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Indocyanine green (ICG), a synthetic fluorescent dye, has historically been used in the photographic industry, and was first applied in medical imaging in 1956.

1 ICG angiography in imaging of choroidal circulation was pioneered by Flower and Hochheimer in 1971, a decade after the first fluorescein angiography described by Novotny and Alvis.2,3 However, technical difficulties meant it was not until the 1980s that the resolution of ICG angiography was improved by Hayashi and DeLaey.4 The most recent significant achievement in its clinical application came with the use of a digital imaging system for high-resolution images, introduced by Yannuzzi and associates in 1992.5

ICG is manufactured in a green, blue-green or green-black powder form, containing a small amount of sodium iodide. This dye has fluorescent qualities. ICG's peak absorption is between 800-810nm, with an emission peak of 835nm (within the infrared spectrum),6 while fluorescein sodium's peak absorption is 485-500nm, and its peak emission is 520-530nm7 (Figure 1).

The longer wavelength absorption of ICG allows visualisation of the choroid, as it is not blocked by retinal pigment (melanin and xanthophyll), unlike fluorescein sodium. In addition, its optical properties permit observation of choroidal pathology through overlying haemorrhages, serous fluid and lipid exudation.

For performing angiography, ICG is injected intravenously and consequently imaged through its journey along ocular vessels. It is known that 98 per cent of indocyanine green is bound to plasma proteins, especially globulins such as A1-lipoproteins.8 Consequently, the dye is prevented from escaping the choroid, enabling enhanced visualisation of choroidal vasculature.

ICG is excreted by the liver into the bile. The dye does not enter the cerebrospinal fluid or the placenta. However, ICG has not yet been proved safe for use in pregnancy. This procedure is not advised for patients with a previous history of allergic reactions (especially to iodine or shellfish), asthma, ischaemic heart disease and liver failure. Indocyanine green angiography is a relatively safe procedure, with few side effects, discolouration of the stool being the most common. In addition, intermittent dizziness, nausea and vomiting occur in approximately 0.5 per cent of patients.9 Anaphylaxis and cardiac arrest have been reported in the literature at a rate of 0.05 per cent.10

Clinical applications and interpretation of ICG angiography in AMD

Indocyanine green angiography is highly sensitive for the identification of choroidal pathology, including: Age-related macular degeneration (AMD), chorioretinal inflammatory disease (birdshot retinochoroidopathy) and intraocular tumours (choroidal haemangiomas, choroidal melanoma). In AMD, ICG angiography is valuable for detecting choroidal neovascularisation, defining whether a patient would be suitable for treatment and for subsequent monitoring.

AMD is the most common cause of irreversible visual loss in developed countries. It usually occurs in patients over the age of 50. The main contributory factors to this disease are inheritance, diet, smoking, blood pressure and lifestyle. Recent studies suggest that genetic alterations may contribute to more than 50 per cent of AMD.11 Smoking increases the risk of AMD approximately three times and accounts for about 30 per cent of macular degeneration.12 A healthy diet, balanced with fruits and vegetables, may help slow the progression of AMD.

Based on diagnostic investigations, age-related macular degeneration is divided into two forms, 'dry' and 'wet'. The dry type is by far the most common, affecting 90 per cent of AMD patients. It causes gradual loss of central vision. At present, there is no treatment for this type of AMD. The wet form accounts for just 10 per cent of AMD but progresses quickly, resulting in new blood vessels formation behind the retina, subsequent bleeding and scarring. Early diagnostic and treatment of patients with this form can prevent the progression of the disease and the loss of vision. Based on clinical manifestation, there are the following types of wet AMD: classic, occult choroidal neovascularisation, idiopathic polypoidal choroidal vasculopathy and retinal angiomatous proliferation.

Occult choroidal neovascularisation (occult CNV)

Based on fluorescein angiography, occult CNV is characterised as a poorly defined membrane located in the macular area. Choroidal capillaries, proliferating through a break in Bruch's membrane, can cause AMD with or without serous pigment epithelial detachment (PED). ICG angiography of CNV, without serous PED, shows vascular hyperfluorescence in the transit phase, followed by late staining of the abnormal vessels (Figure 2). CNV with serous PED reveals hypofluorescence of the PED and hyperfluorescence of choroidal capillaries (Figure 3).

