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.^10–13 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.

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

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.)

Fig. 66.3 Hemorrhagic retinal pigment epithelial detachment. (A) Sketch of hemorrhagic detachment in which the blood has also dissected underneath the sensory retina. (B) Fundus photograph of hemorrhagic pigment epithelial detachment.

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

Breakthrough vitreous hemorrhage

In most cases of neovascular AMD, the peripheral visual field remains unaffected. If bleeding breaks through the retina into the vitreous cavity, however, patients may complain of severe and sudden visual loss involving the peripheral visual field, as well as the central field. This may be accompanied by pain believed to result from stretching of the nerve fibers within the choroid.²¹

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.^24–26 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.^29–33 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.

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.

Fig. 66.5 Disciform scar. (A) Sketch demonstrating that most of the sensory retina, pigment epithelium, and inner choroid has been replaced by a fibrovascular scar. (B) Fundus photograph of a disciform scar after choroidal neovascularization. (C) Fundus photograph of a disciform scar in which continued subretinal fluid and lipid from persistent choroidal neovascularization at the periphery of the fibrous tissue can be seen.

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

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.

Fig. 66.6 Algorithm for management of neovascular age-related macular degeneration suspected or diagnosed on clinical examination. AMD, age-related macular degeneration; CNV, choroidal neovascularization; OCT, optical coherence tomography; MPS, Macular Photocoagulation Study; VEGF, vascular endothelial growth factor.

(© Neil M. Bressler, MD, Johns Hopkins University, 2011.)

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.^19,41–43 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.

Fig. 66.7 (A) Early transit phase of fluorescein angiogram showing fine net of vessels corresponding to part of choroidal neovascular lesion (black arrows). (B) Late phase of the fluorescein angiogram, demonstrating an increase in the degree and size of fluorescence. In both panels (A) and (B) there is blocked fluorescence resulting from overlying hemorrhage (white arrows).

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

Fig. 66.8 (A) Transit phase of fluorescein angiogram, showing hyperfluorescence corresponding to atrophic zones of the retinal pigment epithelium (transmission, or window, defect) and easily visualized choroidal vessels (too large to be vessels of choroidal neovascularization). (B) Hypofluorescence does not increase in size and fades with the later phases of the angiogram. This is in contrast to the pattern seen in choroidal neovascularization (Fig. 66.5).

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

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.

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.)

Fig. 66.10 Occult choroidal neovascularization (CNV) with poorly demarcated boundaries accompanied by classic CNV. (A) Subretinal fluid and hemorrhage in eye with drusen. (B) Early phase of fluorescein angiogram shows both feeder vessels to classic CNV and fibrovascular pigment epithelial detachment (PED). Blocked fluorescence due to thick blood obscures inferior boundary of occult CNV. (C) Mid-phase stereoscopic photographs of angiogram show leakage from classic CNV. (D) Late phase of angiogram shows other areas of late leakage of undetermined source with no discernible, discrete, well-demarcated area of hyperfluorescence from classic CNV or fibrovascular PED detectable in early or mid-phase frames of angiogram that might be considered a source of late leakage.

(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.

Fig. 66.11 Fluorescein angiogram of serous retinal pigment epithelial detachment. (A) Early transit phase of a fluorescein angiogram demonstrates uniform fluorescence under the dome of the detachment. Note the deformation of the otherwise round detachment by a notch of the hyperfluorescence (arrow). (B) Later phase of the fluorescein angiogram demonstrates persistent hyperfluorescence that does not extend beyond the margins of the hyperfluorescence seen in the early transit phase.

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

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

Fig. 66.12 Classic and occult choroidal neovascularization (CNV) and elevated blocked fluorescence (EBF) with well-demarcated borders. (A) Recurrent subfoveal CNV. Note small area of hemorrhage temporal to recurrence. (B) Early phase of fluorescein angiogram shows sharp demarcation of hyperfluorescence of classic CNV. (C) Mid-phase photograph of angiogram with fluorescein leakage from classic CNV and sharply demarcated hyperfluorescence of elevated retinal pigment epithelium due to fibrovascular pigment epithelial detachment and indicative of occult CNV. Elevated blocked fluorescence still obscures choroidal fluorescence and possibly the inferior boundary of CNV. (D) Late phase of angiogram demonstrates fluorescein leakage from both classic and occult neovascularization. Note hardly discernible EBF. (E) Composite drawing using multiple stereoscopic photographs of angiogram shows interpretation of boundaries of lesion. Since each lesion component (classic CNV, occult CNV, blood, and EBF) has well-demarcated boundaries, boundaries of entire lesion are considered well demarcated.

(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.)

Fig. 66.13 (A) Subfoveal choroidal neovascularization (CNV) and contiguous blood. (B) Early phase of fluorescein angiogram shows classic CNV with blocked fluorescence corresponding to contiguous blood that obscures boundaries of CNV along temporal border. Remaining blocked fluorescein surrounding CNV (elevated when viewed stereoscopically) was probably due to the fibrous component of CNV. (C) Late phase of fluorescein angiogram demonstrates that borders of CNV, blood, and elevated blocked fluorescence (green, red, and blue, respectively, in (D) were derived from viewing the entire stereoscopic fluorescein angiogram taken according to study protocol. (D) Drawing demonstrates that combined areas of blood and elevated blocked fluorescence that obscured borders of CNV did not exceed area of visible CNV.

