Investigations with ICGA and ocular applications date back to 1970 when Kogure et al.⁵ performed intra-arterial choroidal absorption angiography in monkeys. The quality of the images, using false-color infrared film along with the route of administration, limited this technique's usefulness. Reports describing intravenous injection of the dye and the use of black and white infrared film for absorption angiography followed.⁶ These changes allowed easier, more consistent angiograms. In 1973, Flower and Hochheimer⁷ described a method of ICG fluorescence angiography, providing improved resolution of the choroidal vasculature compared with absorption angiography.

Although a variety of fundus conditions were subsequently studied using ICG fluorescence angiography, clinically useful choroidal images remained elusive due to the limited ability of available systems to enhance low ICG dye fluorescence.⁸ In 1986 Hayashi et al.⁹ reported the use of an infrared-sensitive video camera to perform ICGA. Compared to prior film studies, videoangiography, along with improvements in illumination and excitation-barrier filter separation, advanced image quality.

Numerous reports followed indicating a potentially significant advantage of ICGA over FA in imaging choroidal pathologic processes. In 1989, Destro and Puliafito¹ demonstrated improved visualization of choroidal neovascularization (CNV) using ICGA compared with FA in selected cases. They also introduced the concept of late imaging, whereby images obtained after clearing of ICG dye from the choroidal circulation show persistent hyperfluorescent pathology against a dark background.

The use of higher-resolution digital monitors (1024-line) coupled with infrared-sensitive video cameras, described by Guyer et al.³ and then Yannuzzi et al.⁴ in 1992, provided even better images. ICG enhanced visualization of choroidal lesions, such as CNV, compared with FA was consistently obtained in several large clinical series.^4,10,11 Similar ICGA diagnostic yields in the setting of exudative macular degeneration were also obtained by investigators using SLO systems.^12,13

ICG is more highly bound to blood proteins than sodium fluorescein. Nearly 98% of circulating ICG is bound to various serum proteins, such as albumin and a-lipoprotein.^15,19,20 (Fluorescein dye is only 60% to 80% protein bound.) This high degree of binding and possible preferential binding to high–molecular-weight lipoproteins may explain the dye's apparent poor penetration of capillary fenestrations in the choriocapillaris. This tendency of ICG to remain intravascular facilitates visualization of the choroidal vasculature.^15,19,20

After intravenous injection, ICG is rapidly eliminated by the liver and exhibits minimal uptake in the peripheral tissues. ICG is not chemically altered in the liver and has been recovered in the bile unchanged.^15,21 There is no apparent reabsorption in the bowel. The dye is not detected in the cerebrospinal fluid and does not appear to cross into the placental circulation.²²

In the ophthalmic literature, a comprehensive analysis revealed seven reactions in a consecutive series of 1923 ICGA procedures performed in 1226 patients.²⁴ These reactions included nausea and vomiting in two cases, urticaria in two cases, vasovagal reactions in two cases, and acute hypotension in one case. This represents a 0.3% adverse reaction rate for ICGA. A review of the literature from this report identified 18 severe reactions and 3 deaths. With approximately 1 million doses sold at that point, a 1 in 333,333 incidence of death was estimated. There have been two additional cases of anaphylactic shock following ICGA.^25,26 In comparison, FA has an estimated adverse reaction rate of between 2.7% and 11.7% along with a death rate of approximately 1 in 222,000 angiograms²⁷; therefore, ICGA appears to be a safer test.

Given the chemical characteristics and pharmacodynamics along with the profile of patients who experienced some of the more serious adverse reactions associated with the use of ICG dye, ICGA is contraindicated in patients with iodine or shellfish allergies, liver disease, and end-stage renal disease. It should also be avoided in pregnancy at this time, given the lack of human toxicity data in this area.²⁸ Extravasation of the dye causes local tissue irritation and can produce tenderness, but no significant permanent tissue damage has been reported.

Digital imaging cameras are similar to 35-mm film cameras. Instead of a shutter and exposure of a silver-based film, an electromechanical shutter opens, sending light to a computer coupling device (CCD) containing light-sensitive elements called pixels. The camera then converts the analog signal to a digital signal and stores the image in a hard drive for immediate viewing. The CCD in an ICG camera is designed to sense infrared light wavelengths. The images are captured at one frame per second and displayed on a high-resolution video monitor. The stored images are then printed as hard copies or saved as digital files. The combination of an infrared light-sensitive camera with a digital imaging system allows high-resolution (1024 line) images needed for useful clinical ICG angiography. Computer software also allows clinicians to digitally enhance the ICGA images. These contrast-enhanced angiograms allow for higher diagnostic yield when compared to nonenhanced images.²⁹

