16.3 Indocyanine Green (ICG) Angiography: Principles, Indications & Choroidal Pathology

Indocyanine Green (ICG) Angiography: Principles, Indications & Choroidal Pathology

Quick Summary: While sodium fluorescein angiography (FA) is optimal for evaluating the retinal circulation and the integrity of the inner blood-retinal barrier, indocyanine green angiography (ICGA) is the undisputed gold standard for visualizing the choroidal vasculature. Operating in the near-infrared spectrum (805 nm excitation / 835 nm emission) with 98% plasma protein binding and exclusive hepatic excretion, ICG dye penetrates through RPE melanin, subretinal fluid, and hemorrhage to reveal deep chorioretinal pathology that remains completely invisible on conventional FA.

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1. Biophysical Principles & Infrared Optical Physics

Indocyanine green ($C_{43}H_{47}N_{2}NaO_{6}S_{2}$, molecular weight 774.96 Da) is a water-soluble, amphiphilic tricarbocyanine dye. Its physical properties address the fundamental optical limitations that prevent fluorescein from effectively imaging the choroid:

The Near-Infrared Optical Window

• Excitation Peak: 805 nm (near-infrared spectrum, in blood/plasma).
• Emission Peak: 835 nm (near-infrared spectrum, in blood/plasma).
• In contrast to fluorescein (excitation 465–490 nm, emission 520–530 nm in the visible spectrum), the near-infrared wavelengths of ICG confer three decisive optical advantages:
  1. Melanin Transparency: The optical absorption of retinal pigment epithelium (RPE) melanin is high in the blue-green spectrum, absorbing up to 85% of fluorescein light. Above 800 nm, melanin absorption drops precipitously, rendering the RPE monolayer essentially translucent to near-infrared light.
  2. Hemoglobin Transparency: Oxygenated and deoxygenated hemoglobin absorb visible blue-green light heavily. In the near-infrared window (>800 nm), hemoglobin absorption falls by more than an order of magnitude. Consequently, ICG excitation and emission photons penetrate directly through preretinal, intraretinal, and subretinal hemorrhages.
  3. Reduced Optical Scattering: Longer wavelengths experience markedly less Rayleigh and Mie scattering from ocular media opacities, including mild nuclear cataracts, corneal haze, vitreous debris, and lipid/protein exudates.

Macromolecular Plasma Protein Binding

• In circulating blood, 98% of ICG binds avidly to plasma proteins:
  • ~80% binds to globulins and lipoproteins (high-density lipoproteins [HDL] and low-density lipoproteins [LDL]).
  • ~20% binds to serum albumin.
• In contrast, sodium fluorescein is only 60–80% loosely bound to albumin, leaving 20–40% free unbound dye.
• Hemodynamic Impact: The choriocapillaris possesses large fenestrations (60–80 nm in diameter). Small free fluorescein molecules escape these pores almost instantaneously, producing a blinding, diffuse background "choroidal flush" that completely obscures the architectural details of choroidal vessels within 30 to 60 seconds. Because ICG is 98% locked into massive lipoprotein complexes, it remains largely intravascular, allowing sharp, high-contrast, long-duration imaging of the choroidal vessel architecture across all phases of the study.

Hepatic Clearance vs. Renal Excretion

• Metabolism: ICG is taken up rapidly and selectively by hepatic parenchymal cells (hepatocytes) and excreted completely unchanged into the bile; it is ultimately eliminated through the feces.
• Zero Renal Elimination: There is no glomerular filtration or tubular secretion of ICG.
• Clinical Safety Advantage: Unlike sodium fluorescein, which is cleared renally and requires caution or dialysis coordination in patients with end-stage renal disease (ESRD), ICG is safe in patients with renal failure and hemodialysis dependence. However, it is contraindicated in severe hepatic insufficiency or biliary cirrhosis.
• Unlike fluorescein, ICG does not cause bright yellow-orange discoloration of the urine.

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2. Patient Safety, Dosage & Iodine Allergy Protocols

Reconstitution Protocol & Saline Hazard

• ICG is supplied as a sterile lyophilized powder (typically 25 mg or 50 mg vials).
• Mandatory Solvent: ICG must be dissolved strictly with the manufacturer-supplied sterile aqueous solvent (sterile water).

