Neovascular (Exudative or “Wet”) Age-Related Macular Degeneration

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Chapter 66 Neovascular (Exudative or “Wet”) Age-Related Macular Degeneration

Epidemiology

Age-related macular degeneration (AMD) is the major cause of severe visual loss in older adults1 if left untreated.2 Most AMD patients have macular drusen or retinal pigment epithelial abnormalities or both.3 Approximately 10% of AMD patients manifest the neovascular form of the disease.4 Neovascular AMD includes choroidal neovascularization (CNV) and associated manifestations such as retinal pigment epithelial detachment (PED), retinal pigment epithelial tears, fibrovascular disciform scarring, and vitreous hemorrhage.3 In the absence of antivascular endothelial growth factor (anti-VEGF) therapy, the vast majority of people with severe vision loss (20/200 or worse in either eye) from AMD have the neovascular form.4

Clinical (including biomicroscopic) presentation

Overview

Blurred vision and distortion, especially distorted near vision, are the symptoms most patients with CNV notice first.3,9 Patients also may complain of decreased vision, micropsia, metamorphopsia, or a scotoma; however, many times they volunteer no symptoms or report only vague visual complaints.8 Symptoms generally arise from subretinal fluid, intraretinal fluid, blood, or destruction of photoreceptors and the retinal pigment epithelium (RPE) by fibrous or fibrovascular tissue.1013 In some cases, areas of distortion or scotoma can be mapped out on an Amsler grid. Visual acuity, although frequently decreased, may not always be affected. Functional vision generally declines in accordance with Snellen visual acuity. Thus patients with poor Snellen acuity generally report decreased ability to perform functional tasks (e.g., face recognition, telling time) with the affected eye.14

In some patients with AMD, CNV may appear as a gray–green elevation of tissue deep to the retina with overlying detachment of the neurosensory retina (Fig. 66.1). The gray–green color may arise from hyperplastic RPE in response to the CNV,15 as has typically been seen in patients, usually younger individuals, with ocular histoplasmosis syndrome (OHS), pathologic myopia, and other conditions complicated by CNV. This gray–green appearance is not always present in older individuals with AMD. Often, the presence of blood or lipid or a sensory retinal detachment in an elderly patient with vision loss indicates the presence of CNV. The CNV capillary network may become more apparent when the overlying RPE has atrophied. Occasionally, a shallow neurosensory detachment may be the only presenting sign of underlying CNV. Elevated RPE, also termed a pigment epithelial detachment (PED), even without overlying subretinal fluid, may also suggest the presence of CNV to be identified subsequently by a fluorescein angiogram. RPE folds beneath a shallow RPE elevation usually indicate the presence of CNV.16 These subtle clinical findings can easily be missed without careful stereoscopic slit-lamp biomicroscopic examination, facilitated with a contact lens.

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Fig. 66.1 Fundus photograph of choroidal neovascularization. Note area of hemorrhage (large arrows), as well as neurosensory retinal detachment (small arrows).

(Reproduced with permission from Elman MJ. Age-related macular degeneration. Int Ophthalmol Clin 1986;26:117–44.)

Retinal pigment epithelial detachments

Retinal PEDs appear clinically as sharply demarcated, dome-shaped elevations of the RPE (Fig. 66.2). They usually transilluminate if they are filled with serous fluid only. Often, there is accompanying RPE atrophy and “pigment figure” formation. Pigment figures, a reticulated pattern of increased pigmentation extending radially over the PED, indicate chronicity of disease and probably have no prognostic significance. Although an overlying sensory retinal detachment may be a clue to the presence of CNV beneath a PED,17 sometimes a shallow neurosensory detachment may occur as a result of breakdown of the physiologic RPE pump or from disruption of the tight junctions between adjacent RPE cells in the absence of CNV. Unlike a PED, the borders of a neurosensory detachment are not sharply demarcated. The presence of a PED may or may not be a feature of CNV. The fluorescein angiographic pattern (see subsequent discussion) can differentiate a drusenoid PED,18 which does not have CNV, from a fibrovascular PED, which is a form of occult CNV,19 as well as from a serous PED, which may or may not overlie an area with CNV.19 Several clinical signs suggest the presence of CNV underlying an area of PED identified biomicroscopically, including overlying sensory retinal detachment and lipid, blood, and chorioretinal folds radiating from the PED.3 Blood within or surrounding a PED implies the presence of CNV (Fig. 66.3). When confined to the sub-RPE space, the blood may appear as a discretely elevated, green or dark-red mound. The hemorrhage can dissect through the RPE into the subsensory retinal space or into the retina. Rarely, blood may pass through the retina into the vitreous cavity, causing extensive vitreous hemorrhage. The Submacular Surgery Trials (SST) Research Group suggested that this event was more likely in predominantly hemorrhagic lesions that were large (>12 disc areas) or associated with very poor visual acuity (worse than 20/1280 Snellen equivalent).20

