Chapter 6.8 Yanoff & Duker

Chapter Chapter 6.8 - Fluorescein angiography angiography;; indocyanin indocyaninee green angiography angiography;... ;...

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Yanoff & Duker: Ophthalmology, 3rd ed. Copyright © 2008 Mosby, An Imprint of Elsevier

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

Definition ▪

Fluorescein angiography (FA) is a modality t hat uses intravenous intravenous fluorescein dye to image the retinal and choroidal circulation in evaluating evaluating vascular diseases of the retina including including diabetic retinopathy, choroidal neovascularization, neovascularization, vascular occlusions, cystoid macular edema, and central serous chorioretinopathy.

▪

Indocyanine Indocyanine gre en angiography (ICG) is an infrared-base d imaging technique using using a molecule larger than fluorescein that is mostly protein-bound and highlights the choroidal circulation.

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Optical coherence tomography (OCT) is an imaging system that uses light to measure the diff erences in reflectivity of tissue to produce two-d imensional imensional images that approximate the histologic appearance of the retina.

FLUORESCEIN ANGIOGRAPHY INTRODUCTION The development 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 d iagnose and guide the treatment of the most common retinal diseases encountered in ophthalmology. Recent technological advances advances in digital imaging and computer analysis have further expanded the clinical and research applications of fluorescein angiography. angiography.

PURPOSE OF THE TEST Because the fluorescein molecule is relatively small and typically unbound in the circulation it free ly crosses the walls of small choroidal vessels but remains within retinal vessels and t he large choroidal vessels in normal individuals. individuals. This makes FA primarily a study of t he retinal vasculature; vasculature; however, s ome 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 ser ous chorioretinopathy, and venous venous occlusive disease can be clearly demonstrated w ith FA and the images can be used to guide treatment.

PROPERTIES OF SODIUM FLUORESCEIN DYE The sodium fluorescein molecule molecule has several characteristics that make it ideally suited for ophthalmic imaging. Most important is fluorescence– its a bility 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)) a nd excitation (520–530 nm (yellow-green w avelength)). avelength)). Sodium fluorescein dye usually is available as aliquots of 2–3 mL of 25% or 5 mL of 10% sod ium fluorescein in a sterile aqueous solution. Still no evidence evidence exists of increased side effects w ith 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, albumin, while the remainder re mains unbound. 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 high-quality fundus camera and a photographer that is experienced and familiar with both the photogr aphic system and the posterior segment anatomy. The spherical refractive error of the patient is corrected b y simultaneously simultaneously focusing the cross hairs in the eyepiece r eticle and on the fundus. The focusing focusing wheel is used only for fine focus of the ret inal pathology. The joystick of the fundus camera is used to align the camera to the pat ient’s eye. Proper a lignment lignment results in even illumination illumination of the fundus. Misalignment Misalignment results in peripheral and central defects in the images. These can be ameliorated with caref ul lateral movement of the joystick. Variable amounts of magnification can usually be selected and this should be tailored t o the pathology being examined. examined. The dye is typically injected via the antecubital vein in a rapid but controlled manner to maximize the contrast of the ear ly filling phase of theangiography theangiography.. 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 should begin immediately so initial choroidal and retinal filling can be captured.

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

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

Moderate Ur ticar ia Syncope

Severe

Incidence

Inci Inciden dence ce of 0–5 0–5% % (base (based d on 87% of resp respon onden dents ts)) 1:82 1:337

O ther

1:769

Overall

1:63

Respiratory

1:3800

Cardiac

1:5300

Seizur es

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 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. angiography. [6] [7]

INTERPRETATION OF RESULTS Normal Fluorescein Angiogram After injection into the antecubital vein, vein, dye fir st enters the short posterior ciliary ar teries and is visualized in the choroid and optic nerve head 10–15 seconds later in most normal individuals. individuals. This initial filling filling is dependent on the cardiovascular condition and age of the patient as well as the speed o f injection. The choroidal circulation is seen initially as t he 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 vasculature detail is obscured. A cilioretinal artery is seen simultaneously simultaneously with the fluorescence of the choroidal circulation in 10–15% of patients.

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Chapter 6.8 - Fluorescein angiography; indocyanine green angiography;...

