4 Fundus Angiography
The unique optical properties of the eye permit a more detailed noninvasive examination of human vasculature than in any other tissue. As the ocular fundus represents the most easily visualized capillary bed in the human body, examination of its angiographic pattern can yield information not only useful for ophthalmic practice but also of interest in the study of associated systemic pathology. There are two intravenous angiographic dyes- sodium fluorescein and indocyanine green (ICG)- used in fundus angiography. Although these two dyes produce significantly distinct angiographic patterns as a result of their different physical and chemical properties, angiography is performed in a similar fashion and interpretation of the image follows similar schema. They are discussed in a comparative way.
4.1 Brief History
4.1.1 Fluorescein Angiography
Von Baeyer 1 first synthesized sodium fluorescein in 1871 and its use in the diagnosis of corneal conditions followed shortly thereafter. In 1882, Ehrlich 2 demonstrated the intraocular presence of fluorescein dye in a rabbit eye following parenteral administration. In 1960, MacLean and Maumenee 3 reported on the intravenous use of fluorescein in humans. They performed angioscopy at the slit lamp with a cobalt blue filter but did not photograph the results. While useful for diagnosis, this technique did not result in permanent images that could be used for comparison, discussion, or documentation. Simultaneous advances in fundus photography, especially the advent of the electronic flash, permitted Novotny and Alvis 4 to perform the first successful human fluorescein angiogram. In the ensuing 35 years of clinical use, fluorescein angiography has become an essential tool in the diagnosis and management of many retinal disorders.
4.1.2 Indocyanine Green Angiography
Indocyanine Green (ICG) was used for fundus angiography much later than sodium fluorescein. It was originally used in cardiac and liver function tests. It has been used for over 30 years, but its early use in fundus imaging was limited by the low sensitivity of the film-based systems utilized at the time. With the refinement of camera, filters, and techniques, by 1972, Flower and Hochheimer had performed ICG angiograms in humans. 5 , 6 In 1986, Hayashi et al 7 reported improved image acquisition using infrared digital fundus videoangiography. In the early 1990s, Guyer et al 8 and Yannuzzi et al 9 demonstrated higher quality images using newer high-resolution (1,024 lines) digital systems. At the same time, scanning laser ophthalmoscope (SLO)-based systems also emerged and have since been shown to produce comparable quality ICG angiogram images. 10
4.2 Properties of the Dye
Differences between the two dyes are shown in Table 4-1. Sodium fluorescein is a highly water-soluble yellow-red dye with peak absorption in the blue spectrum (490 nm) and emission in the yellow-green spectrum (525 nm) (Fig. 4-1). This difference in excitation and emission spectra permits coupled photographic filters to separate incoming and exiting light. Once injected, the dye is 60 to 80% bound to plasma proteins. Sodium fluorescein does not cross intact retinal endothelial tight junctions (inner blood–retinal barrier) or intact zonula occludens of the retinal pigment epithelium (RPE) (outer blood–retinal barrier). However, the fenestrations of the choroidal capillaries permit free leakage of the dye into the choroidal extracellular space.
ICG is a water-soluble dark-green dye with peak absorption between 790 and 805 nm and emission at 835 nm (see Fig. 4-1). 11 Its large molecule size, high affinity for serum proteins, and fluorescence in the near-infrared spectrum make it a useful adjunct to sodium fluorescein. Chemically, the ICG molecule has both lipophilic and hydrophilic characteristics. It is approximately 98% protein-bound in the circulation—80% to globulins and 20% to alpha1-lipoprotein and albumin. 12 Therefore, less dye penetrates the fenestrations of the choriocapillaris, allowing enhanced imaging of choroidal vessels. Its near-infrared spectral properties allow greater penetration through retinal pigment epithelial pigmentation, macular xanthophyll, and blood. The combination of less leakage and greater penetration of fluorescence through overlying pigments makes ICG ideal for angiographic examination of the choroid and choroidal-based abnormalities.
4.3 Technique of Angiography
Although different exciter and barrier filter settings are needed for the imaging system due to different peak absorption and emission wavelength between the two dyes, fluorescein angiography and ICG angiography are performed in a similar way.
After informed consent is obtained, color and red-free fundus photographs are usually taken. Since the first few seconds of the angiogram are often clinically useful, the dye is usually injected through a butterfly-type needle with the patient still seated at the fundus camera. After the needle is inserted, blood should be refluxed into the tubing to ensure intravascular injection since extravasation is painful and can lead to tissue necrosis. The antecubital vein is the preferred injection location. Once the dye is injected, the timer is started. Video or photographs are taken rapidly for the first several seconds and then at approximately 1-minute intervals for several more minutes to cover the complete filling of both the choroidal and retinal vascular systems. The entire photographic process- extending from 5 to 10 minutes- is usually enough for fluorescein angiography. However, ICG angiography usually needs up to 30 minutes. Middle phase photographs are taken between 8 and 12 minutes after injection and then the final photographs are taken approximately 20 to 30 minutes from the time of injection. Some examiners inject a small amount of dye during the late phases to better visualize the retinal and choroidal vessels. 13
During fluorescein angiography, administration of sodium fluorescein is performed in a bolus fashion using either 2 to 3 mL of 25% solution or 5 mL of 10% solution. The dye is circulated and eliminated rapidly, primarily by the kidneys. Patients should be warned of transient changes in skin and urine color. During the period of skin discoloration, patients may have increased photosensitivity; thus, lightly pigmented patients should be urged to avoid excessive sun exposure for 24 to 36 hours. During ICG angiography, a 25-mg bolus of the ICG dye is injected. Since the dye is excreted by the liver, 14 there will be no urine color change afterwards.