image

Fig. 66.2 Fundus photograph in which a round, sharply demarcated mound indicates the detached retinal pigment epithelium.

(Reproduced with permission from Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 1988;32:375–413.)

Massive subretinal hemorrhage

Massive subretinal hemorrhage is an unusual complication of neovascular AMD. If – extremely rarely – total hemorrhagic retinal detachment occurs, secondary angle closure glaucoma may develop. These patients may report sudden visual loss followed by pain.22 Anticoagulation therapy may contribute to massive subretinal hemorrhage. In one report,23 19% of AMD patients with massive subretinal hemorrhage were taking sodium warfarin or aspirin. Although sodium warfarin therapy may have contributed to the massive subretinal hemorrhage, the antiplatelet therapy was likely a chance association because several Macular Photocoagulation Study (MPS) reports did not observe any increased risk of hemorrhage associated with the use of aspirin.2426 Furthermore, comparing baseline characteristics in study participants with predominantly choroidal neovascular lesions in the SST Group N Trial27 with participants with predominantly hemorrhagic lesions,20 no difference in use of aspirin was detected. Recent epidemiology studies found an association of aspirin use with neovascular AMD, but this finding does not necessarily confirm or refute an association of aspirin with the development of predominantly hemorrhagic lesions or massive subretinal hemorrhages.28

We believe the strongest evidence suggests that patients with AMD who need to follow a regimen of aspirin therapy should continue to do so without unnecessary fear they will increase their risk of vitreous hemorrhage.

Retinal pigment epithelial tears

RPE dehiscence or tears have been described as a complication associated with CNV, often in an eye with a serous or fibrovascular PED, and secondary to or unassociated with laser photocoagulation.2933 One report34 suggested that CNV underlying a detached RPE can contribute to RPE tear formation. Tears occur at the junction of attached and detached RPE, perhaps when the PED can no longer resist the stretching forces from the fluid in the sub-RPE space emanating from the underlying occult CNV (Fig. 66.4) or from the contractile forces of the underlying fibrovascular tissue that may be intimately associated or entwined with the overlying RPE. When the RPE tears, the free edge of the RPE retracts and rolls toward the mound of fibrovascular tissue. Acutely, a serous detachment of the sensory retina may be caused by the leaking of fluid from the exposed choriocapillaris.18 This is rarely seen after a few days following the tear.

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Fig. 66.4 Sketch of tear or rip of the retinal pigment epithelium (RPE), showing contracted RPE tear. Cc + C, choriocapillaris and choroid.

(Reproduced with permission from Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 1988;32:375–413.)

Disciform scars

Histologically, CNV usually is accompanied by fibrous tissue, even when no fibrous tissue is readily apparent on initial presentation to an ophthalmologist.10,35,36 This fibrous tissue may be accompanied by CNV (fibrovascular tissue) or not (fibroglial tissue).10 The fibrous tissue complex may be beneath the RPE (usually proliferating within the inner aspect of an abnormally thickened Bruch’s membrane), and has been termed type I, or between the RPE and the photoreceptors, termed type II.34 While some people speculate that these types differentiate classic CNV from occult CNV,37,38 there is little evidence to support that these histologic types are always differentiated by histopathologic correlation.39 Often, over time, the plane of the RPE is destroyed by the fibrovascular or fibroglial tissue, so the location of the CNV with respect to the RPE can no longer be identified readily. When the fibrous tissue becomes apparent clinically, the CNV and fibrous tissue complex may be termed a disciform scar.

