Everything You Need To Know To Find The Best Indocyanine Green Angiography
Objectives:
Describe the anatomy and physiology of choroidal circulation.
Review the personnel, equipment, preparation, and technique of indocyanine green angiography.
Outline the characteristics of various retinal and choroidal diseases on an indocyanine green angiogram.
Explain the importance of the availability of an interprofessional team for monitoring the patient and managing complications during indocyanine green angiography.
Access free multiple choice questions on this topic.
Introduction
Indocyanine green angiography (ICGA) is a valuable technique for visualizing choroidal circulation and its abnormalities. Even though fundus fluorescein angiography (FFA) provides detailed imaging of retinal circulation, it struggles with choroidal visualization due to poor transmission of fluorescence through the retinal pigment epithelium (RPE), media opacities, and retinal exudates. The properties of indocyanine green (ICG) allow it to pass through RPE, lipid exudates, and serosanguineous fluid more effectively. ICG has an absorption peak at 790 to 805 nm and emits fluorescence at a peak of 835 nm.
ICGA's infrared rays can penetrate better through the RPE, macular xanthophyll pigments, and media opacities than fluorescein. Moreover, 98% of ICG in serum is protein-bound, resulting in limited diffusion through the fenestrations of the choriocapillaris, compared to the rapid diffusion and blurring effect seen with fluorescein angiography (FA).
ICG was approved for human use by the Food and Drug Administration (FDA) in 1956 and was first used for human choroid angiography by RW Flower in 1972. Initially, images lacked clarity due to the low fluorescence efficiency of the ICG molecule compared to FA. However, advancements in imaging systems, especially scanning laser ophthalmoscopes (SLO), have greatly improved image quality. In the current era of anti-vascular endothelial growth factor (anti-VEGF) agents and optical coherence tomography (OCT), choroidal neovascular membrane (CNVM) monitoring has become more manageable.
Despite these advancements, ICGA continues to be a crucial imaging modality for evaluating various conditions such as idiopathic polypoidal choroidal vasculopathy (IPCV), retinal angiomatous proliferation (RAP), central serous chorioretinopathy (CSCR), ocular inflammatory diseases like sympathetic ophthalmia (SO) and Vogt-Koyanagi-Harada (VKH) syndrome, and ocular tumors.
Anatomy and Physiology
The choroid receives its blood supply from the ophthalmic artery, a branch of the internal carotid artery. The medial and lateral posterior ciliary arteries (PCAs), branching off from the ophthalmic artery, give rise to both long and short PCAs. The short PCAs supply the posterior choroid, extending from the posterior pole to the equator, while the long PCAs supply the choroid anterior to the equator.
Bruch's membrane, the innermost layer of the choroid, consists of five sublayers. Outside Bruch's membrane are three vascular layers: the inner choriocapillaris, the middle Sattler's layer, and the outer Haller's layer. The choriocapillaris lobule, supplied by terminal choroidal arterioles, serves as the functional unit of choroidal circulation and is independent of adjacent lobules. Blood drains from the choroid through vortex veins, which also show segmental distribution without anastomosis with other veins.
The choroidal blood flow is among the highest in the body, providing ten times more blood per unit of tissue weight than the brain. This high blood flow helps maintain high oxygen tension in the choroid, facilitating oxygen diffusion to the retina. During dark conditions, when photoreceptors are metabolically active, up to 90% of the retina's blood supply comes from the choroid. The choriocapillaris walls are fenestrated, allowing high permeability for glucose and small molecules, but not for larger proteins like ICG, which is 98% protein-bound. In contrast, fluorescein is only 80% protein-bound and diffuses more readily.
Indications
The indications of ICGA include:
Exudative age-related macular degeneration (wet AMD)
Idiopathic polypoidal choroidal vasculopathy (IPCV or PCV)
Retinal angiomatous proliferation (RAP)
Central serous chorioretinopathy (CSCR)
Retinal arterial macroaneurysm (RAM)
Choroidal melanoma
Choroidal hemangioma
Choroidal tumors
Birdshot chorioretinopathy (BSCR)
Multifocal choroiditis
Multiple evanescent white dot syndrome (MEWDS)
Serpiginous choroidopathy
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)
Punctate inner chorioretinopathy (PIC)
Acute zonal occult outer retinopathy (AZOOR)
White Dot Syndromes
Chorioretinal atrophy
Sympathetic ophthalmia (SO)
Vogt Koyanagi Harada syndrome (VKH)
Ocular inflammatory diseases
ICG is also used to determine liver function, hepatic blood flow, and cardiac output. ICGA has been used intraoperatively during the surgical management of intracranial aneurysms.
