Figure 10.1 FA patterns as they pertain to AMD.
Hyperfluorescence in AMD can be the result of loss of the normal barrier to background choroidal fluorescence known as transmitted fluorescence. Examples include hard drusen, nongeographic atrophy (non-GA) of the RPE in which abnormal background fluorescence fades during the course of the study (window defect), and geographic atrophy (GA) of the RPE in which atrophy of the choriocapillaris reveals the staining of the underlying sclera (13). Leakage of dye into a confined space is characterized by progressive, uniform hyperfluorescence known as pooling, which can be seen with soft drusen and serous RPE detachment. Abnormal blood vessels are noteworthy for their lack of intercellular tight junctions allowing permeability to fluorescein. CNV and intraretinal neovascularization (IRN) in AMD lead to early and progressive hyperfluorescence with late leakage.
INDICATIONS FOR FA IN AMD
While FA is an integral part in the care process of AMD, it does not replace history and careful ophthalmic examination in assessing a patient, and it is not required for all patients or at each visit (9). FA is indicated for any patient with AMD and vision loss, metamorphopsia, or new scotoma in which CNV is suspected (14,15). Because not all patients with neovascular AMD are symptomatic, those at high risk for developing CNV should be carefully examined for signs of such changes (16). While stereoscopic slit lamp ophthalmoscopy can usually detect evidence of CNV (including subretinal fluid, hard exudate, blood, pigment epithelial elevation, or a gray-green membrane), angiography is needed to detect the size, exact location, and leakage characteristics of the lesion (17). CNV may be undetectable by clinical examination alone. In patients with clinical signs of advanced nonneovascular AMD, FA may be helpful in assessing progression of pigment epithelial atrophy, particularly if vision changes are reported.
Because of the increasing incidence of AMD with age, elderly patients with media opacity that may limit careful macular examination, such as cataracts or keratopathy, may benefit from FA (13). Angiography may reveal neovascular or nonneovascular changes that might alter the treatment recommendations or preoperative counseling regarding cataract extraction or corneal transplantation.
FA is a crucial part of the postoperative assessment in patients with CNV who have undergone thermal laser photocoagulation or verteporfin PDT because of the greater sensitivity in detecting CNV, revealing a significant percentage of recurrent lesions not suspected on clinical examination (18). Based on the MPS, for treatment of classic CNV including well-demarcated boundaries with thermal laser, the initial postoperative FA is indicated between 2 and 4 weeks to confirm that the entire CNV lesion has been treated and is obliterated. If adequate treatment is present, repeat FA should be performed in 4 to 6 weeks followed by intervals at the discretion of the treating physician (9). According to the TAP and Verteporfin in Photodynamic Therapy (VIP) studies following verteporfin PDT, the evidence suggests repeat FA should be performed at 3-month intervals with retreatment as indicated (19). Like the MPS, TAP, and VIP, similar angiography protocols should be used, including early-, mid-, and late-phase 30-degree film stereophotos centered on the macula after rapid (less than 6 seconds) injection of 5 mL of 10% of sodium fluorescein solution (10).
Over the past two decades, a great deal of effort and expense has gone into the study of new treatments for neovascular AMD. These studies could not be carried out without the ability of FA to objectively document treatment response. Ongoing trials with injected antiangiogenic drugs, non–verteporfin PDT, prophylactic laser to high-risk nonneovascular AMD, transpupillary thermotherapy, radiation therapy, selective feeder vessel laser therapy, serum apheresis, submacular surgery, and macular translocation all include FA in their pretreatment and posttreatment protocol. Currently, there are insufficient data to direct the use of FA after these unproven treatments (9).
ANGIOGRAPHIC PATTERNS IN AMD
The majority of patients with AMD have the nonneovascular form, which consists of drusen and RPE abnormalities. Several types of drusen exist that differ histopathologically and angiographically. Hard drusen are small (63 μm), round discrete deposits on ophthalmoscopy that correspond to lipidized RPE or accumulation of hyaline material in the inner and outer collagenous zones of the Bruch’s membrane (20). In FA, hard drusen typically appear as transmission defects due to overlying RPE thinning or depigmentation (21). Angiography often reveals a greater number of hard drusen than can be seen clinically (22).
