Indocyanine green angiography (ICGA) provides improved imaging of choroidal vasculature compared to fluorescein angiography. Because of the excitation and emission properties of indocyanine green (excitation at 790 nm and emission at 835 nm), pathologies involving retinal and choroidal vascular systems can be imaged even in the presence of overlying melanin, serosanguinous fluid, xanthophyll pigment, or lipid exudations.

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History

Indocyanine green (ICG) was developed in Kodack laboratories, and its physical and physiological properties were first described by Fox and Wood in .[1] Kogure and others first used ICG to visualize the fundus of an owl monkey in the s.[2] However, it was not routinely used in humans until s because of technological limitations of the fundus cameras. There was an uptick in ICGA administration in the s due to improvements in digital video angiography, scanning laser ophthalmoscopy, and optical systems of fundus cameras.[3][4] In addition, the advent of ICGA allowed for better detection of occult choroidal neovascularization (CNV), which in turn led to an increase in the number of eyes that were eligible for photocoagulation which, at the time, was the only treatment option for CNV.[5] Since the s, in the era of anti-vascular endothelial growth factor (anti-VEGF) therapy which does not require accurate localization of the CNVs, ICGA has been mostly limited to the indications summarized below.[6] However, ICGA, combined with FA, OCT, and OCTA, is still extremely useful in clinical practice.

Retinal angiomatous proliferation (RAP): 75-year-old patient with a decrease in visual acuity and metamorphopsia in right eye. This RAP lesion is focally hyperfluorescent in this late-phase FA (left) and hypocyanescent in midphase ICGA (right). Note the feeding and draining retinal arteriole and venule ending at the lesion. This image was originally published in the Retina Image Bank® website. Gabriela Lopezcarasa Hernandez, MD. Photographer Azucena Rios. Retinal Angiomatous proliferation. Retina Image Bank. ; . © The American Society of Retina Specialists.

75-year-old patient with a decrease in visual acuity and metamorphopsia in right eye. This RAP lesion is focally hyperfluorescent in this late-phase FA (left) and hypocyanescent in midphase ICGA (right). Note the feeding and draining retinal arteriole and venule ending at the lesion. This image was originally published in the Retina Image Bank® website. Gabriela Lopezcarasa Hernandez, MD. Photographer Azucena Rios. Retinal Angiomatous proliferation. Retina Image Bank. ; . © The American Society of Retina Specialists.

Properties

Two properties make ICG an effective dye for visualizing choroidal vasculature. First, indocyanine green&#;s affinity to circulating proteins is high (95%), limiting its leakage from vessel walls. Comparatively, more heavily leaking fluorescein (only 80% bound) from the retinal and choriodal vessels can obscure the details of adjacent retinal and choroidal vasculature. Another drawback of fluorescein dye in visualizing the choroid is that fluorescein molecule absorbs and emits shorter wavelength photons. Since the retinal pigment epithelium (RPE) also absorbs and emits photons around this wavelength, the resulting scatter from RPE can obscure the choroidal vessels. Indocyanine, however, absorbs and emits photons in the infrared spectrum, allowing the viewer to see the choroid through the retinal pigment epithelium or disease processes such as overlying hemorrhage.[7]

See &#;Dyes in Ophthalmology&#; for more information.

Uses

For a thorough review of the uses of indocyanine green, see Cohen et al.&#;s &#;Is indocyanine green still relevant?&#; editorial in Retina .[8]

In the era of anti-VEGF treatments, the localization of CNV is not absolutely necessary for managing exudative ARMD as it was in the past. However, ICGA is utilized by many clinicians in combination with other retinal imaging modalities to identify the subtype of CNV in AMD (type 1: sub-retinal pigment epithelium, type 2: subretinal, and type 3: intraretinal) and to differentiate ARMD lesions from simulating lesions.[8]

Polypoidal choroidal vasculopathy (PCV): The PCV lesion shows hyperfluorescence and hypercyanescence on intermediate-phase FA (left) and ICGA (right). This image was originally published in the Retina Image Bank® website. Gareth Lema MD, PhD. Photographer Sandra Boglione.Polypoidal Choroidal Vasculopathy - IVFA/ICGA. Retina Image Bank. ; . © The American Society of Retina Specialists.

The PCV lesion shows hyperfluorescence and hypercyanescence on intermediate-phase FA (left) and ICGA (right). This image was originally published in the Retina Image Bank® website. Gareth Lema MD, PhD. Photographer Sandra Boglione.Polypoidal Choroidal Vasculopathy - IVFA/ICGA. Retina Image Bank. ; . © The American Society of Retina Specialists.

Type 1 macular neovascularization (MNV), with CNV network located under the RPE, is the most common form of exudative AMD. Type 1 CNV corresponds to &#;occult CNV&#; based on the Macular Photocoagulation Study and is identified as fibrovascular pigment epithelium detachment with a late stippled fluorescence or a late leakage from an undetermined source (LLUS). Often, clinical examination, OCT, and FA are sufficient for the diagnosis and follow-up; however, ICGA may be required when the lesion is covered with hemorrhage or if there is a question about the presence of accompanying type 3 MNV (retinal angiomatous proliferation &#; RAP) that is reported in about one fourth of the eyes with type 1 CNV. The presence of a RAP lesion has at least two clinical significances. First, RAP is shown to have a more aggressive clinical course that needs frequent and long-term injection of anti-VEGF agents. Second, it has been shown that RAP lesions respond better to treatment with anti-VEGF agents combined with photodynamic therapy (PDT). ICGA may delineate the presence of type 1 CNV usually around the perimeter of pigment epithelial detachment or show the feeder and draining vessels. RAP lesions are similarly seen as an interconnected retinal arteriole and venule branch.

