Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

Side Effects

Transient nausea and occasional vomiting 30 to 60 seconds after administration are the most common reactions, experienced in fewer than 5% of patients. Moderate adverse reactions, occurring in fewer than 1% of patients, include thrombophlebitis,nervepalsy,temperatureelevation, and localized tissue necrosis. There is a very low incidence of severe potentially lifethreatening reactions such as laryngeal edema, bronchospasm, anaphylaxis, circulatory shock, and myocardial infarction. Yannuzzi et al have reported a single death among 220,000 fluorescein angiography studies surveyed.

The Different Phases of Fluorescein

Studies

Fluorescein angiography documents both the static functional anatomy and the fluid dynamics of the eye. When the interpretation is being made, it is important to review the proper sequence of phases.

Fluorescein studies are typically divided into four phases: pre-filling, transit, recirculation, and late.

1)The pre-filling or pre-arterial phase occurs after administration but before fluorescein dye enters the circulation of the eye. Angiograms taken during the pre-filling phase are useful controls to establish background levels of pseudofluorescence or autofluorescence that might otherwise lead to interpretation errors.

2)The transit phase corresponds to the first complete passage of fluorescein through the choroidal and retinal vasculature, and occurs within about 30 seconds of dye injection. Following perfusion of the choroid and choriocapillaris, there are three functional subdivisions of the transit phase: the arterial phase, which corresponds to complete arterial filling, the capillary (and arteriovenous) phase, which

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culminates in the first evidence of laminar venous flow, and the venous filling (or laminar) phase, which occurs as the veins completely fill and the arteries begin to empty of dye.

3)The recirculation phase corresponds to the first return of fluorescein bearing blood to the eye after its passage through the general circulation, and is complete about 3 minutes into the study. Recirculation fluorescence is considerably dimmer than transit fluorescence. Early staining or leakage is generally noted during this stage of the study.

4)The late (or elimination) phase represents the complete removal of fluorescein dye from the circulation, leaving only spots of residual leakage and late staining. For all practical purposes, elimination is virtually complete 30 minutes after administration.

Normal Angiographic Pattern

Sequence of Events

The interpretation of any angiogram, whether normal or abnormal, requires the evaluation of each anatomic component of the posterior portion of the eye; the choroid, retina, disc, and macula. Each component must be evaluated at specified time intervals. It is helpful to analyze an angiogram with respect to the pathologic lesions that may be seen at different stages and in different locations.

The illustrations shown in Figures 1A, 2A, 3, 4, 5A, 6A, 7A, and 10A. are special creations by Jaypee-Highlights to show the function of the retinal vasculature through fluorescein studies during different stages of the circulation. The figures on the right side of each of these illustrations are actual fluorescein angiography photos that reveal the appearance of each of those stages during angiography.

Afterfluoresceinisinjectedintotheantecubital vein, the time it takes to reach the eye depends upon the patient’s arm-to-retina circulation time. This is typically 12 to 15 seconds. However it can range from 5 to 30 seconds, depending upon cardiac output, viscosity of the blood, and the caliber of the blood vessels. Circulation time will increase with the presence of any disease that affects the myocardium and great vessels, causing congestion in the pulmonary and systemic circulation or obstruction in the vascular system.

During the pre-arterial or pre-filling phase, fluorescein enters the choroidal vasculature through the posterior ciliary arteries. In a very lightly pigmented fundus, filling of large choroidal arterioles may be faintly perceived (Figures 1A and 1B) although in general the first discernible presence of fluorescein is the patchy background corresponding to perfusion or early filling of the choriocapillaris (Figures 2A and 2B).

Even in normal patients, the filling pattern of the choriocapillaris is patchy and variable. In most studies, details of the choriocapillaris are not discernible, and only a “choroidal flush”

Figure 1-A: Early Filling of Large and Medium Sized Choroidal Arterioles. This series of illustrations shows the retina (R) and choroid (C) in cross section during fluorescein angiography, along with its corresponding magnified fundus appearance at each stage above at

(A). First, there is early filling of large (L) and medium sized (M) choroidal arterioles with fluorescein (green) as seen in the fundus and cross section views. The fluorescein has not reached the level of the choriocapillaris

(Y) at this stage . Note early filling of a retinal vessel

(V) located within the nerve fiber layer (N) of the retina.

(Art from Jaypee-Highlights Medical Publishers Inc.).

Figure 1-B: Early Filling of Large and Medium Sized Choroidal Arterioles with Fluorescein. Earliest phase of the fluorescein study. (Photograph presented as a courtesy of William Tasman from his classic book “Clinical Decisions in Medical Retinal Disease”, Chapter 1 by Jay Federman, M.D., published by Mosby, Inc., 1994.)