Clinically, disciform lesions may vary in color, although typically they appear white to yellow. Hyperpigmented areas may be present depending on the degree of RPE hyperplasia within the scar tissue. Disciform fibrovascular scars may continue to grow, with neovascularization recurring along the edge, invading previously unaffected areas (Fig. 66.5). Varying degrees of subretinal hemorrhage and lipid may overlie or surround the scar. Occasionally, fibrovascular scars may precipitate massive transudation of fluid, mimicking a retinal detachment. The scars may be accompanied by massive lipid, as might be seen in retinal telangiectasis from Coats disease, and hence are sometimes called a “senile Coats response” in AMD. Disciform scars occasionally masquerade as choroidal tumors when much pigment is seen.34 Not infrequently, anastomoses are observed between the retina and the fibrovascular tissue.13 As a rule, most fibrovascular scars involve the fovea and cause severe visual loss. However, surviving islands of intact photoreceptor cells noted histologically may explain the better visual performance than would be predicted from the morphologic appearance alone in some scars. Reading vision, rarely better than 20/200, becomes severely compromised in most cases with extensive scars.

Fluorescein angiographic features

Overview

Whenever one suspects CNV for which treatment might be indicated, one should consider obtaining stereoscopic fluorescein angiography promptly (Fig. 66.6), even in an era of optical coherence tomography (OCT). The treating ophthalmologist is about to embark on a recommendation for treatment involving drugs which carry risks, potentially large expenses, and requiring many years of follow-up. Although the clinical picture may be “obviously” CNV, other lesions masquerading for CNV can exist (see below) having a fluorescein angiogram at the time of diagnosis reduces the possibility that an error in diagnosis will be made. In addition, fluorescein angiography frequently allows one to determine the pattern (classic or occult), boundaries (well defined or poorly defined), composition (e.g., predominantly CNV, predominantly classic CNV, predominantly CNV with a minimally classic composition, predominantly CNV with an occult with no classic composition, predominantly hemorrhagic), and location of the neovascular lesions with respect to the geometric center of the foveal avascular zone (FAZ). Although many physicians no longer refer to CNV composition, entry criteria for many and even most of the treatment trials cited later in this chapter relied in part on lesion composition. If one chooses to treat only patients who would have been eligible for, e.g., the MARINA trial, baseline angiography is necessary. High-quality stereoscopic fluorescein angiograms, together with meticulous slit-lamp biomicroscopic examination (ideally with a contact lens examination using topical anesthesia and hard contact lens wetting solution to avoid degradation of any subsequent image acquisition that might occur if an ophthalmic demulcent is used), facilitate detecting obvious and subtle features of CNV on angiography.14,19,40 It should be noted that the descriptive terms below refer to patterns of fluorescence on fluorescein angiography that have been shown to be reliable and reproducible in multicenter clinical trials,19,41,42 and in practice, and are not related to terms based on other imaging such as OCT, indocyanine green angiography, histopathology, or immunohistochemistry.

