INDOCYANINE GREEN ANGIOGRAPHY

Indocyanine green (ICG) is a water-soluble dye that was developed in 1955. In the 1970s ICG dye was first used to image the posterior segment of the eye. As ICG dye fluoresces too weakly to be used with conventional photographic techniques, initial results were disappointing due to poor image quality. The advent of digital videoangiography systems has improved the quality of ICG angiography, making it now a more widely employed diagnostic test.

Clinical Features

Technique

Indocyanine green angiography can be performed alone or in conjunction with FA. To perform ICG angiography, 25 to 50 mg of ICG dye is injected intravenously. The higher doses are used in cases of media opacity, small pupil, or extensive hemorrhage and/or pigment. Fundus images are then taken on a digital videoangiography system. Images are typically obtained at least 20 minutes and sometimes up to 60 minutes after intravenous administration.

Several properties of ICG dye render it useful as an adjunct to fluorescein angiography (FA). Indocyanine green dye has a peak absorption and emission in the near infrared. These characteristics allow greater transmission of both exciting and emitting energy through hemorrhage, abnormal pigment, turbid subretinal fluid, and the retinal pigment epithelium than the visible light spectrum employed in FA. In addition, ICG dye is 98% bound to serum protein, and thus leaks slowly or not at all from the choroidal circulation, allowing choroidal vascular detail to remain clear.

These properties allow ICG dye to be potentially useful in the diagnosis and management of choroidal neovascularization due to age-related macular degeneration. Indocyanine green angiography may be useful in delineating choroidal neovascularization beneath hemorrhage, serous exudate, and abnormal pigment, allowing ICG-guided treatment of choroidal neovascular lesions that are poorly defined and thus untreatable with FA alone. However, a well-designed, randomized, controlled clinical trial to demonstrate the role of ICG angiography in the management of age-related macular degeneration has yet to be performed.

Indocyanine green angiography has also been used to study other disorders such as central serous retinopathy, inflammatory choroidal disorders, multiple evanescent white dot syndrome, Stargardt disease, and Vogt-Koyanagi-Harada syndrome. For example, in Vogt-Koyanagi-Harada syndrome and in central serous retinopathy, ICG angiography may demonstrate choroidal abnormalities not seen on FA. Indocyanine green angiography may also be useful in distinguishing between choroidal mass lesions such as choroidal melanoma and circumscribed choroidal hemangioma.

Side Effects

Adverse reactions to ICG dye are less frequent than with fluorescein dye. In one large series, the rate of mild adverse reactions to ICG dye was 0.15%. The most common mild adverse reactions included nausea, vomiting, sneezing, and pruritus. Moderate adverse reactions such as syncope, pyrexia, and local tissue necrosis occur in 0.2% of patients. The overall risk of death from ICG angiography has been estimated to be 1 in 333 333.

A fluorescein angiogram demonstrates areas of hyperfluorescence in this patient with multiple evanescent white dot syndrome.

A fluorescein angiogram demonstrating a serous pigment epithelial detachment in a patient with age-related macular degeneration.

The indocyanine green angiogram may be helpful in the diagnosis of multiple evanescent white dot syndrome, as small areas of hypercyanescence are noted scattered throughout the posterior pole. These areas roughly correspond to those of hyperfluorescence noted on the fluorescein angiogram.

The late-phase indocyanine green angiogram of the same patient demonstrates a hot spot of hypercyanescence. Laser photocoagulation directed at the hot spot may, in some cases, hasten resolution of the serous pigment epithelial detachment.

The early phase of the indocyanine green angiogram demonstrates intrinsic vascularity within a circumscribed choroidal hemangioma.

Fifteen to 30 minutes following the indocyanine green angiogram, choroidal hemangiomas may demonstrate a characteristic “wash out” appearance.

ELECTRORETINOGRAPHY

The full-field light-evoked electroretinogram (ERG), which is obtained by a brief flash of light, is the record of a diffuse electrical response generated by the retina. The full-field ERG is characterized by a negative waveform (termed the a-wave), which represents the photoreceptor response, followed by a positive waveform (termed the b-wave), which represents the Müller and bipolar cell response. Oscillatory potentials are small wavelets on the ascending b-wave. The origin of the oscillatory potentials is unclear; loss of the oscillatory potentials is seen in diabetic retinopathy and in some individuals with congenital stationary night blindness. It is important to note that the full-field ERG is a mass

response of the entire retina. The values of the amplitude of each of these main components of the ERG and how quickly they reach their peak (termed implicit time) may help in the evaluation of certain retinal disorders. Furthermore, responses from the cones and rods can be separated as a result of their differential threshold to light, as rods are 10 000 times more sensitive to light than cones.

The photopic ERG tests cone function by keeping the patient in a light-adapted state, thereby bleaching or suppressing the rod response. The ERG response is then evoked with a bright white flash. Cone activity can also be evaluated using the flicker study (cones respond to flicker stimuli greater than 30 cycles per second, while rods do not). The scotopic ERG tests rod function by keeping the patient in a dark-adapted state for 45 minutes or longer and using a dim white or blue flash, below cone threshold, to evoke the ERG response

from the rods.