Figure 2-A: Early Filling of the Choriocapillaris. Shown is early filling of the choriocapillaris (Y) with fluorescein (green). As seen in the fundus view, the fluorescein flows in a patchy manner (black arrow) from the efferent side of the circulation. Some is beginning to leak into the extravascular space (white arrow) near Bruch’s membrane (BR).(Art from Jaypee-Highlights Medical Publishers Inc.).

Figure 2-B: Early Filling of the Choriocapillaris with Fluorescein. Medium-sized and smaller arterioles are seen leading to patches of fluorescein filled choriocapillaris. (Photograph presented as a courtesy of William Tasman from his classic book “Clinical Decisions in Medical Retinal Disease”, Chapter 1 by Jay Federman, M.D., published by Mosby, Inc., 1994.)‘

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will appear on the angiogram. Shortly after filling of the choriocapillaris, the first appearance of fluorescein in the arteries signifies the beginning in transit of the arterial phase, which extends until the arteries are completely filled.

Because of the capillary fenestrations in the choriocapillaris, intravascular choroidal fluorescein rapidly leaks into the extravascular space (Figure 2A), beginning at the inner choroidal layers directly below Bruch’s membrane (Figure 3).

Fluorescein diffuses throughout the inner choroidal layers, rapidly reaching equilibrium between the intravascular and extravacular compartments and including the inner scleral

Figure 3: Complete Filling of the Choriocapillaris. Next follows complete filling of the choriocapillaris (Y) with fluorescein (green). The fluorescein has now begun to leak into the extravascular choroidal stroma. An extravascular flush appears in Bruch’s membrane (BR) and the extravascular inner choroidal layers (arrow). There is filling of additional retinal vessels (V) located within the nerve fiber layer of the retina. Note the appearance of the complete filling of the choriocapillaris in the fundus view above.(Art from Jaypee-Highlights Medical Publishers Inc.).

fibers (Figure 4). During the somewhat later venous filling phase of the study extravascular fluorescein begins to appear, to a lesser extent, in the stroma of the outer choroid (Figure 4).

As the study progresses, the process of choroidal perfusion is reversed. The combined result of dye leakage, elimination, and distribution through the entire blood volume is that the intravascular fluorescein concentration quickly drops below the extravascular concentration.

Beginning in the inner choroidal layers, the medium-sized choroidal vessels are darkly silhouettedagainstthestillfluorescentextravascular background (Figure 5A-B).

The recirculation phase of the angiogram follows the transit phase and represents the first return of blood containing fluorescein (a small amount) to the eye. This occurs after the blood has passed through the kidneys.

Figure 5A: Visualization of Medium-sized Choroidal Vessels. As fluorescein re-circulates and is diluted through the entire blood volume, the intravascular choroidal concentration (black arrow) drops below the extravascular concentration (white arrow). The concentration in the outer choroidal extravascular space (green arrow) is the same as within the entire choroidal intravascular space (black arrow). Since the concentration is greater in the inner choroidal layers, medium-sized vessels (M) within the inner and middle choroid, as seen in the fundus view, can be visualized during the early phases of the study. Note that these medium-sized choroidal vessels stand out in dark relief against the more concentrated dye in the extravascular inner choroidal space. (Art from Jaypee-Highlights Medical Publishers Inc.).

Figure 5B:(Photograph presented as a courtesy of William Tasman from his classic book “Clinical Decisions in Medical Retinal Disease”, Chapter 1 by Jay Federman, M.D., published by Mosby. Inc. 1994).

As observed over time, fluorescein leaks back into the choroidal vessels from, successively, the choriocapillaris, outer choroid, and inner scleral layers. During the later stages of this process the extravascular fluorescein concentration is greater in the outer choroid than in the inner choroid, and large choroidal vessels stand out in dark relief (Figures 6A-B) The fluorescence in the recirculation phase is very dim in contrast to that of the transit phase in which the dye in the blood is in much higher concentration.

The zonula occludens of the retinal pigment epithelium prevents diffusion or transport of fluorescein directly from the choroid to the outer retinal layers. Approximately 1 second after the choroidal flush, fluorescence is perceived in the central column of large arterioles, and rapidly increases in intensity, filling the arterioles completely.

Fluorescein next crosses the capillary network, revealing fine details of its structure in the perifoveal region where background choroidal fluorescence is masked by the densely pigmented RPE.