Classic choroidal neovascularization

The fluorescein angiographic appearance of classic CNV consists of a discrete, well-demarcated focal area of hyperfluorescence that can be discerned in the early phases of the angiogram, sometimes before dye has completely filled the retinal vessels during choroidal filling.19,41,42 Although fluorescein can occasionally be observed within the actual capillary network of CNV in the early phase of the angiogram (Fig. 66.7A), the ability to visualize the appearance of actual new vessels is not needed to diagnose classic CNV and is not a specific feature of classic versus occult CNV.19,4143 Since both classic and occult patterns of CNV contain new vessels histologically, early-phase angiography may be able to demonstrate these vessels in either pattern. As the angiogram is evaluated within the area of classic CNV, hyperfluorescence increases in intensity and extends beyond the boundaries of the hyperfluorescent area identified in earlier phases of the angiogram through mid- and late-phase frames. Fluorescein may also pool in subsensory retinal fluid overlying the classic CNV (Fig. 66.7B), best seen when visualizing early- and late-phase frames of classic CNV on stereoscopic images. This presentation of classic CNV is in contrast to the appearance of an area of RPE atrophy on fluorescein angiography. RPE atrophy, like classic CNV, is hyperfluorescent during the early phase of the angiogram (Fig. 66.8A). The increased fluorescence through the atrophic patch results from increased transmission of fluorescein through an overlying RPE with a reduced amount of pigment that normally obscures the choroidal blush (sometimes termed a window, or transmission, defect). Unlike the increase in extent and intensity of hyperfluorescence due to leakage from the fluorescence of classic CNV, RPE atrophy does not show leakage of fluorescein at its boundaries through the mid- and late-phase frames. The fluorescence fades after several minutes (Fig. 66.8B), without leakage of fluorescein beyond the boundaries of hyperfluorescence defined in the early stages. Two other lesions in AMD that may show an area of discrete hyperfluorescence in the early phase of the angiogram include a serous PED and a rip or tear of the RPE (angiographic features that differentiate these abnormalities from classic CNV are discussed later). Neither one of these latter abnormalities should show fluorescein leakage in later phases of the angiogram at the boundary of the hyperfluorescence noted in earlier phases.

Occult choroidal neovascularization

Occult CNV refers to two hyperfluorescent patterns on fluorescein angiography.19,41,42 The first pattern, termed a fibrovascular pigment epithelial detachment (FVPED), is best appreciated with stereoscopic views, usually at approximately 1–2 min after dye injection. It appears as an irregular elevation of the RPE, often stippled with hyperfluorescent dots (Fig. 66.9). The boundaries may or may not show leakage in the late-phase frames as fluorescein collects within the fibrous tissue or pools in the subretinal space overlying the FVPED. The exact boundaries of a FVPED can usually be determined most accurately only when fluorescence sharply outlines the elevated RPE. The amount of elevation depends on the quality of the stereoscopic photographs and the thickness of the fibrovascular tissue. Stereoscopic pairs of fluorescein angiogram frames can sometimes facilitate identification of the boundaries of the elevated RPE, although not always, as the elevation can slope gradually down to the normal level of the RPE. The second pattern, late leakage of an undetermined source (Fig. 66.10), refers to late choroidal-based leakage in which there is no clearly identifiable classic CNV or FVPED in the early or mid-phase of the angiogram to account for an area of leakage in the late phase. Often this pattern of occult CNV can appear as speckled hyperfluorescence with pooling of dye in the subretinal space overlying the speckles. Usually the boundaries of this type of CNV cannot be determined precisely, and a lesion with this component should not be considered for photocoagulation treatment if it contributes to poorly demarcated boundaries of the lesion.

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Fig. 66.9 Classic and occult choroidal neovascularization (CNV) with well-demarcated borders. (A) Color photograph shows scar from prior photocoagulation surrounded by several clues to suggest recurrent CNV, including subretinal hemorrhage, subretinal lipid, irregular elevation of retinal pigment epithelium (RPE) below the area of prior laser treatment, and overlying subretinal fluid. (B) Early phase of fluorescein angiogram shows area of classic CNV, scar from prior laser treatment, and irregular elevation of RPE with stippled hyperfluorescence representing fibrovascular pigment epithelial detachment (PED) inferior and temporal to the scar. (C) Stereoscopic photograph of the same eye 1 min after fluorescein injection. Note fluorescein leakage already apparent from classic CNV and increased intensity of stippled hyperfluorescence corresponding to fibrovascular PED. The boundaries of the fibrovascular PED remain well demarcated. (D) Angiogram taken 10 min after fluorescein injection shows persistence of fluorescein staining and leakage within a sensory retinal detachment overlying the lesion. It is difficult to determine the precise demarcation of fluorescence outlining the elevated RPE from these photographs alone. Although a fairly well-demarcated border can be seen in (C), the intensity of fluorescence at the boundary of elevated RPE is quite irregular in these late-phase photographs, with some areas fading relative to fluorescence of remaining areas of elevated RPE (D). (E and F) Composite drawings using multiple stereoscopic photographs from angiogram show interpretation of the boundaries of the lesion. At each clock-hour, the boundary of the lesion is clearly demarcated; the lesion included classic CNV, which occupies the foveal center.

