Photoreceptor Integrity in MEWDS: Longitudinal Structure-Function Correlations

Abstract

Purpose: The purpose of this study was to investigate structure-function correlations in multiple evanescent white dot syndrome (MEWDS) using microperimetry (MP) and spectral-domain optical coherence tomography (SD-OCT).

Methods: Single-center prospective observational study including 14 eyes from 13 patients with MEWDS monitored over a median of 49.5 days (interquartile range = 29-92 days). Investigations focused on best-corrected visual acuity (BCVA), foveal granularity, and the Photoreceptor Reflectivity Ratio (PRR) as a measure of photoreceptor integrity. MP assessed average retinal threshold sensitivity (RTS) and bivariate contour ellipse area (BCEA) for fixation stability. A linear mixed model was used to test associations and interactions among RTS, time, and clinical variables. A hierarchical linear mixed model was used to analyze structure-function relationships, addressing both individual and location-specific variations.

Results: Overall, 2340 MP locations were tested. PRR revealed a transient decrease within 30 days post-presentation, indicative of early photoreceptor disruption, followed by a progressive increase, signaling recovery. Significantly lower foveal sensitivity (RTS = 14.8 ± 7.4 vs. 22.5 ± 4.4 decibel [dB], P = 0.04) and increased fixation spread (63% BCEA = 1.26 ± 0.97 vs. 0.48 ± 0.35 deg2, P = 0.06) were noted in eyes with foveal granularity compared to those without. A significant increase in RTS was demonstrated over time (0.066 dB/day, P < 0.001), with a central-to-peripheral gradient of improvement. The interaction between follow-up time and baseline BCVA (P < 0.001) indicated more rapid improvement in eyes with worse initial vision. There was a robust, nonlinear association between PRR and RTS across all tested locations (P < 0.001), becoming asymptotic for sensitivity losses exceeding 20 dB.

Conclusions: Photoreceptor reflectivity accurately aligned with visual function in MEWDS on longitudinal examinations. The central-to-peripheral gradient of improvement may suggest specific vulnerabilities underlying the area around the disc.

Figure 1.

Sequential functional and structural analysis in a patient with MEWDS. This figure visually represents the changes in retinal sensitivity and photoreceptor integrity in a patient with MEWDS across multiple time points: baseline, 2 weeks, 6 weeks, and 3 months. The left column is the microperimetry which demonstrates the 68-stimuli pattern covering the central 10 degrees of the retina, assessing the retinal threshold sensitivity (RTS) at various points within the macular region. The resulting sensitivity map provides a detailed overview of the functional status of the macula. The right column is the photoreceptor reflectivity ratio (PRR) maps derived from optical coherence tomography. Co-registered over the scanning laser ophthalmoscopy (SLO) fundus image from the microperimetry, these maps offer a visual and quantitative assessment of photoreceptor layer integrity across the retinal volume. Structure-function correlation is obtained for 64/68 central stimuli. The color-coded representation shows darker blue areas indicating lower PRR values, suggestive of reduced photoreceptor reflectivity, whereas the brighter yellow areas correspond to higher PRR values, indicative of healthier or recovering photoreceptor areas. The RTS values from the microperimetry are superimposed on the PRR map at all examined locations, directly comparing functional sensitivity and structural integrity. Throughout follow-up, an overall increase in PRR values correlating with improvements in retinal sensitivity are noticed.

Figure 2.

Retinal threshold sensitivity (RTS) and structure-function relationship in MEWDS. (A) Spaghetti plot of retinal threshold sensitivity (RTS) over time for each eye, measured in decibels (dB), illustrating the trajectory of visual function recovery. (B) Local analysis depicting the correlation between photoreceptor reflectivity ratio (PRR) as observed on optical coherence tomography (OCT) and corresponding retinal sensitivity at each specific test location as measured by microperimetry. (C) Global analysis showing the aggregate correlation between overall PRR on OCT and the averaged retinal sensitivity from all test locations on microperimetry, reflecting the average structure-function relationship in MEWDS.

Figure 3.

