Indocyanine green angiography (ICGA) is a fluorescence imaging test in which ICG dye is injected intravenously and the fundus is photographed using near-infrared light. It allows detailed observation of choroidal vessels that are difficult to visualize with fluorescein angiography (FA).
ICG (indocyanine green) is a dark greenish-blue water-soluble dye with a molecular weight of approximately 775 (about 2.3 times that of fluorescein used in FA, which is about 332). The following optical properties are advantageous for choroidal imaging.
FA uses visible light with excitation at 465–490 nm and fluorescence at 520–530 nm, whereas ICGA uses near-infrared light that is less absorbed by RPE melanin. This wavelength characteristic enables visualization of sub-RPE and choroidal lesions that are difficult to depict with FA.
The main differences between FA and ICGA are shown below.
FA (Fluorescein Angiography)
Molecular weight: 332
Plasma protein binding rate: Approximately 80% → significant extravascular leakage
Excitation/Emission wavelengths: 465-490 nm / 520-530 nm (visible light range)
Main structures visualized: Retinal vessels, RPE damage, inner CNV
RPE permeability: Low → choroid difficult to visualize
ICGA (Indocyanine Green Angiography)
Molecular weight: 775
Plasma protein binding rate: ~98% → minimal extravascular leakage
Excitation/Emission wavelengths: 785 nm / 835 nm (near-infrared range)
Main structures visualized: Choroidal vessels, sub-RPE lesions, BVN
RPE permeability: High → clear visualization of choroid
In the 1960s, Fox and Wood first applied ICG in ophthalmology. In the 1970s, Kogure et al. reported its use for fluorescein fundus angiography, and clinical application became widespread in the 1990s with the advent of digital technology.
FA is excellent for evaluating retinal vascular disorders and RPE function, while ICGA is superior for visualizing choroidal vessels and sub-RPE lesions. ICGA is essential for PCV and diseases with choroidal vascular hyperpermeability (e.g., central serous chorioretinopathy). The two are often performed simultaneously.
ICGA plays different roles in each subtype of age-related macular degeneration.
ICGA is the gold standard for the definitive diagnosis of polypoidal choroidal vasculopathy. 2) It is also the most validated method for differentiating typical nAMD from polypoidal choroidal vasculopathy/AT1 (pachychoroid neovasculopathy type 1). 4)
It delineates the extent and degree of choroidal vascular hyperpermeability and is useful for determining the irradiation site for photodynamic therapy (PDT).
ICGA shows a characteristic filling pattern (early intense hyperfluorescence → late washout).
Choroidal neovascularization around lacquer cracks can be visualized more clearly than with FA.
Evaluates choroidal circulation better than FA. Also useful in ocular ischemia due to giant cell arteritis (GCA). 5)
There are mainly two types of imaging devices for ICGA.
Most devices allow simultaneous imaging with FA (excitation 488 nm).
ICG preparations (e.g., Ophthagreen® in Japan) are used.
Mydriasis is achieved with Mydrin P® or similar, ensuring adequate dilation (pupil diameter of 6 mm or more is desirable).
In ICGA, the vascular structures visualized differ depending on the imaging phase. The three main phases are shown in the table below.
| Phase | Time Course | Main Structures Visualized |
|---|---|---|
| Early phase | Up to 1 minute | Filling of choroidal arteries, veins, and choriocapillaris |
| Intermediate phase | 5–15 minutes | Simultaneous filling of retina and choroid; detection of lesions |
| Late phase | 15 minutes~ | Decrease in background fluorescence, lesion sharpening |
ICG fluorescence intensity decreases exponentially over time, so care must be taken with light intensity settings. Generally, it is set high at the start of imaging, lowered when fluorescence is confirmed, and raised again toward the late phase.
There may be a mild stinging sensation when the contrast agent is injected intravenously, but the examination itself is essentially painless. Eye drops for pupil dilation are required, and after dilation, glare and blurred near vision may occur for several hours. Driving a car or motorcycle should be avoided on the day of the examination.
In normal eyes, the choroidal arteries, veins, and choriocapillaris fill sequentially in the early phase, and uniform background fluorescence is obtained in the intermediate phase. In the late phase, background fluorescence gradually decreases, and the silhouette of large vessels emerges.
