Fig. 1.1
Fundus autofluorescence using ultra-wide-field imaging in a patient with vitelliform stage. The lesion is intensively hyperautofluorecent
1.6 Fluorescein and Indocyanine Angiography
The yellowish material in the vitelliform and the pseudohypopyon stages causes blocking effect on fluorescein angiography. Fluorescein angiography also shows hyperfluorescence in the early phase due to transmission defects linked to RPE and chorioretinal atrophy and on the late phase due to material staining.
Indocyanine green angiography can be helpful when choroidal neovascularization is suspected because neovascularization is often difficult to identify on fluorescein angiography. In addition, indocyanine green angiography may show hyperfluorescent spots in the peripheral retina that are not seen on fundus examination and fluorescein angiography [26].
1.7 Optical Coherence Tomography
With the advent of optical coherence tomography (OCT), it has been possible to anatomically investigate, in vivo, the vitelliform lesions. Spectral-domain (SD) OCT findings have been reported in all of the progressive stages of the disease, including the previtelliform stage [20], and proposed that early changes in Best VMD may involve the layer between the RPE and the EZ, first with accumulation of material beneath the sensory retina and then with disruption. The RPE is also affected in the disease course, with hypertrophy, disruption, and attenuation [20].
The previtelliform stage can show a thicker and more reflective appearance of the interdigitation zone (the layer between the RPE and EZ) (Figs. 1.2 and 1.3) [18, 20]. Vitelliform lesions are highly reflective, located between the EZ and the RPE (Figs. 1.3 and 1.4) [18, 20]. Pseudohypopyon lesions are characterized by two different zones: in the upper part of the lesion, the SD-OCT scans show an hyporeflectivity located between the RPE and the EZ, with clumping of hyperreflective material on the posterior retinal surface; in the lower part of the lesion, where the material is still visible, the SD-OCT scan shows the yellowish material that, similarly to the typical vitelliform lesion, appears as a highly reflective area located in the subretinal space (Figs. 1.5 and 1.6) [18, 20]. Vitelliruptive lesions are characterized by an optically empty lesion between the RPE and the EZ, with clumping of hyperreflective material on the posterior retinal surface (similar to the upper part of the pseudohypopyon) (Fig. 1.7) [20]. Furthermore, on some parts, the OCT scan may reveal hyperreflective mottling on the RPE layer (see Fig. 1.7), probably representing areas of focal hypertrophy. Atrophic lesions are characterized by thinning of all the retinal layers and diffuse loss of the EZ within the macular area, with enhanced RPE reflectivity (Fig. 1.8) [20]. Fibrotic lesions are characterized by a prominent, highly hyperreflective thickening at RPE level often associated to hyporeflective spaces part above the hyperreflective lesion (see Fig. 1.8).
Fig. 1.2
Blue fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT) from a patient affected with previtelliform lesion. Blue FAF frame shows no increased macular autofluorescence. SD-OCT scans show a slight thickening of the hyperreflective band located between the hyperreflective photoreceptor inner segment (IS) ellipsoid portion (ellipsoid zone, EZ) and the hyperreflective retinal pigment epithelium (RPE)/Bruch’s membrane complex (Adapted from Querques et al. [18] with the kind permission of Molecular Vision, Department of Ophthalmology, Emory University)
Fig. 1.3
Spectral-domain optical coherence tomography (SD-OCT) images from a normal subject, a patient with the previtelliform stage, and a patient with the vitelliform stage of vitelliform macular dystrophy. (Top left) SD-OCT scan of normal macula. Colour fundus photographs of the right eye of two patients (middle left) Case 1 and (top middle) Case 2 showing no major alterations except for foveal granularity. SD-OCT scans from (bottom left) Case 1 and (bottom middle) Case 2 showing a thicker and more reflective appearance of the interdigitation zone/Verhoeff membrane [VM] (enlarged view, arrowheads) in the central region compared with the normal human macula. (Bottom left) Normal appearance of all major intraretinal layers for Case 1. (Bottom middle) Focal disruption of ellipsoid zone and VM (open arrow) for Case 2. (Top right) Colour fundus photograph of the left eye macula of a third patient showing the typical well-circumscribed yellow lesion, which looks like the yolk of an egg. (Bottom right) SD-OCT scan showing a highly reflective area, located between the hyporeflective outer nuclear layer and the hyperreflective retinal pigment epithelium (RPE) layer. Focal disruption of the ellipsoid zone/interface of inner segment – outer segment (IS/OS) over the lesion and an almost normal appearance of all major intraretinal layers can be detected, although the macular retina is raised by the material, resulting in the partial disappearance of the foveal depression (enlarged view). ELM external limiting membrane (From Querques et al. [20], with the kind permission of Elsevier)
Fig. 1.4
Blue fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT) from a patient affected with vitelliform lesion. Blue FAF frames show a highly autofluorescent macular lesion (left panel, arrowhead). SD-OCT scans show a hyperreflective dome-shaped lesion located in the subretinal space, between the hyperreflective photoreceptor inner segment (IS) ellipsoid portion (ellipsoid zone, EZ) and the hyperreflective retinal pigment epithelium (RPE)/Bruch’s membrane complex (right panel) (Adapted from Querques et al. [18] with the kind permission of Molecular Vision, Department of Ophthalmology, Emory University)
Fig. 1.5
