Chapter 6.8 - Fluorescein angiography; indocyanine green angiography;... http://www.mdconsult.com/das/book/body/158877901-18/885608974/...

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Yanoff & Duker: Ophthalmology, 3rd ed.

Copyright © 2008 Mosby, An Imprint of Elsevier

Chapter 6.8 – Fluorescein Angiography, Indocyanine Green Angiography, and Optical Coherence Tomography
F. Ryan Prall,
Jeffrey L. Olson,
C.J. Barnett,
Naresh Mandava

Definition

▪ Fluorescein angiography (FA) is a modality that uses intravenous fluorescein dye to image the retinal and choroidal circulation in evaluating vascular diseases of the
retina including diabetic retinopathy, choroidal neovascularization, vascular occlusions, cystoid macular edema, and central serous chorioretinopathy.
▪ Indocyanine green angiography (ICG) is an infrared-based imaging technique using a molecule larger than fluorescein that is mostly protein-bound and highlights the
choroidal circulation.
▪ Optical coherence tomography (OCT) is an imaging system that uses light to measure the differences in reflectivity of tissue to produce two-dimensional images that
approximate the histologic appearance of the retina.

FLUORESCEIN ANGIOGRAPHY
INTRODUCTION
The development of FA increased the understanding of retinal and choroidal pathology and has become the standard both in the literature and in clinical practice to diagnose and guide the
treatment of the most common retinal diseases encountered in ophthalmology. Recent technological advances in digital imaging and computer analysis have further expanded the clinical
and research applications of fluorescein angiography.

PURPOSE OF THE TEST

Because the fluorescein molecule is relatively small and typically unbound in the circulation it freely crosses the walls of small choroidal vessels but remains within retinal vessels and the
large choroidal vessels in normal individuals. This makes FA primarily a study of the retinal vasculature; however, some information can be obtained regarding choroidal circulation and
retinal pigment epithelium (RPE) as well. Vascular anomalies both seen and unseen by biomicroscopy such as those found in diabetic retinopathy, central serous chorioretinopathy, and
venous occlusive disease can be clearly demonstrated with FA and the images can be used to guide treatment.

PROPERTIES OF SODIUM FLUORESCEIN DYE

The sodium fluorescein molecule has several characteristics that make it ideally suited for ophthalmic imaging. Most important is fluorescence– its ability to absorb a photon of light of one
wavelength and emit a photon of light of a second wavelength. Sodium fluorescein is yellow-red in color, with a molecular weight of 376.67. It has a narrow spectrum of absorption
(465–490 nm (blue)) and excitation (520–530 nm (yellow-green wavelength)). Sodium fluorescein dye usually is available as aliquots of 2–3 mL of 25% or 5 mL of 10% sodium fluorescein
in a sterile aqueous solution. Still no evidence exists of increased side effects with the higher concentration, [4] [5] so many practitioners prefer to use the smaller volume of the more
concentrated solution. Approximately 80% of fluorescein dye binds to plasma proteins, principally albumin, while the remainder remains unbound. The dye is metabolized by both the liver
and kidneys and is eliminated in the urine within 24–36 hours.

PROCEDURE
Good-quality FA images are dependent on a high-quality fundus camera and a photographer that is experienced and familiar with both the photographic system and the posterior segment
anatomy. The spherical refractive error of the patient is corrected by simultaneously focusing the cross hairs in the eyepiece reticle and on the fundus. The focusing wheel is used only for
fine focus of the retinal pathology.

The joystick of the fundus camera is used to align the camera to the patient’s eye. Proper alignment results in even illumination of the fundus. Misalignment results in peripheral and central
defects in the images. These can be ameliorated with careful lateral movement of the joystick. Variable amounts of magnification can usually be selected and this should be tailored to the
pathology being examined.

The dye is typically injected via the antecubital vein in a rapid but controlled manner to maximize the contrast of the early filling phase of the angiography. Extravasation of the dye should
be avoided as infiltration is painful and may rarely lead to tissue necrosis. A timer is started and image acquisition should begin immediately so initial choroidal and retinal filling can be
captured.

COMPLICATIONS
Adverse reactions to intravenous fluorescein angiography range from mild to severe. [5] [8] [9] [10] [11] [12] Mild reactions are defined as transient and resolve spontaneously; most
commonly these are nausea (approximately 3–15%), vomiting (up to 7%), and pruritus. Moderate adverse reactions resolve with medical intervention; these include urticaria, syncope,
thrombophlebitis, pyrexia, local tissue necrosis, and nerve palsy. Severe reactions are those that require intensive intervention and the patients may have poor recovery; these include
laryngeal edema, bronchospasm, anaphylaxis, shock, myocardial infarction, cardiac arrest, tonic-clonic seizures, and death. [5] The incidence of adverse reactions has been reported in a
multicenter, collaborative study ( Table 6-8-1 ).

