Fluorescein Angiography

Fluorescein angiography is an imaging test that shows the blood flow in the retina and choroid. Fluorescein sodium dye is injected into a vein, and a special camera with filters takes rapid photographs as the dye passes through the retinal vessels. The dye shines yellow green when lit with blue light, and it shows leaking, blocked, abnormal and new vessels that are not clear on normal examination.

The dye travels from the arm to the eye in about 10 to 15 seconds. Photographs are taken at about 1 second intervals in the early phase, as the dye fills the choroid, retinal arteries (arterial phase), capillaries and veins (arteriovenous phase), and late images follow at 5 to 10 minutes to show leakage and staining. The test takes about 10 to 30 minutes, after the pupils are dilated.

The retinal vessels have tight junctions, so dye does not leak in normal retinal vessels (the inner blood retinal barrier), while the choroidal vessels leak freely but are blocked by the retinal pigment epithelium.

Fluorescein angiography was the main tool for the diagnosis of macular and retinal vascular disease for decades. Optical coherence tomography and optical coherence tomography angiography (which shows vessels without dye) now replace it for many indications, but it remains valuable for leakage, ischaemia, peripheral retinal disease, and wide field imaging. Mild nausea affects up to about 5 to 10% of patients, and serious reactions are rare.

Indications.

• Diabetic retinopathy and macular oedema: to show leaking microaneurysms, ischaemia, and new vessels.
• Retinal vein and artery occlusions: to show non-perfusion, leakage and new vessels.
• Age related macular degeneration and choroidal neovascularisation (including in myopia and other causes), and central serous chorioretinopathy.
• Retinal vasculitis and uveitis (including Behçet disease, sarcoidosis, and tuberculosis), and cystoid macular oedema.
• Unexplained visual loss, optic disc swelling (to separate true papilloedema from pseudopapilloedema from drusen), and ocular tumours.
• Retinopathy of prematurity, sickle cell retinopathy, and other peripheral vascular disease.
• Planning and follow up of laser and injection treatment.

Not indicated in patients who cannot tolerate the injection or when optical coherence tomography angiography gives the answer.

Contraindications and precautions.

• Previous severe allergic reaction to fluorescein: an absolute contraindication.
• Allergy to other substances, asthma and previous mild reactions: caution, with resuscitation equipment and trained staff available.
• Pregnancy (particularly the first trimester): avoided unless the benefit is clear. Breastfeeding mothers are advised to stop feeding for a period (the dye passes into milk).
• Severe renal impairment: the dose is reduced, and the dye clears slowly.
• Patients on beta blockers: reactions may be more severe and harder to treat.
• Patients with poor venous access, and those who cannot sit at the camera.
• Dilated pupils and media clear enough to take images.

Preparation and technique.

The patient is told that the skin and urine will turn yellow for 24 to 48 hours, and that nausea can occur. Consent is obtained, allergies and medicines are checked, and the pupils are dilated. Resuscitation equipment and drugs for anaphylaxis (adrenaline, antihistamine, hydrocortisone, oxygen) are kept ready.

A cannula is placed in an antecubital vein, and baseline colour and red free photographs are taken. The dye is injected as a rapid bolus, and photographs begin at the time of injection, in each eye, with early frames at rapid intervals and late frames after 5 to 10 minutes. The patient stays under observation for about 30 minutes after the test.

Normal appearances.

The choroid fills first with a patchy flush, and then the retinal arteries fill and the capillaries and veins fill in turn with laminar flow along the veins. The retinal vessels stay filled with dye and do not leak. The foveal avascular zone is a dark, round area at the centre of the macula. In late images, the dye fades from the vessels, with faint staining of the optic disc margin and sclera, and no leakage.

Interpretation.