Choroidal Hemangioma: (A) shows fundus photo (left), FA(middle), and ICGA (right). FA revealed leakage from an ill-defined lesion superotemporal to the disc, while the ICGA showed diffuse and intense hypercyanescence of choroidal vessels, consistent with a choroidal hemangioma. (B) shows OCT of the same eye with foveal detachment and choroidal elevation (star). (C) B-scan ultrasonography and A-scan ultrasonography. A Masquerade Case: Choroidal Hemangioma Misdiagnosed As Central Serous Retinopathy © by Lai L, Javier T, Lee S, Gallemore RP. is licensed under Creative Commons Attribution &#; Non-Commercial (unported, v3.0) License.

(A) shows fundus photo (left), FA(middle), and ICGA (right). FA revealed leakage from an ill-defined lesion superotemporal to the disc, while the ICGA showed diffuse and intense hypercyanescence of choroidal vessels, consistent with a choroidal hemangioma. (B) shows OCT of the same eye with foveal detachment and choroidal elevation (star). (C) B-scan ultrasonography and A-scan ultrasonography. A Masquerade Case: Choroidal Hemangioma Misdiagnosed As Central Serous Retinopathy © by Lai L, Javier T, Lee S, Gallemore RP. is licensed under Creative Commons Attribution &#; Non-Commercial (unported, v3.0) License.

Type 2 CNV known as &#;classic CNV&#; is located under the retina and above the RPE and is visualized nicely with ICGA as the network of abnormal vessels in the setting of improved delineation of retinal and choroidal circulations. This improved spatial and temporal visualization with ICGA allows identification of the feeding choroidal vessels into the type 2 CNV lesion. 

Aneurysmal type 1 MNV or polypoidal choroidal vasculopathy (PCV) is characterized by a growth of cavernous thin-walled vessels between the RPE and the Bruch&#;s membrane and is often associated with multiple, recurrent, serosanguineous detachments of the RPE and neurosensory retina secondary to leakage and bleeding from the polypoid lesions. ICGA delineates the polypoid or &#;bulging&#; capillaries through the overlying RPE and serosanguinous fluid with higher sensitivity and specificity and provides a better insight into the possible clinical course and prognosis. PCV polyps (that may be located in the peripapillary area or at the macula) start to fill before retinal vessels and continue to fill long after retinal vessels are filled. Thus, polyps are usually seen as early small hypercyanescence that leak slowly as the surrounding hypocyanescence become increasingly hypercyanescent. In later phases, dye gradually and uniformly &#;washes out&#; from the bulging polypoidal lesions.

PCV can be misdiagnosed or confused with chronic central serous chorioretinopathy or with classic or occult CNV in the setting of AMD. Indeed, in some patients, a transitional phase between these two pathologies can contain PCV patholgies. PCV lesions are usually responsive to more frequent anti-VEGF treatment with or without photodynamic therapy. In this setting, ICGA can guide management primarily by:

1. Revealing the polypoidal lesions and the branching vascular networks.

2. Identify active PCV for selective treatment with photodynamic therapy (PDT)

3. Identify recurrences after PDT (seen as late geographic hypercyanescence).[9][10][11]

Central Serous Chorioretinopathy (CSCR): Mid-phase FA (right) shows a smokestack leak,age and ICGA (left) shows a pinpoint hypocyanescent spot corresponding to the leakage site and the adjacent hypercyanescent areas. This image was originally published in the Retina Image Bank® website. Hamid Ahmadieh, MD. Photographer Hamid Ahmadieh, MD. Acute Central Serous Chorioretinopathy. Retina Image Bank. ; 735. © The American Society of Retina Specialists.

Mid-phase FA (right) shows a smokestack leak,age and ICGA (left) shows a pinpoint hypocyanescent spot corresponding to the leakage site and the adjacent hypercyanescent areas. This image was originally published in the Retina Image Bank® website. Hamid Ahmadieh, MD. Photographer Hamid Ahmadieh, MD. Acute Central Serous Chorioretinopathy. Retina Image Bank. ; 735. © The American Society of Retina Specialists.

Choroidal tumors

ICGA and ultrasonography help identify choroidal hemangiomas and differentiate them from simulating tumors such as choroidal melanoma or metastasis. Choroidal hemangioma has a distinctive filling pattern on ICGA: progressive filling of abnormal choroidal vessels in the early phase, followed by an intense hypercyanescence at 2-4 minutes, with decreased cyanescence of the tumor at later frames compared to the rest of the choroid, known as the washout phenomenon.[12][13][14][15][16]

Although other choroid tumors do not have a characteristic ICGA feature, ICGA may still be used to differentiate them from simulating nontumor lesions such as peripheral exudative hemorrhagic chorioretinopathy (PEHCR). [8]

Choroidal hypervascularity in the pachychoroid spectrum of diseases such as central serous chorioretinopathy (CSCR) may be better delineated with ICGA. ICGA may show an area of choroidal hypervascularity larger than the leakage spot seen in FA and is especially helpful in guiding photodynamic therapy to include entire hypervascular and leaking areas.[17][18] In addition, chronic CSCR complicated with CNV with or without leakage and hemorrhage may be better delineated with ICGA.