(Reproduced with permission from Macular Photocoagulation Study Group. Subfoveal neovascular lesions in age-related macular degeneration: guidelines for evaluation and treatment in the Macular Photocoagulation Study. Arch Ophthalmol 1991;109:1242–57.)

Other terms relevant to interpreting fluorescein angiography of choroidal neovascularization

The terms lesion component versus lesion are important to differentiate in the discussion of fluorescein interpretation and treatment of CNV.19,41,42 Lesion component is classic or occult CNV or any of four angiographic features that could obscure the boundaries of classic or occult CNV. These four features include: (1) blood that is visible on color fundus photographs and thick enough to obscure the normal choroidal fluorescence; (2) hypofluorescence due to hyperplastic pigment or fibrous tissue, or blood not visible on color fundus photographs; (3) a serous detachment of the RPE (Fig. 66.11); and (4) scar from CNV which either stains or blocks fluorescence (depending on the extent of RPE within the scar). The first two of these four features block the angiographic view of the choroid, making it impossible to determine whether CNV is located in the area of this component. The bright, reasonably uniform, early hyperfluorescence associated with a serous detachment of the RPE (described later) may obscure hyperfluorescence from classic or occult CNV and therefore interfere with the ability to judge whether CNV extends under the area of the serous detachment. The term lesion, in contrast, refers to the entire complex of lesion components.

The terms well-defined (synonymous with well-demarcated) and poorly defined (synonymous with poorly demarcated or ill-defined) refer to a description of the boundaries of the entire lesion (not of individual lesion components). In a well-defined lesion, the entire boundary for 360 degrees is well demarcated (for example, Figs 66.9, 66.12, 66.13). If the entire boundary is not well demarcated for 360 degrees, then the lesion is poorly defined (for example, Fig. 61.9). Thus the terms well-defined and classic should not be used interchangeably, nor should poorly defined and occult. Well-defined and poorly defined describe lesion boundaries (for a lesion that may be composed of classic CNV, or occult CNV, or both). Classic and occult CNV refer to patterns of fluorescence. In addition, the term poorly defined should not be used to describe situations in which blood blocks the ability to see fluorescence from CNV,19,41,42 even though earlier publications had alluded to descriptions incorporating this possibility.44

The term predominantly CNV indicates that at least 50% of the lesion is composed of either classic CNV or occult CNV, or both, while the term predominantly hemorrhagic indicates that at least 50% of the lesion is composed of hemorrhage.41,42 These terms are critical in the management of AMD (Fig. 66.14), since treatments for CNV with anti-VEGF therapy, or less frequently, with laser photocoagulation, photodynamic therapy (PDT), or surgery, have been tested only in lesions that are predominantly CNV or predominantly hemorrhagic. After determining whether a lesion’s composition is predominantly CNV, it should be determined whether the lesion is predominantly classic, rather than minimally classic or occult with no classic. If predominantly classic, then treatment could be considered with or without evidence of presumed recent disease progression (defined as evidence of blood associated with CNV, or definite visual acuity loss within 3 months, or definite growth of the lesion within 3 months). If minimally classic or occult with no classic, treatment has been shown to be beneficial compared with no treatment only with evidence of presumed recent disease progression, although a therapeutic trial of anti-VEGF therapy might be considered if visual acuity loss already had occurred and one believed that visual acuity improvement might occur with anti-VEGF therapy because of the presence of intraretinal or subretinal fluid judged to be contributing to visual acuity loss and judged likely to resolve with visual acuity improvement following initiation of anti-VEGF therapy.

