Indocyanine Green Angiography
Indocyanine green angiography (ICGA) provides improved imaging of choroidal vascular circulation relative to other modalities such as fluorescein angiography. Therefore, it allows better visualization of choroidal pathologies and can even allow viewing of this vascular system when there is an obstructing disease process in the retina (e.g. hemorrhage, drusen, etc.). ICGA can help with diagnostic confirmation and management of choroidal disease processes.
The physical and physiological properties of indocyanine green (ICG) were first described by Fox and Wood in 1960. ICG was first used in vivo in 1970 by Kogure and others to visualize the fundus of an owl monkey. It was not routinely used in humans in the 1970s because of technological limitations, making it infeasible to use in the clinical setting. However, there was an uptick in its usage in the 1990s due to improvements in digital angiography, scanning laser ophthalmoscopy, optical alignment, and video monitors. The advent of ICGA allowed for better detection of occult choroidal neovascularization (CNV), which in turn lead to an increase in the number of eyes that were eligible for photocoagulation which, at the time, was the only treatment for CNV. However, when anti-vascular endothelial growth factor (anti-VEGF) was shown to improve mean visual acuity in patients with CNVs, there was a decreased need to use ICGA to pinpoint areas of occult CNV for phototherapy.
There are two properties that make ICG an effective dye for visualizing choroidal vasculature. The first is that a high proportion of indocyanine binds to circulating proteins and the second is the wavelength spectrum at which it absorbs and fluoresces photons.
- Ninety-eight percent of indocyanine is bound to serum protein, causing the molecule to be sequestered inside the choriocapillaris instead of escaping through its fenestrations. Comparatively, leaking fluorescein (only 80% bound) from the choriocapillaris can obscure the details of the underlying choroidal vasculature.
- Another drawback of fluorescein dye in visualizing the choroid is that the molecule absorbs and emits photons of a shorter wavelength. This can be an issue because the retinal pigment epithelium also absorbs and emits photons around this wavelength and the resulting scatter from the epithelium can subsequently obscure the choroid. Indocyanine, however, absorbs and emits photons in the infrared spectrum, allowing the viewer to see the choroid through the retinal pigment epithelium or through disease processes such as hemorrhage.
See “Dyes in Ophthalmology” for more information.
For a thorough review of the uses of indocyanine green see Cohen et al.’s “Is indocyanine green still relevant?” editorial in Retina 2011.
Although the identification of CNV is not as crucial for the management of ARMD patients as it was in the past, ICGA should still be utilized in cases of ARMD when there is doubt in the diagnosis. If, after FA and OCT, one cannot exclude conditions such as central serous chorioretinopathy or idiopathic polypoidal choroidal vasculopathy, ICGA can provide additional objective information to differentiate these entities from CNV.
One of the most important uses of ICGA is for patients with PCV. It can help guide treatment primarily in three ways:
1. ICG can help reveal the entire disease, particularly the polypoidal lesions and the branching vascular networks.
2. It can help identify active PCV for selective treatment
Together with ultrasonography, ICGA is effective at identifying choroidal hemangiomas. This is because it has a very distinctive filling pattern on ICGA: In the early phase there is progressive filling of of abnormal choroidal vessels, followed by very intense hyperfluorescence at 2-4 minutes, with decreased fluorescence of the tumor at later frames compared to the rest of the choroid - this is known as the washout phenomenon. ICGA has not proved particularly useful for the diagnosis of other tumors of the choroid.
Using ICGA in the setting of pathologic myopia may be of use in getting a clearer view of the pathology. ICGA can be used to visualize CNV inside areas with lacquer cracks or underneath subretinal hemorrhages related to these newly formed lacquer cracks.
Angioid streaks are typically more clearly visualized, more numerous, and larger when using ICGA as compared to FA or fundus exam.
ICGA is helpful in the diagnosing of these white dot syndromes, particularly if the white retinal dots are of an atypical nature or have already faded away. ICGA in these scenarios can show a hyperfluorescent area surrounding the optic nerve, and numerous hyperfluorescent dots scattered throughout the posterior pole.
In this disease process, ICGA can show a unique fluorescence pattern in areas exhibiting white spots due to what is likely delayed choroidal filling.
Differences (e.g. background can be dark in early phase with many hyperfluorescent lesions seen in the intermediate phase, suggesting a choroidal circulatory disturbance in the acute phase) in ICGA patterns in Vogt-Koyanagi-Harada disease can help distinguish between acute and chronic phases of this disease. ICGA can also be used to monitor if steroid treatment is effective.
Differences (e.g. dark hyperfluorescent dots persist throughout the late phases of ICGA in the chronic form of the disease, but not in the active form) in ICGA imaging in the intermediate phase and late phase of birdshot chorioretinopathy can help to monitor treatment effects by visualizing the presence and resolution of active disease.
While posterior inflammation involving the choroid could be seen in many infectious processes, it does not help with the diagnosis or management of many of the conditions.
ICGA commonly shows hyperfluorescent curvilinear areas forming a reticular pattern in this dystrophy, therefore ICGA could be useful in making a discrepancy between typical and atypical flavimaculatus.
ICG is injected at a loading dose of 25 mg either immediately after fluorescein injection or as a mixture of both fluorescein and ICG. There are three temporal phases for ICG imaging, similar to fluorescein angiography. The three phases are:
Early phase - 1 minute after injecting the eye, this is when larger choroidal arteries and veins are highlighted, as the dye is still making its way through the choriocapillaris.
Middle phase - 5 to 15 minutes after injection, at this time the choroidal vasculature is now more diffuse and less distinct.
Late phase - >15 minutes after dye injection, during this phase a hyperfluorescent lesion is more visible against the slowly fading background.
An editorial described that there were four reports of patients who have experienced an adverse reaction out of a total of 240,000 indocyanine intravenous injections. One patient had urticaria and then three with anaphylactic reactions with one resulting in death. Another study looked at 1923 patients with ICG angiograms and only one had a severe adverse reaction (a decrease in blood pressure without anaphylaxis).
1. Prior allergic reaction to ICG
2. Iodine allergy (ICG is dissolved in an aqueous sodium iodide solvent).
1. End stage renal disease
2. Liver disease
3. Pregnancy (Category C)
Overall, ICGA is a safe and important imaging modality that differs from fluorescein angiography in that its properties allow better view of the choroidal vasculature and related pathologies. Although no longer used as often in cases of AMD, ICGA is still particularly helpful in guiding treatment in PCV and CSC and for the diagnosis of choroidal hemangiomas.
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