• Hyperfluorescence (brighter than expected): leakage (dye escapes and increases in area and brightness over time, such as oedema, new vessels, or active choroidal neovascularisation), pooling (in a space such as a pigment epithelial detachment), staining (a late stain of tissue such as drusen or a scar), and window defects (loss of pigment epithelium that lets choroidal fluorescence show through, without leakage).
• Hypofluorescence (darker than expected): blocked fluorescence (blood, pigment or exudate in front of the vessels) or filling defects (non-perfusion, loss of the capillary bed, occlusion).
• Diabetic retinopathy: microaneurysms as dots, areas of capillary non-perfusion, enlarged foveal avascular zone, leakage causing macular oedema, and new vessels with profuse leakage.
• Retinal vein occlusion: delayed venous filling, non-perfusion and leakage. Retinal artery occlusion: delayed arterial filling.
• Choroidal neovascularisation: classic (early lacy hyperfluorescence with late leakage) or occult patterns.
• Central serous chorioretinopathy: a smoke stack or ink blot leak at the level of the pigment epithelium.
• Papilloedema: leakage from disc vessels, while drusen stain but do not leak.
• Vasculitis: leakage and staining of vessel walls, with capillary dropout.
• The images are interpreted together with colour photographs and optical coherence tomography.

Critical values and findings needing immediate action.

• Anaphylaxis (hypotension, wheeze, laryngeal oedema, urticaria): stop the injection, call for help, and give adrenaline, oxygen, fluids and airway support.
• Extravasation of dye into the tissue with severe pain: stop, elevate the arm, apply a cold compress, and watch for skin damage.
• New vessels, or widespread non-perfusion in proliferative disease: urgent referral for laser or injection treatment.
• Active choroidal neovascularisation: referral for injection treatment within days.
• Signs of a vascular occlusion with a systemic cause (carotid disease, cardiac embolism): urgent medical assessment.

Limitations and artefacts.

• The test shows the retinal and choroidal circulation poorly in the deepest choroid, because the pigment epithelium blocks the view, and indocyanine green angiography is used for choroidal vessels.
• Poor images from media opacities, small pupils, poor fixation, a bad injection with slow dye entry, and wrong timing of the photographs.
• Pseudofluorescence (the filters let some light through, causing a fluorescence even before the injection), and auto fluorescence of drusen and optic disc drusen, are artefacts, and baseline images help.
• The test does not show the layers of the retina, and optical coherence tomography is needed for fluid and structure.
• Interpretation takes experience, and the appearance of leakage is not specific to one disease.
• Yellow skin and urine discolouration for 1 to 2 days, and a false rise in some urine and blood tests, may confuse the patient.

Complications.

• Nausea (up to about 5 to 10%), and vomiting (about 1 to 2%), usually short lived, within a minute of injection.
• Skin and urine yellowing, and mild itch or hives (about 1 to 2%).
• Extravasation, with pain and local tissue damage (rare).
• Serious allergic reactions: bronchospasm, laryngeal oedema, hypotension and anaphylaxis (about 1 in 1000 to 1 in 10,000 or fewer), and a rare death (about 1 in 220,000).
• Vasovagal reactions and syncope.

Special groups.

• Pregnancy: avoided, particularly in the first trimester, with non-contrast tests used as an alternative.
• Breastfeeding mothers: advised to stop breastfeeding for a period after the test.
• Children and infants: wide field fluorescein angiography is done under anaesthesia for retinopathy of prematurity and retinoblastoma assessment in specialist centres.
• Patients with renal failure: reduced dose and slower clearance.
• Diabetic patients: results direct laser or injection treatment, and are repeated if the disease changes.
• Regions: optical coherence tomography is not available in many places, so fluorescein angiography remains the main test for macular and vascular disease. Staff trained in resuscitation, a cannula, and emergency drugs are needed for each test. Retinal vascular disease from diabetes, hypertension, sickle cell disease, tuberculosis, and other infections is common.

Follow up tests.

• Optical coherence tomography and optical coherence tomography angiography.
• Indocyanine green angiography for choroidal disease.
• Colour fundus photography and wide field imaging.
• Blood tests: glucose, glycated haemoglobin, lipids, inflammatory markers, infection screening, and blood count with electrophoresis when sickle disease is suspected.
• Carotid Doppler ultrasound, echocardiography and cardiac rhythm monitoring in retinal artery occlusion.
• Visual field testing.
• Repeat angiography after treatment, and referral to a retina service.