Angioid Streaks: Late phase ICG angiography image of the left eye of a 59-year-old man with angioid streaks demonstrating hypercyanescence of the cracks in the Bruchs membrane. This image was originally published in the Retina Image Bank® website. Hamid Ahmadieh, MD. Photographer Hamid Ahmadieh, MD. Acute Central Serous Chorioretinopathy. Retina Image Bank. ; 951. © The American Society of Retina Specialists.

: Late phase ICG angiography image of the left eye of a 59-year-old man with angioid streaks demonstrating hypercyanescence of the cracks in the Bruchs membrane. This image was originally published in the Retina Image Bank® website. Hamid Ahmadieh, MD. Photographer Hamid Ahmadieh, MD. Acute Central Serous Chorioretinopathy. Retina Image Bank. ; 951. © The American Society of Retina Specialists.

ICGA may provide a clear view of the complications associated with pathologic myopia. CNV lesions associated with lacquer cracks (such as lesions underneath subretinal hemorrhages related to newly formed lacquer cracks) are better visualized with ICGA.[19]

Angioid streaks are typically visualized with ICGA more clearly, extensively, and prominently as compared to FA or fundus exam.[20]

Inflammatory

ICGA is helpful in the diagnosis of white dot syndromes, particularly if the fundus lesions are of an atypical appearance or have already faded away.[21] In MEWDS, ICGA shows numerous hypercyanescent dots scattered throughout the posterior pole and a hypocyanescent area surrounding the optic nerve. The hypocyanescent areas on ICGA disappear over time as the inflammation resolves. [22][23][24]

Multiple evanescent white dot syndrome (MEWDS): Late phase angiographic images from a patient with MEWDS; FA (left) and ICGA. ICGA shows hypocyanescent patches corresponding to MEWDS lesions. American Academy of Ophthalmology, , Accessed: 10/1/ https://www.aao.org/education/image/indocyanine-green-angiography

Late phase angiographic images from a patient with MEWDS; FA (left) and ICGA. ICGA shows hypocyanescent patches corresponding to MEWDS lesions. American Academy of Ophthalmology, , Accessed: 10/1/ https://www.aao.org/education/image/indocyanine-green-angiography

Acute posterior multifocal placoid pigment epitheliopathy is a multifocal inflammation involving the choriocapillaris, and the resulting delayed and defective choroidal filling may manifest as a unique pattern of multifocal hypocyanescence in areas seen in the retinal examination as white spots.[25]

Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE): A 27-year-old male with APMPPE. In the fundus photograph, there are multiple yellow placoid lesions in the posterior pole of both eyes. ICGA revealed more lesions than those observed in fundoscopy. The OCTA segmented at the level of the choriocapillaris revealed areas of ischemia in close correspondence with the hypocyanescent lesions. The OCT with superimposed flow shows disruption and hyperreflectivity of the external retinal layers in the affected areas and the absence of flow in the choriocapillaris underneath. This image was originally published in the Retina Image Bank® website. Claudia Farinha. Photographer Pedro Melo. Acute Posterior Multifocal Placoid Pigment Epitheliopathy. Retina Image Bank. ; . © The American Society of Retina Specialists.

A 27-year-old male with APMPPE. In the fundus photograph, there are multiple yellow placoid lesions in the posterior pole of both eyes. ICGA revealed more lesions than those observed in fundoscopy. The OCTA segmented at the level of the choriocapillaris revealed areas of ischemia in close correspondence with the hypocyanescent lesions. The OCT with superimposed flow shows disruption and hyperreflectivity of the external retinal layers in the affected areas and the absence of flow in the choriocapillaris underneath. This image was originally published in the Retina Image Bank® website. Claudia Farinha. Photographer Pedro Melo. Acute Posterior Multifocal Placoid Pigment Epitheliopathy. Retina Image Bank. ; . © The American Society of Retina Specialists.

Although ICGA is not crucial for diagnosing VKH, active disease can be differentiated from completely treated and inactive VKH by the ICGA pattern. ICGA signs of acute VKH include early choroidal vessel hypercyanescence, intermediate to late phase fuzziness of choroidal stromal vessels, disc hypercyanescence, and hypocyanescent dark dots (HDDs).  ICGA is an excellent modality to detect subtle choroidal inflammation in subclinical VKH reactivation, thus helping to monitor adequate response to corticosteroid treatment.[26][27]

Deep, cream-colored lesions diffusely scattered throughout the fundus in Birdshot chorioretinopathy (BS) appear as round or oval hypocyanascent spots with a similar size spread across the fundus, particularly affecting the nasal quadrants. FA does not show these lesions well, and ICGA often shows more spots than clinical examination. Other ICGA features include an alteration of the vascular pattern of the choroid, with choroidal vessels appearing fuzzy and indistinct in the intermediate phases of the angiogram and a late diffuse hypercyanescence resulting from the ICG dye leaking through the inflamed choroidal vessels. In the chronic phase of the disease, the hypocyanescent dots persist in the late phases of the angiogram and correspond to chorioretinal scars. [28]

Choroidal Granulomas

Choroidal granulomatous diseases such as sarcoidosis and tuberculosis may manifest as hypocyanascent lesions that reflect filling defects in the areas occupied by a collection of granulomatous cells. [29][30]

Vogt-Koyanagi-Harada disease (VKH): Simultaneous early phase FA (left) and ICGA (right) images of a 42-year-old woman with VKH showing hypocyanescent dark dots corresponding to hypoperfused areas in choroid. This image was originally published in the Retina Image Bank® website. Claudia Farinha. Photographer Pedro Melo. Acute Posterior Multifocal Placoid Pigment Epitheliopathy. Retina Image Bank. ; . © the American Society of Retina Specialists.