Comprehensive multimodal imaging and functional assessment of a patient with MEWDS over time. (A) The baseline color fundus photograph exhibits faint white-yellow spots characteristic of MEWDS and central foveal granularity (white rectangle). (B) The baseline late phase indocyanine green angiography (ICGA) reveals the hypofluorescent spots and dots around the posterior pole, mid-periphery, and around the disc, including a prominent spot in the fovea with a hyperfluorescent halo. (C) The baseline late-phase fluorescein angiography (FA) displays wreath-like hyperfluorescence, leakage from the optic disc and large venules. (D) The baseline blue-light fundus autofluorescence (FAF) shows hyperautofluorescent spots correlating with those seen in color fundus and ICGA. (E) The baseline microperimetry indicates a global reduction in retinal threshold sensitivity (RTS) with darker areas representing deeper scotomata. Absolute scotoma areas correspond closely to the hypofluorescent spots on ICGA, and less precisely to the FAF spots. The blue points represent the cloud of points describing the preferred retinal locus (PRL), and the purple lines illustrate the bivariate contour ellipse area (BCEA), indicative of fixation spread. At baseline, both the PRL and BCEA are spread out, suggesting a less focused fixation area. (F) Baseline optical coherence tomography (OCT) shows diffuse disruption of the ellipsoid zone (EZ) and the interdigitation zone (IZ) with mild RPE thickening (arrow). Small projections of hyper-reflective material extend toward the inner retina crossing the external limiting membrane (arrowhead). (G) The 2-week FAF demonstrates a gradual fading of hyperautofluorescent spots. (H) The 2-week microperimetry shows improvement in macular sensitivity, more marked in the central fovea, with persistent deeper scotomata in the extramacular and peripapillary regions. The BCEA becomes markedly smaller, and the cloud of PRL more concentrated around the fovea. (I) The 2-week OCT reveals thinning of the RPE, persistent diffuse multifocal damage of the EZ, absence of the IZ, and disappearance of the hyper-reflective subretinal material. (J) The 6-week FAF shows the disappearance of the original hyperautofluorescent spots replaced by tiny hyperautofluorescent dots. (K) The 6-week microperimetry demonstrates a further improvement in macular sensitivity with a noticeable centrifugal pattern of improvement. (L) The 6-week OCT exhibits almost complete restoration of the EZ and partial reconstitution of the IZ. (M) The 3-month FAF shows almost complete normalization of the autofluorescence signal. (N) The 3-month microperimetry indicates normalization of foveal sensitivity with persistent relative scotomata in the extramacular and peripapillary regions. (O) The 3-month OCT demonstrates complete reconstitution of both the EZ and IZ.

Figure 4.

Longitudinal multimodal imaging and microperimetry in a patient with MEWDS. (A) The baseline Multicolor fundus photograph reveals irregular retinal reflectivity with tiny hypopigmented spots in the macula, indicative of foveal granularity (white rectangle). (B) The baseline fundus autofluorescence (FAF) shows hyperautofluorescent spots predominantly in the mid-periphery, suggesting active inflammatory lesions. (C) The baseline fluorescein angiography (FA) displays characteristic wreath-like hyperfluorescence and vascular leakage. (D) The baseline indocyanine green angiography (ICGA) exhibits hypofluorescent spots with a prominent hypofluorescent plaque in the macula. (E) The baseline microperimetry illustrates significantly reduced retinal sensitivity in the macula and peripapillary region, with relative preservation in the perifoveal area. The spread of fixation, as indicated by the 63% and 95% bivariate contour ellipse area, is broad and predominantly vertical. (F) The baseline horizontal OCT scan shows diffuse loss of the ellipsoid zone (EZ) in areas correlating with reduced sensitivity (dashed lines) and accumulation of hyper-reflective, ill-defined material beneath the fovea. (G–L) The follow-up MP and OCT at 2 weeks, 6 weeks, and 3 months demonstrates a gradual improvement in retinal sensitivity, following a characteristic centrifugal pattern, and a corresponding restoration of the EZ/IZ bands.