Contraindications
ICG is generally safe and well-tolerated, but there are some contraindications for its use in ophthalmology. It should not be used in patients with allergies to iodine or shellfish, those with uremia, and those with a history of severe hypersensitivity. ICGA is also not recommended for those with liver disease since ICG is exclusively eliminated through the liver. ICG is classified as a pregnancy category C drug, indicating a lack of adequate human studies to establish safety.
Equipment
A fundus camera with excitation and a barrier filter is essential for ICGA. Two types of fundus cameras are commonly used: digital flash cameras and confocal scanning laser ophthalmoscopes (SLOs). Digital flash cameras, like the FF 450 plus by Zeiss and TRC-50DX by Topcon, use white light with specific filters for excitation and barrier wavelength ranges. SLOs, such as the Spectralis by Heidelberg and the California by Optos, use laser monochromatic light for excitation and barrier filtration.
The standard intravenous dose of ICG for adults is 25 mg in a 5 ml solvent. Essential equipment includes a 23-gauge scalp vein needle set, a 5 ml syringe with a needle, alcohol swabs, a tourniquet, and an armrest. An emergency kit for managing anaphylaxis should always be ready before starting the procedure.
Personnel
The healthcare team for ICGA typically includes an ophthalmologist, technician, optometrist, nursing staff, and an anesthetist.
Preparation
Informed consent is necessary before the procedure, and the risks and benefits should be explained to the patient. A thorough history of allergies and systemic comorbidities should be taken, and fasting for two to four hours is recommended. The standard adult dose of ICG is 25 mg in a 5 ml solvent. In SLO systems, it is dissolved in 3 ml of solvent, and 1 ml of the solution is injected, followed by a 5 ml saline flush.
Ensure that the pupils are well-dilated before the procedure and have an emergency kit available. Take a few color fundus images to check for clarity and focus. The patient should be comfortably seated with their arm on the armrest and chin on the chinrest. The scalp vein set is inserted into a vein on the ventral forearm, ensuring proper placement by drawing some blood or flushing with saline.
Technique or Treatment
Once the patient's chin is on the chin rest, an assistant holds the patient's head to prevent movement during imaging. Control photographs are taken as soon as the dye is injected, automatically starting the timer. Images are captured at 1.5 to 2-second intervals. After the choroidal arterial and venous systems are filled with the dye, images are taken at a slower pace, including pictures of the fellow eye.
Normal ICGA Phases
Stage 1: Starts 2 seconds after dye injection and is characterized by the rapid filling of choroidal arteries, choriocapillaris, and early filling of choroidal veins.
Stage 2: Three to five seconds post-injection, larger choroidal veins and retinal arterioles fill with dye.
Stage 3: From 6 seconds to 3 minutes post-injection, the choroidal watershed zone gets filled with dye as larger choroidal veins and arteries begin to fade.
Early phase - The early phase has three stages:
The middle phase (3 to 15 minutes) is marked by the fading of the retinal and choroidal vessels.
Late phase (15 to 60 minutes) shows staining of the extra-choroidal tissue, giving the illusion that choroidal vasculature is hypofluorescent compared to the background tissue. The retinal vessels are not visible during this phase.
Complications
Adverse effects of ICGA are less common compared to FA. Extravasation of the dye can cause a stinging sensation. Mild side effects like nausea and vomiting occur in 0.15% of patients. Moderate adverse events such as urticaria and vasovagal reactions are observed in 0.2% of patients. Urticarial can be treated with antihistamines. Severe adverse events, including anaphylaxis, occur in 0.05% of patients, with a higher incidence in those with uremia compared to the general population.
Clinical Significance
Exudative Age-Related Macular Degeneration (exudative AMD or wet AMD)
ICGA helps delineate the extent of occult CNVM, which accounts for 60-85% of CNV in wet AMD. In ICGA, three morphologic variants of CNVM are noted: hot spot or focal spot, plaque (poorly defined or well-defined), and mixed (hot spot and plaque present).