Simultaneous early phase FA (left) and ICGA (right) images of a 42-year-old woman with VKH showing hypocyanescent dark dots corresponding to hypoperfused areas in choroid. This image was originally published in the Retina Image Bank® website. Claudia Farinha. Photographer Pedro Melo. Acute Posterior Multifocal Placoid Pigment Epitheliopathy. Retina Image Bank. ; . © the American Society of Retina Specialists.

ICGA can help to differentiate between active, inactive, and healed serpiginous choroidopathy (SC) lesions.[31][32][33] In subclinical and clinically active lesions, ICGA will typically show one of the two patterns: 1) early and late hypocyanescence with ill-defined margins, or 2) early hypocyanescence with increased cyanescence toward late-phase of ICGA. ICGA in healed SC lesions will show early and late-phase hypocyanescence with well-defined margins.

Ocular Infections

While posterior inflammation involving the choroid could be seen with ICGA in many infectious processes, ICGA often does not offer additional information to help with the diagnosis or management of ocular infectious conditions.[8]

Trauma

ICGA can reveal choroidal involvement as with traumatic choroidopathies such as choroidal rupture and traumatic ocular hypotony. However, since ICGA adds little diagnostic or prognostic information, it is rarely ordered in ocular trauma settings.[34][35] [36][37]

Procedure

The standard dosing for ICG with scanning laser ophthalmoscopy camera systems is 25 mg of ICG dissolved in 3 ml of saline and 1 ml of the solution is injected. For combined FA and ICGA, saline is replaced with fluorescein sodium solution at 10, 20, or 25% concentrations. There  are three temporal phases for ICGA imaging, similar to fluorescein angiography:[7][38]

Birdshot Chorioretinopathy - ICG shows numerous scattered small hypocyanescent spots, not necessarily corresponding to lesions seen on FA or clinical examination This image was originally published in the Retina Image Bank® website. Armando L. Oliver, MD. Photographer Moises Castro. Birdshot ICG OD. Retina Image Bank. ; . © The American Society of Retina Specialists.

- ICG shows numerous scattered small hypocyanescent spots, not necessarily corresponding to lesions seen on FA or clinical examination This image was originally published in the Retina Image Bank® website. Armando L. Oliver, MD. Photographer Moises Castro. Birdshot ICG OD. Retina Image Bank. ; . © The American Society of Retina Specialists.

Early phase - within the first minute after injecting the eye, when larger choroidal arteries and veins are highlighted but retinal arteries are not filled.[38] Choroidal vessels start to fill from larger outer Haller&#;s layer vessels followed by intermediate Sattler&#;s layer. The choriocapillaris layer fills last but camera resolutions are not high enough to identify individual choriocapillaris. Thus, filling of choriocapillaris is usually seen as indistinct general haze, more evident in the posterior pole.

Middle phase - up to 5 to 10-15 minutes after injection. Retinal arteries and veins as well as the choroidal vasculature are filled.  Choroidal cyanescence will become more diffuse and less distinct in this phase as the choriocapillaris is filled.[38]

Late or recirculation phase - more than 10-15 minutes after the dye is injected. During this phase, a pathologic hypercyanescent lesion is more visible against the slowly fading background.[38]

Safety

ICGA is a safe and well-tolerated imaging study with extremely rare toxicity and allergic reactions such as nausea, vomiting, sneezing, and pruritus in 0.15% of the procedures, moderate allergic reactions such as urticaria and pyrexia in 0.2% of the patients, and severe reactions such as bronchospasm and anaphylactic reaction in 0.05% of the patients.[39] An editorial described four reports of patients who have experienced an adverse reaction out of 240,000 indocyanine intravenous injections, one patient had urticaria and three patients had anaphylactic reactions, with one resulting in death.[7][40]

Absolute contraindications

1. Prior allergic reaction to ICG

2. Iodine/Iodide allergy: Although prior allergy to contrast dyes containing iodine or allergic reaction to shellfish are traditionally mentioned as contraindications for ICGA, such &#;allergic reactions&#; against indocyanine green are not biologically plausible. Unlike x-ray contrast media, iodine containing disinfectant solutions, or iodine containing medications such as amiodarone where iodide is bound to the main large molecule and can be identified by immune system as antigen, the ICG molecule does not contain the ion iodide and small sodium iodide molecule that is added to stabilize ICG in saline solution, are not detectable by immune system as antigens. Nevertheless, it is a common agreement to avoid ICGA if there is a history of allergy to iodine. In addition, since up to 840μg of iodide can be administered with ICGA imaging, there is a risk of thyroid storm in individuals with uncontrolled hyperthyroidism. In these situations, ICG should be used with caution or not used at all. Infracyanine green is an iodine free preparation of ICG available for those with an absolute contraindication to ICG and can be given with some modifications in the administration techniques. [38]

Relative contraindications

1. End stage renal disease

2. Liver disease

3. Pregnancy (Category C: adequate safety studies have not been conducted)[7]

Summary

ICGA is a safe and important imaging modality that offers a better view of the choroidal vasculature and related pathologies. Although it is not used as often as before in managing choroidal neovascular lesions, ICGA is still helpful in guiding the treatment of PCV and CSC and diagnosing choroidal hemangiomas and ocular inflammations primarily affecting the choroid.