TABLE 6-8-1 -- INCIDENCE OF ADVERSE REACTIONS TO INTRAVENOUS FLUORESCEIN ANGIOGRAPHY

Reaction Incidence
Mild Incidence of 0–5% (based on 87% of respondents)
Moderate Urticaria 1:82
Syncope 1:337
Other 1:769
Overall 1:63
Severe Respiratory 1:3800
Cardiac 1:5300
Seizures 1:13 900
Death 1:221 781
Overall 1:1900

While not considered complications, the yellowing of the skin most commonly seen in fair-skinned individuals may lead to photosensitivity and patients should be cautioned about ultraviolet
exposure. Although no reports of adverse reactions or risks to the pregnant woman or fetus have occurred, pregnancy, especially during the first trimester, is a relative contraindication to
fluorescein angiography. [6] [7]

INTERPRETATION OF RESULTS
Normal Fluorescein Angiogram

After injection into the antecubital vein, dye first enters the short posterior ciliary arteries and is visualized in the choroid and optic nerve head 10–15 seconds later in most normal
individuals. This initial filling is dependent on the cardiovascular condition and age of the patient as well as the speed of injection. The choroidal circulation is seen initially as the choroidal
flush – a mottled and patchy fluorescence created as dye fills the choriocapillaris. The patchy appearance is created as separate lobules of the choriocapillaris fill sequentially. As dye
leaks from the choriocapillaris during the early phases of the angiogram Bruch’s membrane is stained and choroidal vasculature detail is obscured. A cilioretinal artery is seen
simultaneously with the fluorescence of the choroidal circulation in 10–15% of patients.

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The retinal circulation begins to fluoresce at 11–18 seconds, 1–3 seconds after the onset of choroidal filling. The retinal arterial system should fill completely in about 1 second. The early
arteriovenous phase is characterized by the passage of fluorescein dye through the central retinal arteries, the precapillary arterioles, and the capillaries, while the late arteriovenous phase is
characterized by the passage of dye through the veins in a laminar pattern. During the late arteriovenous phase maximal fluorescence of the arteries occurs, with early laminar filling of the veins.
Laminar filling of veins is caused by the preferential concentration of unbound fluorescein along the vessel walls. Several factors are responsible for the laminar pattern of venous filling; these
include the more rapid flow of plasma along the vessel wall, as well as the higher concentration of erythrocytes in the central vascular lumen.

Maximal fluorescence is achieved in the juxtafoveal or perifoveal capillary network after 20–25 seconds. The normal capillary-free zone, or foveal avascular zone, is approximately 300–500 µm
in diameter. A dark background to this capillary-free zone in the macula is created through blockage of choroidal fluorescence by both xanthophyll pigment and a high density of RPE cells in the
central macula. This phase of the angiogram has been termed the peak phase as maximal fluorescence of the capillaries and enhanced resolution of capillary detail occurs ( Fig. 6-8-1 ). The
management of microvascular diseases of the retinal capillaries, such as diabetic macular edema, requires excellent peak-phase imaging.

Fig. 6-8-1 Peak phase angiogram. Approximately 25 seconds after injection, maximal fluorescence of the retinal circulation is evident. Note the intricate detail of the perifoveal capillary network.

The first pass of fluorescein through the retinal and choroidal vasculature is complete after 30 seconds. The recirculation phases, characterized by intermittent mild fluorescence, follow. After
approximately 10 minutes, both the retinal and choroidal circulations generally are devoid of fluorescein. Many normal anatomical structures continue to fluoresce during the late angiogram, such
as the disc margin and optic nerve head. The staining of Bruch’s membrane, choroid, and sclera is more visible in patients who have lightly pigmented RPE.

Abnormal Fluorescein Angiography

A basic understanding of the anatomy of both the retinal and choroidal circulations and the complex anatomical relationships between the layers of the retina, RPE, and choroid is crucial in the
interpretation of fluorescein angiography. The terms hypofluorescence and hyperfluorescence are used routinely in the interpretation of fluorescein angiograms. [13] [14] [15] [16] [17] [18] [19]
Hypofluorescence is a reduction or absence of normal fluorescence ( Box 6-8-2 ), while hyperfluorescence is increased or abnormal fluorescence ( Box 6-8-3 ).