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The retinal circulation begins to fluoresce at 11–18 seconds, 1–3 seconds af ter the onset of choroidal filling. The retinal arterial system should fill completely in about 1 second. The ear ly 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 t hrough the veins in a laminar pattern. During the late arteriovenous phase maximal fluorescence of the ar teries occurs, w ith 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 t he laminar patt ern of venous filling; these include the more r apid flow of plasma along the vessel wall, as we ll as the higher concentration of erythrocytes in the central vascular lumen. Maximal fluorescence is achieved in the juxtafoveal or perifoveal capillary network after 2 0–25 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 bo th 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 Br uch’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 bot h the retinal and choroidal circulations and the complex anatomical relationships between the layers of the ret ina, 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 (a djust 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 t o 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 ret inal 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 bra nch 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 (sector al infarct (we dge-shaped), malignant hypertension, toxemia, lupus choroidopathy, renal disease)

•

atrophy or ab sence 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 f luorescence) or vascular filling defects. Blocked fluorescence can provide clues as t o 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 e lement 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 ret inal 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 art erioles lie in the nerve fiber layer, w hile 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 w ith any of the previously described pathological entities located anterior to t he 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, pa tchy choroidal filling and a consistently darker macular region. Xanthophyll and a high density of RPE (melanin) are r esponsible for blockage o f 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 t he blockage of choroidal fluorescence. Also, lipofuscin deposits block choroidal fluorescence and are see n in fundus flavimaculatus (Stargardt’s disease) and Best’s disease. The most common causes of blocked choroidal fluorescence are subretinal hemorrhage and turbid ser osanguineous fluid beneath a RPE det achment, as seen in choroidal neovascularization (CNV) secondary t o age-r elated macular degeneration. Vascular filling defects produce hypofluorescence because of the r educed or absent p erfusion of tissues. Retinal vascular filling defects can involve large-, medium-, or small-caliber vessels. Central or b ranch retinal artery occlusions show hypofluorescence in the distribution of the ar terial tr ee 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 r etinopathy 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 ret ina. Imaging of the choriocapillaris and other str uctures 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 w ith diffuse involvement of t he 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 d egeneration of the choriocapillaris also is noted in choroideremia. Also, vascular filling defects of the optic nerve head may be noted by f luoresceinangiography. Ischemic optic neuropathy manifests as sector ial or complete op tic disc hypofluorescence, while

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other atrophic or hereditary anomalies of the opt ic nerve head have diffuse hypofluorescence. Congenital anomalies, including optic nerve head colobomas, optic nerve hypoplasia, and opt ic 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 ar ea with a r elative 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 for m 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, arter ial venous malformations, and Coats’ disease, commonly cause hyperfluorescence in the distribution of the vascular pa thology. 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 fluoresceinangiography depending on the vascularity of t he 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 f luorescein dye into the vitreous cavity and often is located adjacent t o 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 b lood 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 pr ofound 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. Of ten, 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 pat tern is important in their differ entiation. 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 ot her 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 t he 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 t o the deposition of f luorescein dye within the involved tissue and occurs in both normal and pathological states. Normal structures, such as the op tic disc and sclera, may stain. Scleral staining is seen more easily in high myopes and patients who have lightly pigmented fundi, because enhancement of tr ansmission occurs through atrophic o r absent RPE. Diseases that result in widespre ad chorioretinal atrophy, such as gyrat e atrophy and ser piginous choroidopathy, demonstrate significant scleral staining. The degree of staining is dependent on the competence of the choriocapillaris, beca use severe atrophy limits the amount of fluorescein that leaks fr om the choroidal vessels. Finally, staining also is se en 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 f undus camera. This was introduced in vivo in 1995 and re searchers have recently been evaluating its p otential use in common retinal diseases including AMD, AMPPE, pseudoxanthoma elasticum, and central serous chorioretinopathy. It relies o n 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 t he 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 t o demonstrate the choroidal vasculature in sufficient detail to make it useful in the evaluation of many pathological processes in the choroid. I CG is a large r molecule than fluorescein and is mostly protein bound. This difference keeps the molecule in the choroidal circulation and makes ICGangiography ideal for det ecting 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 t reatments 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 w ith CNV secondary to AMD, ICG can contribute to the visualization of the pathology and theref ore increase the number of pat ients 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 a lso 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 ar e seen, the optic disk and large vessels are dark and abnormalities, including CNV which may re main hyperfluorescent. Terms specifically related t o 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 pr otein bound. The advantage of being more protein bound is that t he amount of leakage through the fenestrat ions of the choriocapillaris is reduced, w hich results in enhanced definition of larger choroidal vascular channels, the normal choroidal circulation, and CNV. Fluorescein angiography normally does not demonstrate the choroidal cir culation well, because the unbound fluorescein molecule is very small and rapidly leaks fro m 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 s pectrum. The RPE and choroid absorb appr oximately 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 penetrat e the pigmented layers of the fundus much better t han light in the visible spectrum used by fluorescein angiography. Similarly, near-infrared light is able t o penetrate lipid dep osits, serous exudate, and hemorrhage bette r 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 r ecurrent CNV. In some cases, however, recurr ent 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 co nsistent with recurrent, poorly de fined 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 fluoresceinangiography (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 see n 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 differ entiation 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 d issolved in the manufacturer’s diluent and administered intravenously as a bolus, after which a normal saline flush is given. If b oth fluorescein and ICG angiography are perfor med sequentially, an intravenous catheter may be placed to save t he 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, star ting immediately after injection. The video gain and excitation illumination levels should not be changed during the transit phase unless image bloom o ccurs (an increased f luorescence 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 t he excitation level can be increased during the late phase of the I CG 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 b ut occur in equal incidence following ICG and f luorescein 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 ob scured forms of CNV, the images obt ained are examined for abnormal areas of hyperfluorescence. Comparison of the I CG angiogram is made against the fluorescein angiogram and slit-lamp biomicroscopy images of the fundus in an attempt to correlate t he findings. Although no randomized studies have been carried out to prove the ef ficacy 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 w ith those studied with fluorescein angiography alone.