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Continuing Education Activity

Indocyanine green angiography is an important invasive imaging modality among many diagnostic imaging modalities used in retinochoroidal diseases. It helps to study the anatomy, physiology, and pathology of choroidal and retinal circulation. It has an important role in the diagnosis of various ocular pathologies. This activity describes the anatomy of choroidal circulation and reviews the techniques and interpretation of indocyanine green angiography. It also highlights the role of the interprofessional team in monitoring the patient and managing adverse events during the procedure.

Objectives:

• Describe the anatomy and physiology of choroidal circulation.

• Review the personnel, equipment, preparation, and technique of indocyanine green angiography.

  Additional reading:
  The Ultimate Buyer's Guide for Purchasing Disposable Skin Staplers

  For more information, please visit Retinal Camera.

• 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.

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Introduction

Indocyanine green angiography (ICGA) is used to image the choroidal circulation and its abnormalities.[1] Even though fundus fluorescein angiography (FFA) is a good tool for imaging retinal circulation in great detail, its ability to image the choroidal circulation is limited by the poor transmission of fluorescence through retinal pigment epithelium (RPE), media opacities, and retinal exudates.[2] The physical characteristics of indocyanine green (ICG) allow its visualization through RPE, lipid exudates, and serosanguineous fluid. Indocyanine green has an absorption peak at 790 to 805 nm and a peak emission spectrum at 835 nm.[3]

As its absorption and emission spectrum is of a higher wavelength than that of fluorescein, the infrared rays to and from ICG can penetrate better through the RPE, macular xanthophyll pigments, and media opacities. Also, 98% of ICG in serum is protein-bound, allowing only limited diffusion through the fenestrations of the choriocapillaris, whereas FA diffuses quickly, blurring the anatomy of the choroid.[4][5]

ICG was approved for human use by Food and Drug Administration (FDA), the USA, in .[6] ICG angiography (ICGA) of the human choroid was first performed by R W Flower in .[7] Initially, the clarity of images was poor as the ICG molecule has poor fluorescence efficiency compared to FA. But, technological advances in imaging systems (scanning laser ophthalmoscope or SL- based systems) led to the development of high-resolution cameras that could capture ICGA images with great clarity. In the era of anti-vascular endothelial growth factor (anti-VEGF) agents and optical coherence tomography (OCT), the monitoring of the choroidal neovascular membrane (CNVM) has become easier.[8][9]

Still, ICGA continues to be an important imaging modality in clinical practice in evaluating various disorders, including idiopathic polypoidal choroidal vasculopathy (IPCV), retinal angiomatous proliferation (RAP), central serous chorioretinopathy (CSCR), ocular inflammatory conditions including sympathetic ophthalmia (SO) and Vogt Koyanagi Harada syndrome (VKH); and ocular tumors.[10][11]

Anatomy and Physiology

The blood supply of the choroid is from the ophthalmic artery, the first branch of the internal carotid artery.[12] The medial and lateral posterior ciliary arteries (PCAs) arise from the ophthalmic artery, which continues as long PCAs after giving 10 to 20 short PCAs. The short PCAs pierce the sclera near the optic nerve and supply the choroid, whereas the two long ciliary arteries pierce the sclera further away from the optic nerve and run in the suprachoroidal space anteriorly. The short PCAs supply the posterior part of the choroid extending from the posterior pole to the equator. The long PCAs supply whole of the choroid anterior to the equator and a small portion posterior to the equator. The PCAs behave as end arteries and do not anastomose with each other. This leads to the formation of the choroidal watershed zones.[13]

The innermost layer of the choroid is Bruch membrane. The Bruch membrane is composed of five sublayers- the basement membrane of retinal pigment epithelium, the inner collagenous layer, the middle elastic layer, the outer collagenous layer, and the basement membrane of choriocapillaris. Outside the Bruch membrane, there are three vascular layers- the inner choriocapillaris composed of a highly anastomosed capillary network, the middle Sattler layer formed by medium-sized arterioles, and the outer layer of larger arterioles, the Haller layer.[14] The choriocapillaris lobule is the functional unit of choroidal circulation that is functionally independent.[15] 

The functional lobules are more evident during the filling and draining phases of the fluorescein angiogram.[16] A terminal choroidal arteriole supplies each choriocapillaris lobule. There is no anastomosis with the adjacent choriocapillaris lobule. The blood from the choroidal circulation is drained through the vortex veins. The venous system also has segmental distribution. There is no anastomosis between the veins draining to each vortex vein.[17]

The blood supply to the choroid is probably the highest among any tissue in the human body per unit of tissue weight. It is ten times higher than that of the brain. This extremely high blood flow helps maintain higher oxygen tension in the choroid than in the retina. This helps in the diffusion of oxygen from the choroid to the retina. The choroidal circulation is the major supply of oxygen to the retina. During the dark, when the photoreceptors are highly metabolically active, up to 90% of the blood supply to the retina is from the choroidal circulation. The walls of the choriocapillaris are fenestrated, which allows high permeability of glucose and other small molecules.[18] 

But larger proteins are not permeable through the fenestrations. ICG  is 98% protein-bound making it largely impermeable through the choriocapillaris wall.[4] On the contrary, fluorescein is only 80% protein bound.[19] So it readily diffuses out of the choriocapillaris.[20]

Indications

The indications of ICGA include:

• Exudative age-related macular degeneration (wet AMD) [21]

• Idiopathic polypoidal choroidal vasculopathy (IPCV or PCV) [22]

• Retinal angiomatous proliferation (RAP) [23]

• Central serous chorioretinopathy (CSCR) [10]

• Retinal arterial macroaneurysm (RAM) [24]

• • 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 [25]

• Chorioretinal atrophy

• • Sympathetic ophthalmia (SO) [26]

  • Vogt Koyanagi Harada syndrome (VKH) [27]

  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.[28][29]

Contraindications

ICG is a relatively safe and well-tolerated dye. It has only a few contraindications in ophthalmological use. In patients who are allergic to iodide or shellfish, ICGA should not be performed. Also, it is contraindicated in patients with uremia and those with a history of severe hypersensitivity.[30] 

ICG is exclusively eliminated through the liver. So in patients with liver disease, ICGA is not recommended.[31] According to FDA classification, ICG is a pregnancy category C drug. That means there are no adequate studies on humans to establish safety.[32] The aqueous solution of ICG has to be used within 6 hours. An interval of at least one week is necessary after ICGA for radioactive iodine uptake studies.

