Residency · Residency · Ophthalmology

Fluorescein and Indocyanine Green Angiography

Introduction

Fluorescein angiography (FA) and indocyanine green angiography (ICGA) are essential diagnostic imaging modalities in ophthalmology. FA provides detailed visualization of the retinal and superficial choroidal circulation, while ICGA penetrates the RPE and macular pigment to reveal the deeper choroidal vasculature. Understanding the principles, phases, normal patterns, and pathologic findings of each modality is fundamental to retinal disease diagnosis and management.

Fluorescein Angiography

Pharmacology of Sodium Fluorescein

Sodium fluorescein: water-soluble, low molecular weight (376 Da) dye. Absorption peak: 465-490 nm (blue light); emission peak: 520-530 nm (yellow-green light) 80% protein-bound in plasma; the unbound 20% fluoresces and leaks from fenestrated vessels. Metabolized by the liver; excreted renally (urine yellow-green for 24-36 hours) Does not cross the blood-retinal barrier (tight junctions of retinal capillary endothelium) under normal conditions. Does cross the choriocapillaris (fenestrated endothelium)

Technique

Intravenous injection of 5 mL of 10% or 2 mL of 25% sodium fluorescein via antecubital vein. Sequential fundus photographs using excitation filter (blue, 465-490 nm) and barrier filter (yellow-green, 520-530 nm) Photograph both eyes; begin photographing the eye of interest. Timer starts at injection; images captured at defined intervals.

Adverse Reactions

Mild (common): nausea (most common, 5-10%), vomiting, skin yellowing, yellow urine. Moderate (uncommon): urticaria, pruritus, syncope. Severe (rare, 1:10,000-1:200,000): anaphylaxis, bronchospasm, cardiac arrest, death (1:220,000) Relative contraindications: pregnancy (Category C; crosses placenta), severe renal disease. Have resuscitation equipment available.

Normal Phases of Fluorescein Angiography

Choroidal Phase (Pre-Arterial, 8-12 seconds)

Choroidal flush: patchy fluorescence from filling of the choriocapillaris. Cilioretinal artery fills simultaneously if present (fed by posterior ciliary arteries)

Arterial Phase (10-12 seconds)

Filling of retinal arterioles from the central retinal artery. Laminar flow visible (fluorescein concentrated centrally)

Arteriovenous (Capillary) Phase (13-15 seconds)

Complete arteriolar filling; capillary bed perfusion. Early venous filling begins (lamellar flow in veins)

Venous Phase (15-30 seconds)

Progressive venous filling; early, mid, and late venous phases. Veins fill from the walls inward (lamellar pattern)

Late (Recirculation) Phase (5-10 minutes)

Fluorescein concentration decreases; staining of vessel walls and optic disc. No leakage from normal retinal vessels or RPE.

Hyperfluorescence Patterns

Leakage: dye escapes through incompetent barriers; increases in size and intensity over time (e.g., CNV, CME, NVD/NVE) Staining: dye accumulates in tissue; persistent late hyperfluorescence without progressive enlargement (e.g., drusen, scar, disc staining) Pooling: dye collects in an anatomic space (e.g., subretinal fluid in CSC, serous PED) Window defect (transmission): RPE atrophy allows increased visualization of choroidal fluorescence; early hyperfluorescence without progressive change in size (e.g., geographic atrophy, RPE defect)

Hypofluorescence Patterns

Blocked fluorescence: substance absorbs or obscures fluorescence (e.g., hemorrhage, pigment, lipid) Vascular filling defect: absence of normal fluorescence from non-perfusion (e.g., capillary dropout in diabetic retinopathy, arterial occlusion, ischemia)

Indocyanine Green Angiography

Pharmacology of ICG

Indocyanine green: water-soluble, high molecular weight (775 Da) tricarbocyanine dye. Absorption peak: 790-805 nm; emission peak: 830-835 nm (near-infrared) 98% protein-bound (primarily albumin); very low leakage from even fenestrated vessels. Allows choroidal vessel visualization through overlying RPE, melanin, hemorrhage, lipid, and fluid. Metabolized by the liver; excreted in bile (NOT renal) Contains iodide: contraindicated in patients with iodine allergy or shellfish allergy.