BOX 6-8-1

TYPICAL PHOTOGRAPHIC PROCEDURE

Appropriate camera and film (color for fundus photography, black and white for fluorescein angiography)
Correct flash setting for film used
Focus cross hairs
Correct viewing intensity (as low as possible for patient comfort, but adequate to focus)
Photograph patient identification label
Position patient at camera (adjust camera height and chin rest)
Adjust camera in relation to patient’s eye
Fixate eye using a fixation target
Choose correct field size based upon pathology to be evaluated
Focus on retina (remember to visualize cross hairs)

BOX 6-8-2

CAUSES OF HYPOFLUORESCENCE
BLOCKED RETINAL FLUORESCENCE

Media opacity
Vitreous opacification (hemorrhage, asteroid hyalosis, vitritis)
Subhyaloid hemorrhage
Intraretinal pathology (hemorrhage (vein occlusion), edema)

BLOCKED CHOROIDAL FLUORESCENCE

All entities that cause blocked retinal fluorescence

Outer retinal pathology (lipid, hemorrhage, xanthophyll (normal pigment))
Subretinal pathology (hemorrhage, lipid, melanin, lipofuscin, fibrin, inflammatory material)
Subretinal pigment epithelium pathology (hemorrhage)
Choroidal pathology (nevus, melanoma)

VASCULAR FILLING DEFECTS

Retina
• occlusion or delayed perfusion
• central or branch artery occlusions
• capillary nonperfusion secondary to diabetes, vein occlusion, radiation, etc.
• atrophy or absence of vessels or retina
Choroid
• occlusion of large choroidal vessels or choriocapillaris (sectoral infarct (wedge-shaped), malignant hypertension, toxemia, lupus choroidopathy, renal disease)
• atrophy or absence of choroidal vessels or choriocapillaris (choroideremia, acute multifocal placoid pigment epitheliopathy)
Optic nerve
• occlusion (ischemic optic neuropathy)
• atrophy or absence of tissue (coloboma, optic nerve pit, optic nerve hypoplasia, optic atrophy)

BOX 6-8-3

CAUSES OF HYPERFLUORESCENCE
PSEUDOFLUORESCENCE

AUTOFLUORESCENCE

TRANSMITTED FLUORESCENCE

Geographic atrophy
Bull’s eye maculopathy
Macular hole
Atrophic chorioretinal scar

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Drusen

ABNORMAL VESSELS

Retina
• angioma; Wyburn-Mason syndrome
• cavernous hemangioma
• vascular tumor
• retinoblastoma
Choroid
• melanoma
• plaque; choroidal neovascularization
• choroidal hemangioma
Optic nerve
• peripapillary vascular loops

LEAKAGE

Retinal vessels
• venous occlusive disease
• frosted angiitis
• phlebitis
Neovascularization

POOLING

Neurosensory detachment
• central serous chorioretinopathy
• optic nerve pit (slow filling)
• Best’s disease
Subretinal neovascularization
Retinal pigment epithelium detachment
• serous
• fibrovascular

STAINING

Staphyloma
Disc
Sclera
Chorioretinal scar

Hypofluorescence

Hypofluorescence can be categorized into blockage (masking of fluorescence) or vascular filling defects. Blocked fluorescence can provide clues as to the level of the blocking material, such as
vitreal, retinal, or subretinal. Only structures or material anterior to the area of fluorescence can block fluorescence.

Blocked retinal fluorescence may be caused by any element that diminishes the visualization of the retina and its circulation ( Fig. 6-8-2 ). Media opacities secondary to corneal pathology or
cataract can block or reduce retinal fluorescence. In addition, hemorrhage on the surface of the retina (preretinal) or debris in the vitreous cavity, such as inflammatory cells or cells from
hemorrhage, can mask fluorescence.

Fig. 6-8-2 Blockage. In this early phase angiogram, preretinal blood inferiorly (arrow) blocks both retinal and choroidal circulation. Superior to the fovea, subretinal blood (arrowhead) blocks choroidal
fluorescence, but the retinal circulation is clearly seen.

Blockage of retinal fluorescence also may localize the pathology to the inner retina. The retinal circulation is unique in that the large retinal vessels and precapillary, first-order arterioles lie in the
nerve fiber layer, while the capillaries and postcapillary venules are located in the inner nuclear layer. Flame-shaped hemorrhages are superficial and block all retinal vascular fluorescence, while
deeper dot or blot hemorrhages (or intraretinal lipid) block capillary fluorescence but do not block larger superficial vessels.