• [!CAUTION] NEVER Reconstitute ICG with Normal Saline: Reconstituting ICG with 0.9% sodium chloride (normal saline) or other halide-containing solutions causes immediate chemical precipitation of the dye, rendering it unusable and hazardous for intravenous injection. Once reconstituted with sterile water, the solution should be injected promptly because the dye begins to aggregate in aqueous solution over time.

The Iodine Allergy Contraindication

• Commercial formulations of ICG powder contain approximately 5% sodium iodide by weight to ensure adequate chemical solubility and prevent molecular aggregation.

• [!WARNING] Absolute Allergy Contraindication: A documented history of severe allergy, urticaria, or anaphylaxis to iodine, shellfish (mollusks/crustaceans), or iodinated radiographic contrast media is an absolute contraindication to indocyanine green administration. Technologists must explicitly screen for iodine and shellfish allergies before reconstituting the vial.

Adverse Event Profile & Emergency Management

• ICG is exceptionally well tolerated compared to sodium fluorescein:
  • Nausea and Vomiting: Occurs in less than 0.15% of ICG injections (compared to 5% to 10% with sodium fluorescein).
  • Severe Anaphylactoid Reactions: Extremely rare, occurring in approximately 1 in 40,000 to 1 in 300,000 administrations.
  • Preparation: Despite the low adverse event rate, institutional safety mandates that an emergency crash cart equipped with epinephrine (1:1,000 IM/SC), diphenhydramine, methylprednisolone, supplemental oxygen, and suction equipment be immediately on hand during every ICGA procedure.

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3. Transit Phases of Indocyanine Green Angiography

ICGA transit differs significantly from FA. Because ICG has a low fluorescence quantum yield (only ~4% that of fluorescein), high-sensitivity infrared digital sensors (or confocal scanning laser ophthalmoscopes [cSLO]) are required, and the study extends over 30 minutes:

1. Early Phase (0 to 60 Seconds)

• Hemodynamics: Dye enters via the posterior ciliary arteries within 10–15 seconds post-injection. Large choroidal arteries (in Haller's layer) and medium-sized vessels (in Sattler's layer) fill rapidly. Choriocapillaris lobules fill in a mosaic pattern.
• Retinal arterioles fill slightly after or concurrently with choroidal vessels, but appear dimmer than on FA due to rapid choroidal blood flow.
• Diagnostic Target: Best phase to capture rapid transit, high-flow vascular loops, feeder vessels in CNV, and early polypoidal lesions.

2. Intermediate / Mid Phase (3 to 15 Minutes)

• Hemodynamics: The large choroidal vessels begin to empty their dye into the vortex veins. The background choroidal glow becomes diffuse and homogeneous as dye slowly permeates the extravascular choroidal stroma. Retinal vascular lumens become faint.
• Diagnostic Target: Ideal for visualizing choroidal hyperpermeability patches in pachychoroid spectrum disease, delineating the boundaries of occult CNV plaques, and detecting inflammatory choroidal hypofluorescent dark dots.

3. Late Phase (15 to 30+ Minutes)

• The "Choroidal Inversion" Phenomenon: In normal eyes, intravascular dye has completely cleared from the large choroidal vessels. The large choroidal vessels now appear as dark, hypofluorescent silhouettes (negative contrast) against a faint, diffuse background hyperfluorescence produced by scleral and stromal dye retention.
• Diagnostic Target: Abnormal structures that retain ICG dye—such as occult CNV "plaques", persistent polyp margins, or chronic inflammatory granulomas—stand out with striking hyperfluorescent contrast against the inverted dark background.