Two confocal scanning high-speed infrared laser ophthalmoscopes are being used in clinical practice (Heidelberg Retina Angiograph (HRA), Heidelberg Engineering GmbH, Heidelberg, Germany, and Rodenstock SLO, Canon, Tokyo, Japan). The high-speed ICGA (HS-ICGA) HRA allows frame capture up to 20 frames per second. Due to the confocal system and laser illumination, the HRA detects faint hyperfluorescence and digitizes with high pixel resolution. These 30-degree field-of-view images are usually obtained in the transit phase of the ICGA after a 0.3 mL bolus of ICG injected rapidly after a 5-mL saline flush. This imaging system allows high resolution and evaluation of vessels with a diameter of 50 microns.

Gelisken et al.³² examined 100 consecutive occult CNV patients with SLO versus high-resolution digital fundus ICGA. They found that the SLO was superior in detecting well-defined vessel structure, whereas the digital fundus camera best detected focal hyperfluorescent spots and late-appearing plaques.

The “early” phase (0–3 minutes after injection) encompasses the period from the first appearance of ICG dye in the choroidal arterial circulation to the point of maximal ICG choroidal hyperfluorescence, usually occurring within the first minute after the injection of dye (Fig. 1A). During this phase, both medium and large choroidal arteries and veins are well visualized beneath the hyperfluorescent retinal vasculature. Individual choriocapillaris vessels cannot be distinguished. The areas surrounding middle and large choroidal vessels appear relatively hypofluorescent. This “pseudohypofluorescence” is, at least in part, a result of a smaller volume of blood in the choriocapillaris compared with the larger vessels, with the illumination intensity adjusted for the strongest portion of fluorescence.

In the “middle” phase of the angiogram (5–15 minutes after injection), the choroidal veins become less distinct as a nearly homogeneous, diffuse choroidal fluorescence emerges (see Fig. 1B). The fluorescence from the retinal vessels also begins to attenuate. Lesions that demonstrate abnormal hyperfluorescence on ICGA typically begin to stand out in contrast to the fading surrounding normal background fluorescence by this point in the study.

In the “late” phases (beyond 18–22 minutes), all details of normal retinal and choroidal vessels are lost as the hyperfluorescence fades even further (see Fig. 1C). The choroidal vessels now stand out in relief as hypofluorescent channels and retinal vessels are no longer visible, and the optic nerve head is dark. There is maximal contrast with any abnormal hyperfluorescent lesions. The edges of such lesions may exhibit some “fuzziness” at this stage, apparently from limited dye leakage.

For the standard ICGA, 25 mg (12.5 to 50 mg) of ICG dye in the manufacturer's diluent is administered intravenously in a bolus fashion, similar to intravenous fluorescein angiogram protocols. Images are typically obtained at several second intervals until the retinal and choroidal circulations are maximally hyperfluorescent and then at approximately 30- to 60-second intervals for the first few minutes of the study to capture images through the early phase of the angiogram. Subsequent images are typically taken between 8 and 12 minutes for the middle phase and then between 18 and 25 minutes for the late phase. Most importantly, abnormal ICG hyperfluorescence is sufficiently identifiable by 25 minutes, but, occasionally, images obtained 30 to 40 minutes into the study are helpful. To image retinal and choroidal vessels in the late phase of the angiogram, a technique of reinjecting a small amount of ICG dye at 30 to 40 minutes into the study has been described.³³

The available software packages of most digital videoangiogram systems have image-enhancing and image-tracing capabilities. Limited improvement of image contrast can be obtained with various enhancement techniques. The ability to align and superimpose images and tracings (“warp tracing”) can be helpful in determining the location or size of a particular angiographic finding, with respect to other anatomic structures (Fig. 2).^4,11

PATHOPHYSIOLOGY OF CHOROIDAL NEOVASCULARIZATION

In AMD, it has long been postulated that focal choroidal ischemia may play a role in the development of CNV. Macular choroidal vascular “watershed” zones have been known to exist, but their causal relationship to CNV has never been determined. On ICG angiography, these presumed watershed zones appear as areas of relative, abnormal hypofluorescence in the early phases of the angiographic study.⁴⁴ A published ICGA analysis by Ross et al.⁴⁵ revealed a much higher incidence of the presumed watershed zones in the macula of eyes with AMD compared with age-matched control eyes (55% vs. 15%, respectively). Furthermore, Goldberg et al.⁴⁶ found that 92% of eyes that developed choroidal neovascular membranes had watershed zones. These data support the notion that watershed zones play a role in CNV development and that ICG angiography may be useful once again in identifying eyes at the highest risk for the exudative transformation. Other studies have shown that ICGA can distinguish the different types of drusen and, therefore, may be useful to evaluate the risk of progression of AMD.⁴⁷

