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Core Messages

Fluorescein angiography remains the gold standard for diagnosis and treatment decisions of the most commonly treated retinal disorders, e.g., exudative age-related macular degeneration, diabetic retinopathy and retinal venous occlusions. Despite the recent advancements and growing popularity of optical coherence tomography and indocyanine green (ICG) angiography, fluorescein angiography is still indispensable for the identification of choroidal neovascularizations in age-related macular degeneration and macular ischemia in retinal vascular diseases, and, therefore, is likely to remain a key examination method for patients with retinal and choroidal diseases The outstanding value of fluorescein angiography derives from its representation of the integrity of the inner and outer blood-retina barriers. The detection of extravasated unbound fluorescein with fluorescein angiography helps to identify even subtle defects of the blood-retina barriers and thereby helps to

establish the diagnosis and to set up treatment strategies

There is no standard protocol for the interpretation of fluorescein angiographies. Usually, between 30 and 40 pictures are taken from 10 s to 10 min after the intravenous injection of 5 ml 10 % sodium fluorescein. The interpretation is usually divided into arterial phase (12 – 15 s), arteriovenous phase (15 – 35 s) and late phase (5 or 10 min). Ideally, pseudostereo-angiogra- phies with the option of stereo-viewing on review of the pictures should be performed Fluorescein angiography is considered to be a safe diagnostic procedure. Mild reactions, e.g., nausea, occur in about 1:20 angiographies. Moderate complications, e.g., urticaria or dyspnea, can be seen in about 1:60 cases. Severe complications, e.g., anaphylactic shock, have been described in 1:2,000 angiographies. The risk for lethal complications of an angiography has been estimated to be 1:220,000. Fluorescein angiography should not be performed in cases with known allergic reactions to fluorescein

11.1 History

Fluorescein is one of the most potent artificial dyes. It was first synthesized in 1871 by Adolf von Baeyer, a German chemist who in 1905 received the Nobel Prize in chemistry for his work on organic dyes.

The occurrence of fluorescein in the anterior chamber following intravenous injection was first described by Paul Ehrlich in 1882. Further landmarks in the use of fluorescein for posterior segment diseases were the detection of increased fluorescein leakage in chorioretinitis (Burk 1910) and its role in the differential diagnosis of choroidal tumors after intravenous administration (MacLean and Maumenee 1955) [7].

The basic concept of fluorescein angiography (FA) was first described in 1959 by Flocks, Miller and

Chao following initial in vivo experiments in cats. The first FA on a human was performed by Novotny and Alvis soon afterwards [1]. As a landmark in the interpretation of FA and a reference guide to date the

Stereoscopic Atlas of Macular Diseases was first published by Donald Gass in 1969 [3].

Fluorescein angiography has been in routine use for the diagnosis and treatment of posterior segment diseases for about 40 years now. It accelerated the process of understanding many retinal and choroidal diseases. In parallel with the introduction of laser photocoagulation, it built the foundation of a whole new subspecialty branch of ophthalmology, the “medical retina.” Large multicenter randomized trials, basing their initial classification and subsequent course of the disease on FA, set evidence-based standards for the treatment of diabetic retinopathy,

venous occlusive diseases and age related macular degeneration (AMD) [2, 3, 5, 6].

Although electrophysiology and more recently optical coherence tomography and indocyanine 11 II green (ICG) angiography have been vital additional methods for the examination of retinal and choroidal diseases, FA still remains the most important investigation next to ophthalmoscopy for the majority of retinal and choroidal diseases. It continues to be the “gold standard” in the diagnosis and treatment of the three most prevalent diseases seen in the field of “medical retina” – age related macular degeneration, diabetic retinopathy and retinal venous occlusions.

Clinical and research studies, as well as the decision regarding funding of certain therapeutic options, are therefore in large part based on the results of FA.