Retinal pigment epithelium detachments in age-related macular degeneration

Various changes in an eye with AMD may result in elevation or detachment of the RPE, as seen on stereoscopic biomicroscopic or angiographic evaluation. The term RPE detachment or retinal pigment epithelial detachment (retinal PED) secondary to AMD in the ophthalmic literature remains confusing because various RPE detachments may have quite different compositions, fluorescein angiographic appearances, prognoses, and management. Fortunately, these various RPE detachments can usually be differentiated on the basis of fluorescein angiographic patterns of fluorescence. The patterns include the following: (1) fibrovascular PEDs,19 which are a subset of occult CNV (see Figs 66.9 and 66.10); (2) serous detachments of the RPE45 (see Fig. 66.11); (3) hemorrhagic detachments of the RPE, in which blood from a choroidal neovascular lesion is noted beneath or exterior to the RPE (see Fig. 66.3); and (4) drusenoid RPE detachments,9 in which large areas of confluent, soft drusen are noted. It is potentially difficult to differentiate between fibrovascular PEDs and serous PEDs. Using descriptions from the MPS Group, fibrovascular PEDs (as a subset of occult CNV) have been distinguished from a typical serous detachment of the RPE, in that the former do not have uniform, bright hyperfluorescence in the early phase. Instead, they show a stippled fluorescence along the surface of the RPE by the middle phase of the angiogram and may show pooling of dye in the overlying subsensory retinal space in the late phase (see Fig. 66.9). Serous PEDs show uniform, bright hyperfluorescence in the early phase, with a smooth contour to the RPE by the middle phase, and little, if any, leakage at the borders of the PED by the late phase (see Fig. 66.11). The fluorescent pattern of a serous PED obscures the ability to determine whether classic or occult CNV exists within or beneath the area of the serous PED. In contrast, a fibrovascular PED is an area of occult CNV.

A hemorrhagic detachment of the RPE will block choroidal fluorescence because of the mound-like collection of blood beneath the RPE (see Fig. 66.3). Occasionally a hemorrhagic detachment of the RPE may be mistaken for a choroidal melanoma, but usually hemorrhagic detachments of the RPE do not demonstrate low internal reflectivity, as is seen characteristically in choroidal melanomas.

One other feature of AMD that appears as an elevated or detached RPE is a drusenoid RPE detachment,18 which represents extensive areas of large, confluent drusen. Drusenoid RPE detachments can be distinguished from serous detachments of the RPE in that drusenoid RPE detachments fluoresce faintly during the transit and do not progress to bright hyperfluorescence in the late phase of the angiogram. In contrast, serous detachments of the RPE fluoresce brightly in the early-transit phase and remain brightly hyperfluorescent in the late phase. In addition, serous detachments will usually have a smoother, sharper boundary compared with drusenoid RPE detachments. Drusenoid RPE detachments can be distinguished from fibrovascular PEDs in occult CNV by noting that fibrovascular PEDs show areas of stippled hyperfluorescence with persistence of staining or leakage within a sensory retinal detachment overlying the area in the late phase of the angiogram. RPE detachments due to large, soft, confluent drusen are usually smaller, shallower, and more irregular in outline than are fibrovascular PEDs. In addition, the drusenoid RPE detachments often have reticulated pigment clumping overlying the large, soft, confluent drusen, a scalloped border, and have less fluorescence in late-phase frames as compared with earlier-phase frames.

Other angiographic features

Speckled hyperfluorescence

Speckled fluorescence (Fig. 66.15A) in the absence of fluorescein leakage consists of several punctuate spots of hyperfluorescence, usually within 500 µm of each other that are apparent between 2 and 5 minutes after fluorescein injection and cannot be detected in early phase frames in contrast to drusen.46 The fluorescence of these spots persisted or increased in intensity by the late phase of the angiogram (Fig. 66.15B), in contrast to drusen or atrophy of the retinal pigment epithelium which do not remain brightly hyperfluorescent by the late phase of the angiogram. Typically, clusters of speckles would appear at the edge of the CNV lesion, rather than the typical distribution of drusen throughout the macular area. This angiographic feature was previously reported to be associated with recurrent CNV.46 If speckled hyperfluorescence is noted in the presence of fluorescein leakage in the late phase frames in the absence of elevation of the RPE, then the pattern would be considered to meet the definition of late leakage of an undetermined source, a type of occult CNV.

