Indocyanine Green (ICG) Angiography - StatPearls

Indocyanine Green AngiographyIndocyanine Green Angiography - EyeWiki

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.

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 serosanguineous 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 pathologies. PCV lesions are usually responsive to more frequent anti-VEGF treatment with or without photodynamic therapy. In this setting, ICGA can guide management 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 assist in identifying choroidal hemangiomas and differentiating them from simulating tumors such as choroidal melanoma or metastasis. Choroidal hemangioma displays a characteristic filling pattern observed in ICGA: progressive filling of abnormal choroidal vessels in early stages, followed by intense hypercyanescence at 2-4 minutes, and decreased cyanescence at later time frames as compared to the surrounding choroid, known as washout phenomenon.[12][13][14][15][16]

Even though other choroidal tumors do not have distinctive ICGA features, the methodology is still applicable in differentiating these from non-tumor lesions such as peripheral exudative hemorrhagic chorioretinopathy (PEHCR).

The choroidal hypervascularity represented in the pachychoroid spectrum, including central serous chorioretinopathy (CSCR), can be delineated more effectively through ICGA. The examination often reveals larger areas of choroidal hypervascularity than the leakage point observed in FA, thus guiding photodynamic therapy to incorporate the complete hypervascular and leakage area. Furthermore, chronic CSCR complications associated with CNV, irrespective of leakage or hemorrhage, may be better interpreted through 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 clearer insights into complications arising from pathologic myopia. CNV lesions that link with lacquer cracks (for instance, those under subretinal hemorrhages associated with newly formed lacquer cracks) are better delineated through ICGA.

Angioid streaks are often visualized more distinctly, extensively, and prominently via ICGA in contrast to FA or regular fundus evaluations.

Inflammatory

ICGA proves effective for diagnosing white dot syndromes, particularly when fundus lesions exhibit atypical presentations or have already faded away. In instances of MEWDS, imaging demonstrates numerous hypercyanescent dots scattered across the posterior pole alongside a hypocyanescent area surrounding the optic nerve. With inflammation resolution, these hypocyanescent regions disappear over time.

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 involves multifocal inflammation in the choriocapillaris, resulting in delayed and defective choroidal filling, which may manifest as a unique pattern of multifocal hypocyanescence identifiable in areas recognized as white spots during retinal examination.

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 correlating 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 beneath. 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.

Even though ICGA isn't critical for VKH diagnostics, the technique shines in distinguishing active disease from completely treated and inactive VKH based on ICGA-specific patterns. Early signs of VKH include choroidal vessel hypercyanescence and the fuzziness of choroidal stromal vessels during intermediate to late phases, along with disc hypercyanescence and dark hypocyanescent spots. Successful treatment typically leads to resolving these hypocyanescent patches, while their persistence might indicate hidden ongoing inflammation, necessitating heightened immunosupression. ICGA stands out for identifying discreet choroidal inflammation during subclinical VKH reactivation, thus aiding treatment plans.

Widespread, pale lesions within the fundus, as seen in Birdshot chorioretinopathy (BS), appear as equally sized round or oval hypocyanescent spots, especially affecting the nasal quadrants. FA tends to underrepresent these lesions; ICGA frequently detects more spots than clinical assessments. Additional ICGA features indicate anomalies within choroidal vascular patterns, leading to fuzzy and indistinct vessel appearances during the intermediate phases of the angiogram, culminating in diffuse late-stage hypercyanescence resulting from ICG leakage through inflamed choroidal vessels. Throughout the chronic phase, these hypocyanescent dots remain visible throughout late angiogram phases, correlating with chorioretinal scarring.

Choroidal Granulomas

Choroidal granulomatous disorders, such as sarcoidosis and tuberculosis, may present as hypocyanescent lesions indicative of filling defects from granulomatous cell aggregation.

