Ancillary Testing for Retinal and Choroidal Diseases

FLUORESCEIN ANGIOGRAPHY

Since fluorescein angiography (FA) was introduced in the early 1960s, it has become one of the most widely used ancillary tests to image the retina. Although direct examination of the retina with slit lamp biomicroscopy and indirect ophthalmoscopy remains indispensable in the diagnosis and management of retinal disease, FA provides additional information concerning the anatomy, physiology, and pathology of the retina and, to a lesser extent, the choroid.

Sodium fluorescein is orange-red in color, with an absorption peak between 465 and 490 nm and an emission peak between 520 and 530 nm. In the intravascular space, sodium fluorescein is 70% to 80% bound to plasma protein.

Clinical Features

Fluorescein angiography provides clinically useful information for nearly the entire spectrum of posterior segment disorders. The diagnosis and treatment of retinal vascular disease, conditions resulting in choroidal neovascularization, inherited retinal disorders, retinal changes as a result of systemic disease processes, inflammatory ocular disease, and some intraocular tumors can often be enhanced with the use of FA. In some instances, FA may be performed to provide baseline images if it is thought that the condition may progress or change over time.

Technique

Fluorescein angiography is performed by injecting sodium fluorescein dye as a bolus into a peripheral vein. Sodium fluorescein dye is available as 5 mL of 10% concentration.

Following injection, the dye enters the choroidal and retinal circulations, and a fundus camera is used

to document passage of the fluorescein dye. This process is made possible by illuminating the fundus with a blue light (peak absorption of fluorescein), thereby exciting sodium fluorescein molecules to a higher energy state. The sodium fluorescein molecules then return to

their ground state, and in the process release a longerwavelength yellow-green light. Only the yellow-green light is detected by the photographic film.

Photographic images of both the fellow eye and the eye being evaluated are obtained with the majority of early-phase images taken of the eye under evaluation.

Stereoscopic pairs of photographs are taken to facilitate evaluation of the angiogram. The time elapsed from injection to initial vascular filling, as well as the time elapsed from injection to each photograph taken subsequently, is recorded. The images taken during FA

can be either recorded on photographic film or stored electronically.

Side Effects

Adverse effects from FA are generally mild. These include a temporary yellowing of the skin and a yelloworange color to the urine. Other side effects include nausea, vomiting, pruritus, urticaria, syncope, and local reaction due to extravasation of the dye from the injection site. Reactions that are possibly allergic in nature may be managed with antihistamines, but affected patients should be watched carefully for the development of anaphylaxis. Severe reactions such as bronchospasm, laryngeal edema, and myocardial infarction are infrequent but have been reported. The overall risk of death from FA has been estimated to be 1 in 222 000.

Arterial phase: One to 3 seconds after fluorescein reaches the choroid (the prearterial phase), fluorescein is noted in the retinal arteries. The normal time from injection to arterial filling is approximately 12 seconds. (Note the patchy choroidal filling.)

Peak venous phase: Five to 10 seconds after the entire lumen of the veins fill, the peak phase is entered. This typically occurs 20 to 25 seconds after injection, when there is maximal concentration of dye in the retina and choroid.

Arteriovenous phase: After filling the retinal arteries, fluorescein dye flows through the precapillary arterioles, capillaries, postcapillary venules, and then to the retinal veins. In the early arteriovenous phase, thin columns of dye are noted along the walls of the larger veins (laminar flow).

Peak venous phase: The perifoveal capillary network is best visualized in this phase. The foveal avascular zone is the central 400-mm area devoid of blood vessels.

Recirculation phase: Thirty seconds after injection, some of the dye has returned to the heart, and the concentration of dye in the retina begins to fade.

Late phase: Ten minutes after injection, fluorescein dye is generally not present in either the retinal or choroidal circulation, and only faint staining of various structures is noted.

Hyperfluorescence may be defined as an increase in normal fluorescence or an abnormal presence of fluorescein at a given time in the fluorescein angiogram.

Pseudofluorescence may be caused by an overlap of the wavelength of light allowed to pass through the exciter and barrier filters. Autofluorescence may be caused by refractile structures in the eye such as optic nerve head drusen, astrocytic hamartomas, large drusen of the retinal pigment epithelium (RPE), and deposits of lipofuscin seen in some macular dystrophies.

Hyperfluorescence in the fluorescein angiogram may be caused by leakage, staining, or pooling of dye and by transmission or “window” defects. Leakage refers to hyperfluorescence in the angiogram due to extravasation of fluorescein dye into the extravascular space resulting from disruption of retinal endothelial tight junctions. Leakage due to loss of retinal endothelial tight junctions may be seen in diabetic macular edema, cystoid macular edema, and venous occlusive diseases. Leakage may appear as areas of hyperfluorescence that increase in size as the angiogram progresses. Retinal neovascularization from proliferative diabetic retinopathy or other causes may result in leakage of fluorescein into the vitreous. This leakage appears as fluffy, hazy hyperfluorescence that is localized over the pathologic area, above the plane of the retina. This type of leakage is typically best viewed in the late phases of the angiogram.