A recent spur to the use of FA has been the new treatment methods available for AMD, e.g., photodynamic therapy and intravitreal injection of anti-vas- cular endothelial growth factor (VEGF) substances; as a consequence, the number of angiographies performed in tertiary centers has more than doubled over the past 5 years.

Digital imaging systems have overtaken classic b/w film techniques as the standard method of recording FA in most institutions. Comparing both techniques, the advantages of digital systems are the immediate availability of the angiography for diagnosis and treatment with a resolution sufficient for most cases; the possibility of image enhancement and image analysis; the easy storage of images; and the speedy distribution of FA to computers within a department or elsewhere. Disadvantages are that digital systems are more expensive, achieve a lower resolution of single images and imply a technically more complicated method of viewing pseudo-stereo images compared to classic film recordings.

11.2 Concept

Fluorescence is defined as the emission of absorbed radiated energy in the form of electromagnetic radiation with similar or longer wavelength. In the context of fluorescence angiography, this means that an exciting light reaching the fluorescing molecule causes emission of light of a different wavelength that then again can selectively be detected. In practice, the dye molecules not bound to proteins function as manifold sources of light within the tissue. This enables identification of the localization of the dye and results in a much higher contrast than that achievable by the dying properties alone.

Fluorescein sodium (C20H10O5Na2, MW 376) is the most commonly used dye worldwide for FA. Indocyanine green is another dye used for FA.

Fluorescein angiography is used for diagnosis of posterior segment diseases, as a treatment guideline and as a tool for the evaluation of the development and course of the disorder during subsequent treatment or observation.

It is most often employed for diseases of the retina or at the retinal-choroidal junction and, to a lesser extent, for disease of the choroid and the optic nerve head.

The value of the fluorescein sodium for examination of posterior segment diseases in contrast to other dyes derives from the relation of its intraocular distribution to the integrity of the blood-retinal barrier. Unbound fluorescein does not permeate intact inner and outer blood-retinal barriers in significant quantity. If, however, these structures are injured, the permeation and visualization of fluorescein by FA allows identification and localization of the damaged structures as well as that of newly formed vessels or vascular irregularities.

Both the absorption and emission spectrums of sodium fluorescein are dependent on various factors; in intravenous administration they are 465 nm (absorption) and 525 nm (emission).

Approximately 70 – 80 % of the sodium fluorescein binds to plasma proteins; 20 – 30 % does not bind. Injected fluorescein is diluted in the bloodstream to a factor of approximately 600 and disperses throughout the whole body. With the exception of the central nervous system vessels, the retina, and to a limited degree the iris, unbound sodium fluorescein can freely permeate all blood vessels of the body.

The intravenous administration of fluorescein sodium during FA is well tolerated in most cases. Mild reactions, e.g., nausea, occur in about 1:20 angiographies. Moderate complications, e.g., urticaria or dyspnea, can be seen in about 1:60 cases. Severe complications, e.g., anaphylactic shock, have been described in 1:2,000 angiographies. The risk of lethal complications with an angiography has been estimated to be 1:220,000.

11.3 Performing Fluorescein Angiography

The reasons for performing FA, the procedure and its possible side effects should be explained to the patient. As FA is an invasive procedure with potential severe side effects, written consent is required in most countries and institutions.

Equipment: fundus camera with automatic film transport, or a digital camera or scanning laser ophthalmoscope; an electronic flash unit with an exciter filter of 465 – 490 nm (blue green spectrum); and a recording filter of 520 – 530 nm (green-yellow spectrum). Pseudo-stereo viewing usually requires particular software and viewing systems (digital

angiography) or magnifying glasses (film angiography).

Parallel fluorescein and ICG angiographies are currently obtainable with specialized equipment only and are usually not employed in daily practice.

The pupil should be dilated and intravenous access secured.

The staff on duty must be trained in resuscitation and emergency procedures in the rare event of a severe allergic reaction to the dye. Drugs and equipment needed to treat anaphylactic reactions must be readily available.

