Ординатура / Офтальмология / Английские материалы / Atlas of Fundus Autofluorescence Imaging_Holz, Schmitz-Valckenberg, Spaide, Bird_2007
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changes, it may be impossible to obtain an image with sufficient quality to allow for a reasonable interpretation of the FAF findings (see Chap. 4, Fig. 4.4).
In essence, abnormal FAF signals either derive from a change in the number or composition of fluorophores in the RPE cell cytoplasm (i.e., lipofuscin) or from the presence of absorbing or autofluorescent material anterior to the RPE monolayer (Figs. 8.2 and 8.3). In addition, abnormal tissue with fluorophores with spectral characteristics similar to RPE-lipofuscin at the level of the choroid may cause a corres ponding increased FAF signal (Fig. 8.4).
As outlined in the previous chapters and demonstrated in the clinical part of this book, it must be noted that FAF imaging provides information over and above conventional imaging techniques. Therefore, the identification of a pathological change on funduscopy such as drusen under the RPE may not give a clue as to the associated autofluorescence characteristics of these changes. For example, the FAF signal may be normal, decreased, or increased, depending on the molecular composition of the drusen material (more or fewer fluorophores) and the corresponding alteration of the overlying RPE (more or less flattening and reduction in lipofuscin granule density; see Chap. 11). While drusen in association with monogenetic juvenile macular dystrophies tend to be associated with an increased FAF signal, this is usually not the case for drusen in the context of complex, multifactorial age-related macular degeneration.
For the evaluation and interpretation of a FAF image in a individual patient, it may be helpful to correlate the findings with those obtained with reflectance images of the same excitation wavelength and other imaging methods, including fundus photo graphs, optical coherence tomography, and fluorescein angiography.
Below are the major causes and pathophysiologic categories for increased or reduced FAF signals.
Causes for a reduced FAF signal:
Reduction in RPE lipofuscin density
•RPE atrophy (such as geographic atrophy)
•Hereditary retinal dystrophies (such as RPE65 mutations)
Increased RPE melanin content
•e.g., RPE hypertrophy
Absorption from extracellular material/cells/fluid anterior to the RPE
•Intraretinal fluid (such as macular edema)
•Migrated melanin-containing cells
•Crystalline drusen or other crystal-like deposits
•Fresh intraretinal and subretinal hemorrhages
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•Fibrosis, scar tissue, borders of laser scars
•Retinal vessels
•Luteal pigment (lutein and zeaxanthin)
•Media opacities (vitreous, lens, anterior chamber, cornea)
Causes for an increased FAF signal:
Excessive RPE lipofuscin accumulation
•Lipofuscinopathies, including Stargardt disease, Best disease, pattern dystrophy, and adult vitelliform macular dystrophy
•Age-related macular degeneration, such as RPE in the junctional zone preceding enlargement of occurrence of geographic atrophy
Occurrence of fluorophores anterior or posterior to the RPE cell monolayer
•Intraretinal fluid (such as macular edema)
•Subpigment epithelial fluid in pigment epithelial detachments
•Drusen in the subpigment epithelial space
•Migrated RPE cells or macrophages containing lipofuscin or melanolipofuscin (seen as pigment clumping or hyperpigmentation on funduscopy)
•Older intraretinal and subretinal hemorrhages
•Choroidal vessel in the presence of RPE and choriocapillaris atrophy, such as in the center of laser scars or within patches of RPE atrophy
•Choroidal nevi and melanoma
Lack of absorbing material
•Depletion of luteal pigment, such as in idiopathic macular telangiectasia type 2
•Displacement of luteal pigment, such as in cystoid macular edema
Optic nerve head drusen
Artefacts
Acknowledgements
The authors thank Adnan Tufail and Andrew R. Webster at Moorfields Eye Hospital for their help in the collection of images.
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Fig. 8.1 Top row: Normal fundus autofluorescence (FAF) images obtained with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph). The FAF image shows the spatial distribution of the intensity of the FAF signal for each pixel in gray values. By definition, low pixel values (dark) illustrate low intensities, and high pixel values (bright) illustrate high intensities. In the normal subject, dark-appearing retinal vessels due to absorption from blood contents, a dark optic nerve head due to absence of autofluorescent material, and an increased signal in the macular area secondary to absorption from luteal pigment (lutein and zeaxanthin) can be observed. The relative distribution of FAF inten sities can also be illustrated in pseudo-three-dimensional reconstruction techniques (right). Areas with low FAF intensities are shown in blue and can be distinguished from the normal background signal (red). Middle row: Modern imaging systems allow visualization of more details (in the presence of clear media and optimal patient cooperation) and the ability to image even larger retinal areas with up to a 55° field. Note the interindividual differences in macula pigment absorption between these examples from normal subjects.