Fading choroidal neovascularization

CNV may occasionally be recognized in the early- or middle-transit phase of the angiogram with fading in the late phase, so little fluorescein staining or leakage can be discerned in the late phase within an area that was presumed to harbor CNV on the basis of its early-phase features19 (Fig. 66.16). A vascular pattern of the fibrovascular tissue can occasionally be discerned in early-phase frames.43 Most ophthalmologists are reluctant to treat areas of CNV that fade. These areas are usually not associated with overlying subretinal fluid (in conjunction with the lack of fluorescein leakage on angiography), so one can only presume that this region may proceed to disciform scarring. Perhaps these areas represent CNV histologically, but without evidence of subretinal fluid or late leakage, one cannot be certain that this pattern definitively represents CNV, and laser treatment of this area may damage the retina unnecessarily.

Feeder vessels

These vessels may be identified as choroidal vessels apparent during the transit phase of the angiogram and connected unequivocally to leaking choroidal capillaries19 (see Fig. 66.9). Although feeder vessels have been described as extending from a laser-treated area to recurrent CNV across the perimeter of the laser-treated areas, feeder vessels may also be seen in untreated eyes (see Fig. 66.10). In the latter situation, peripheral, untreated areas of CNV may be connected by feeder vessels to more central areas of CNV that are evolving toward natural scar formation.

Retinal lesion anastomosis (“retinal angiomatous proliferans” or “chorioretinal anastomosis”)

Retinal vessels can anastomose with CNV from AMD.47 The vessels can be seen dividing at right angles from the surface of the retina to the neovascular lesion (as may be seen with idiopathic parafoveal telangiectasis).

Loculated fluid

This fluid consists of a well-demarcated area of hyperfluorescence that appears to represent pooling of fluorescein in a compartmentalized space anterior to the choroidal neovascular leakage, usually seen in the late phase of the angiogram.48 Although the loculated fluid may conform to a pattern of typical cystoid macular edema, it can also pool within an area deep to the sensory retina in a shape that does not bear any resemblance to cystoid macular edema.

Retinal pigment epithelial tears

RPE tears have a characteristic fluorescein angiographic appearance.49 The denuded RPE displays marked early hyperfluorescence. Later, staining of the choroid and sclera may be observed, but fluorescein generally does not leak from the denuded area. The folded pigment epithelial mound blocks fluorescence; However, this area may leak later during the angiogram, presumably from underlying CNV. Tears may occur following development of a serous PED in the absence of CNV. In addition, tears may occur following development of CNV, sometimes accompanied by large areas of hemorrhage. Tears in any of these situations may occur without any antecedent treatment or may occur soon after laser photocoagulation or PDT.

Disciform scars

Fibrovascular scars frequently hyperfluoresce from both fluorescein leakage and staining. One may also notice chorioretinal anastomoses or, more precisely, retinal anastomoses into fibrovascular tissue (also called retinal angiomatous proliferans47 or chorioretinal anastomoses or retinal lesion anastomoses). Some descriptions of these vessels have suggested that they can develop prior to the development of CNV (as is seen in the subretinal neovascularization that can develop in an individual with idiopathic parafoveal telangiectasis). Theoretically, these descriptions seem plausible if sufficient VEGF production, which typically would be involved in the development of CNV, first led to the development of proliferation of retinal capillaries. However, there is no evidence that these vessels develop in the absence of CNV from AMD on histopathology. Furthermore, most cases show evidence of CNV in the presence of these anastomoses of retinal vessels with the neovascular lesion, and those cases that do not show obvious CNV often have difficult angiograms to interpret to state with certainty that CNV is not present. The area of anastomosis, when noted before development of extensive visible scar tissue, often shows a bright area of fluorescence in the early phase, occasionally accompanied by a small area of intraretinal hemorrhage. While some reports have suggested that the natural history of lesions with these anastomoses is worse than the natural history without these anastomoses, there is no strong evidence to support this impression at this time.