Vogt-Koyanagi-Harada disease (VKH): Simultaneous early phase FA (left) and ICGA (right) images of a 42-year-old woman with VKH highlighting hypocyanescent dark dots indicating areas of choroidal hypoperfusion. 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 serves to differentiate between active and inactive or healed serpiginous choroidopathy lesions. Subclinical and actively affected lesions yield distinct patterns, showcasing either early and late hypocyanescence with indistinct edges or early hypocyanescence transitioning to increased cyanescence during late ICGA phases. Healing lesions maintain recognized patterns in both early and late phases, preserving defined edges.

Ocular Infections

ICGA frequently assists in confirming choroidal involvement amidst the spectrum of infectious conditions, though it may not provide additional insights for diagnostics or treatments concerning ocular infections.

Trauma

Through ICGA, choroidal involvement can be illustrated following traumatic instances like choroidal rupture or ocular hypotony. However, as ICGA generally offers minimal diagnostic or prognostic insights, its use in ocular trauma is limited.

Procedure

The standard dosing regimen for ICG within scanning laser ophthalmoscope systems involves 25 mg of ICG dissolved in 3 ml of saline, followed by the injection of 1 ml from this solution. For combined imaging with FA and ICGA, the saline is replaced with fluorescein sodium solutions at 10%, 20%, or 25% concentrations. There are three respective temporal phases associated with ICGA imaging—similar to fluorescein angiography.

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 following dye injection reveals larger choroidal arteries and veins, while retinal arteries remain unfilled. Choroidal vessel filling commences from larger outer Haller's layer vessels initially, gradually followed by the intermediate Sattler's layer, ultimately with the choriocapillaris filling last, although camera resolution may not allow for individual identification of choriocapillaris.

Middle phase - spanning approximately 5 to 15 minutes following injection showcases filled retinal arteries, veins, and the choroidal vasculature, accompanied by a diffusion of choroidal cyanescence, which becomes more indistinguishable during this interval.

Late or recirculation phase - occurs post-10-15 minutes of dye injection, during which pathologic hypercyanescent lesions become notably visible against a slowly fading background.

Safety

ICGA is a generally safe and well-tolerated imaging procedure with exceedingly rare cases of toxicity or allergic reactions, such as nausea, vomiting, sneezing, and pruritus in 0.15% of procedures. Moderate allergic reactions, like urticaria and pyrexia, manifest in 0.2% of patients, while severe reactions, including bronchospasm and anaphylactic responses, occur in 0.05% of cases. An editorial outlined four notable incidents from 240,000 intravenous indocyanine injections; urticaria appeared in one instance, while three were linked to anaphylactic reactions, with one leading to a fatal outcome.

Absolute contraindications

1. Prior allergic reaction to ICG

2. Iodine/Iodide allergy: While allergic reactions to iodine or shellfish are often highlighted as contraindications, it is essential to note that reactions to indocyanine green are biologically unlikely. Unlike traditional contrast media, the ICG molecule itself does not contain iodide that could be recognized as an antigen to the immune system. Nonetheless, many specialists suggest avoiding ICGA if a patient has demonstrable allergy to iodine. An additional risk arises with the administration of 840µg or more of iodide through ICGA imaging, presenting potential thyroid storm risks in uncontrolled hyperthyroid individuals. In these situations, ICG should be administered with caution or be avoided entirely. Infracyanine green, an iodine-free alternative to ICG, is available for those having an absolute contraindication to ICG administration.

Relative contraindications

1. End-stage renal disease

2. Liver disease

3. Pregnancy (Category C: to date, comprehensive safety studies remain unfulfilled)

Summary

ICGA stands as both a safe and significant imaging technique which provides enhanced views of choroidal vasculature and its associated pathological conditions. While its application has receded in managing choroidal neovascular lesions, ICGA continues to prove helpful in guiding the treatment of PCV and CSC and for identifying choroidal hemangiomas alongside ocular inflammatory diseases that principally act on the choroid.

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