In recent literature, occult CNV is also subdivided into hot spot and plaque CNV.13 Hot spot CNV is actively proliferating and appears as a well demarcated lesion, less than 1 disc diameter in size. This type of pathology is observed in retinal angiomatous proliferation (RAP), polypoidal choroidal vasculopathy and focal occult CNV. Plaque CNV, is a lesion greater that 1 disc diameter in size. It reveals staining of a non-active area of neovascularisation (not associated with leakage) in the late phase of the ICG angiography.

Idiopathic polypoidal choroidal vasculopathy (IPCV)

Idiopathic polypoidal choroidal vasculopathy is defined by malformation of the choroidal vessel, which end in an aneurysmal bulge (Figure 4). ICG angiography is highly sensitive and specific to this type of pathology.14 It is particularly useful in detecting the location of the 'polyps' in the peripapillary, macular, extramacular areas and also in the far peripheral pole of the retina. In the early transit phase of ICG angiography, we can observe the filling of the large vessels of the IPCV prior to the retinal vasculature. As shown in Figure 4B and 4C, the area within and adjacent to the IPCV is hypofluorescent. In the early recirculation phase we can observe hyperfluorescent polyps in the choroid. Later on, the polyps leak, while the surrounding area changes from being hypofluorescent to becoming hyperfluorescent. The dye then leaks from the polyps ('washout').

Retinal angiomatous proliferation (RAP)

Retinal angiomatous proliferation is the first sign of neovascularisation within the retina.15 The main features of RAP are dilated retinal vessels, retinal haemorrhages (pre-, intra-, and sub-) and exudates which encircle the angiomatous proliferation. This process spreads out into the deep retinal and subretinal space. Retinal-retinal anastomosis is an important feature which shows the connection of the retinal vessels with neovascularisation. ICG angiography shows an area of new vessels (hot spot) which hyperfluoresces (Figure 5C). Later, the complex of intraretinal neovascularisation spreads into the subretinal space (Figure 5D). ICG angiography is important in demonstrating neovascular connections between the choroid and retina, in the form of anastamoses.

Conclusions

ICG angiography is a well established technique, which has a clear advantage over fluorescein angiography in certain types of age-related macular degeneration. This diagnostic procedure has also contributed to the identification of lesions that may be treatable, and may help prevention of further disease. ●

References

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2 Flower R and Hochheimer B. Clinical infrared absorption angiography of the choroids. Am J Ophthalmol, 1972 73:458-459.

3 Novotny H, Alvis D. A method of photographing fluorescence in circulation blood in the human retina. Circulation, 1961 24:82-86.

4 Hayashi K and DeLaey J. Indocyanine green angiography of neovascular membranes. Ophthalmologica, 1985 190:30-39.

5 Yannuzzi L, Slakter J et al. Digital indocyanine green videoangiography and choroidal neovascularisation. Retina, 1992 12:191-223.

6 Cardio-Green. Cockeysville, MD. Becton Dickinson Microbiology Systems, 1990 5-6.

7 Wessing A. Fluorescein Angiography of the Retina. St. Louis: Mosby, 1969: 12-14.

8 Ciardella A, Klais C, et al. Indocyanine Green Angiography. Retinal Imaging 2006: 22-47.

9 Hope-Ross M, Yannuzzi L, Gragoudas E, et al. Adverse reactions due to indocyanine green. Ophthalmology, 1994 101:530-531.

10 Saine P, Tyler M. Ophthalmic Photography, 2nd Edition. Oxford: Butterworth-Heinemann, 2002:161-164.

11 Gold B, Merriam J, Zernant J et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet, 2006 38(4):458-62.

12 Seddon JM, George S, Rosner B. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration.

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13 Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Trabousli EI, 2006:25-30.

14 Yannuzzi LA, Sorenson JS, Spaide RF, et al. Idiopathic polypoidal choroidal vasculopathy. Retina, 199010:1-8.

15 Yannuzzi LA, Negrao S, Lida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina, 200121:416-34.

● Uliana Gout is a final year medical student at Imperial College. Dr Irina Gout is an ophthalmologist and Mr Sundeep Kheterpal is consultant ophthalmic surgeon at The Prince Charles Eye Unit, King Edward VII Hospital, Windsor

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