Technique

25 mg ICG dissolved in 5 mL aqueous solvent; IV injection. Imaging with infrared filters on a confocal scanning laser ophthalmoscope (cSLO) or modified fundus camera. Captures deeper choroidal vasculature not visible on FA.

Adverse Reactions

Less frequent than FA; nausea uncommon. Contraindicated in iodine allergy and pregnancy. Severe anaphylaxis extremely rare.

Normal Phases of ICGA

Early Phase (0-60 seconds)

Choroidal arterial filling; large choroidal vessels visible. Retinal vessels also visible (silhouetted)

Mid Phase (1-15 minutes)

Progressive choroidal vein filling. Choriocapillaris fluorescence creates a diffuse background glow. Individual large choroidal vessels still visible.

Late Phase (15-30+ minutes)

Gradual washout of dye. Large choroidal veins and vortex veins remain visible. Optic disc and sclera may fluoresce.

Clinical Applications of ICGA

Polypoidal Choroidal Vasculopathy (PCV)

Characteristic polypoidal dilations of the inner choroidal vasculature. Branching vascular network visible on mid-to-late phase ICGA. Gold standard for PCV diagnosis. Guides treatment: combination anti-VEGF + photodynamic therapy (PDT)

Choroidal Neovascularization

Occult CNV better delineated on ICGA than FA. Feeder vessels and hot spots identifiable in the late phase. Guides PDT treatment planning.

Central Serous Chorioretinopathy (CSC)

Choroidal hyperpermeability: mid-phase hyperfluorescence. Identifies multifocal choroidal leakage points. Chronic CSC: diffuse choroidal vascular abnormalities.

Inflammatory Conditions

VKH: multiple hypofluorescent dark dots in early phase (choroidal granulomas); late diffuse choroidal staining. Sarcoidosis, multifocal choroiditis: hypofluorescent lesions in the choroid. Birdshot chorioretinopathy: hypofluorescent spots corresponding to lesions.

Comparison of FA and ICGA

Ultra-Widefield Angiography

Wide-field imaging systems (Optos) capture up to 200 degrees in a single image. Identifies peripheral retinal non-perfusion, neovascularization, and vasculitis. Particularly valuable in diabetic retinopathy, RVO, and uveitis. Artifacts from eyelid and lens reflections must be recognized.

OCT Angiography as a Complement

Non-invasive, dye-free imaging of retinal and choroidal vasculature. Detects blood flow by comparing sequential OCT scans (motion contrast) Cannot show leakage (a limitation compared to FA) Excellent for CNV detection, diabetic capillary non-perfusion, macular ischemia. Complementary to, not a replacement for, FA and ICGA in most clinical situations.

Key Clinical Pearls

In fluorescein angiography, leakage increases in size and intensity over time, while window defects remain stable in size with early onset -- this distinction is critical for interpretation. ICG angiography is the gold standard for diagnosing polypoidal choroidal vasculopathy and is essential for evaluating choroidal pathology through overlying hemorrhage or RPE. ICGA is contraindicated in patients with iodine or shellfish allergy; always screen before injection. OCT angiography provides non-invasive vascular imaging but cannot detect leakage, making it complementary to, not a replacement for, conventional dye-based angiography.

References

1. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology. 1986;93(5):611-617.
2. Stanga PE, Lim JI, Hamilton P. Indocyanine green angiography in chorioretinal diseases: indications and interpretation. Ophthalmology. 2003;110(1):15-21.
3. Spaide RF, Fujimoto JG, Waheed NK, et al. Optical coherence tomography angiography. Prog Retin Eye Res. 2018;64:1-55.
4. Cheung CMG, Lee WK, Koizumi H, et al. Pachychoroid disease. Eye (Lond). 2019;33(1):14-33.

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