment of the RPE
The normal adherence of the RPE basement membrane to the inner collagenous zone of Bruch’s membrane may be disrupted by a variety of causes, including increased permeability of the choriocapillaris, degeneration of Bruch’s membrane, degeneration of the RPE and its basement membrane, and exudation from sub-RPE choroidal neovascularization. Whatever the cause, serous exudation from the choriocapillaris or from sub-RPE new vessels may produce a sharply defined, often blister-like, detachment of the RPE ( Figure 2.03 ). Its size varies from subbiomicroscopic to several disc diameters or larger. When the RPE detachment is not caused by choroidal neovascularization, it is usually round or oval in shape and less than one disc diameter in size. It appears solid, and its color varies from that of the normal orange-brown RPE to yellow-gray. There may be a pinkish rim of subretinal fluid around the edge of the RPE detachment ( Figure 2.03 ). When small, an RPE detachment may be seen best in side illumination with the slit lamp. When caused by choroidal neovascularization the serous RPE detachment often has a kidney or notched configuration and biomicroscopically and angiographically demonstrates features suggesting the presence of choroidal neovascularization (see discussion in the next section). In nonvascularized serous RPE detachments fluorescein molecules rapidly diffuse from the choriocapillaris across the full extent of the normally permeable Bruch’s membrane into the sub-RPE exudate to produce the pathognomonic stereo angiographic picture of a sharply localized area of fluorescein staining ( Figure 2.03 ). The fluorescence typically appears slightly later than the background choroidal fluorescence and becomes maximally intense later and persists longer than the surrounding choroidal fluorescence. Even when the RPE is detached, its blood–outer retinal barrier may remain intact and prevent exudation into the subsensory retinal space ( Figure 2.04 ).
A serous RPE detachment may cause loss of central vision in two ways. It may enlarge concentrically until it extends beneath the center of the macula ( Figures 2.03 and 2.04 ), or the detached RPE may decompensate and permit large molecules and water to enter the subretinal space and detach the retina ( Figure 2.04 ). If the breakdown in the RPE barrier is low-grade and not associated with a physical break in the continuity in the RPE, fluorescein molecules may not be able to diffuse across the detached RPE into the subretinal exudate in concentrations sufficient to be visible angiographically (see Figures 2.03 and 3.03A–C). In the presence of a break, however, fluorescein streams into the subretinal exudate (see Figure 3.03 D–I).
Choroidal Neovascularization
Under a great variety of circumstances, neovascular tufts arising from the choroid may either invade and perforate Bruch’s membrane or grow through defects in Bruch’s membrane and proliferate in either the sub-RPE space (type I choroidal neovascularization) or in the subsensory retinal space (type II choroidal neovascularization). The location and growth pattern of the neovascular proliferation are determined primarily by the age of the patient and the pre-existing disease.
Type I Sub-RPE Neovascularization
As part of the normal aging process as well as in certain degenerative and dystrophic disorders (e.g., age-related macular degeneration and pseudoxanthoma elasticum), the firm attachment of the RPE and its basement membrane to the inner collagenous zone of Bruch’s membrane becomes loosened. In these patients new vessels extending from the choroid through Bruch’s membrane find little resistance to their lateral growth into the sub-RPE space ( Figures 2.05 and 2.06 ). Their pattern of growth often simulates that of a sea fan or cartwheel with radial arterioles and venules supplying and draining a circumferential dilated capillary sinus ( Figure 2.07 ). As neovascularization of the sub-RPE space occurs, the new vessels establish a relatively firm adhesion to the overlying RPE. Initially, the blood flow through the neovascular network is sluggish and there is little or no exudation ( Figure 2.06 ). During this period of occult neovascularization, the overlying retina and RPE may be minimally affected, and the network may not be detectable biomicroscopically or angiographically ( Figure 2.06A and B ). These occult neovascular complexes may be one disc diameter or larger and may be irregularly or focally elevated into a mound by virtue of proliferation of accompanying fibroblastic cells and new vessels before development of evidence of the escape of exudate from the blood vessels ( Figure 2.06C ). With an increase in blood flow through the network, the endothelium decompensates, particularly at the outer margin of the network, and exudation extends into the subpigment epithelial space around the network. In such cases when the overlying RPE is thinned and only slightly detached by serous fluid, details of the neovascular network may be easily detected angiographically, even though biomicroscopically the network may be hidden from view by cloudiness of the exudate ( Figure 2.08 ). The exudation may extend through the RPE and detach the overlying retina ( Figure 2.09A and B ).
In other patients, exudation may begin at one margin of the neovascular network and cause serous detachment of a large adjacent area of RPE. Because of the relatively firm attachment of the RPE to the neovascular membrane, these serous detachments of the RPE typically have a reniform or notched shape as a result of their development around the margin of the network, most of which lies outside the area of RPE detachment within the notch ( Figures 2.09C–E and 2.10A–C ). The presence of the new vessel membrane within the notch may or may not be evident angiographically as a mottled area of early hyperfluorescence with or without some evidence of ill-defined late staining. If the detachment extends away from the entire border of the membrane, it may assume a doughnut configuration ( Figures 2.09E and 2.10 II). If a highly elevated serous detachment of the overlying as well as surrounding RPE occurs, the choroidal neovascular network will be completely obscured biomicroscopically and angiographically by the RPE detachment, which usually has an oval or round configuration ( Figure 2.09F ).