Soft drusen are larger (greater than 63 μm) with irregular, poorly defined borders and the propensity to coalesce and become confluent. FA of soft drusen shows progressive hyperfluorescence and dye pooling without leakage beyond its margin (Fig. 10.2). Histopathologically, soft drusen are localized detachments between the RPE and (a) basal laminar deposit in an eye with diffuse basal laminar deposit, (b) basal linear deposit in an eye with diffuse basal linear deposit, or (c) localized accumulation of basal linear deposit in an eye without diffuse basal linear deposit (20–24). Studies have also identified vascularization of soft drusen, which may account for a component of the hyperfluorescence (21).
Figure 10.2 Soft drusen and drusenoid RPE detachment. A. Fundus photograph. Early (B) and late (C) angiogram demonstrating progressive hyperfluorescence from dye pooling. Arrow indicates an area of focal hyperpigmentation.
When soft drusen coalesce, the resulting irregular, shallow elevation of the RPE is referred to as drusenoid RPE detachment (23). Unlike a serous RPE detachment, where FA staining uniformly increases during the study and remains bright in the late phases, drusenoid RPE detachment is less fluorescent and either stains faintly or fades in the late phases of the study (13) (Figs. 10.2 and 10.3).
Figure 10.3 Pigment epithelial detachment. A. Fundus photograph. Early (B) and late (C) angiographs demonstrating the uniform progressive hyperfluorescence, unlike a drusenoid retinal PED, which is less fluorescent and stains faintly in the late phases of the study (see Fig. 10.2).
Basal laminar drusen represent angiographically and histologically distinct deposits, which appear as innumerable, small, round, semitranslucent, yellow lesions on fundus biomicroscopy. FA reveals early, discrete hyperfluorescence and late fading that has been described as “stars in the sky” (25) (Fig. 10.4). Histopathology reveals basal laminar drusen to be nodularity of a diffusely thickened inner Bruch’s membrane (25).
Figure 10.4 Basal laminar drusen. A. Fundus photograph shows innumerable, small, round, semitranslucent, yellow lesions. B. FA reveals early, discrete hyperfluorescence. C. Late fading that has been described as “stars in the sky.”
In addition to drusen, nonneovascular AMD is defined by the presence of RPE abnormalities, including hyperpigmentation, non-GA, and GA. All forms of RPE change may be present in the same eye over time or simultaneously. Focal hyperpigmentation appears as a blocked fluorescence on FA and is characterized by focal RPE hypertrophy and pigment migration into the subretinal space and outer retina (21). Focal hyperpigmentation is often associated with soft drusen, GA, or neovascular AMD but may appear alone (Fig. 10.2).
RPE atrophy is a common feature in AMD and has been documented to replace regressed drusen or follow collapse of a serous RPE detachment (20–26). Non-GA and GA share the common histopathologic feature of RPE loss. However, in GA, this loss is more extensive, and there is associated atrophy of the overlying retina and underlying choriocapillaris leading to the difference in fluorescein appearance (Fig. 10.5). Non-GA typically appears as mottled early hyperfluorescence, which fades late consistent with window defect. Conversely, GA does not hyperfluoresce early because of the loss of underlying choriocapillaris; only larger choroidal vessels are apparent. Late in the FA, well-defined hyperfluorescence from staining of the exposed deep choroid and sclera is apparent (13).
Figure 10.5 Geographic atrophy of the RPE. A. Fundus photograph demonstrating loss of RPE with sharp borders and surrounding large drusen. B. Angiograph reveals well-defined hyperfluorescence from staining of the exposed deep choroid and sclera.
The term neovascular AMD refers to the presence of abnormal blood vessels, serous or hemorrhagic detachment of the pigment epithelium, lipid exudation, subretinal fibrosis, or disciform scar formation. The growth of abnormal blood vessels from the choroid into the Bruch’s membrane, as well as under and into the neurosensory retina, is known as CNV and accounts for the majority of severe vision loss in AMD. Angiographic criteria of classic and occult CNV were defined in the MPS.