Pathogenesis

Choroidal neovascularization

Histopathology

CNV appears as a neovascular sprout growing under or through the RPE through breaks in Bruch’s membrane13 (Figs 66.17, 66.18). Usually this occurs in association with evidence of fibroblasts, myofibroblasts, lymphocytes, and macrophages.50 Various growth factors are suspected to be involved in the development of this CNV, such as vascular endothelial growth factor (VEGF).51 However, while drugs designed to interfere with VEGF have been shown to reduce the risk of vision loss,5257 vision loss still occurred in many treated cases, and it is not yet clear how much these drugs produce an antiangiogenic effect or an antipermeability effect. Following penetration of the inner aspect of Bruch’s membrane, the new vessels proliferate laterally between the RPE and Bruch’s membrane.13 As these neovascular twigs mature, they develop a more organized vascular system stemming from a trunk of feeder vessels off the choroid, as well as proliferation of fibrous tissue. The endothelial cells in the arborizing neovascular tufts lack the barrier function of more mature endothelial cells. Hence these new vessels can leak fluid (and fluorescein) in the neurosensory, subsensory, and RPE layers of the retina. Proteins and lipids may accompany this process and precipitate in any layer of the retina. In addition, the fragile vessels are prone to hemorrhage. Occasionally, blood may extend through all the layers of the retina, breaking through into the vitreous cavity. Ultimately, a fibrovascular scar results, usually causing disruption and death of the overlying sensory retinal tissue accompanied by severe visual loss.

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Fig. 66.18 Sketch of choroidal neovascularization showing ingrowth of vessels from the choriocapillaris, through a break in Bruch’s membrane, into the subretinal pigment epithelial space.

(Reproduced with permission from Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 1988;32:375–413.)

Associated factors

The stimulus for vascular ingrowth of choroidal vessels remains unknown, but several theories have been advanced. Soft drusen have been associated histopathologically with CNV. The soft drusen represent focal accumulation of membranous debris (ultrastructurally termed basal linear deposits) accumulated as a diffuse, shallow layer between the RPE basement membrane and the inner aspect of Bruch’s membrane.11–13,5863 This material should not be confused with basal laminar deposit, which is material that collects between the RPE plasma membrane and the basement membrane of the RPE and accumulates with age but may not lead to vision loss from CNV or geographic atrophy and therefore may not be part of AMD.58,59 The term should also not be confused with basal laminar drusen, also called cuticular drusen. (Basal laminar, or cuticular, drusen usually present in midlife with a myriad of small, translucent drusen that appear like a starry sky on a fluorescein angiogram and may be associated with vitelliform macular detachments: see below.3,64) Some investigators believe that soft drusen represent extracellular matrix material produced by the RPE.58,65 Deposition of this material may suggest a widespread RPE abnormality.20 The diffusely thickened area is weakly attached, allowing the development of localized detachments seen clinically as soft drusen. These localized detachments can coalesce into larger drusenoid or serous RPE detachments.12 Alternatively, drusen may act as an indirect angiogenic factor by attracting macrophages from the choroid.50

Breaks in Bruch’s membrane permit ingrowth of new vessels from the choriocapillaris. However, these breaks can also be seen without ingrowth of choroidal new vessels. Some investigators have suggested that endothelial cells of growing CNV may actually produce the break in Bruch’s membrane rather than grow through pre-existing breaks in Bruch’s membrane.66 An inflammatory component seen in association with AMD may play a role in the development of CNV.67 Eyes with AMD show an increased prevalence of lymphocytes, fibroblasts, and macrophages within Bruch’s membrane as compared with control eyes without AMD. However, these findings are not specific to eyes with neovascular AMD.67,68 The presence of macrophages and lymphocytes near breaks in Bruch’s membrane suggests that leukocytes may be involved in the induction of CNV growth and the release of collagenases from endothelial cells. It is postulated that leukocytes may initially stimulate neovascular proliferation, promote the release of factors leading to breakdown of Bruch’s membrane, and even affect (with pericytes) the dilation of new vessels.69 Whether these inflammatory cells act as mediators of the degenerative changes seen in Bruch’s membrane or directly stimulate new vessel growth remains unknown. Finally, as mentioned above, other angiogenic factors, such as VEGF or a platelet-derived growth factor (PDGF),51,53,70 may contribute to the ingrowth of new vessels from the choroid through Bruch’s membrane into the sub-RPE space. Growth factors leading to neovascular formation may arise from an imbalance between stimulating and inhibiting chemical modulators. The RPE has been implicated as the source of these factors, but RPE cells may also act indirectly through the attraction of macrophages.71