CLASSIC CHOROIDAL NEOVASCULARIZATION

Classic CNV as determined by FA shows a similar appearance on ICGA with well-defined hyperfluorescence throughout the transit phase and leakage obscuring the borders of the lesion in the late frames. However, the leakage in the late frames tends to be less pronounced with ICGA. Overall, ICGA offers no advantage over fluorescein angiography in this setting.

OCCULT CHOROIDAL NEOVASCULARIZATION

Occult CNV assumes a variety of FA patterns.⁴⁸ There can be obscuration of the neovascularization from fluorescein blockage by overlying fluid or pigment or from rapid leakage of the dye in the area of interest. Sometimes there is slow, irregular fluorescein leakage with poorly delineated borders. With occult CNV, there may be varying degrees of uncertainty as to the precise location and extent of the choroidal neovascular membrane using FA alone.

Both fluorescein and ICG dyes appear to be retained by CNV and will, therefore, exhibit hyperfluorescence relative to surrounding tissue.¹ ICGA theoretically provides enhanced visualization of CNV in this setting because the ICG infrared fluorescence better penetrates pigment and fluid than the visible light fluorescence of sodium fluorescein, and the highly protein-bound ICG dye leaks less from abnormal vessels compared with fluorescein dye as described earlier. Several patterns of ICG hyperfluorescence for occult CNV have been observed.^4,11,49,50 These include early-appearing small hyperfluorescent spots (hot spots), plaque-like hyperfluorescence, collections of abnormal vessels, and late-appearing hyperfluorescence with indistinct edges (Figs. 3, 4, and 5). A combination of these patterns can be seen. Although thin blood is easily penetrated by the infrared fluorescence (Fig. 6), thick blood will still obscure the underlying choroidal pattern to some degree. Reichel et al.⁵¹ demonstrated that ICGA was superior to fluorescein angiography in determining the extent of CNV secondary to age-related macular degeneration obscured by hemorrhage.

Several investigators have demonstrated the ability of digital ICG angiography to not only confirm, but also better delineate CNV in certain cases of exudative AMD.^{1,3,4,10–13,33} Early large series by Yannuzzi et al.^4,52 and Regillo et al.,¹¹ using digital videoangiogram systems demonstrated well-defined hyperfluorescent foci of ICG presumably corresponding to the entire choroidal neovascular process in approximately 40% of cases, where FA revealed occult or ill-defined CNV only (see Figs. 3, 4, 5, and 6). A similar yield was reported early on by Kuck et al.,¹³ using SLO-based ICGA.

Furthermore, studies by Regillo et al.,¹¹ Sorenson et al.,⁵³ and Guyer et al.⁵⁴ have shown that laser photocoagulation of well-defined ICG hyperfluorescent foci with treatment guided solely by the ICGA findings resulted in short-term resolution of exudation and stabilization or improvement of vision in 56% to 69% of cases. Although prior studies with AMD patients have shown that occult or ill-defined CNV on FA have, in general, a poor visual prognosis,^55,56 adequate controls are not available to determine whether laser therapy as outlined in these studies significantly altered the natural history. Nonetheless, the data suggest that treatment based on ICGA findings may result in prompt resolution of exudation and improved visual acuity in selected cases. Therefore, this technique has the potential to increase the yield of exudative AMD cases that may be effectively managed by conventional laser photocoagulation treatment methods.

SERIOUS PIGMENT EPITHELIAL DETACHMENTS

In contrast to the bright hyperfluorescence on FA, serous pigment epithelial detachments most often appear either isofluorescent or slightly hypofluorescent; associated hyperfluorescent CNV is, therefore, more easily seen on ICGA (Fig. 7). In AMD, a serous pigment epithelial detachment (SPED) is usually associated with CNV. However, the CNV may not be adequately visualized with fluorescein angiography because of rapid fluorescein pooling into the sub-pigment epithelial space. With ICGA, the neovascular component shows a relative hyperfluorescence, whereas the serous component of the complex is isofluorescent or hypofluorescent due to the minimal amount of ICG leakage(Fig. 7) It was initially hoped that this would lead to an increased yield of successful laser treatment of such lesions. Baumal et al.⁵⁷ demonstrated that ICGA revealed CNV associated with SPED in 83% of eyes in which the CNV was not well delineated by fluorescein angiography. However, laser treatment to the presumed neovascular focus as guided by the ICGA findings did not change the visual outcome compared to controls. Lim et al.⁵⁸ showed a transient stabilization of visual acuity following ICGA-guided laser photocoagulation for CNV associated with SPED. However, the treatment benefit diminished with time. The collective experience of Retina Service members at Wills Eye Hospital indicate that most eyes with SPED do not seem to benefit from treatment, although there are occasional dramatic, favorable results. This is especially true if the neovascularization on ICG angiography is small and located at the edge (rather than within) of the SPED.⁴⁴

