Indocyanine green angiography (ICGA) is a fluorescence angiography 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 about 775 (approximately 2.3 times that of fluorescein used in FA, which is about 332). The following optical properties are advantageous for choroidal angiography.
While FA uses visible light with excitation at 465–490 nm and fluorescence at 520–530 nm, 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.
After administration, ICG plasma concentration decreases exponentially. Its half-life is short, about 3–4 minutes, and it is taken up by hepatocytes and excreted into bile without metabolism (no enterohepatic circulation). This metabolic pathway differs from FA, which is renally excreted. ICGA can be used to some extent even in patients with renal impairment, but caution is needed in hepatic impairment due to delayed excretion.
The main differences between FA and ICGA are shown below.
FA (Fluorescein Angiography)
Molecular weight: 332
Plasma protein binding: ~80% → significant extravascular leakage
Excitation/fluorescence wavelengths: 465–490 nm / 520–530 nm (visible light)
Main targets: Retinal vessels, RPE defects, inner CNV
RPE penetration: Low → difficult to visualize choroid
Metabolism/excretion: Renal excretion
ICGA (Indocyanine Green Angiography)
Molecular weight: 775
Plasma protein binding: ~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 the choroid
Metabolism/Excretion: Hepatic uptake → biliary excretion (no enterohepatic circulation)
In the 1960s, Fox and Wood first applied ICG to ophthalmology. In the 1970s, its use in fluorescein fundus angiography was reported, and in the 1990s, clinical application became widespread with the advent of digital technology.
FA is superior 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). Both 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 between typical nAMD and 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). It is also excellent for visualizing dilated inner choroidal vessels (pachyvessels).
ICGA shows a characteristic filling pattern (early intense hyperfluorescence → late washout).
Choroidal neovascularization around lacquer cracks can be visualized more clearly than with FA.
Choroidal circulation can be evaluated better than with FA. Also useful in ocular ischemia due to giant cell arteritis (GCA). 5)
There are mainly two types of ICGA imaging equipment.
Many of these devices allow simultaneous imaging with FA (excitation 488 nm).
To perform ICGA safely, the following preparations are made 6).
Use an ICG preparation (e.g., Ophthalmic Green® in Japan).
Perform mydriasis with Mydrin P® or similar, ensuring sufficient dilation (pupil diameter of 6 mm or more is desirable).
In ICGA, the vascular structures visualized differ depending on the imaging phase. The main angiographic phases are shown in the table below.
| Phase | Time Course | Main Structures Visualized |
|---|---|---|
| Early phase | ~2 minutes | Onset of filling of choroidal arteries and choriocapillaris |
| Middle phase | 2–10 minutes | Visualization of choroidal neovascularization and abnormal vessels |
| Late phase | 10–30 minutes | Assessment of dye pooling and tissue staining. Differentiation by residual fluorescence in lesions |
In the early phase, filling begins from the short posterior ciliary arteries and flows into the choriocapillaris. In the middle phase, uniform choroidal background fluorescence is obtained, and in the late phase, background fluorescence attenuates and large vessels emerge as silhouettes. Residual fluorescence (staining) is useful for differentiating lesions.
Since ICG fluorescence intensity decreases exponentially over time, attention must be paid to light intensity settings. Generally, it is set high at the start of imaging, lowered once fluorescence is confirmed, and increased again toward the late phase.
When performing FA and ICGA simultaneously, sequential administration of FA followed by ICG, or nearly simultaneous administration, is performed. With the SLO method, both angiographies can be captured simultaneously with a single device.
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 early phase shows filling in the order of choroidal arteries → veins → choriocapillaris, and a uniform background fluorescence is obtained in the middle phase. In the late phase, background fluorescence gradually decreases, and silhouettes of large vessels emerge. Window defects observed in FA do not occur in ICGA because ICG penetrates the RPE and reaches the choroidal vessels.
Hypofluorescent Findings
Blocking: Blockage of ICG fluorescence by thick hemorrhage, pigment, or exudate.
Delayed filling: Delayed arrival due to choroidal ischemia. Seen in giant cell arteritis, triangular syndrome, and Takayasu arteritis.
Filling defect (choriocapillaris non-perfusion): Non-perfusion of the choriocapillaris due to acute inflammation such as APMPPE. Also observed in MEWDS and the acute phase of VKH.