The combined type of CNVM may have marginal, overlying, or remote hot spots. Approximately 60% of eyes with occult CNVM reveal plaques on ICGA, around 30% show hot spots, and the rest have combined lesions. Visual prognosis of plaque may be worse compared to hot spots, the latter being treated more easily with PDT. ICGA helps determine CNVM presence in PEDs. In non-vascularized PEDs, hypocyanescence is noted throughout ICGA phases. In vascularized PEDs, ICGA reveals either plaques or focal CNVM, with some undetectable cases. Vascularized PEDs may show a notch at the margin, indicating CNVM area on FFA as described by Gass. ICGA visualizes subretinal or submacular hemorrhage causes, including wet AMD, PCV, RAM, and lacquer cracks. Typically not used to study classic CNVM on FFA, ICGA provides important information for lesion delineation crucial in photodynamic and laser photocoagulation therapies. Anti-VEGF therapy causes regression of immature vessels but does not affect mature vessels. ICGA helps differentiate between these vessel types, aiding in treatment approaches for non-regressed CNVMs post-anti-VEGF injections.
Retinal angiomatous proliferation (RAP) or Type 3 CNVM
RAP contributes up to 20% of wet AMD cases. ICGA effectively differentiates occult CNVM from RAP, visualizing the feeding retinal arteriole and draining retinal venule in RAP. Typical RAP features include intraretinal hemorrhage, retino-retinal anastomosis, high-flow vascular alterations, retino-choroidal anastomosis, and double retinal and choroidal circulation. RAP is associated with poor functional prognosis unless treated early. The treatment response for RAP is better with a combination of anti-VEGF and PDT rather than anti-VEGF alone.
Polypoidal Choroidal vasculopathy (PCV)
ICGA is highly recommended for identifying PCV lesions and is considered the gold standard for diagnosing PCV. ICGA should be used to rule out PCV in cases of massive spontaneous subretinal or submacular hemorrhage, orange-red subretinal nodules, notched or hemorrhagic PEDs, and poor response to anti-VEGF therapy. PCV, an abnormality in choroidal circulation, results in a vascular network and aneurysmal bulge clinically visible as a reddish-orange polyp. ICGA reveals the PCV network filling slowly and the polyps become visible as hypercyanescent lesions. Differentiating PCV from CNVM, ICGA guides treatment, with PCV responding better to PDT or a combination of PDT and anti-VEGF therapy, rather than anti-VEGF therapy alone.
Central Serous Chorioretinopathy (CSCR)
ICGA in CSCR shows multifocal areas of choroidal hyperpermeability in mid and late phases, surrounding the leak area seen on FFA, in the unaffected retina or fellow eye. The early phase shows a delay in choroidal filling, with the late phase showing persistent hypercyanescence or washout. Chronic CSCR features multifocal areas of inner choroidal hyperpermeability. Identifying these areas helps in treating chronic CSCR using PDT. ICGA differentiates CSCR from PCV and detects underlying CNVM in CSCR.
Retinal Arterial Macroaneurysm (RAM)
RAM can present with pre-retinal, intraretinal, and subretinal hemorrhage. Significant pre-retinal hemorrhage may mask the macroaneurysm on FA, but ICGA can visualize it due to the better penetration of infrared rays through the hemorrhage.
Choroidal Tumors
Choroidal melanoma: ICGA is superior to FA in identifying tumor vasculature and borders. ICGA microcirculation patterns like parallel with cross-linking, loops, arcs with branching, and networks are associated with higher tumor growth rates. Choroidal hemangioma: In circumscribed choroidal hemangioma, ICGA shows the intrinsic vascular pattern 30 seconds post-ICG injection, becoming intensely hypercyanescent at 1 minute, with a rapid washout making the hemangioma appear hypocyanescent in late phases.
White Dot Syndromes
Birdshot chorioretinopathy: ICGA shows hypocyanescent dots corresponding to cream-colored lesions, superior to FA which typically does not visualize these lesions. Multifocal choroiditis: The white lesions appear as hypocyanescent dots in ICGA, useful for monitoring treatment response. MEWDS: Presents with multiple hypocyanescent spots in mid and late ICGA phases, more apparent than in FA. Serpiginous choroidopathy: ICGA reveals larger choroidal alterations than FA, identifying active lesions. APMPPE: ICGA reveals hypocyanescent lesions in all phases, likely due to choroidal hypoperfusion from occlusive vasculitis. PIC: Hypocyanescent spots are noted in all ICGA phases, often more numerous than visible on fundus photo or FFA. AZOOR: ICGA may be normal or show hypocyanescence, with a trizonal pattern in late-stage AZOOR.