Blockage of choroidal fluorescence can occur with any of the previously described pathological entities located anterior to the choroid. In addition, subretinal material in pathological states, such
as hemorrhage, melanin, lipofuscin, lipid, fibrin, and inflammatory material, can block choroidal fluorescence. As noted previously, the normal fluorescein angiogram displays blockage of
choroidal fluorescence as evidenced by early, patchy choroidal filling and a consistently darker macular region. Xanthophyll and a high density of RPE (melanin) are responsible for blockage of
fluorescence in the macula. Melanin can accumulate in RPE cells in many disease processes. It is not uncommon for blockage of choroidal fluorescence to surround a scar secondary to
accumulation of melanin, as a result of a rim of RPE hypertrophy surrounding the scar. Choroidal nevi and choroidal melanomas represent classic examples of the blockage of choroidal
fluorescence. Also, lipofuscin deposits block choroidal fluorescence and are seen in fundus flavimaculatus (Stargardt’s disease) and Best’s disease. The most common causes of blocked
choroidal fluorescence are subretinal hemorrhage and turbid serosanguineous fluid beneath a RPE detachment, as seen in choroidal neovascularization (CNV) secondary to age-related macular
degeneration.

Vascular filling defects produce hypofluorescence because of the reduced or absent perfusion of tissues. Retinal vascular filling defects can involve large-, medium-, or small-caliber vessels.
Central or branch retinal artery occlusions show hypofluorescence in the distribution of the arterial tree involved in the occlusion. The zones of capillary nonperfusion manifest as vascular filling
defects and appear hypofluorescent on fluorescein angiography. This form of vascular filling defect is seen in common disease processes such as diabetic retinopathy and central retinal vein
occlusions ( Fig. 6-8-3 ).

Fig. 6-8-3 Vascular filling defect. In this diabetic with hyperfluorescent neovascularization (arrows), widespread nonperfusion is evident more peripherally (arrowheads).

Choroidal vascular filling defects are more difficult to visualize, because the native RPE prevents adequate visualization of the choroidal circulation. The anatomy of the choroidal vasculature is
more complex than that of the retina. Imaging of the choriocapillaris and other structures within the choroid is limited by the difficult visualization of the choroidal circulation as well as by the
hyperpermeability of choroidal vessels to fluorescein dye. In general, occlusive diseases that involve isolated, larger choroidal vessels manifest as sectorial, wedge-shaped areas of
hypofluorescence. However, it is more common for choroidal hypoperfusion to manifest with diffuse involvement of the choriocapillaris. Systemic diseases, including malignant hypertension,
toxemia of pregnancy, and lupus choroidopathy, produce zones of hypofluorescence secondary to focal choroidal nonperfusion. During the late phases of the angiogram, normally perfused
choriocapillaris may leak into the area of hypofluorescence. Atrophy or degeneration of the choriocapillaris also is noted in choroideremia.

Also, vascular filling defects of the optic nerve head may be noted by fluorescein angiography. Ischemic optic neuropathy manifests as sectorial or complete optic disc hypofluorescence, while

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other atrophic or hereditary anomalies of the optic nerve head have diffuse hypofluorescence. Congenital anomalies, including optic nerve head colobomas, optic nerve hypoplasia, and optic
pits, also may be associated with hypofluorescence.

Hyperfluorescence

Hyperfluorescence is defined as an abnormal presence of fluorescence or an increase in normal fluorescence in the fluorescein angiogram. Frequently, hyperfluorescence is seen with
transmission window defects, an area with a relative decrease or absence of pigment in the RPE or an absence of RPE that allows a view of the underlying choroidal fluorescence. This is seen
with common pathological processes such as chorioretinal atrophic scars, full-thickness macular holes, the atrophic form of macular degeneration, and drusen ( Fig. 6-8-4 ).

Fig. 6-8-4 Window defect. Red-free photograph demonstrates central atrophy from macular degeneration (A). Increasing fluorescence is noted through angiogram (B, C); decreased fluorescence is noted
through window defect in late phase (D).

Retinal vascular anomalies, such as capillary angiomas, arterial venous malformations, and Coats’ disease, commonly cause hyperfluorescence in the distribution of the vascular pathology.
Hyperfluorescence is seen in common abnormalities of native blood vessels including telangiectasias, aneurysms, anastamoses, dilation, and tortuosity. Classically, neovascularization within the
retina and choroid manifests with late leakage of fluorescein dye or hyperfluorescence but may also show early hyperfluorescence. Finally, choroidal tumors, such as melanomas or choroidal
hemangiomas, may cause hyperfluorescence on fluorescein angiography depending on the vascularity of the lesion.

