9.6.7Indocyanine Green Technique

The dye injection for indocyanine green angiography is similar to that done for fluorescein angiography. The photographer should be ready to record images fairly soon after injection, because the choroidal vessels fill before the retinal vessels. Midphase photographs are taken at two different time points – one around 5 min and the second about 10 min after injection. Late phase photographs are taken about 30 min after injection. Generally, scanning laser systems record the filling phases with greater temporal resolution than do fundus camera systems. On the other hand, late phase photographs are better imaged with fundus cameras.

9.7Fluorescein Angiographic Interpretation

In serum, about 80% of the fluorescein is bound to protein and 20% is unbound; the binding alters the absorption and emission spectra slightly. The unbound fluorescein is freely diffusible. It is normally restricted in its diffusion by the blood ocular barrier, which is a combination of two separate anatomical boundaries controlling the flow of solutes and fluid into the eye. The outer portion of the blood ocular barrier is formed by the retinal pigment epithelium. The inner portion of the blood ocular barrier is formed by the walls of the retinal vessels.

9.7.1Filling Sequence

The larger choroidal vessels start to fluoresce first, about 1 s before the retinal arterioles. With fluorescein angiography, the retina circulation is easier to appreciate because it exists largely in two dimensions, it fills from one central point, and it lies over the pigmented RPE which provides a contrasting background. The initial phase of fluorescein filling is called either the “early phase” or the “arterial phase.” The dye front quickly moves through the retinal vessels, but the photographer may be able to demonstrate the dye front moving through the retinal arteriolar system in one of the early fluorescein frames. Successively smaller retinal arterioles fill as the dye front approaches the capillary bed. When the dye front reaches the capillaries, the retinal fluorescence suddenly increases with a blush of luminescence, this time from the retina. While it is not possible to see the vessels of the choriocapil-

laris, it is easy to see individual perifoveal capillaries in a patient with no media opacities.

The dye front then reaches the post-capillary venules and then the larger veins. This trip occurs within a few seconds in a healthy individual, but in an elderly person, the artery-to-vein time may be increased. The dye bolus eventually leaves the eye, and for a few seconds, the total fluorescence from the fundus appears to decrease somewhat. Shortly later, the bolus of dye recirculates through the body and reappears in the ocular circulation. With the reappearance of the dye, the fundus fluorescence increases somewhat. The stage of the angiogram within a minute after injection of dye is sometimes referred to as the recirculation phase. The recirculation phase is readily evident to the photographer or when looking at a video playback from a scanning laser ophthalmoscope, but is less evident when looking at still pictures. Images taken 1–3 min after injection are commonly referred to as midphase photographs. The total fluorescence, though, decreases with time as the dye is removed from the blood stream. After about 5 min or so, the fundus is much darker than after the initial injection of dye. This stage is considered to be the late phase of the angiogram.

9.7.2The Macula

The macular area has a unique pattern of fluorescence as determined by its anatomy. During the fluorescein angiogram, the fovea appears darker than the surrounding areas for several reasons. The fovea itself is avascular, and so, no retinal capillary blush occurs. The macula appears yellow because xanthophyll pigment absorbs shorter wavelengths of light, reducing any excitation of fluorescein dye. The retinal pigment cells in the macular region are taller and have more melanin pigments than the retinal pigment epithelial cells elsewhere, and therefore, both the excitation and the resultant fluorescent light from the underlying choroidal vessels are reduced.

9.8Deviations from Normal Angiographic Appearance

Hyperfluorescence is when there is an excess of fluorescence, either because an excess of angiographic dye is present in any unit volume of the fundus, or because our visualization of the fluorescent material is enhanced. Under normal circumstances, the presence of melanin in the choroid and retinal pigment epithelium and the presence of xanthophyll pigment in the macula form an

Table 9.1 Fluorescein hyperfluorescence characteristics associated with age-related macular degeneration

the increased penetration through melanin in the RPE and choroid, blood and exudation, indocyanine green frequently can show details of vascular structures in the choroid not apparent during fluorescein angiography. One variant of choroidal neovascularization, polypoidal choroidal vasculopathy, has a distinctive appearance in indocyanine green angiography. There are vascular channels with aneurysmal dilations at the outer border of the vascular lesion.

impediment to our visualization of choroidal fluorescence. A decrease in any of these factors would allow for a greater transmission of fluorescence to be visible, and the resultant regions are called transmission defects. A second reason for hyperfluorescence can be the abnormal accumulation of dye either within the vascular space of abnormalities in the vasculature or in extravascular leakage. An obvious example of excessive vessels is the presence of choroidal neovascularization. Leakage can also occur from vessels. By convention, leakage of fluorescein into a space results in pooling of the fluorescein while leakage into a tissue is called staining.

There are two main causes for hypofluorescence: Either there is less fluorescein present or there is something blocking our view of the fluorescein (Tables 9.1 and 9.2).

9.10.1 Drusen

Drusen have been divided into a number of groups chiefly based on their size and appearance. Drusen may be large, >125 mm (about the diameter of an arcade vein near the optic disk), intermediate 63–124 mm, or small, <63 mm. The retinal pigment epithelium often is thinner over the surface of a druse, producing a transmission defect. Smaller drusen can sometimes appear bright early in a fluorescein angiogram. On occasion there may be a myriad of small drusen, termed cuticular drusen. During fluorescein angiography, basal laminar drusen appear as a “starry sky” of thousands of points of light. Not uncommonly cuticular drusen may be associated with a deposition of yellow subretinal material that mimics vitelliform dystrophy. Patients with this deposition of material frequently have fluorescein leakage that may mimic CNV (Fig. 9.4).