Choroidal atrophy: Pathologic myopia, post-photocoagulation scars, late-stage AMD.
Hyperfluorescent Findings
Staining: Persistent hyperfluorescence in the late phase. Seen in scars and Bruch’s membrane changes.
Tissue staining: Slow extravascular leakage 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: Characteristic early nodular hyperfluorescence in polypoidal choroidal vasculopathy, showing washout in the late phase.
Abnormal vascular network (BVN): Visualization of a branching vascular network preceding polypoidal choroidal vasculopathy.
Choroidal neovascular network: A hyperfluorescent reticular structure that persists into the late phase in age-related macular degeneration Type 1 macular neovascularization.
Systematically organize the differential diagnosis of hypofluorescence and hyperfluorescence.
| Classification | Mechanism | Representative Diseases |
|---|---|---|
| Hypofluorescence: Blockage | Thick hemorrhage, hard exudates, or pigmentation blocks ICG | Macular hemorrhage, hard exudates, choroidal nevus |
| Hypofluorescence: Delayed Filling | Reduced perfusion of choroidal arteries | GCA, triangular syndrome, Takayasu arteritis |
| Hypofluorescence: Choriocapillaris Non-perfusion | Non-filling of the choriocapillaris | APMPPE, MEWDS, acute VKH |
| Hypofluorescence: choroidal atrophy | Thinning of choroidal stroma | Pathologic myopia, post-photocoagulation scar, late-stage AMD |
| Hyperfluorescence: increased vascular permeability | Leakage from dilated choroidal vessels | CSC, dilated choroidal vessels around PCV |
| Hyperfluorescence: polypoidal dilation | Nodular dilation from BVN | PCV (early nodular hyperfluorescence → late washout) |
| Hyperfluorescence: choroidal neovascularization | ICG accumulation in MNV | AMD Type 1, Type 2, Type 3 |
| Hyperfluorescence: staining/tissue staining | Dye accumulation in tissue | Scar, Bruch’s membrane changes, drusen |
Lipid accumulation in Bruch’s membrane prevents ICG from reaching the RPE properly. This results in localized hypofluorescent spots in the late phase of ICGA (ASHS-LIA: area of decreased late-phase hypofluorescence after ICG angiography). 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 because it involves intravenous injection, side effects may occur. According to a report by Hope-Ross (1994), the overall frequency of side effects is approximately 0.15%, and severe anaphylactic shock occurs in about 0.05% of cases. The frequencies of major side effects are shown in the table below.
| Severity | Symptoms | Frequency (approximate) |
|---|---|---|
| Mild | Nausea, vomiting, feeling of warmth | Approximately 0.15% |
| Moderate | Urticaria, fever, blood pressure changes | Approximately 0.2% |
| Severe | Anaphylactic shock | Approximately 0.05% |
For reference, FA has been reported to have a mortality risk of approximately 1 in 200,000 5), and ICGA requires a similar level of risk management.
After the examination, blood pressure should be measured, and the patient’s condition should be confirmed before discharge 6). If adverse effects occur, it is recommended to report them 6).
ICG preparations (e.g., 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. Switching to iodine-free infrared cyanine green may be considered.
ICG is an amphiphilic cyanine dye with a molecular weight of 775. Below, the pharmacological properties of ICG and a comparison with FA are shown.
Abnormal vascular networks (BVN) are detected as high-flow areas on OCTA, but ICGA is superior for detecting polypoidal lesions. 2) The relatively slow blood flow within polyps and the high intravascular retention of ICG allow gradual filling and clearer visualization in the late phase.
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 noted 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 two 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 is not available.
Cheung et al. (2025) reported an AUC of 0.90 for OCT-based non-ICGA diagnostic criteria. 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 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, and it is expected to be put into practical use as a diagnostic support tool. 2)
ICGA is still necessary for the definitive diagnosis of polypoidal choroidal vasculopathy. OCTA is excellent for detecting BVN and evaluating blood flow, but ICGA has been reported to be superior in detecting polypoidal lesions. 2) Although non-ICGA diagnostic criteria are being developed (AUC 0.90), ICGA is currently indispensable for the standard diagnosis of polypoidal choroidal vasculopathy.