Equipment

A fundus camera with excitation and a barrier filter is used for taking photographs. There are two categories of fundus cameras used for ICGA, digital flash cameras and confocal scanning laser ophthalmoscopes (SLOs). In a digital flash camera (including FF 450 plus by Zeiss and TRC-50DX by Topcon), the light source is white light. Its excitation filter transmits rays of wavelength between 640 and 780 nm and barrier filter between 820 and 900 nm. In SLOs (including Spectralis by Heidelberg, Mirante by Nidek, and California by Optos), laser monochromatic light is used for excitation. The Spectralis uses a diode laser (790 nm) for excitation.[33] A barrier filter of 830 nm is used in Spectralis. Dynamic ICGA is possible in the SLO system as it can capture 12 to 15 images per second.[34]

The standard intravenous dose of ICG for an adult individual is 25 mg in 5 ml solvent.[35] A 23 gauge scalp vein needle set, a 5 ml syringe with a needle, alcohol swab, tourniquet, and armrest are also required. A standard emergency kit for the management of anaphylaxis should always be kept ready before starting the procedure.

Personnel

The team of health care workers for carrying out ICGA includes an ophthalmologist, technician, optometrist, a nursing staff, and an anesthetist.

Preparation

Informed consent should be taken from the patient before starting the procedure. The risks and benefits of the procedure should be explained to the patient. A thorough history of the allergies and systemic comorbidities of the patient should be taken&#;two to four hours of fasting before the procedure are recommended. The adult dose of ICG is 25 mg in 5 ml of solvent. If SLO systems are used, 25 mg of ICG is dissolved in 3 ml of solvent, and only 1 ml of solution is injected. A 5 ml saline flush should be given immediately after injecting the dye. 

It should be made sure that pupils are well dilated before starting the procedure. The emergency kit should be available. A few color fundus images should be taken to check for clarity and focus. The patient should be comfortably seated, and the arm should be placed on the armrest. The chin should be kept on the chinrest. The patient should understand that the images will be taken first in the primary gaze and later in different gazes. The scalp vein set is inserted into a vein in the ventral aspect of the forearm. It is important to ensure that the needle is inside the vein by drawing some blood or flushing with saline.

Technique or Treatment

After placing the patient's chin on the chin rest, the assistant holds the head of the patient to prevent head movements while capturing images. The moment dye is injected, control photographs are taken, which automatically switches on the timer. Pictures are taken at an interval of 1.5 to 2 seconds. After the choroidal arterial and venous system is filled with the dye, photographs are taken at a slower pace. Pictures of the fellow eye also have to be taken. 

Normal ICGA Phases

1. 1. Stage 1: Begins 2 seconds after the injection of the dye. It is marked by rapid filling of choroidal arteries and choriocapillaris and early filling of choroidal veins. The choroidal watershed zone and the retinal vasculature remain dark in this stage. 

   2. Stage 2: Three to five seconds after ICG injection, larger choroidal veins, and retinal arterioles fill the dye.

   3. Stage 3: (6 seconds to 3 minutes) - The choroidal watershed zone gets filled with the dye, and larger choroidal veins and choroidal arteries begin to fade. 

   Early phase - The early phase has three stages:

2. The middle phase (3 to 15 minutes) is characterized by fading of the retinal and choroidal vessels.

3. Late phase (15 to 60 minutes) - Staining of the extrachoroidal tissue is noted. It gives an illusion that choroidal vasculature is hypofluorescent compared to the background tissue. Retinal vessels are not visualized during this phase. [3]

Complications

[36]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 are seen in 0.15% of patients. Moderate adverse events like urticaria, vasovagal events are seen in 0.2% of patients. Urticaria can be treated using antihistamines. The incidence of severe adverse events is 0.05%. Anaphylaxis can occur in patients with iodine allergies. The incidence of adverse events is more common in patients with uremia compared to the general population.[37]

Clinical Significance

Exudative Age-Related Macular Degeneration (exudative AMD or wet AMD)

ICGA helps to delineate the extent of occult CNVM. Occult CNVM comprises 60-85% of CNV in wet AMD.[38][39] In ICGA, three morphologic variants of CNVM have been described: hot spot or focal spot, plaque (poorly defined or well defined), and mixed or combined (both hot spot and plaque are present).[35] 

The combined type of CNVM may have a hot spot or multiple hot spots at the edge of the plaque (marginal hot spots), hot spots over the plaque (overlying hot spots), or hot spots away from the plaque (remote spots). In eyes with occult CNVM, a majority (around 60%) of eyes reveal plaques on ICGA, and approximately 30% of eyes show hot spots. The rest of the eyes have combined lesions. The visual prognosis of plaque may be worse compared to hot spots, and hot spots may be treated easily with PDT.[40] 