Figure 6-A: Visualization of Large Choroidal Vessels. As the recirculation phase progresses, fluorescein concentrations in the inner and outer choroid become equal (not shown). In the later and elimination phases, the extravascular concentration in the inner choroid (white arrow) continues to drop below that in the more slowly purged outer choroid layers (green arrow). Large vessels (L) in the outer choroid layers are surrounded by extravascular regions with much higher fluorescein concentration (green arrow). These large vessels

(L) can be visualized in dark relief as seen in the fundus view above. Note that the retinal vessels (V) within the nerve fiber layer of the retina have now been purged of dye, and also appear in dark relief against the light background of the remaining dye within the outer choroid. (Art from Jaypee-Highlights Medical Publishers Inc.).

Figure 6B: Visualization of large choroidal vessels. Large vessels in the outer choroid layers stand out in dark relief against the more concentrated extravascular fluorescein. (Photograph presented as a courtesy of William Tasman from his classic book “Clinical Decisions in Medical Retinal Disease”, Chapter 1 by Jay Federman, M.D., published by Mosby, Inc., 1994.)

Abnormal vessels that may be supplied by the choroidal system, such as neovascularization of the disc in diabetic retinopathy and subretinal neovascularization in senile macular degenerationandocularhistoplasmosissyndrome, often fill before the normal retinal vessels.

ABNORMAL ANGIOGRAPHIC

PATTERNS

Hyperfluorescence and Hypofluorescence

Abnormal fluorescein angiographic patterns result from disruption of the normal functional relationships between the various structures in the eye. The terms “hyperfluorescence” and “hypofluorescence” are the key abnormalities. They refer to departures from the normal pattern of fluorescence in the eye. They may relate to various ocular pathologies.

Hyperfluorescence may correspond to: 1) the presence of fluorescein in a location where it is not normally found as shown

in Figs. 7AB, 8, 9.

2)an abnormally high concentration of fluorescein in an appropriate location, and/or

3)abnormal visibility of a normal dye distribution and concentration because of defects in overlying structures that would ordinarily obscure it such as the RPE.

Hypofluorescence may be caused by:

1)the complete absence of fluorescein in a location where it is normally found,

2)an abnormally low concentration of fluorescein in some region, and/or

3)the abnormally obstructed visibility of light from normal dye distribution and concentration because of overlying pathology.

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Figure 7A: Hyperfluorescence of a Retinal Pigment Epithelium Detachment. An example of hyperfluorescence

(H) seen in the fundus view is due to accumulation of dye in an abnormal location (arrow), in this particular case, a localized serous detachment of the retinal pigment epithelium (P). Retina (R), choriocapillaris (Y) and large choroidal vessels (L).(Art from Jaypee-Highlights Medical Publishers Inc.).

Figure 7B: Hyperfluorescence in a patient with retinal pigment epithelium detachment. This localized area or hyperfluorescence has resulted from an accumulation or dye under the RPE. (Photograph presented as a courtesy of William Tasman from his classic book “Clinical Decisions in Medical Retinal Disease”, Chapter 1 by Jay Federman, M.D., published by Mosby, Inc.,1994).

Hyperfluorescence

An excellent example of hyperfluorescence caused by the accumulation of dye in an abnormal location is found in focal detachment of the retinal pigment epithelium (Figures 7A-B). Dye-containing fluid that accumulates between the RPE and Bruch’s membrane in the region of the serous detachment of the RPE produces a hyperfluorescent patch with sharp and abrupt borders (Figure 7B).

Fluorescein angiography, is useful to exclude disorders such as hemorrhage under the

retinal pigment epithelium or retina. Fluorescein angiography may provide useful information in the evaluation of malignant melanomas which include early mottled or patchy hyperfluorescence (Figure 8) and discrete pinpoint leakage (Figure 9).

Solidtumorssuchaschoroidalmelanomas or metastatic lesions show hyperfluorescence causedbyelevatedfluoresceindyeconcentrations in the uveal stroma near the tumor site (Figures 8 and 9). The increased vascularity of these tumors results in early-phase hyperfluorescence of vessels. Fluorescein then leaks into the extravascular space. Choroidal hemangiomas

Figure 8: Patchy Hyperfluorescence from Malignant Melanoma. A 67 year old female was found to have a pigmented tumor in her left eye. Her visual acuity was reduced to 20/60 due to a macular pucker. The tumor measured 11 mm in diameter and was 2.4 mm thick. On fluorescein angiography, the tumor showed a mottled and patchy hyperfluorescence. (Photo courtesy of Robert Johnson, M.D.)