Hypofluorescent Findings
Blocking: Blockage of ICG fluorescence by thick hemorrhage, pigment, or exudate.
Delayed filling: Delayed arrival due to choroidal ischemia. GCA, triangular syndrome.
Filling defect: Non-filling of choriocapillaris due to acute inflammation such as APMPPE.
Hyperfluorescent Findings
Pigment staining: Persistent hyperfluorescence in the late phase. Scarring, Bruch’s membrane changes.
Tissue staining: Slow leakage into extravascular space and accumulation in tissue.
Increased vascular permeability: Hyperfluorescence of choroidal vessels associated with pachychoroid. Typical in central serous chorioretinopathy and polypoidal choroidal vasculopathy.
Morphological abnormalities
Polypoidal dilatation: Early nodular hyperfluorescence characteristic of polypoidal choroidal vasculopathy. Shows washout in the late phase.
Abnormal vascular network (BVN): Visualization of branching vascular network preceding polypoidal choroidal vasculopathy.
Choroidal neovascular network: Hyperfluorescent reticular structure persisting into the late phase in age-related macular degeneration Type 1 macular neovascularization.
Lipid accumulation in Bruch’s membrane creates areas where ICG cannot adequately reach the RPE. These areas are observed as localized hypofluorescent spots (ASHS-LIA: area of decreased late-phase hypofluorescence after ICG angiography) in the late phase of ICGA. 4) This is an important finding for understanding the pathology of age-related macular degeneration and polypoidal choroidal vasculopathy.
ICGA is a relatively safe examination, but side effects can occur because it is an intravenous drug. The frequency of major side effects is shown in the table below.
| Severity | Symptoms | Frequency (approximate) |
|---|---|---|
| Mild | Nausea, vomiting, hot sensation | Approximately 0.15% |
| Moderate | Urticaria, fever, blood pressure changes | Approximately 0.2% |
| Severe | Anaphylactic shock | Approximately 0.05% |
For reference, the risk of death from FA is reported to be about 1 in 200,000, 5) and similar risk management is required for ICGA.
ICG preparations (such as Ophthagreen®) contain sodium iodide as a stabilizer. A history of iodine allergy is an absolute contraindication for ICGA, and allergy history must be confirmed before administration. In some cases, switching to iodine-free infracyanine green may be considered.
ICG is an amphiphilic cyanine dye with a molecular weight of 775. The pharmacological properties of ICG and a comparison with FA are shown below.
Abnormal vascular networks (BVN) are detected as high blood flow on OCTA, but ICGA is superior for detecting polyp lesions. 2) This is thought to be because blood flow within polyps is relatively slow, and the high intravascular retention of ICG allows filling to become clearer over time.
TelCaps (Telangiectatic Capillary anomalies) are large capillary anomalies (diameter ≥150 μm) with high affinity for ICG. 1) These lesions are difficult to detect with FA or OCTA and are attracting attention as a cause of anti-VEGF treatment-resistant macular edema.
Perrin and Porter (2024) reported a case series of ICGA-guided photocoagulation (TelCaps PDT) for TelCaps. 1) In 13 eyes with diabetic macular edema, TelCaps-targeted photocoagulation resulted in significant improvement over 2 years. A prospective RCT involving 270 patients is currently underway in France.
Efforts are underway to enable diagnosis of polypoidal choroidal vasculopathy in facilities where ICGA cannot be performed.
Cheung et al. (2024) reported that the AUC of OCT-based non-ICGA diagnostic criteria was 0.90. 4) These criteria combine OCT findings of pachychoroid (choroidal thickening, central serous chorioretinopathy-like changes, and findings equivalent to BVN).
However, at present, this does not replace ICGA, and ICGA remains essential for the definitive diagnosis of polypoidal choroidal vasculopathy.
Automatic differentiation between polypoidal choroidal vasculopathy and age-related macular degeneration using machine learning analysis of OCT images is being studied, 2) and its practical application as a diagnostic support tool is expected.
ICGA is still necessary for the definitive diagnosis of polypoidal choroidal vasculopathy. OCTA is superior for detecting BVN and evaluating blood flow, but ICGA is reported to have superior sensitivity for detecting polypoidal lesions. 2) Although non-ICGA diagnostic criteria are being developed (AUC 0.90), ICGA remains indispensable for standard diagnosis of polypoidal choroidal vasculopathy at present.