PRE– AND POST–LASER TREATMENT

ICGA may be a useful adjunct to FA in determining the presence or extent of recurrent CNV.^4,11,53 Photocoagulated areas on ICGA are completely hypofluorescent, and, compared with FA, there is greater contrast between the photocoagulated site and any associated persistent or recurrent CNV (Fig. 8). Preliminary data reveal a good correlation between treatment success and the lack of any residual abnormal ICG hyperfluorescence, indicating that the ICGA may accurately identify the presence of CNV.^11,53 This is further supported by a human clinicohistopathologic study in which a well-delineated plaque of hyperfluorescence on the ICGA corresponded precisely with abnormal subretinal pigment epithelial fibrovascular tissue identified by histopathologic examination of serial sections.⁵⁹ Regillo et al.⁶⁰ evaluated persistent and recurrent choroidal neovascularization and found ICGA to improve visualization of ill-defined choroidal neovascular complexes seen on fluorescein angiography. However, ICGA was not useful when evaluating post-treatment fluorescein angiograms negative for any CNV or when the FA showed well-defined CNV.

ATYPICAL NEOVASCULAR MACULAR DEGENERATIONS

Idiopathic Polypoidal Choroidal Vasculopathy

Polypoidal choroidal vasculopathy is a form of CNV with recurrent subretinal and sub-RPE serosangiousmacular detachments. The condition originally was thought to occur mainly in African-American women ages 40 to 80 years who are hypertensive or diabetic.⁶¹ However, recent studies have found this condition in Caucasian and Asian patients.⁶² IPCV demonstrates branching inner choroidal vessels with terminal aneurysmal-like dilatations. These lesions are most commonly found in the peripapillary region. However, isolated lesions can also be found in the macula or peripheral fundus.⁶³IPCV appears as early, intense unilateral or multifocal hyperfluorescent “hot spots” on ICGA. The late phase of the ICGA shows a washout from the center of the polypoidal lesion with staining of the surrounding choroidal vasculature^64–70 (Fig. 9) We have used ICGA to aid in the diagnosis of a case of presumed idiopathic polypoidal choroidal vasculopathy.^64,65 The characteristic multiple, saccular aneurysmal-like dilatations in the choroid were readily apparent under associated blood and exudate (Fig. 12). Conventional thermal laser photocoagulation of these choroidal vascular anomalies can lead to resolution of the exudative manifestations, and the ICGA may serve to guide treatment analogous to localizing and directing laser treatment in selected cases of exudative macular degeneration.⁶³ Successful treatment of IPCV lesions with photodynamic therapy has also been described.⁷¹

Retinal Angiomatous Proliferation

Retinal angiomatous proliferation (RAP) is a form of neovascular AMD in which the neovascularization appears to originate in the inner retinal layers then extends into the subretinal space, sometimes leading to a retinal-choroidal anastomosis. RAP lesions have a well-defined retinal–retinal anastomosis between the normal retinal vasculature and deep retinal vascular complex. With conventional fundus-camera based ICGA, RAP lesions show intense focal hyperfluorescence (hot spot) corresponding to the intraretinal neovascular focus. The lesion becomes more hyperfluorescent in the mid and late phases of the ICG as the dye leaks intraretinally.⁷² With SLO-based ICGA, both retinal feeding and draining vessels are often readily identified. RAP lesions are most easily detected when associated with a SPED with a background of ICGA hypofluorescence (Fig. 10) Identification of early stage RAP lesions may allow for successful treatment by a variety of approaches, such as conventional thermal laser treatment, photodynamic treatment (PDT), or surgical ablation of the anastomotic retinal vessels.^73,74

Choroidal Feeder Vessel Treatment

Using SLO-based ICGA, investigators have been able to identify choroidal “feeder” vessels of AMD-related subfoveal choroidal neovascularization. The SLO allows for rapid image acquisition with rates of up to 20 frames per second. This allows for differentiating choroidal arteries from veins, which is not possible with fundus camera-based ICGA. Using SLO–ICGA and concentrating on the early choroidal filling phase, investigators have been able to identify choroidal vessels that directly feed CNV in selected cases (Fig. 11) Treatment of these “feeder” vessels with laser photocoagulation may or may not result in long-term involution of CNV.^75–79 Further study with this treatment approach is needed.