Leakage of fluorescein dye is defined as hyperfluorescence of fluorescein in the extravascular space. Typically, the area of fluorescence increases in both size and intensity as the study
progresses ( Fig. 6-8-5 ). As discussed earlier, retinal neovascularization manifests with late leakage of fluorescein dye into the vitreous cavity and often is located adjacent to an area of
capillary nonperfusion. Often, fluorescein angiography is used to detect neovascularization that is subclinical or cannot be identified by ophthalmoscopy. Other retinal vascular abnormalities,
such as vasculitis or inflammatory lesions, can cause leakage of fluorescein into the retina or vitreous because of the increased permeability of blood vessels. The classic appearance of
intraretinal leakage is seen with macular edema. The two most common causes of macular edema are diabetes, which is associated with focal parafoveal microaneurysms; and postoperative
cystoid macular edema, which is associated with late leakage (in a petaloid pattern) of fluorescein dye into the cystoid spaces of the outer plexiform layer ( Fig. 6-8-6 ). Optic nerve pathology,
such as seen in papilledema and ischemic optic neuropathy, produces profound leakage of the optic nerve head during the late phase of the angiogram as a result of capillary leakage.
Importantly, the normal optic disc also has some minimal leakage along its margins secondary to leakage from adjacent choroidal capillaries. Often, both the distribution of leakage on the optic
nerve head and the intensity of hyperfluorescence help in the diagnosis.

Fig. 6-8-5 Branch vein occlusion. Red-free photograph (A) demonstrates intraretinal hemorrhages along the inferotemporal arcade. Angiogram demonstrates progressive leakage of dye indicating vascular
incompetence and macular edema. Note the blocking effect of the intraretinal hemorrhage (B–D).

Fig. 6-8-6 Cystoid macular edema. Late-phase angiogram demonstrates a petalloid pattern of macular edema and mild leakage from the optic nerve head in this postoperative patient.

Hyperfluorescence secondary to subretinal and choroidal pathology is more difficult to correlate histopathologically; however, the timing, pattern, and location of hyperfluorescence are
reproducible in many diseases. Pooling refers to the accumulation of fluorescein dye into an anatomical space, while staining indicates the deposition of fluorescein into tissues. Pooling is seen
in both neural retina and RPE detachments. Its rapidity and pattern is important in their differentiation. For example, in central serous chorioretinopathy, neurosensory retinal detachments
fluoresce slowly, if at all, because fluorescein must pass through small leaks in the RPE ( Fig. 6-8-7 ). On the other hand, RPE detachments in macular degeneration are characterized by the
rapid pooling of fluorescein under the dome of the detachment, because no barrier exists to the permeability of the choriocapillaris ( Fig. 6-8-8 ). Note that imaging of the underlying choroid is
hampered by this phenomenon.

Fig. 6-8-7 Central serous retinopathy. Large arrow indicates areas of retinal pigment epithelium leakage of fluorescein, which pools in the overlying neurosensory detachment (arrowheads).

Fig. 6-8-8 Fluorescein pooling. Red-free photograph (A) shows a retinal pigment epithelium (RPE) detachment and drusen present centrally. Note increasing fluorescence of the RPE detachment
throughout the angiogram (B–D).

Staining in fluorescein angiography refers to the deposition of fluorescein dye within the involved tissue and occurs in both normal and pathological states. Normal structures, such as the optic
disc and sclera, may stain. Scleral staining is seen more easily in high myopes and patients who have lightly pigmented fundi, because enhancement of transmission occurs through atrophic or
absent RPE. Diseases that result in widespread chorioretinal atrophy, such as gyrate atrophy and serpiginous choroidopathy, demonstrate significant scleral staining. The degree of staining is
dependent on the competence of the choriocapillaris, because severe atrophy limits the amount of fluorescein that leaks from the choroidal vessels. Finally, staining also is seen in disciform
scars and damaged RPE tissue.

Autofluorescence

Imaging of fundus autofluorescence is a new technique that enables clinical evaluation of the RPE by using a scanning laser ophthalmoscope or special filters on a fundus camera. This was
introduced in vivo in 1995 and researchers have recently been evaluating its potential use in common retinal diseases including AMD, AMPPE, pseudoxanthoma elasticum, and central serous
chorioretinopathy. It relies on the emission of light primarily by lipofuscin, a molecule that accumulates in the RPE after oxidative breakdown of molecules in the RPE. Lipofuscin produces
reactive oxygen species and may lead to RPE apoptosis. The amount of autofluorescence correlates directly to the amount of lipofuscin in cells and this may be a sign of damaged or vulnerable
RPE cells.