This fluorescein-based classification was applied for the purpose of determining which patients would benefit from thermal laser photocoagulation intended to eradicate the entire neovascular lesion. Clearly distinguished boundaries were deemed essential to determine the location of the lesion and the distance from the lesion border to the center of the foveal avascular zone.
The interpretation of CNV evolved during the course of the MPS and later investigations into the following system described. The MPS has defined the term lesion component as the area of the retina containing CNV or interfering with the ability to define the boundaries of CNV. A neovascular lesion represents the entire complex of lesion components and may include the CNV and the features that block the view of the boundaries (27).
Classic or well-defined CNV is an area of early hyperfluorescence with well-demarcated boundaries and progressive pooling of dye leakage in the overlying subretinal space in the later phases of the angiogram that usually obscures the boundaries of the CNV (28).
Initially, the boundaries are well demarcated, allowing the clinician to accurately determine the location of the lesion and the distance from the lesion border to the center of the foveal avascular zone. Occasionally, the capillaries of the CNV appear as a lacy cartwheel network in the early phase. Because the new vessels leak, progressive hyperfluorescence and blurring of the lesion edge continue during the course of the FA (Fig. 10.6). This leakage may pool in the subretinal space if a neurosensory retinal detachment is present or may collect in the outer plexiform layer in the form of cystic retinal edema. Dye pooling well demarcated in a confined space of a localized sensory retinal detachment or within intraretinal cystic spaces has been termed loculated fluid (29). Loculated fluid was a common finding in patients with new subfoveal CNV in the MPS and may confuse the treating physician as to the boundary of the lesion. A variant of classic CNV has been described in which new vessel filling is slower and the boundaries are not distinguished until approximately 2 minutes after dye injection. Despite a slow fill, the boundaries present initially correspond to the area of leakage in the late frames (8). Classic CNV has been further categorized based on location with respect to the fovea: (a) Extrafoveal CNV is greater than 200 μm from the foveal center, (b) juxtafoveal CNV is located between 1 and 199 μm from the foveal center, and (c) subfoveal CNV is located under the center of the fovea. In the TAP and VIP studies, lesion component proportions were further delineated. A neovascular lesion in which the CNV component is greater than 50% of the total lesion size is defined as predominately classic. Lesions in which the classic CNV component comprises less than 50% of the total area are referred to as minimally classic (30).
Figure 10.6 Classic choroidal neovascularization. Early (A) and late (B) angiographs showing early well-demarcated hyperfluorescence with late leakage.
Occult or poorly defined forms of CNV are classified in two distinct patterns of hyperfluorescence, fibrovascular pigment epithelial detachment (PED) and late-phase leakage of undetermined source (28). Fibrovascular PED is defined as an irregular elevation of the RPE detected on stereoangiography associated with stippled hyperfluorescence apparent 1 to 2 minutes after fluorescein injection with persistent staining or leakage of dye in the overlying subretinal space by 10 minutes (Fig. 10.7). Fibrovascular PED differs from classic CNV in that the early hyperfluorescence is not as discrete or as bright and the boundaries usually remain indeterminate. In addition, the smooth RPE elevation, uniform progressive hyperfluorescence, and late, well-demarcated pooling of a classic, serous PED should not be confused with fibrovascular PED.
FIGURE 10.7 Mid (A) and late (B) angiogram of occult CNV in the form of fibrovascular PED. There is stippled hyperfluorescence apparent 1 to 2 minutes after fluorescein injection with ill-defined leakage in the late frames.
Occult CNV with late-phase leakage of undetermined source lacks a discernible, well-demarcated area of leakage in the early frames of the FA. Speckled hyperfluorescence with no visible source becomes apparent 2 to 5 minutes after dye injection and later pools in the overlying subretinal space (Fig. 10.8). This differs from the slow-filling variant of classic CNV in that the leakage source is never apparent.
Figure 10.8 Occult CNV in the pattern of late leakage of undetermined source. A. Fundus photograph. B. Early-frame angiograph demonstrating no apparent leakage source. C. Late frames reveal leakage into the subretinal space.