(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.)

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.

Fig. 66.14 Algorithm for verteporfin therapy or laser photocoagulation or observation for symptomatic patients with age-related macular degeneration, pathologic myopia, or other causes of choroidal neovascularization (CNV) in which the natural course is likely worse without treatment. MPS, Macular Photocoagulation Study, and now largely replaced by anti-VEGF therapy as outlined in Fig. 66.21.

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.

Fig. 66.15 (A and B) Example of speckled fluorescence noted in an eye with choroidal neovascularization. Multiple punctuate spots of hyperfluorescence within 500 µm of each other are apparent in a late phase frame (B) but cannot be detected in early phase frame (A). Note the typical appearance of clusters of speckles at the edge of the CNV lesion.

(© Neil M. Bressler, MD, Johns Hopkins University, 2011.)

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.

Fig. 66.16 Fading fluorescence of occult choroidal neovascularization (CNV) contiguous with classic CNV. (A) Early phase of angiogram shows classic CNV with contiguous areas of slightly elevated hyperfluorescent retinal pigment epithelium (RPE) with a vascular pattern, presumably a fibrovascular pigment epithelial detachment, and other less well-demarcated areas of hyperfluorescence nasal to the fovea. (B) Later phase of angiogram shows fluorescein leakage from classic CNV. However, areas of elevated hyperfluorescent RPE on early phase of angiogram (left) begin to fade, and vascular pattern is no longer apparent. Faded area is not considered a lesion component because hyperfluorescence does not meet minimal leakage/staining standard for occult CNV.

(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.)

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,^52–57 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.

Fig. 66.17 Photomicrograph of choroidal neovascularization (outlined by small arrows) beneath the retinal pigment epithelium growing through a break in Bruch’s membrane (large arrows).

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

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.)

Choroidal neovascularization

CNV may arise in association with a number of conditions other than AMD, such as OHS, pathologic myopia, angioid streaks (especially when associated with pseudoxanthoma elasticum), choroidal ruptures, and idiopathic causes. Whether AMD is present when CNV arises in patients older than 50 years without drusen is controversial.

CNV may masquerade as central serous chorioretinopathy. Although the classic case of central serous chorioretinopathy shows a “smokestack” configuration on fluorescein angiography, the more common presentation is a dot of hyperfluorescence that merely increases in size and intensity of fluorescence, much like a small area of CNV. One must strongly consider CNV in patients aged 50 and older who have typical central serous chorioretinopathy. In these cases the increased age contrasts to the third to fifth decades, when central serous chorioretinopathy is most commonly seen. Presentation of central serous chorioretinopathy in an elderly patient with drusen can be difficult to distinguish and should alert one to the possibility of CNV, necessitating careful follow-up. If CNV is indeed present, growth of the area of hyperfluorescence might be detected while treatment may still be beneficial.

Basal laminar, or cuticular, drusen may be complicated by foveal detachments of vitelliform material in one or both eyes that may mimic neovascular AMD. Contact lens examination with transillumination of the fundus in these cases reveals an appearance similar to that of pigskin, with a myriad of small drusen. Angiographically, literally hundreds of bright spots appear very early during the angiogram, an appearance that has been described as a “starry sky.” These patients are usually asymptomatic until they accumulate vitelliform lesions in the fovea. The ensuing foveal detachment by this material, which can be unilateral or bilateral, simulates the foveal detachment that occurs with subfoveal CNV. The hyperfluorescence usually progressively fills the area of vitelliform material, rather than showing one area of bright fluorescence early that leaks late in classic CNV. Unlike subfoveal CNV, which most often progresses to a disciform scar with visual acuity of 20/200 or worse, eyes with a foveal detachment secondary to cuticular drusen resolve without scarring. The retina then may or may not have an area of RPE atrophy about one to two disc areas in size. Foveal acuity with atrophy is more often in the range of 20/80 to 20/125, in contrast to the more severe visual loss that accompanies true subfoveal CNV. Patients with cuticular drusen can still develop typical drusen associated with AMD or CNV.

Pattern dystrophies of the RPE may also have vitelliform detachments in which the angiographic pattern can mimic CNV. When one identifies any condition with a vitelliform detachment, it is critical to determine if the late-phase bright fluorescence is progressive fluorescein staining of the vitelliform material or leakage of fluorescein from CNV. The former would not benefit from laser photocoagulation, whereas the latter might. As discussed earlier, usually the fluorescence from a vitelliform detachment shows one or more areas of hyperfluorescence in the early phase of the angiogram with progressive hyperfluorescence of the entire area of yellow vitelliform material by the late phase. In contrast, a diffuse area of hyperfluorescence in the late phase that corresponds to classic CNV (rather than the stippled fluorescence of occult CNV) should show an area of bright hyperfluorescence in the early phase that is only slightly smaller than the area of hyperfluorescent leakage in the late phase.