OPTICAL COHERENCE TOMOGRAPHY INTRODUCTION OCT is a method f or high-resolution cross-sectional imaging of t he retinal layers. This imaging technique is mechanistically similar to ultrasonographic imaging, except that r eflected 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 differe nces 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 q uickly and with better r esolution 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 r esolution to 7–8 µm. Several recent studies have demonstrated a new ultra-high resolution OCT that allows the evaluation of retinal pathology at the ce llular 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 r eproducibility. It is noninvasive, comfortable, and safe for the patient, and can be repeate d as oft en 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 t he OCT and asked to place their chin and forehead in the machine much like a slit lamp. Adjustments can be made t o ensure proper height and comfor t for the patient. Mydriasis is p referred 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 fo cus the image and move the fixation target so t he area of interest can be pr operly 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 ar e yellow, gre en, and blue. The vitreous is typically black as it is not reflective, although the posterior hyaloid fac e 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 top ographic graph of t he posterior pole can be created with thickness estimates for nine segments within the macula. It is important t o review the accuracy of t he line placement as erroneous readings can be given if the OCT does not recognize the true anterior and p osterior 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 t o further success in the treatment of retinal disease.

REFERENCES 1.. MacLe an A.L., Maumenee A.E.: Hemangioma of the choroid. Am J Ophthalmol 1960; 50:3-11. 2.. Flocks M. , Miller J., Chao P.: Retinal circulation time with the aid of fundus cinematography. Am J Ophthalmol 1959; 48:3-6. 3.. Novotny H.R., Alvis D.L.: A method of photogr aphing fluorescence in circulating blood in the human retina. Circulation 1961; 24:82-86. 4.. Justice Jr. J., Paton D., Beyrer C.R., Seddon G.G.: Clinical comparison of 10% and 25% intravenous sodium fluorescein solutions. Arch Ophthalmol 1977; 95:2015-2016. 5.. Yannuzzi L.A., Rohrer M.A., Tindel L.J., et al: Fluorescein angiography complication survey. Ophthalmology 1986; 93:611-617. 6.. Halperin L.S., Olk J., Soubrane G., Coscas G.: Safety of fluorescein angiography during pregnancy. Am J Ophthalmol 1990; 109:563-566. 7.. Greenberg F., Lewis R.A.: Safety of fluorescein angiography during pregnancy. Am J Ophthalmol 1990; 110:323-325.[Letter] 8.. Amalric P., Biau C., Fenies M.T.: Incidents et accidents au cours de líangiographie fluoresceinique. Bull Soc Ophtalmol Fr 1968; 68:968-972. 9.. Stein M.R., Parker C.W.: Reactions following intravenous fluorescein. Am J Ophthalmol 1971; 72:861-868. 10.. Levacy R., Justice Jr. J.: Adverse reactions to intravenous fluorescein. Int Ophthalmol Clin 1976; 16:53-61. 11.. Butner R.W., McPherson A.R.: Adverse reactions in intravenous fluorescein angiography. Ann Ophthalmol 1983; 15:1084-1086. 12.. Ma rcus D.F., Bovino J.A., Williams D.: Adverse reactions during intravenous fluoresceinangiography. Arch Ophthalmol 1984; 102:825-833. 13.. Delori F., Ben-Sira I., Trempe C.: Fluorescein angiography with an optimized filter combination. Am J Ophthalmol 1976; 82:559-566. 14.. Gass J.D.M.: Stereoscopic atlas of macular diseases: diagnosis and treatment , 4th ed.. St Louis, Mosby-Year Book, 1997. 15.. In: Gitter K.A., Schatz H., Yannuzzi L.A., McDonald H.R., ed. Laser photocoagulation of retinal disease, San Francisco: Pacific Medical Press; 1988. 16.. In: Justice Jr. J., ed. Ophthalmic photography , Boston: Little Brown; 1982. 