MISCELLANEOUS MACULAR DEGENERATION STUDIES

Studies have suggested that ICGA may have predictive value for the development of CNV in AMD. Different groups of investigators have found that eyes known to have dry AMD with only drusen and alterations in the retinal pigment epithelium and no leakage on fluorescein angiography occasionally harbor ICG hyperfluorescent plaques. The plaques were discovered incidentally in patients in whom the fellow eyes had active exudative signs. By following these patients over time, it was determined that the eyes that were clinically dry with ICG hyperfluorescent plaques were much more likely to develop exudative manifestations than dry AMD eyes without ICG abnormalities.^80,81 Therefore, in people with dry AMD in one eye and a history of CNV in the fellow eye, the presence of incidental, abnormal ICG hyperfluorescence in the “dry” eye may be a predictive indicator of future exudative changes in that eye.⁴⁴

As expected, the different patterns of fluorescence of these tumors appear to reflect their different choroidal vascular architecture with only minimal or no leakage of the ICG dye. Choroidal hemangiomas consistently exhibit a relatively unique fluorescence pattern, and ICGA may be a helpful test in differentiating these lesions from potentially simulating tumors, such as amelanotic choroidal melanomas and choroidal metastases.⁸⁷ How ICGA compares with other diagnostic tests, such as FA and ultrasonography, in terms of sensitivity and specificity in this area is not known. Further investigation is needed to better assess its clinical utility in this area.

In pathologic myopia, CNV is usually well demarcated and easily detectable with fluorescein angiography. Therefore, ICG angiography is rarely utilized in this setting. However, when hemorrhage is present, it is not unusual for fluorescein angiography to fail in differentiating between CNV and lacquer crack formation as possible sources of blood. The prognosis (and possibly management) can be very different between these sources, with the latter entity alone usually resulting in a much more favorable visual outcome. ICG angiography can be useful in this setting. Abnormal hyperfluorescence from CNV will often penetrate thin layers of blood, and lacquer cracks show as hypofluorescent rather than hyperfluorescent lines.^88,89,90

There have been numerous reports of ICG angiographic findings with a variety of chorioretinal inflammatory diseases, such as multiple evanescent white-dot syndrome (MEWDS),^38,91 acute posterior multifocal placoid pigment epitheliopathy (APMPPE),^37,92,93 idiopathic enlarged blind spot syndrome,⁹⁴ angioid streaks,^95,96 Vogt-Koyanagi-Harada (VKH) syndrome,⁹⁷ and multifocal choroiditis.⁹⁸ In MEWDS, ICGA demonstrated multiple hypofluorescent lesions that obscured the underlying choroidal vessels.³⁸ These spots were more apparent and widespread compared with either ophthalmoscopic or fluorescein angiographic findings. ICGA-based choroidal blood flow analysis in two patients with APMPPE revealed a significant delay in choroidal filling and large areas of choroidal vascular nonperfusion in the acute stage of the disease.³⁷ In both conditions, the ICGA abnormalities completely disappeared as the conditions clinically resolved. Evaluation of the idiopathic enlarged blind spot syndrome with ICGA has revealed choroidal involvement with hypofluorescence involving the peripapillary area and the entire posterior pole.⁹⁴ ICGA for multifocal choroiditis showed multiple hypofluorescent spots in the posterior pole. This may be useful in distinguishing CNV from acute inflammatory foci in the macula.⁹⁸

Kohno et al.⁹⁹ have also demonstrated via ICGA an underlying choroidopathy following blunt trauma with lack of visual recovery. ICGA has also been used to confirm the diagnosis of a vortex vein varix in a patient suspected of having a choroidal tumor.¹⁰⁰ The technique was able to demonstrate dynamic pooling of ICG dye in the abnormal vortex vein ampulla as the field of gaze was shifted.

These findings are more often of academic interest in helping elucidate disease pathophysiology and determining relationships among these disease entities. At this time, ICGA, in general, has limited routine clinical utility in these conditions.

In general, laser treatment directed at abnormal ICG lesions should be performed only when there is a reasonable degree of certainty that the lesion identified is the source of the clinically apparent exudative manifestations. ICG abnormalities far outside the area of exudative signs or in the absence of exudative signs should be closely observed.⁴⁴

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