Spectral-domain optical coherence tomography (SD-OCT) scans of a pseudohypopyon-stage vitelliform macular dystrophy patient. Colour fundus photograph (top) of the right eye of a patient showing the yellow material that accumulates inferiorly to form a pseudohypopyon appearance, characterized by two different zones (upper and lower). (Middle) In the upper part of the lesion, SD-OCT scans show a hyporeflective zone with clumping of hyperreflective material on the posterior retinal surface, located between the RPE and the ellipsoid zone/the interface of inner segment – outer segment (IS/OS) of the photoreceptors (corresponding to the interdigitation zone/VM). (Bottom) In the lower part of the lesion, where the material is still visible, the SD-OCT scans show the yellowish material that appears as a highly reflective area located between the hyporeflective outer nuclear layer and the hyperreflective RPE layer, consistent with the vitelliform lesion. A focal disruption of the ellipsoid zone (i.e. the IS/OS) over the lesion (enlarged view), and an almost normal appearance of all major intraretinal layers can be detected in both the upper and the lower part of the lesion (From Querques et al. [20], with the kind permission of Elsevier)
Fig. 1.6
Blue fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT) from a patient affected with pseudohypopyon lesion. Blue FAF frame and SD-OCT scan (top and bottom panels, respectively) show a partial reabsorption of the hyperautofluorescent (arrowhead)/hyperreflective material (asterisk) and replacement by a fluid component (Adapted from Querques et al. [18] with the kind permission of Molecular Vision, Department of Ophthalmology, Emory University)
Fig. 1.7
Spectral-domain optical coherence tomography (SD-OCT) scans obtained from a vitelliruptive stage vitelliform macular dystrophy patient. (Top) Colour fundus photograph of the right eye of a patient showing the vitelliruptive lesion characterized by a scrambled-egg appearance with dispersion of the vitelliform material without any signs of atrophy or fibrosis. (Bottom) SD-OCT scan showing an optically empty lesion between the RPE and the photoreceptor ellipsoid zone (i.e. the IS/OS), comparable with the upper part of the pseudohypopyon, with clumping of hyperreflective material on the posterior retinal surface. In some parts, the SD-OCT scan reveals hyperreflective mottling on the RPE layer. Focal disruption of the ellipsoid zone (i.e. the IS/OS) over the lesion and almost normal appearance of all major intraretinal layers can be observed (From Querques et al. [20], with the kind permission of Elsevier)
Fig. 1.8
Spectral-domain optical coherence tomography (SD-OCT) scans obtained from atrophic and fibrotic stage vitelliform macular dystrophy patients. Colour fundus photographs of the right eye of (top left) a patient and (top right) of another patient showing, respectively, the atrophic lesion, characterized by atrophy with or without residual dispersed material, and the fibrotic lesion, characterized by the appearance of macular fibrosis, without any detectable active choroidal neovascularization. (Bottom left) SD-OCT scans showing the atrophic lesion characterized by thinning of all the retinal layers (enlarged view, thin arrows) and diffuse loss of the ellipsoid zone (i.e. the IS/OS) (enlarged view, open arrows), with enhanced reflectivity of the RPE, which seems to spread far behind it, and still some hyperreflective mottling on the RPE layer (arrowhead) associated with areas of focal RPE loss. (Bottom right) On SD-OCT, the fibrotic lesion is characterized by a prominent highly hyperreflective thickening at RPE level, inducing marked anterior bulging, accompanied by thinning of the sensory retina and diffuse loss of the ellipsoid zone above it (enlarged view, open arrows) (From Querques et al. [20], with the kind permission of Elsevier)
1.8 Multimodal Imaging
Blue FAF and SD-OCT represent noninvasive imaging techniques to monitor Best VMD [5, 18]. The previtelliform lesions are characterized on blue FAF by absence or only slight autofluorescence and on SD-OCT by a slight thickening of the hyperreflective band located between the RPE and EZ (the interdigitation zone). The vitelliform lesion is characterized on blue FAF by a well-circumscribed high autofluorescence within the macula and on SD-OCT by a dome-shaped hyperreflectivity located in the subretinal space. Pseudohypopyon lesions are characterized on blue FAF by a well-circumscribed high autofluorescence within the inferior macula and on SD-OCT by a hyperreflectivity located in the inferior-macula subretinal space; the partial reabsorption of the hyperautofluorescent (FAF) and hyperreflective (SD-OCT) material is replaced by a fluid component, showing no increased fluorescence on FAF or reflectivity on SD-OCT examination and sedimentation of residual material according to the laws of gravity (the hyperautofluorescent [FAF] and hyperreflective [SD-OCT] material located in the inferior macula). Vitelliruptive lesions are characterized by no increased autofluorescence and reflectivity on blue FAF and SD-OCT; however, some residual dispersed autofluorescent material, and clumping of hyperreflective material on the posterior retinal surface, may be detected on FAF and SD-OCT, respectively. Atrophic lesions appear with a decreased autofluorescence on blue FAF and by diffuse loss of photoreceptor and other sensory retina layers on SD-OCT. Fibrotic lesions are characterized by inhomogeneous areas of absolute hypoautofluorescence mixed with hyperautofluorescence (due to some residual dispersed autofluorescent material) on blue FAF and by a prominent, highly hyperreflective thickening at the RPE level.
1.9 Electrophysiology
In Best VMD, a decreased to absent light rise on the EOG is typically observed [27]. However, several studies indicate that the EOG can be sometimes normal in BEST1 mutation carriers [28]. An Arden ratio (light peak/dark trough) of 1.5 or lower is typically the threshold for diagnosis of Best VMD [29, 30], though there have been several cases with Arden ratios >1.5 reported [31, 32]. The low Arden ratio helps differentiating Best VMD from all other bestrophinopathies, other diseases that may present with an apparent vitelliform lesion and all other inherited maculopathies.
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