Leakage of large proteins and extravasation of erythrocytes from the neovascular complex, causing large serous RPE detachments, often produce other biomicroscopic and angiographic clues to the presence of neovascularization. Biomicroscopic clues include yellow subretinal and intraretinal exudate or blood near the margin of the detachment (see Figure 3.02D), dark sub-RPE “fluid level” at the inferior edge of the detachment (see Figure 3.19G), and uneven elevation of the detached RPE not explained by gravity. Angiographic clues to the presence of occult neovascularization include delayed and incomplete staining of the sub-RPE exudate (see Figure 3.21). The neovascular membrane is most likely to be located in the less fluorescent zone of greatest opacification of the sub-RPE exudate. Accurate localization of new vessel membranes lying beneath large serous RPE detachments, however, is not possible with fluorescein angiography because of rapid movement of the dye through Bruch’s membrane throughout the extent of the detached RPE. In these types of RPE detachments computer-enhanced indocyanine green (ICG) angiography appears to provide a more accurate means of localizing the sub-RPE new vessel membranes. ICG dye is tightly bound to the serum proteins and gradually stains the choroidal neovascular membranes (CNVMs) but does not, as occurs with fluorescein, diffuse rapidly into the sub-RPE exudate.
Detection and accurate localization of choroidal neovascular networks may be difficult because of rapid diffusion of fluorescein into the exudate overlying and surrounding the network, variability of blood flow within the network, and partial obscuration of the network by cloudy exudate, blood, or melanin pigment. The use of stereoscopic fluorescein angiography to detect irregular nonstaining areas of shallow elevation of the RPE caused by occult neovascularization, and detection of other biomicroscopic and angiographic clues to the presence and location of CNVMs are important to the proper management of the patient.
Type II Subretinal Choroidal Neovascularization
Type II subretinal choroidal neovascularization occurs primarily in younger and middle-aged patients with acquired damage to the choriocapillaris–Bruch’s membrane–RPE complex caused by focal choroiditis (presumed ocular histoplasmosis syndrome, punctate inner choroiditis, serpiginous choroiditis, toxocariasis), retinochoroiditis (toxoplasmosis), trauma (choroidal rupture), choroidal hamartomas (osteomas), optic disc anomalies (optic disc drusen, optic disc pits, and colobomas), and retinal dystrophies (Best’s disease). In these patients, new blood vessels extending from the choroid through the acquired defects in Bruch’s membrane as they grow laterally in the subretinal space encounter the firm adherence of the surrounding RPE to the underlying Bruch’s membrane. The path of the advancing neovascular complex is therefore directed anteriorly beneath the sensory retina rather than beneath the RPE ( Figures 2.11 and 2.12 ). As the capillary network enters the space between the retinal receptor cells and the apical processes of the RPE, it stimulates the RPE cells to proliferate and to attach themselves by their cell bases to the advancing sheet of new vessels in an effort to envelop them. This reactive RPE proliferation initially results in a zone of hyperplasia of the RPE at the advancing border of the membrane, often producing a hyperpigmented ring ophthalmoscopically. As the fibrovascular membrane continues to expand laterally into the subretinal space, a monolayer of inverted, variably pigmented RPE cells with their base directed toward the new vessels grows along the posterior surface of the membrane. This inverted layer of RPE cells is firmly attached by the base of the RPE cells to the posterior surface of the membrane, and is loosely attached by the apical processes of the RPE to the apical processes of the native RPE. Anteriorly the proliferating layer of RPE cells has more difficulty keeping pace with the advancing neovascular membrane that is usually separated from the overlying retinal receptor cells by a layer of subretinal exudate (see chapter 3 for clinicopathologic correlations of type II membranes). Biomicroscopically this expanding fibrovascular membrane typically produces a gray or partly pigmented subretinal sheet or mound of tissue extending away from the edge of the pigment ring. This is usually accompanied by varying amounts of subretinal exudate and/or blood. Except for the tendency for the new vessels to grow in a sea fan configuration in both type I and type II neovascularization, their pattern of growth otherwise is distinctly different histopathologically. In spite of these histopathologic differences, however, biomicroscopically and angiographically the two types of neovascularization are not always easy to differentiate from each other. The presence of a black or slate-colored subretinal halo or mound at the site of origin of the new vessel and the absence of evidence of either solid or serous RPE detachment suggest type II neovascularization. With further fibrovascular proliferation, exudation, and hemorrhage the pigment halo or mound may be obscured and there may be no biomicroscopic clues to differentiate type I from type II neovascularization. In such cases the age of the patient and the nature of the underlying eye disease are most important in determining which type of neovascularization is present. Patients under 50 years of age without evidence of retinal dystrophies affecting the RPE–Bruch’s membrane complex, e.g., pseudoxanthoma elasticum and pattern dystrophy, are most likely to have type II neovascularization. Determination of the type is of relatively little importance in regard to indications and techniques used for laser photocoagulation treatment of the membranes. Differentiating the two types, however, is important if surgical excision of the new vessel membrane is contemplated ( Figures 2.11, 2.12 , and 3.52). Excision of type II membranes allows the sensory retina to reattach to the underlying native RPE, and in some cases there may be excellent recovery of visual acuity ( Figures 2.12 and 3.52). Excision of type I membranes, on the other hand, results in loss of the native RPE and an absolute scotoma corresponding to the site of the membrane ( Figure 2.13 ). Thus surgical removal of type I subfoveal membranes appears to offer no advantages over laser photocoagulation in regard to visual rehabilitation or preservation and has the disadvantage of risks associated with one, and in most cases two, intraocular operative procedures.