Clinical Features

The ERG is clinically useful in a number of hereditary and degenerative retinal diseases. An extinguished ERG may be seen with retinitis pigmentosa, ophthalmic artery occlusion, diffuse unilateral subacute neuroretinitis, other causes of chorioretinitis (birdshot chorioretinopathy), carcinoma-associated retinopathy, toxic retinopathy, and nutritional deficiencies. In addition, the ERG may help identify eyes with progressive visual loss due to a retained intraocular foreign body. Certain metals such

as copper, iron, and magnesium may cause severe and progressive retinal degeneration.

Reduction of the b-wave amplitude is associated with retinal ischemia, and may be helpful in distinguishing ischemic vs nonischemic central retinal vein occlusions. A b-wave to a-wave ratio of less than 1 is associated with an increased risk of neovascular glaucoma. A normal a-wave associated with a reduced b- wave also may be observed in congenital stationary night blindness and X-linked juvenile retinoschisis.

An abnormal photopic ERG in the setting of a normal scotopic ERG is consistent with the diagnosis of cone dystrophy or achromatopsia. A normal ERG can be seen in some optic neuropathies, thus distinguishing optic nerve disease from retinal disease.

Technique

To record the ERG, the eyes are dilated and dark adapted for 45 minutes. Following that, topical anesthesia is administered and a corneal contact lens electrode is applied. The full-field ERG is elicited within a ganzfeld dome, which provides a homogeneous distribution of light over the central 120º of the retina. As the patient fixates on a light-emitting diode, a dim white or blue flash is used to evoke the scotopic or rod-mediated ERG. Next, the photopicor cone-mediated ERG is evoked.

Side Effects

Side effects of ERG testing are limited to surface irritation and potential corneal abrasion as a result of the corneal electrode. These complications can be minimized with the use of careful technique and proper lens sizing. For example, the common Burian-Allen electrode is available in a variety of sizes to fit premature infants

to adults.

50 1-R uV/div

5 MS per Division

A normal scotopic white electroretinogram is demonstrated. Note the presence of the early a-wave (downward deflection) generated by the photoreceptors, followed by the b-wave (upward

deflection), a function of the inner retinal layers (bipolar and Müller cells).

Oscillatory potentials are small wavelets seen on the ascending b-wave. The origin of oscillatory potentials is unclear; they are reduced in ischemic states

(eg, diabetic retinopathy).

30 Hz Flicker

The photopic electroretinogram tests cone function by keeping the patient in a light-adapted state, thereby suppressing the rod response.

A normal, 30-Hz photopic flicker electroretinogram is demonstrated. This waveform is predominantly cone generated.

Retinitis pigmentosa is the most common hereditary retinopathy characterized by the degeneration of rods and cones. Clinical features include optic disc pallor, vessel attenuation, and peripheral pigmentary alterations.

30 minute scotopic white

Photopic flicker 30 HZ

An attenuated scotopic white electroretinogram in a patient with retinitis pigmentosa is consistent with diffuse rod dysfunction. The photopic flicker is also markedly reduced, indicating diffuse cone dysfunction.

Choroideremia is an X-linked inherited retinal degeneration characterized by diffuse atrophy of the retinal pigment epithelium and choriocapillaris. Visual symptoms include poor night vision and visual field loss.

The scotopic electroretinogram in patients with choroideremia is markedly attenuated or extinguished.

Advanced chloroquine toxicity is manifest by extensive peripheral pigmentary alterations in addition to the characteristic bull’s eye maculopathy.

The electroretinogram in advanced chloroquine toxicity maybe severely reduced or nondetectable as a result of diffuse rod and cone dysfunction.

Birdshot chorioretinopathy is a member of the inflammatory white dot syndromes. The cause is unclear, but a strong association has been noted with HLA-A29.

30 minute scotopic white

Photopic flicker 30 HZ

Birdshot chorioretinopathy may be associated with an extinguished electroretinogram (ERG). Other inflammatory conditions associated with abnormal ERGs include diffuse unilateral subacute neuroretinitis and acute zonal occult outer retinopathy.

Reduction of the b-wave amplitude is associated with retinal ischemia and may be helpful in distinguishing ischemic vs nonischemic central retinal vein occlusions.

30 minute scotopic white

Photopic flicker 30 HZ

A b-wave to a-wave ratio of less than 1 in the scotopic electroretinogram is associated with an increased risk of neovascular glaucoma.

30 minute scotopic white

Photopic flicker 30 HZ

X-linked juvenile retinoschisis is characterized by cystlike alterations in the fovea. Approximately 50% of patients have peripheral retinoschisis. The histological defect is a splitting of the retina at the nerve fiber layer.

The characteristic electroretinographic abnormality in X-linked juvenile retinoschisis is a normal a-wave but an abnormal b-wave.

30 minute scotopic white

Photopic flicker 30 HZ

Cone dystrophy is a retinal degeneration affecting primarily cones. Ophthalmoscopic findings may be very subtle clinically (mild temporal disc pallor with or without bull’s eye maculopathy).

Cone dystrophy is characterized by an extinguished photopic and 30-Hz flicker electroretinogram (ERG). The scotopic ERG may be normal.