Since its first description by Jampol in 1984,1 there is an ongoing debate regarding the exact depth of the white dots in multiple evanescent white dot syndrome (MEWDS) and what retinal layer is primarily involved in the inflammatory process between the photoreceptors, the retinal pigment epithelium (RPE), the choroid, or a combination of all layers.1–4 Although MEWDS and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) have been both classified as “white dot syndromes” or more recently as “primary inflammatory choriocapillaritis,”5 the depth of the lesions and the layer primarily involved in the inflammatory process seem to differ between both entities.
In MEWDS, although a hypoperfusion of the choriocapillaris is usually ruled out, a primary impairment of the photoreceptors or RPE is debated.1,2,6,7 Although recent publications have attempted to give a comprehensive interpretation of the various signs of MEWDS based on multimodal imaging,2,6 the hypofluorescence of the white spots, which appear only in the mid and late phases of the indocyanine green angiography (ICGA) remains partially unexplained.
Conversely in APMPPE, it is well accepted that the white plaques, which are also hypofluorescent in the late phase of the ICGA, are the consequence of a multifocal choriocapillaris occlusion.8,9
The aim of this report was to determine the location of the causal lesion in MEWDS through multimodal imaging comparison between one case of MEWDS and one case of APMPPE.
Case 1: APMPPE
A 35-year old man presented with a vision loss in the right eye (RE) for 3 days. Best-corrected visual acuity was 20/20. Fundus examination of the RE showed 3 whitish plaques in the posterior pole of which one was close to the fovea (Figure 1A). The left eye (LE) also presented several similar plaques.
In the early phase of the fluorescein angiography (FA), the plaques were hypofluorescent and several other foci of hypofluorescence, not seen on color photographs, were present in the posterior pole (Figure 2A). Two of the 3 whitish plaques became slightly hyperfluorescent and the remaining plaque was not stained in the late phase of the FA (Figure 2B). In the early phase of the ICGA, the plaques were hypofluorescent but large choroidal vessels crossing the plaques were seen, indicating that the hypofluorescence was due to a hypoperfusion of the choriocapillaris (Figure 3A). In the late phase of the ICGA, the plaques remained hypofluorescent, even those that did not correspond to a whitish lesion on the color photograph (Figure 3B).
An optical coherence tomography (OCT) B-scan passing through the temporo-foveal plaque showed a disintegration of the interdigitation zone, a loss of visibility of the ellipsoid zone, and a hyper-reflectivity extending through the outer nuclear layer (ONL) and Henle fiber layer (Figure 4A).
Case 2: Multiple Evanescent White Dot Syndrome
A 24-year old woman presented with a vision loss in the RE for 4 days. Best-corrected visual acuity was 20/40. Fundus examination of the RE showed multiple discrete round white spots and dots of various sizes in the posterior pole and beyond the temporal arcades. The term of “spot” was used to characterize the larger lesions, and “dot” for the smaller ones. There was also a typical foveal granularity (Figure 1B). The white spots were silent in both the early and late phases of the FA (Figure 2, C and D). In the early phase of the ICGA, the spots were not visualized. Some small areas of delayed choriocapillaris filling were compatible with the normal filling of the choriocapillaris (Figure 3C). The late stage of the ICGA (30 minutes) was completely different, showing multiple dark spots corresponding to the white spots visible on the fundus color photograph and to additional dots. They were spread over the posterior pole and beyond the temporal arcades and nasal to the optic disk that was surrounded by a hypofluorescent ring. In addition, numerous hypofluorescent spots were present between the dots or overlying the spots (Figure 3D), as noted in a recent publication.6
A horizontal OCT B-scan passing through the foveal center showed multiple areas of attenuation or disruption of the ellipsoid zone, several areas of hyper-reflectivity in the outer part of the ONL corresponding to the hypofluorescent spots on ICGA, a vertical hyper-reflective line crossing the foveal center, and some foci of hyper-reflectivity in the inner part of the ONL corresponding to dark spots (Figure 4, C and D).