A particular distribution of small drusen is seen in malattia leventinese, an inherited disorder traced back to descendents from a Swiss valley. These eyes have a radial distribution of small drusen associated with pigmentary changes. Soft drusen usually are not readily visible in the early phases of a fluorescein angiogram, but may stain later (Fig. 9.1). Subretinal drusenoid deposits, also known as reticular pseudodrusen, are subretinal drusen that do

Fig. 9.4 This patient has numerous small drusen with some larger drusen visible in the posterior pole (upper left). There also is a subtle collection of light yellow material in the central fovea. The fluorescein angiogram shows innumerable small drusen that are hyperfluorescent (upper right) [24]. There is an increased amount of fluorescence in the central macula, which may mimic

that from choroidal neovascularization. Bottom, the optical coherence tomography scan shows the mound-like elevations of the drusen, but no neovascularization. There is subretinal fluid, which is a very common finding in patients with early detachment related to cuticular drusen [25].

Fig. 9.5 Top, a patient with classic CNV who shows subretinal blood (left), early hyperfluorescence (middle), and late leakage (right). Bottom, a patient with predominantly

occult CNV: (left) a diffuse elevation at the level of the RPE; (middle) early hypofluorescence; (right) late, poorly defined hyperfluorescence

vascular anastomosis to the endovascular process in the fellow eye [29]. Focal hyperpigmentation has two main OCT correlates: the first is localized thickening of the RPE layer and the second is small hyperreflective aggregates in the outer retina.

An additional pigmentary alteration is atrophy, which can occur in sharply defined areas of severe atrophy, known as geographic atrophy, or in less well-defined, more granular regions of less severe atrophy known as non-geographic atrophy. The outer borders of a region of geographic atrophy are slightly hyperpigmented at the level of the retinal pigment epithelium, and this hyperpigmented zone occasionally is hyperautofluorescent [30], suggesting as one of many possibilities, the cells bordering areas of geographic atrophy may contain excessive lipofuscin. During fluorescein angiography, there is a welldemarcated region of late hyperfluorescence without signs of leakage. This hyperfluorescence is from visible staining of deeper layers of the eye, such as the sclera, without normal blockage by overlying pigment. The angiographic appearance early in the fluorescein depends on the amount of retained choriocapillaris. Generally geographic atrophy shows increasing fluorescence during the early and midphases of the fluorescein angiogram. More austere forms of geographic atrophy show early fluorescence of the

larger choroidal vessels and a lack of overlying choriocapillaris. Geographic atrophy appears hypofluorescent during indocyanine green angiography because of the lack of choriocapillaris and because of the lack of an overlying retinal pigment epithelium, which shows normal physiologic staining late in the angiographic sequence.

9.12Neovascular AMD

Vascular ingrowth causes physiologic and architectural alteration in the macular region, and this alteration can be detected and evaluated with angiography (Fig. 9.5). The vessels usually grow in the inner portion of Bruch’s membrane, although they may penetrate into the subretinal space. The angiographic appearance of choroidal neovascularization is governed by the location, density, and maturity of the new vessels as well as the amount and character of the intervening tissue. CNV manifesting as delineated hyperfluorescence early in the angiographic sequence with leakage later is termed classic, while vessels that are not particularly hyperfluorescent that show leakage late are termed “occult.” At one time occult CNV was divided into late leakage of undetermined source or as a fibrovascular pigment epithelial detachment. With

Fig. 9.6 (Upper left) This patient has choroidal neovascularization with retinal vessels that appear to descend to anastomose with the neovascular process. (Top right) The fluorescein angiogram demonstrates the CNV, but not the anastomosis. (Lower left)

The indocyanine green angiogram shows evidence of retinal vascular anastomosis with the underlying CNV. (Lower right) An enlargement with contrast enhancement more clearly shows the anastomotic vessels

the advent of improved imaging, particularly optical coherence tomography, nearly all patients with occult CNV prove to have a fibrovascular PED.

Generally CNV seen as classic during fluorescein angiography is not imaged as dramatically by indocyanine green angiography. Classic CNV does not show prominent leakage during ICG angiography, probably because of the higher protein binding of ICG. Occult CNV, either fibrovascular PEDs or late leakage of undetermined source, shows a variety of patterns during ICG angiography. Curiously, areas of CNV that appear very poorly defined during fluorescein angiography can be well defined during ICG angiography. Most regions of occult CNV appear as relatively large plaques during ICG angiography. Some occult lesions show minimal if any abnormalities during ICG angiography.

Indocyanine green angiography is indispensible in three main conditions.

–Retinal vascular anastomosis to CNV is usually easier to demonstrate with ICG angiography as compared with fluorescein angiography (Fig. 9.6). While this may not be important for anti-vascular endothelial growth factor (VEGF) based therapies, it probably is an indication that thermal laser photocoagulation would prove to be unsuccessful.

–The second main use of ICG angiography is to differentiate central serous chorioretinopathy (CSC) from occult CNV. Eyes with CSC have dilated vessels in the filling phases, multifocal choroidal vascular hyperpermeability in the midphases, and silhouetting of the larger vessels in the later portions of the angiogram. Occult CNV shows a

Fig. 9.8 This Asian patient had an extensive region of neovascularization, yet retained 20/30 acuity. (Upper right) The vascular network is not readily visible, but the aneurysmal changes are (arrowheads). (Upper right) Indocyanine green angiography shows prominent aneurysmal dilations. Visualization of the vascular network is partially obscured by the

simultaneous visualization of the underlying choroidal vessels. (Lower left) The vascular network is easier to visualize in the midframes of the angiogram while the aneurysmal dilations remain readily visible (arrowheads). (Lower right) There is late staining of the walls of the aneurysmal dilations (arrowheads) and washout of the dye centrally