ICGA helps determine the presence of CNVM in a retinal pigment epithelial detachment (PED). In a PED without CNVM (non-vascularized PED), hypocyanescence is noted throughout the phases of ICGA. In eyes with proven occult CNVM with serous PED (vascularized PED) on FFA, 62% showed plaque (size more than one disc area), 38% of eyes showed focal CNVM (with a maximum size of one optic disc area), and in 4% of eyes ICGA could not detect a CNVM.[41] Vascularized PEDs may show a notch at the margin, which may suggest the area of CNVM on FFA as described by Gass.[42] 

Advantages of ICGA include the ability to visualize CNVM or other causes of subretinal or submacular hemorrhage. The causes of submacular hemorrhage, as revealed by ICGA in a study on 51 eyes, included wet AMD (around 53%), PCV (about 37%), retinal arterial macroaneurysm (about 6%), and lacquer cracks.[43] ICGA is usually not used to study classic CNVM on FFA as it may not provide clinically relevant additional information.

Clear lesion delineation is crucial in treatment modalities like photodynamic therapy (PDT) and laser photocoagulation. Anti-VEGF therapy causes regression of only immature vessels. It does not affect mature vessels.[44] ICGA helps in differentiating immature and mature vessels. This may be of great help, especially in non-regressed CNVMs after multiple anti-VEGF injections. 

Retinal angiomatous proliferation (RAP) or Type 3 CNVM

RAP may contribute to up to 20% of cases of wet AMD. ICGA also aids in differentiating occult CNVM from retinal angiomatous proliferation (RAP). The feeding retinal arteriole and the draining retinal venule in RAP can be visualized in ICGA.[45] Typical features of RAP include intraretinal hemorrhage, retino-retinal anastomosis visible in the early phase of ICGA, high-flow vascular alterations, retino-choroidal anastomosis, and double retinal and choroidal circulation.[46][47]

Cystoid macular edema and PED may be associated.[48] RAP is associated with a poor functional prognosis unless treated at an early stage.[49] Also, the treatment response of RAP is better with combined anti-VEGF and photodynamic therapy compared to anti-VEGF alone.[50][51]

Polypoidal Choroidal vasculopathy (PCV)

ICGA is highly recommended for identifying PCV lesions, and ICGA is considered the gold standard for diagnosing PCV.[35][52] ICGA should be advised to rule out PCV in the eyes with:

• Massive spontaneous subretinal or submacular hemorrhage

• Orange-red subretinal nodule

• Notched or hemorrhagic PED, and 

• Poor response to anti-VEGF therapy. [52]

PCV is an abnormality of choroidal circulation in which a vascular network is formed in the inner choroidal layers with an aneurysmal bulge usually at the margin of such network. The aneurysmal bulge is clinically visible as a reddish-orange polyp-like structure.[53] 

In ICGA, even though the PCV network starts getting filled with the dye earlier than the retinal vessels, it gets filled slowly. Later the polyps become visible as hypercyanescent lesions. The EVEREST study on PCV used the following criteria to diagnose PCV: early focal subretinal hypercyanescence appearing within 6 minutes of ICG administration with at least one of the following:

• associated branching vascular network,

• pulsatile polyp,

• nodular appearance on stereoscopic view,

• hypocyanescent halo around polyp within 6 minutes,

• orange subretinal nodule on stereoscopic color fundus photo that corresponds to the polyp on ICGA, and

• massive submacular hemorrhage (minimum size of 4 disc area). [54]

It is important to differentiate PCV from CNVM as PCV responds better with photodynamic therapy (PDT) or a combination of PDT and intravitreal anti-VEGF therapy rather than anti-VEGF therapy alone.[54][55] Peripheral exudative hemorrhagic chorioretinopathy (PEHCR) has been divided into two groups: with and without peripheral PCV. The peripheral PCV subtype shows polyps on ICGA in eyes with PEHCR.[56]

Central Serous Chorioretinopathy (CSCR)

ICGA of CSCR is characterized by multifocal areas of choroidal hyperpermeability in the mid and late phases.[57] These areas of hyperpermeability may surround the area of leak seen on FFA, in the unaffected retina, or in the fellow eye. The early phase shows a delay in the choroidal filling. The late phase of ICGA may show persistent hypercyanescence or washout. Chronic CSCR is characterized by multifocal areas of inner choroidal hyperpermeability. Identifying these areas of leaks helps in the treatment of chronic CSCR using PDT.[58] 

ICGA also helps to differentiate CSCR from PCV and helps detect underlying CNVM in CSCR.[59] Other ICGA features of CSCR include presumed occult serous PEDs,[60] delayed arterial filling of choroid and choriocapillaris, punctate hypercyanescent spots,[61] with choriocapillaris and venous congestion.[36] 

ICGA forms an important investigation for the recently described pachychoroid disease spectrum, including CSCR, PCV, pachychoroid pigment epitheliopathy (PPE), pachychoroid neovasculopathy (PNV), focal choroidal excavation,[62] and peripapillary pachychoroid syndrome (PPS).[63]

Retinal Arterial Macroaneurysm (RAM)

Retinal arterial macroaneurysm can present with pre-retinal, intraretinal, and subretinal hemorrhage. In case of significant pre-retinal hemorrhage, FA may not visualize the macroaneurysm due to the masking effect of the hemorrhage. But ICGA can visualize the macroaneurysm as the infrared rays can penetrate better through the hemorrhage.[64]