In AMPPE, the RPE is damaged by multifocal choriocapillaris closure.8–10 It has also been shown in an animal model that the choriocapillaris closure may cause mild multifocal damage to the RPE.11 The initial hypofluorescence on ICGA and FA was due to the lack of choriocapillaris perfusion. In the late phase, there was some leakage of fluorescein, which is a small diffusible molecule that remains present in the extravascular space and may probably enter in structurally damaged RPE cells.11 Conversely, indocyanine green (ICG) does not stain the ischemic RPE, which could explain why the white plaques remained dark in the late phase of the ICG angiogram. The ischemic RPE damage caused the photoreceptor impairment visible on OCT (ellipsoid zone disruption, hyper-reflectivity, or edema of the ONL). Enhanced depth imaging OCT studies have also demonstrated a lucency10 or hyporeflectivity at the choriocapillaris underlying the placoid lesions in the acute phase of APMPPE, suggestive of obliteration or compression of the smallest choroidal vessels, and corresponding to hypofluorescent plaques on ICGA.
In MEWDS, it is usually accepted that no choriocapillaris perfusion defect is observed. In a recent series (6), no signs of choroidopathy were observed on FA or on ICGA. Unlike APMPPE, there was no hypofluorescence of the spots in the early phase of the FA or ICGA. The analysis of choroidal OCT has found a transient choroidal thickening in the acute phase of MEWDS in some cases but no structural changes have been observed so far at the choriocapillaris.6 Therefore, there could be some degree of inflammation at the choroid in MEWDS, either as a primary or secondary structure contiguous to the RPE. There is also usually no breakdown of the barrier function of the RPE explaining the absence of fluorescein leakage in the late phase. However, some structural damage to the photoreceptors was visible on OCT (ellipsoid zone disruption, hyper-reflectivity in the ONL) and has been reported on adaptive optics12 although less pronounced than in APMPPE. The photoreceptor impairments that cause vision loss, photopsia, and microscotomas, cannot by themselves explain the progressive hypofluorescence of the spots on ICGA, which appeared between 15 to 30 minutes after injection, and for which no satisfactory explanation was provided.
It is known that ICG is rapidly removed from the blood circulation and that its initial concentration in the blood is decreased by approximately 15% after 30 minutes13 to become undetectable on infrared light stimulation. Indocyanine green may remain fixed on proteins in the extravascular choroidal space but on histological specimen, only a faint staining of some large choroidal vessels was still fluorescent on infrared images after 30 minutes as shown in monkey models and in a human eye enucleated for a recurrent melanoma.14 However, the RPE was strongly fluorescent so that the fluorescence of the RPE accounted for most of the fluorescence of the fundus in the late phase of the ICGA.14 Indocyanine green uptake by RPE cells has also been reproduced in vitro,15 although its mechanism remains unknown.
The absence of late ICG fluorescence in both AMPPE and MEWDS is thus better understandable.
In APMPPE, there was no flow in the choriocapillaris beneath the plaques, but we could also assume that if some ICG reached the RPE, the latter was probably unable to internalize the dye. In MEWDS, there is no choroidal ischemic component, which explains that the early phase of both the FA and ICGA was normal. But the more likely hypothesis is that in MEWDS, the RPE is not able to uptake ICG from the choroidal circulation at the spots, which reflects a dysfunction detrimental to the photoreceptors. Although we do not know what are the normal RPE functions that are impaired when ICG cannot enter the RPE cells, they are enough impaired to cause photoreceptor structural changes visible on OCT. However, in some cases of MEWDS, some hyperfluorescent dots in a wreath-like pattern may be seen in the early phase of the FA.2 These dots are usually less numerous and spread than the spots visualized in the late phase of the ICGA. They may correspond to areas of RPE dysfunction with alteration of the outer blood-retinal barrier and infiltration of fluorescein molecules through the damaged RPE.
The specific cause of both MEWDS and APMPPE is unknown. Therefore, the classification of both diseases remains mainly based on their morphological features and multimodal imaging findings. Although it cannot be ruled out that MEWDS could be a photoreceptor disorder with secondary RPE abnormalities, modern multimodal imaging findings rather suggest that MEWDS is a primary epitheliopathy, which seems as a reversible nondestructive RPE dysfunction. On the contrary, APMPPE is a true choroidopathy.
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