The angiography is usually performed by a specialized photographer or an ophthalmologist. The experience and skill of the photographer are of vital importance for achieving high quality angiograms. In contrast, angiographies of poor quality are more often than not useless and require a repeat procedure many hours or days afterwards.

A standard image of 30° is used for most diseases; alternatively 20° (high magnification) and 50° or 60° (wide angle) exposures are used.

Color fundus photograph and b/w exposures of both eyes should be taken before angiography.

The angiography is started by an intravenous bolus administration of 5 ml 10 % sodium fluorescein (2.5 ml for patients with renal insufficiency). The quicker the injection, the higher the contrast in the early phases of the angiography. A stopwatch is set off at the start of the injection to monitor the chronology of the exposures.

First exposures are obtained after 10 – 15 s at first appearance of the dye within the choroidal and retinal circulations (pre-arterial and early arteriovenous phase). Rapid sequential exposures (approximately one image per second) are then taken (arteriovenous phase) until the maximum fluorescence is reached after 25 – 35 s.

After completion of the arteriovenous phase, additional exposures of the fundus periphery (for example, in diabetic retinopathy) or the fellow eye (for example, in macular degeneration) can be made.

Pseudo-stereo photographs can be obtained by lateral shifts of the camera on sequential frames. A true stereoangiography requires specialized equipment where two pictures can be taken with a fixed angle at the same time.

Angiography is concluded with the last exposures being taken 5, 10 or 15 min after the initial injection (late phase).

There is no universal protocol for the timing of exposures. Protocols used in different institutes and studies vary, depending on the profile of the disease and the institution. For most clinical studies, certification of the equipment, the photographer and the examiner is required.

Usually, about 30 pictures are taken per angiography session. Typical shots resembling the early arteriovenous phase, arteriovenous phases and late phases can be selected and printed for documentation. Stor-

ing all images for analysis is recommended for all II 11 cases.

In situations where the angiography could not be performed in a suitable way, it can be repeated after 2 – 4 h in most cases. However, in larger studies, a 48- h interval is generally recommended.

11.4Interpretation of Fluorescein Angiography

For the assessment of angiographies, the appropriate conditions should be in place. For example, digital angiographies should be viewed on a large high resolution screen with stereo-viewing capabilities wherever possible. FA captured on film should either be viewed with magnifying glasses on a light box or enlarged to high quality prints. In some reading centers, angiographies on b/w film are still the gold standard due to the higher resolution and easier stereoviewing of these images.

Assessment and interpretation of angiography are biased by the quality and timing of the angiography and the expertise of the examiner. Intraand interobserver differences similar to those found in the evaluations of chest X-rays exist even among expert examiners. In case of doubt, additional advice should be sought, which nowadays is facilitated by the possibility of mailing digital angiographies via the internet.

As there is no standardized procedure for the recording of the angiography, neither is there a standardized protocol for its interpretation. Most investigators would base their interpretation on the evaluation of color and red-free pictures, the early arteriovenous phase, the arteriovenous phase and the late phase. Pseudo-stereo interpretation should be standard for interpretation of exudative AMD lesions as most treatment guidelines are based on stereoimages.

During angiography, the fluorescein dye fills the retinal and choroidal vessels in a reproducible manner (Figs. 11.1 – 11.4). Exceptions from the standard angiography patterns are identified and classified in relation to the anatomical structures and the timepoint at which they can be detected during the course of the angiography. The most common diseases examined with fluorescein angiography and their typical findings are illustrated in Table 11.1.

11 II

a

c

b

Fig. 11.1. a Color image of normal central retina. The fovea appears darker due to the higher concentration of melanin in the central retinal pigment epithelium (RPE) and lipofuscin in the outer retinal layers. b Picture of a patient following removal of an idiopathic subretinal membrane. Parts of the RPE and the choriocapillaris have been removed together with the subretinal membrane. This enables identification of the different vascular networks during fluorescein angiography. c Diagram illustrating the different layers in b. Area A choriocapillaris and RPE removed, area B choriocapillaris still present but RPE removed