Choroidal Tumors

Choroidal melanoma - ICGA is superior to FA in identifying the tumor vasculature and borders. The tumor microcirculation patterns in ICGA, such as parallel with cross-linking, loops, arcs with branching, and networks, are associated with a higher rate of tumor growth.[65]

Choroidal hemangioma - In circumscribed choroidal hemangioma, the intrinsic vascular pattern is seen 30 seconds after injection of ICG. The lesions become intensely hypercyanescent at 1 minute. In the late phases of the angiogram, the dye washes out from the lesion rapidly compared to the background choroid making the hemangioma appear hypocyanescent.[66]

White Dot Syndromes

Birdshot chorioretinopathy - In ICGA, hypocyanescent dots correspond to the cream-colored lesions in birdshot chorioretinopathy. ICGA is superior to FA in this disease as these lesions are not usually visualized in FA.[67]

Multifocal Choroiditis - The white lesions in multifocal choroiditis are visualized as hypocyanescent dots in ICGA. ICGA can be used to monitor the treatment response as the number and size of these hypocyanescent areas decrease with successful treatment with systemic steroids.[68]

Multiple evanescent white dot syndrome (MEWDS) - MEWDS presents with unilateral diminution of vision. It is common in young females. It has a transient and self-limiting course. ICGA reveals multiple hypocyanescent spots in the mid and late phases. These spots are more apparent in ICGA compared to FA.[69]

Serpiginous choroidopathy - In serpiginous choroidopathy, ICGA reveals choroidal alterations even if there is no clinical or FA evidence. In ICGA, the active lesions appear to be larger compared to FA. Thus it helps in the identification of active lesions. Also, choroidal activity can be present even after the cessation of retinal activity. This can be identified using ICGA.[70]

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) - In acute APMPPE, ICGA reveals hypocyanescent lesions in both the early and late phases of the angiogram. This is hypothesized to be due to choroidal hypoperfusion secondary to occlusive vasculitis.[71]

Punctate inner chorioretinopathy (PIC) - Hypocyanescent spots are noted in all phases of ICGA, which may be more in number than is visible on fundus photo or FFA.[72][73]

Acute zonal occult outer retinopathy (AZOOR) - Fundus autofluorescence shows very typical features. ICGA may be normal or may show hypocyanescence. In late-stage AZOOR, a trizonal pattern may be noted. The area outside the lesion shows normal cyanescence (zone 1). The margin shows late extrachoroidal leakage (minimal) (zone 2). Zone 3 or the area inside the lesson shows hypocyanescence due to choriocapillaris atrophy.[74]

Chorioretinal Atrophy

In Stargardt disease, there is a complete loss of choriocapillaris ('dark atrophy' or complete absence of choriocapillaris on ICGA) whereas, in geographical atrophy secondary to age-related macular degeneration (ARMD), residual choriocapillaris are present. ICGA aids in differentiating between late-onset Stargardt disease from chorioretinal atrophy. Hypocyanescence is seen in the late phases of ICGA in the case of Stargardt disease.[75] In dry AMD with geographic atrophy, the areas of atrophy become isocyanescent in the late phase of ICGA.

Ocular inflammatory Diseases

Sympathetic Ophthalmia: ICGA shows hypocyanescent patches, some of which may become isocyanescent in the late phase.[76]

Vogt Koyanagi Harada (VKH) syndrome: The ICGA features in the acute phase include early hypercyanescence and leakage from choroidal stromal vessels, hypocyanescent spots, fuzzy large choroidal vessels, and hypercyanescence of the optic disc.[77] The hypocyanescent spots resolve with adequate therapy. The persistence of such ICGA lesions despite therapy may denote the presence of subclinical inflammation that may lead to sunset glow fundus and suggest the need to increase the immunosuppression in such cases.[77] ICGA may be used to detect subclinical recurrence of VKH syndrome.[78]

Enhancing Healthcare Team Outcomes

The team of the ophthalmologist and the assisting nurse takes consent and counsels the patient before the procedure. Pushing the ICG dye while the ophthalmologist or the technician is capturing the images, monitoring the patient for any adverse reactions during the procedure is also carried out by the nursing staff. Anesthetists or critical care specialists are required in cases of severe allergy and anaphylactic reaction. An interprofessional team approach helps to prevent and manage complications. It helps in carrying out ICG angiography with minimal risk.

Figure

FA (A), ICGA (B), color fundus photo (C) and optical coherence tomography image (D) of the left eye of a patient with circumscribed choroidal hemangioma with macular edema Contributed by Sabareesh Muraleedharan,MS, Aravind eye hospital, Madurai

Figure

Polypoidal Choroidal Vasculopathy. These images show features of a left eye with polypoidal choroidal vasculopathy through fluorescein angiography (A) and indocyanine green angiography (B). Contributed by S Muraleedharan, MS; Aravind Eye Hospital

Figure

FA (A) and ICGA (B) of the right eye of a patient with RAM at superotemporal arcade with vitreous hemorrhage Contributed by Sabareesh Muraleedharan,MS, Aravind eye hospital, Madurai

Figure

FA (A), ICGA (B) and color fundus photo (C) of the right eye of a patient with MEWDS Contributed by Sabareesh Muraleedharan,MS, Aravind eye hospital, Madurai

Figure

Color fundus photo (A), FA (B) and ICGA (C) of the right eye of a patient with RAP Contributed by Sabareesh Muraleedharan,MS, Aravind eye hospital, Madurai

Disclosure: Sabareesh Muraleedharan declares no relevant financial relationships with ineligible companies.

Disclosure: Koushik Tripathy declares no relevant financial relationships with ineligible companies.