INDOCYANINE GREEN ANGIOGRAPHY

INTRODUCTION
ICG angiography is an infrared-based, dye-imaging technique that is able to demonstrate the choroidal vasculature in sufficient detail to make it useful in the evaluation of many pathological
processes in the choroid. ICG is a larger molecule than fluorescein and is mostly protein bound. This difference keeps the molecule in the choroidal circulation and makes ICG angiography
ideal for detecting and evaluating choroidal abnormalities. ICG as an adjunctive procedure increases our ability to image the choroids, therefore expanding our understanding of choroidal
pathology and hastening the development of treatments for diseases such as choroidal neovascularization.

It is most useful for the evaluation of patients who have exudative changes from CNV. While classic CNV can be easily delineated with FA, 85% of CNV are occult lesions, which, by definition,
are not as easily defined with FA. So in a majority of patients with CNV secondary to AMD, ICG can contribute to the visualization of the pathology and therefore increase the number of patients
that can be treated with laser photocoagulation. In addition, ICG angiography allows more directed laser treatment and is used to detect occult recurrences of CNV following laser
photocoagulation.

The initial appearance of dye in the large choroidal arteries and veins marks the beginning of the early phase of the angiogram about 1 minute after injection. Retinal vessels are also seen in this
phase. During the middle phase, 5–15 minutes post injection, a diffuse homogeneous choroidal fluorescence is seen as the choroidal veins and retinal vasculature become less distinct.
Abnormalities typically begin to appear hyperfluorescent during this phase. In the late phase, after 15 minutes, no vascular details are seen, the optic disk and large vessels are dark and
abnormalities, including CNV which may remain hyperfluorescent.

Terms specifically related to ICG imaging of CNV include focal CNV (sometimes referred to as a hot spot), which most often represents either an area of occult CNV or an intraretinal
angiomatous proliferation (RAP lesion). Hot spots, by definition, are less than 1 disc diameter in size and are well delineated ( Fig. 6-8-9 ). Typically, these lesions are not obscured by
hemorrhage or exudate. Placoid hyperfluorescence describes an area of occult CNV that is larger than 1 disc area in size ( Fig. 6-8-10 ) that may or may not be well defined during the early
phase of the ICG angiogram. During the late phase of the ICG angiogram, the staining of CNV may be well defined and is not obscured by hemorrhage or exudate. If the borders are not distinct
because of late leakage of ICG or the borders are obscured by hemorrhage or exudate, the lesion is not considered to be well defined by ICG angiography. For CNV that is well defined or

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classic in appearance on fluorescein angiography, the appearance on ICG angiography is variable. [23]

Fig. 6-8-9 Indocyanine green imaging. Right side (A): fluorescein angiography of patient with idiopathic polypoidal choroidal vasculopathy with a hemorrhagic pigment epithelial detachment. Left side (B):
indocyanine green angiography demonstrates a choroidal neovascular membrane (arrow) and characteristic saccular dilations of the choroidal vasculature (arrowhead).

Fig. 6-8-10 Normal optical coherence tomography. Normal foveal contour is seen in conjunction with normal retinal architecture. ILM (arrows); retinal pigment epithelium (arrowheads).

UTILITY OF THE TEST

The greatest utility for ICG angiography is in the identification and delineation of poorly defined or occult CNV. [24] ICG adds a new dimension to imaging the posterior pole beyond what can
normally be evaluated with FA. It has several major differences from FA that allow this. After intravenous injection, ICG is bound readily and rapidly to serum proteins. In fact, 98% of ICG is
transported in the blood bound to serum proteins, which compares with only 60–80% of fluorescein that is protein bound. The advantage of being more protein bound is that the amount of
leakage through the fenestrations of the choriocapillaris is reduced, which results in enhanced definition of larger choroidal vascular channels, the normal choroidal circulation, and CNV.
Fluorescein angiography normally does not demonstrate the choroidal circulation well, because the unbound fluorescein molecule is very small and rapidly leaks from the choriocapillaris,
obscuring the underlying choroidal vessels. Poorly defined or occult CNV appears to be stained by ICG during the late phase of the ICG angiogram. Late leakage from abnormal blood vessels
probably causes fibrous tissue to be stained with ICG.