Figure 9: Hyperfluorescence with Pinpoint Leakage in Malignant Melanoma. A 79 year old female noted blurred vision in her left eye. The visual acuity measured 20/50 due to diabetic retinopathy. A 12 mm diameter pigmented choroidal mass was found. The maximal thickness measured 5.9 mm. Note the hyperfluorescence over the tumor with several punctate areas of hyperfluorescence. (Photo courtesy of Robert Johnson, M.D.)

The absence of fluorescein in a location where it is normally found may be attributable to either a lack of perfusion or the absence of tissue itself. In patients with a coloboma there is early-phase hypofluorescence because the choriocapillaris is missing. Only the large vessels of the choroidal vasculature fluoresce and are clearly visible without the obstruction of an overlying RPE.

Hypofluorescence is also caused by blocked transmission of choroidal fluorescence. This may occurs when fluid, exudates, hemorrhage, pigment, scar, inflammatory material, etc. accumulates in front of the choroidal vasculature and deep to the retinal vasculature.

A hemorrhagic detachment of the RPE produces a corresponding region of hypofluorescence (Figures 10A-B). A choroidal nevus is hypofluorescent, presumably because the crowded pigmented cells of the nevus displace and block fluorescein dye.

Another cause of abnormal hypofluorescence is attributable to vascular filling defects. With blocked fluorescence, the fluorescein is present in the circulations of the fundus, but is not visible because a tissue or fluid barrier

Figure 10A: Hypofluorescence of a Hemorrhagic Detachment of the RPE. Shown is hypofluorescence in a patient with hemorrhage (H) under the retinal pigment epithelium (P). There is normal fluorescein perfusion of the intravascular (black arrows) and extravascular (white and green arrow) choroidal spaces, but transmission is blocked (B), as seen in the fundus view, by an overlying hemorrhagic RPE detachment (P,H). Retina (R).(Art from Jaypee-Highlights Medical Publishers Inc.).

Figure 10B: Hypofluorescence in a Patient with Hemorrhage Under the Retinal Pigment Epithelium. The corresponding hypofluorescent area is due to blockage or obscuration of the normal choroidal fluorescence by

Disease”, Chapter 1 by Jay Federman, M.D., published by Mosby, Inc., 1994).

conceals it. With a vascular filling defect, fluorescein can not be seen because it is not present. Since fluorescein reaches the retina and choroid by way of vessels, lack of the fluorescein dye in either vascular system indicates an obstructive problem.

Choroidal Vascular Filling Defect

The normal choroidal vasculature is usually difficult to document with fluorescein angiography because of the pigment epithelial barrier. When choroidal vascular filling defects exist, the pigment epithelium is often secondarily depigmented or atrophied. In these cases the hypofluorescence caused by the vascular filling abnormality of the choroid and choriocapillaris can be documented angiographically.

When choroidal vessels do not fill, dark patches of hypofluorescence beneath the retina appear early in the angiogram. The distribution and morphology of the hypofluorescence vary according to the disease process. Because the choroidal circulation is completely separate from the retinal circulation, choroidal vascular filling defects do not correlate with the retinal vascular distribution.

ANGIOGRAPHIC INTERPRETATION

OF MOST IMPORTANT

PATHOLOGICAL CONDITIONS

Diabetic Retinopathy

Non-Proliferative Diabetic Retinopathy

In non-proliferative (background) retinopathy, the very earliest sign that can

be detected by fluorescein angiography is the dilatation of the retinal veins. It also can be seen that the walls of the veins are damaged in the areas showing staining with fluorescein dye. Subsequent changes are the appearance ofmicroaneurysms,hemorrhagesandexudates. As the number of microaneurysms increases, many of the retinal capillaries lose their pericytes and endothelial cells, and become nonfunctional. These areas of nonfunctional capillaries are demonstrated angiographically to be non-perfused. If an area of non-perfu- sion becomes quite large, it may appear as cotton-wool spots.

Pre-Proliferative Diabetic Retinopathy

Between non-proliferative and proliferative retinopathy, there is a pattern of retinal changes that has been called preproliferative diabetic retinopathy. These changes such as soft exudates (cotton-wool spots), venous abnormalities and intraretinal microvascular abnormalities (IRMA), can be well demonstrated by angiography as a flat network of tortuous capillaries that do not follow the normal capillary network and do leak (Figure 11)

Proliferative Diabetic Retinopathy

The appearance of new vessel formation either on the disc or elsewhere in the retina signals a proliferative diabetic retinopathy. It can be shown by angiography in many eyes in whom neovascularization is present on the disc. The new vessel formation on the disc fills with fluorescein before most of the retinal vessels. New vessels elsewhere in the retina appear to fill with the arterial phase of the angiogram. In the late stages of the