17.. Rabb M.F., Burton T.C., Schatz H., Yannuzzi L.A.: Fluorescein angiography of the fundus: a schematic approach to interpretation. Surv Ophthalmol 1978; 22:387-403. 18.. Schatz H.: Flow sheet for the interpretation of the fluorescein angiograms. Arch Ophthalmol 1976; 94:687-694. 19.. Schatz H., Burton T.C., Yannuzzi L.A., Rabb M .F.: Interpretation of fundus fluorescein angiography , St Louis, Mosby-Year Book, 1978. 20.. Flower R.W., Hochheimer B.F.: Clinical infrared absorption angiography of the choroid. Am J Ophthalmol 1972; 73:458-459.[Letter]. 21.. Or th D.H., Patz A., Flower R.W.: Potential clinical applications of indocyanine green choroidal angiography – preliminary report. Eye Ear Nose Throat Mon 1976; 55:15-28. 22.. Destro M.C., Puliafito C.A.: Indocyanine green videoangiography of choroidal neovascularization. Ophthalmology 1989; 96:846-853. 23.. Reichel E.: Choroidal neovascularization associated with age-related macular degeneration. In: Reichel E., Puliafito C.A., ed. Atlas of indocyanine green angiography , New York: IgakuShoin; 1996:12-43. 24.. Guyer D.R., Ya nnuzzi L.A., Slakter J.S., et al: Digital indocyanine green videoangiography of occult choroidal neovascularization. Ophthalmology 1994; 101:1727-1735. 25.. Cohen S.M., Shen J.H., Smiddy W.E.: Laser energy a nd dye fluorescence transmission through blood in vitro. Am J Ophthalmol 1995; 119:452-457. 26.. Reichel E., Duker J.S., Puliafito C.A.: Indocyanine green angiography and choroidal neovascularization obscured by hemorrhage. Ophthalmology 1995; 102:1871-1876. 27.. Sorenson J.A., Y annuzzi L.A., Slakter J.S., et al: A pilot study of digital indocyanine green videoangiography for re current occult choroidal neovascularization in age-related macular degeneration. Arch Ophthalmol 1994; 112:473-484. 28.. Reichel E., Pollock D., Duker J.S., et al: Indocyanine green angiography in the detection of marginal persistence and recurrence o f choroidal neovascularization. Ophthalmic Surg 1995; 26:513-518. 29.. Avvad F.K., Duker J.S., Reichel E., et al: The digital indocyanine green videoangiography characteristics of well-def ined choroidal neovascularization. Ophthalmology 1995; 102:401-405. 30.. Guyer D. R., Yannuzzi L.A., Slakter J.S., et al: Digital indocyanine green videoangiography of central ser ous chorioretinopathy. Arch Ophthalmol 1994; 112:1057-1062. 31.. Spaide R.F., Yannuzzi L.A., Slakter J.S., et al: Indocyanine green videoangiography of idiopathic polypoidal choroidal vasculopathy. Retina 1995; 15:100-110. 32.. Slakter J.S., Yannuzzi L.A., Sorenson J.A., et al: A pilot study of indocyanine green videoangiography-guided laser photocoagulation of occult choroidal neovascularization in age-related macular degeneration. Arch Ophthalmol 1994; 112:465-472. 33.. Regillo C.D., Benson W.E., Maguire J.I., et al: Indocyanine green angiography and occult choroidal neovascularization. Ophthalmology 1994; 101:280-288. 34.. Lim J.I., Sternberg P.S., Capone Jr. A., et al: Selective use of indocyanine green angiography for occult choroidal neovascularization. Am J Ophthalmol 1995; 120:75-82. 35.. Baumal C., Reichel E., Duker J.S., et al: I ndocyanine green hyperfluorescence associated w ith serous retinal pigment epithelial detachment in age-related macular degeneration. Ophthalmology 1997; 104:761-769. 36.. Boppart S.A., Bouma B.E., Pitris C., et al: In vivo cellular optical co herence tomography imaging. Nat Med 1998; 4:861-865. 37.. Hee M.R., Huang D., Swa nson E.A., Fujimoto J.G. : Polarization sensitive low-coherence reflectomete r for birefringence characterization and ranging. J Opt Soc Am B Opt Phys. 1992; 9:903-908. 38.. Gloesmann M., Hermann B., Schubert C., et al: Histologic correlation of pig r etina radial strat ification with ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci. 2003; 44:1696–703

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Chapter 6.8 Yanoff & Duker

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