Special Considerations
The transient skin discoloration that occurs after intravenous injection of sodium fluorescein dye may make some patients more photosensitive. Lightly pigmented patients should be advised to avoid excessive sun exposure for 24 to 36 hours after fluorescein angiography.
4.4 Adverse Reactions to the Dyes
The incidences of adverse reaction to the two dyes are shown in Table 4-2. Although generally safe overall, angiography has a small but significant rate of adverse reactions. These reactions can be mild, medium, or severe, and can even cause death. 15 Mild reactions, such as pruritus, nausea, and vomiting, are described as transient reactions and not requiring treatment. Manifestations of more serious reactions are urticaria, syncope, pyrexia, and local tissue necrosis. Often, oral or intramuscular diphenhydramine is useful in relieving these symptoms. Severe reactions may involve cardiac, pulmonary, or nervous system. These reactions, such as anaphylaxis, seizures, shock, and myocardial infarction, require intensive medical intervention. For this reason, emergency resuscitative equipment should be available. Extravasation of dye can cause local tissue irritation and tenderness, but no significant permanent tissue damage is likely. The results of laboratory tests performed after fluorescein angiography may be erroneous because of interference by intravenous fluorescein. 16 The adverse reaction rate (including the death rate) to ICG is lower than that to sodium fluorescein. In general, ICG is better tolerated than sodium fluorescein. Since the preparation contains sodium iodide, the use of ICG is contraindicated in patients with iodine or shellfish sensitivities. It is also contraindicated in patients with significant liver or renal disease, as the adverse reactions have been observed to be more common and severe in these individuals. Although no reports of adverse effects during pregnancy have been reported, 17 , 18 until further safety studies are undertaken, use in pregnant women should be avoided unless absolutely critical for diagnosis or management.
Adverse reactions | Sodium fluorescein | Indocyanine green |
Mild | 1–10% | 0.15% |
Moderate | 1.6% | 0.2% |
Severe | 0.05% | 0.05% |
Death | 1:222,000 | 1:333,333 |
4.5 Interpretation of Fundus Angiography
The interpretation of the two types of angiograms follows a similar schema. The schema follows a logical progression beginning with the initial determination of abnormal hypofluorescence or hyperfluorescence on the angiogram. Using a similar medical algorithm, utilizing successive single decisions may lead to the solution of the problem and correct diagnosis. Since the ICG molecule has a higher protein-bound rate, and penetrates the fenestrations of choriocapillaris less than fluorescein, the ICG angiogram enhances the image of choroidal vessels and the optic nerve is always dark during the ICG angiogram due to lack of choroidal vessels. On the other hand, the dark area of the macula seen in fluorescein angiograms cannot be seen in ICG angiograms because the near-infrared spectral properties of the latter allow greater penetration through RPE pigmentation and macular xanthophyll. The main differences between the two normal angiograms are summarized in Table 4-3.
Fluorescein angiogram | Indocyanine green angiogram | |
Optic disc | Bright | Dark |
Macula | Dark | Isofluorescence |
Retinal small vessels | Clear delineation | Unapparent |
Choroid vessels | Unapparent | Clear delineation |
4.5.1 Normal Fundus Angiogram
Fluorescein Angiogram
Fluorescein angiograms are typically divided into prefilling, transit, recirculation, and late phases. The transit phase is subdivided into arterial, laminar venous, and full venous filling phases (Fig. 4-2). As discussed previously, prior to injection, several color and red-free photographs are taken. These are useful for identifying landmarks and correlating areas of clinically evident pathology with their angiographic features.
After the excitation and emission filters are inserted, photographs are taken to help identify areas of pseudofluorescence and autofluorescence. Pseudofluorescence results from mismatching of these photographic filters and is rarely encountered nowadays with improvements in angiography equipment. Autofluorescence results from tissues that behave similarly to fluorescein in that they emit light in the yellow-green spectrum when illuminated by blue light even in the absence of the dye. 19 These include optic nerve head drusen, flecks associated with fundus flavimaculatus, astrocytic hamartomas, deposits of lipofuscin, and Best’s vitelliform lesions. 20 Autofluorescence of the lens has been related to metabolic control in diabetics. 21
Pearls
Abnormal fundus findings which may show hyper-autofluoresce include optic nerve head drusen, flecks associated with fundus flavimaculatus, astrocytic hamartomas, deposits of lipofuscin, and Best’s vitelliform lesions.
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