Another advantage of ICG angiography is its fluorescence in the near-infrared spectrum. The RPE and choroid absorb approximately two thirds of light at 500 nm but only one third of light at
800 nm. Therefore, light at wavelengths in the near infrared are able to penetrate the pigmented layers of the fundus much better than light in the visible spectrum used by fluorescein
angiography. Similarly, near-infrared light is able to penetrate lipid deposits, serous exudate, and hemorrhage better than visible light. [25] [26]

Also, ICG angiography is useful for the detection of occult forms of persistent or recurrent CNV following laser treatment. [27] [28] Fluorescein angiography is considered the ancillary test of
choice for the identification of recurrent CNV. In some cases, however, recurrent CNV may be suspected on clinical examination, yet clear evidence of new vessels may not be ascertained using
fluorescein angiography. In such situations, ICG angiography has proved to be a useful adjunct, because it may delineate hot spots consistent with recurrent, poorly defined CNV. When
recurrent CNV is suspected but not observed on fluorescein angiography, well-defined (and potentially treatable) recurrent CNV can be detected in an additional 15% of cases using ICG
angiography.

Well-defined or classic CNV has a variable appearance on ICG angiography. When the late leakage is associated with a well-defined CNV on fluorescein angiography (type II occult CNV),
ICG angiography may delineate more completely the extent of the lesion. Therefore, in eyes suspected to harbor classic and type II occult CNV, ICG angiography may delineate more
completely both well-defined and ill-defined lesions and serve as a guide for treatment. [29]

Studies of ICG angiography in patients who are affected acutely with central serous chorioretinopathy reveal diffuse hyperfluorescence during the early stage of the angiogram, presumably
caused by hyperpermeability of the choroid ( Fig. 6-8-11 ). RPE detachments are observed more readily on ICG angiography and are characterized as a ring of hyperfluorescence that
surrounds a hypofluorescent spot. Areas of ICG hyperfluorescence can be seen in eyes that have inactive disease or in the inactive or “normal” fellow eye, and they may indicate higher risk of
involvement of the fellow eye not seen with fluorescein. [30]

Fig. 6-8-11 Macular hole. Optical coherence tomography demonstrates a stage 4 macular hole. Vitreous separation is indicated by arrow and arrowheads indicate retinal edema at the cuff of the macular
hole.

For the assessment of choroidal tumors and inflammatory conditions, ICG angiography appears to be of limited value. Idiopathic polypoidal choroidal vasculopathy has a characteristic
appearance on ICG angiography, which is useful for the differentiation of this condition from occult CNV. [31]

Also, choroidal hemangiomas demonstrate a classic appearance of dye “washout” with a hyperfluorescent rim.

PROCEDURE
The technical aspects of the capture of images described herein relate to the use of intravenous doses of 25 mg of ICG. Higher dosages typically result in larger degrees of hyperfluorescence
and thereby change excitation. The ICG dye is dissolved in the manufacturer’s diluent and administered intravenously as a bolus, after which a normal saline flush is given. If both fluorescein and
ICG angiography are performed sequentially, an intravenous catheter may be placed to save the patient from multiple needle sticks.

Excitation illumination should be at a maximum, with a video gain of +6 db. Approximately 10 images are acquired over the initial 30 seconds, starting immediately after injection. The video gain
and excitation illumination levels should not be changed during the transit phase unless image bloom occurs (an increased fluorescence that obscures images). If this happens, the excitation
level is reduced. The best images are retained and, ideally, the transit of ICG through the choroidal vasculature is captured again every 15 seconds. Late images at 5, 10, 15, and 20 minutes
after injection also are obtained. Alteration of the excitation level can be increased during the late phase of the ICG angiogram if signal intensity is reduced. During the very late stages, both
excitation and video gain can be increased; however, a concomitant reduction in detail results.

COMPLICATIONS
ICG has proved to be a safe and well-tolerated dye for diagnostic imaging. Minor adverse reactions are uncommon following ICG injection but include discomfort, nausea, vomiting, and
extravasation of dye. True, life-threatening anaphylactic reactions are very rare but occur in equal incidence following ICG and fluorescein injection (1:1900). Current contraindications to ICG
angiography include prior anaphylactic reaction to ICG dye or contrast agents that contain iodide, liver disease, uremia, and pregnancy. Approximately 5% of current commercial ICG dyes
contain iodide and, therefore, ICG is contraindicated in patients who have iodide allergies.

INTERPRETATION OF RESULTS
Software available with the ICG system enables the user to manipulate the angiographic images. For example, the “trace” function allows areas to be copied from the ICG angiogram and
placed at the precise location on a red-free photograph. This is helpful when ICG angiography is used as a guide for laser photocoagulation.