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Fig. 8.1 (Continued) Bottom row: Confocal scanning laser microscope image of the polygonal retinal pigment epithelium cell monolayer (left) and schematic drawing (right) showing a predominant location of lipofuscin granules (red) at the peripheral cell margin, while absorbing melanin granules are oriented toward the apical cell center and the cell nucleus at the basal side
Fig. 8.2 Top row: Example of increased fundus autofluorescence (FAF) signals (right) corresponding to funduscopically visible (left) yellowish lesions in a patient with Stargardt disease. Middle row: Example of increased FAF signal corresponding to funduscopically visible yellowish and in part hyperpigmented, reticular lesions in a patient with pattern dystrophy. Bottom row: Example of increased FAF image signal corresponding to macular edema in the presence of diabetic maculopathy. Exudates and hemorrhages are characterized by low FAF levels due to absorption phenomena. Additional areas with decreased intensity can be observed and appear to be normal on fundus photography
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Fig. 8.3 Example of decreased fundus autofluorescence
(FAF) corresponding to retinal pigment epithelium atrophy and crystalline drusen in a patient with geographic atrophy secondary to age-related macular degeneration. Levels of increased FAF can be observed surrounding the atrophy as retinal areas with excessive lipofuscin accumulation. For comparison, near-infrared reflect ance (lower left) and blue-light reflectance (lower right) are illustrated as well. Note also prominent reticular drusen outside atropic patches (see chapter 11.4)
Fig. 8.4 Example of marked ey decreased fundus autofluorescence (FAF) intensity over the whole posterior pole in the presence of severe retinal pigment epithelium (RPE) atrophy in a patient with Usher syndrome. Underlying choroidal vessels that are usually obscured by the RPE can now be observed on FAF imaging by levels of increased FAF. Note that optic disc drusen are present, showing increased FAF. For comparison, near-infrared reflect ance (lower left) and blue-light reflectance (lower right) are illustrated as well
Part II
Clinical Application
Macular and Retinal Dystrophies |
9 |
Andrea von Rückmann, Fredrick W. Fitzke, |
Steffen Schmitz-Valckenberg, Andrew R. Webster, Alan C. Bird
It is well established that autofluorescent material accumulates in the retinal pigment epithelium (RPE) in many macular and retinal dystrophies and that the extracellular deposits may also fluoresce. However, until recently information has been limited because observations have been made as a result of histological studies alone. It is unknown whether variance in fundus autofluorescence (FAF) is consistent from one condition to another, and the time course of the accumulation of autofluorescent material has not been documented. Given that many disorders are involved that are presumed to have different underlying defects, some variation might be expected from one condition to another. It is evident that in-vivo recording of RPE autofluorescence would allow many more observations to be made and that recording lipofuscin accumulation may give important clues as to the pathogenesis and progress of a number of retinal diseases.
Various alterations of the normal distribution of FAF intensities have been described in macular and retinal dystrophies. Funduscopically visible pale yellowish deposits at the level of the RPE/Bruch’s membrane in Best disease, adult vitelliform macular dystrophy, and Stargardt macular dystrophy/fundus flavimaculatus are spatially confined to markedly increased FAF intensities [4, 25]. Focal flecks in Stargardt disease are much more clearly delineated on FAF images compared with fundus photographs. They show a bright FAF signal that may fade as atrophy develops. These findings are in accordance with histopathological data that have shown that these flecks represent aggregates of enlarged RPE cells engorged to 10 times their normal size with lipofuscin [6, 13, 24]. In a clinical study, including electrophysiological tests, of 43 patients with Stargardt disease, Lois and coworkers demonstrated a functional correlate of FAF abnormalities [9, 10]. They showed that low levels of FAF intensity in the fovea were associated with peripheral cone and rod dysfunction, whereas no functional abnormalities in patients with normal or high FAF signal could be measured (see Chap. 10). As in all forms of macular dystrophies examined systematically to date, background autofluorescence in Stargardt disease appears to be elevated, implying a generalised abnormality of the RPE [25]. This observation confirms the impression derived from histological studies that inherited macular dystrophies affect the entire RPE.
Using FAF imaging, there is no correlation with the fluorescein angiographic sign of a dark choroid. Lorenz and colleagues described absent or minimal FAF inten sities in patients with early-onset severe retinal dystrophy associated with mutations on both allelels of RPE65 (see Fig. 9.9) [11]. The lack or severe decrease of FAF sig-
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nal would be consistent with the biochemical defect and could be used as a clinical marker of this genotype. Another study demonstrated that patients with Leber’s congenital amaurosis having vision reduced to light perception and undetectable electroretinograms may still exhibit normal or minimally decreased FAF intensities [22]. This suggests that the RPE/photoreceptor complex is, at least in part, functionally and anatomically intact. This finding would have implications for future treatment, indicating that photoreceptor function may still be rescuable in such patients.
In patients with vitelliform macular dystrophies, FAF patterns have been described as spokelike, diffuse, or a combination of the two [2, 23]. It has been speculated that these areas with increased FAF do not represent lipofuscin accumulation at the level of the RPE but rather shed photoreceptor outer segments associated with sub-reti- nal fluid.
FAF imaging may show abnormal distributions of intensities in subjects with mutations known to cause macular and retinal dystrophy but with no manifest ophthalmoscopic or functional abnormalities. This means that this technique allows detection of the abnormal phenotype in some disorders when it is not otherwise evident. In Figs. 9.1–9.18, FAF findings in different macular and retinal dystrophy are illustrated.
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Fig. 9.1 Stargardt macular dystrophy/fundus flavimaculatus, early stage. Fundus photographs and fundus autofluorescence (FAF) images (30° and montage) of a 27-year-old woman with 6/60 visual acuities in both eyes. In early stages, FAF imaging typically shows a central oval area of reduced signal surrounded by small disseminated spots of reduced and increased intensity [10, 28]. Central retinal pigment epithelium (RPE) atrophy is also present, showing very decreased FAF intensity. At the periphery, fundus photographs show well-defined yellowish deposit at the level of the RPE. These flecks correspond to punctate spots with bright FAF signal. They can be better delineated and their number appear to be greater on the FAF images. The montage images demonstrate that the spots with markedly increased signal are scattered over the whole fundus