Leakage may also result from the breakdown of the tight junctions between retinal pigment epithelial cells, such as in central serous chorioretinopathy. Subretinal neovascularization, regardless of cause, will also result in leakage, as the new vessels lack tight junctions. Leakage due to subretinal neovascularization is best viewed by assessing both the early and late phases of the fluorescein angiogram. The early phases show irregularly shaped, flat, or sometimes elevated areas of hyperfluorescence that may leak profusely into the subretinal or subpigment epithelial space in the late phases. A lacy pattern to the abnormal subretinal vessels sometimes can be seen on the early-phase angiogram.

Hyperfluorescence due to pooling occurs as a result of dye accumulation within an anatomic or potential space. The increased concentration of fluorescein dye in the area of pooling results in the development of hyperfluorescence. Fluorescein may pool into either the subretinal space or the space created when the RPE separates from Bruch’s membrane. When the retina separates from the RPE, a gradual angle is formed where the retina remains attached to the RPE. This feature makes it difficult to determine the extent of retinal detachment both ophthalmoscopically and on the angiogram. Conversely, in the case of a retinal pigment epithelial detachment, the angle between attached and detached

RPE is wide because of the firm adhesion between the RPE and Bruch’s membrane. This feature allows hyperfluorescent pooling due to retinal pigment epithelial detachments to have clearly discernable borders on the fluorescein angiogram.

Hyperfluorescence due to pooling beneath the RPE may be seen in serous retinal pigment epithelial detachments due to age-related macular degeneration or central serous retinopathy. Hyperfluorescence due to pooling in the subretinal space may be seen in Vogt-Koyanagi- Harada disease, in which pooling of dye occurs as a result of exudative retinal detachment.

Hyperfluorescence may also be due to staining, which represents an accumulation of fluorescein into tissues. Disciform scars from age-related macular degeneration, some large drusen, and damaged RPE may stain. Scleral staining may occur when loss of the RPE and choroid is total, such as in a chorioretinal scar. In this situation, dye leakage from the choroid surrounding the scar stains the sclera in the late phases of the angiogram; typically, no staining is seen in the early phases.

A focal loss of the RPE or decrease in pigment in the RPE can result in a window defect, another type of hyperfluorescence commonly seen on fluorescein angiography. The hyperfluorescence typically appears early in the fluorescein angiogram, at the time of choroidal filling. The brightness of the window defect varies with the brightness of the underlying choroid: window defects are brightest during the early phases of the angiogram and gradually fade. As leakage is not present with window defects, the configuration and area of hyperfluorescence does not change throughout the angiogram. Window defects may be seen in atrophic age-related macular degeneration, in certain toxicities, and occasionally with full-thickness macular holes.

Autofluorescence in a patient with prominent optic disc drusen. Autofluorescence also has been described with astrocytic hamartomas and in some types of macular drusen.

An early-phase angiogram of a patient with a branch retinal vein occlusion. There are irregularities of the retinal vessels in the inferotemporal region of the macula.

Transmission or “window” defect seen in a fluorescein angiogram of a patient with a bull’s eye pattern of macular atrophy resulting from chloroquine toxicity. Loss of the retinal pigment epithelium allows transmission of the underlying choroidal fluorescence.

This later-phase angiogram of the same patient demonstrates leakage of dye from the irregular retinal vessels.

Hyperfluorescence of a serous pigment epithelial detachment. Fluorescein dye accumulates, or pools, in the sub-retinal pigment epithelial space. The presence of a focal hot spot, notch, or irregular filling pattern suggests associated choroidal neovascularization.

This late-phase angiogram demonstrates staining of drusen. Hyperfluorescence is observed as fluorescein accumulates within the drusen material. Atrophy of the overlying retinal pigment epithelium may contribute as well to the hyperfluorescence seen with drusen.

An unusual pattern of atrophy in a young man with a family history of neurofibromatosis. Atrophy of the retinal pigment epithelium allows transmission of hyperfluorescence from the underlying choroidal vessels.

Transmission or “window” defect is seen in age-related macular degeneration with geographic atrophy of the retinal pigment epithelium.

This is an early arteriovenous phase angiogram of a patient with diabetic retinopathy. The small hyperfluorescent spots throughout the macula are microaneurysms.

Late-phase angiogram of the same patient demonstrates diffuse leakage of fluorescein dye.

This is an early arteriovenous phase angiogram of a patient with visual loss 6 weeks after uncomplicated cataract surgery. The parafoveal capillaries demonstrate mild irregularities.

Late-phase angiogram of the same patient reveals the characteristic “petaloid” pattern of hyperfluorescence that occurs with cystoid macular edema.

This is an early arteriovenous phase angiogram in a patient with idiopathic juxtafoveal retinal telangiectasis. The nasal and temporal parafoveal capillary networks are telangiectatic.

Central serous chorioretinopathy is characterized by a hyperfluorescent spot located superonasal to the center of the fovea.

Late-phase angiogram of the same patient demonstrates hyperfluorescence produced by leakage from the irregular retinal capillary beds.

Late-phase angiogram of the same patient demonstrates the classic “smokestack” appearance of hyperfluorescence as a result of fluorescein leakage from the choroid through the RPE subretinal space.

Toxemia of pregnancy is characterized by serous exudative retinal detachments resulting from hypertensive choroidopathy.

Late-phase fluorescein angiogram of the same patient reveals leakage of fluorescein dye into the subretinal space.