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4. Key Clinical Indications & Choroidal Pathologies

Polypoidal Choroidal Vasculopathy (PCV)

• Clinical Overview: A distinct subtype of neovascular AMD (frequently classified as Type 1 CNV variant or aneurysmal type 1 neovascularization), highly prevalent in Asian and African-descent populations. Characterized by recurrent subretinal hemorrhages and orange-red subretinal nodules.
• The Diagnostic Gold Standard: On FA, PCV lesions are often totally obscured by thick subretinal blood or appear as non-specific occult leakage or fibrovascular PEDs. ICGA is mandatory for definitive diagnosis.
• Classic ICGA Findings:
  1. Branching Vascular Network (BVN): A network of abnormal, inner choroidal vessels visible in the early-to-mid frames.
  2. Aneurysmal Polyps: Terminal, saccular dilatations at the borders of the BVN that light up with intense early hyperfluorescence ("light-bulb polyps").
  3. Late Behavior: Polyps display either late central wash-out with a hyperfluorescent rim ("hypofluorescent halo") or persistent late staining.
• Therapeutic Impact: ICGA precisely guides thermal laser photocoagulation or photodynamic therapy (PDT) with verteporfin to obliterate active polyps while sparing normal tissue.

Occult (Type 1) Choroidal Neovascularization

• In neovascular AMD, Type 1 CNV resides beneath the RPE monolayer. On FA, it produces ill-defined late leakage of undetermined source.
• On ICGA, occult CNV is classified into two distinct morphology patterns:
  1. Focal "Hot Spot": A solitary, intense, well-demarcated hyperfluorescent focus ≤1 disc diameter that appears in the mid-to-late phases, representing a focal neovascular feeder vessel or micro-loop.
  2. Late "Plaque": A well-circumscribed zone of late hyperfluorescence >1 disc diameter that illuminates in the 20-to-30-minute frames, delineating the true anatomical perimeter of the sub-RPE neovascular complex.

Central Serous Chorioretinopathy (CSCR) & Pachychoroid Disease

• Pathophysiology centers on choroidal congestion and hyperpermeability associated with abnormally thickened choroid (pachychoroid) and dilated Haller layer veins (pachyvessels).
• ICGA Findings:
  • Early-to-mid phase demonstrates dilated, engorged choroidal veins with delayed regional emptying.
  • Mid-phase reveals geographic patches of intense choroidal hyperpermeability (dye leaking from congested choriocapillaris into the stroma) that persist into late frames.
  • ICGA frequently uncovers subclinical areas of choroidal hyperpermeability in the asymptomatic contralateral eye, proving CSCR is a bilateral choroidal disease.

Inflammatory Chorioretinopathies (Posterior Uveitis)

• Vogt-Koyanagi-Harada (VKH) Disease: Bilateral granulomatous panuveitis. ICGA demonstrates:
  • Delay in early choriocapillaris lobular filling.
  • Numerous regularly distributed hypofluorescent dark dots in the early-to-mid phases, representing non-perfused choriocapillaris lobules or focal granulomatous inflammatory stromal infiltrates.
  • Hyperfluorescent optic disc leakage in late frames.
• Birdshot Chorioretinopathy: Oval, creamy fundus lesions show multiple hypofluorescent dark spots along the choroidal vessels on ICGA. These spots are far more numerous than the lesions visible on ophthalmoscopy, providing the most sensitive objective marker of active choroidal inflammation and therapeutic efficacy.
• Multiple Evanescent White Dot Syndrome (MEWDS): Characteristic punctate hypofluorescent spots in late ICGA frames clustered around the fovea and peripapillary region.

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5. Direct Comparative Matrix: Fluorescein (FA) vs. Indocyanine Green (ICGA)

The table below contrasts the fundamental characteristics of the two primary ophthalmic angiographic dyes:

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6. Clinical Pearls & Technologist Safety Rules

[!IMPORTANT] Renal Failure Safety: Patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) on hemodialysis can safely undergo ICGA because the dye is cleared entirely by the liver. In contrast, sodium fluorescein is cleared renally; if FA is performed on a dialysis patient, the yellow skin discoloration and residual circulating dye persist for days until the next dialysis cycle.

[!CAUTION] Never Forget the Solvent Check: Always verify the reconstitution fluid. Grabbing a 10 mL flush of normal saline out of habit will ruin the ICG vial immediately by precipitating the dye into flocculent aggregates. Always use the sterile aqueous diluent provided in the ICG kit.