For the evaluation of occult or obscured forms of CNV, the images obtained are examined for abnormal areas of hyperfluorescence. Comparison of the ICG angiogram is made against the
fluorescein angiogram and slit-lamp biomicroscopy images of the fundus in an attempt to correlate the findings. Although no randomized studies have been carried out to prove the efficacy of
ICG-guided laser treatment, practitioners in general treat focal hot spots that are not subfoveal in location. Hot spots that are associated with serous RPE detachments have a less favorable
prognosis and may not be treated. [32] [33] [34] [35] Therefore, an additional 10–20% of patients who have exudative, age-related macular degeneration may be eligible for laser treatment if ICG
angiography is used, compared with those studied with fluorescein angiography alone.

OPTICAL COHERENCE TOMOGRAPHY

INTRODUCTION
OCT is a method for high-resolution cross-sectional imaging of the retinal layers. This imaging technique is mechanistically similar to ultrasonographic imaging, except that reflected and
backscattered light is used to create the image instead of sound waves. Infrared light (approximately 830 nm) is scanned across the retina and focused with an internal 78 D lens that can be
adjusted for fine focus. A second beam internal to the OCT unit is used as a reference and a signal is formed by measuring the amount the reference beam is altered to match the reflected
beam from the retina. [36] The original OCT machines used a Michaelson interferometer to quantify these differences in reflectivity and create a signal whereby highly reflective tissue is red,
moderately reflective is yellow or green, and low reflectivity is represented by blue. This is known as low-coherence interferometry (time domain detection). [37] More recently, machines that
employ spectral (Fourier) domain detection have been introduced. These machines are able to capture images more quickly and with better resolution than the older time domain systems.

The use of light allows for high resolution. The initial versions of OCT, OCT1 and OCT2, used a series of 100 successive measurements and had a resolution of approximately 10 µm. OCT3
uses 500 axial scans taken in 1 second and has increased the resolution to 7–8 µm. Several recent studies have demonstrated a new ultra-high resolution OCT that allows the evaluation of
retinal pathology at the cellular level. [38] It achieves a resolution of 2–3 µm but is not yet commercially available. Other advantages of OCT include its ease of use and reproducibility. It is
noninvasive, comfortable, and safe for the patient, and can be repeated as often as required. In addition, OCT is able to image through most media opacities including vitreous hemorrhage,
cataract, and silicone oil. However, images cannot be obtained of the retina under gas.

PROCEDURE
The patient is positioned at the OCT and asked to place their chin and forehead in the machine much like a slit lamp. Adjustments can be made to ensure proper height and comfort for the
patient. Mydriasis is preferred but is not absolutely necessary. An infrared image of the patient’s fundus can be seen on the screen and a joystick is used to focus the image and move the
fixation target so the area of interest can be properly scanned. Multiple scanning sequences and programs can be used but the majority involve the acquisition of multiple radial scans.

OCT INTERPRETATION

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The OCT images correspond to the histologic appearance of the retina. The superior reflection on an OCT scan corresponds to the nerve fiber layer and is red representing high reflectivity. An
external red line on the bottom of the OCT scan represents RPE, Bruch’s membrane, and the choriocapillaris. Between these, a thin red line marks the junction of the inner and outer segments.
Inner cellular layers have lower reflectivity and are yellow, green, and blue. The vitreous is typically black as it is not reflective, although the posterior hyaloid face can sometimes be seen ( Fig.
6-8-10 ).

The OCT is exceptionally useful for demonstrating and quantifying retinal and vitreoretinal disorders such as macular hole ( Fig. 6-8-11 ), macular edema ( Fig. 6-8-12 ), and vitreomacular
traction syndrome ( Fig. 6-8-13 ). Further, interpretation of OCT images is relatively straightforward, requiring only knowledge of the underlying histologic architecture.

Fig. 6-8-12 Macular edema. Widespread intraretinal edema (asterisks) is present in this patient with an underlying choroidal neovascular membrane (arrowheads).

Fig. 6-8-13 Vitreomacular traction. An incomplete posterior vitreous separation (arrows) with traction on the fovea (arrowhead) is evident.

Software programs allow for measurement of retinal thickness. A line is drawn at the anterior extent of the internal reflective band and at the posterior extent of the posterior reflective band. By
taking multiple radial scans through the macula a topographic graph of the posterior pole can be created with thickness estimates for nine segments within the macula. It is important to review
the accuracy of the line placement as erroneous readings can be given if the OCT does not recognize the true anterior and posterior extent of the retina.

CONCLUSION
Together OCT, FA, and ICG offer a powerful arsenal for diagnosis of retinal disease. Each has increased our understanding of retinal pathology and guided the development of new treatments.
Continued technological improvements will likely lead to further success in the treatment of retinal disease.

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