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. Author manuscript; available in PMC: 2018 Apr 1.
Published in final edited form as: Retina. 2017 Apr;37(4):741–748. doi: 10.1097/IAE.0000000000001203

Photoreceptor Inner Segment Morphology in Best Vitelliform Macular Dystrophy

Drew Scoles 1, Yusufu N Sulai 2, Robert F Cooper 3, Brian P Higgins 2, Ryan D Johnson 2, Joseph Carroll 2,3,4,5, Alfredo Dubra 2,3,4,5, Kimberly E Stepien 2
PMCID: PMC5362286  NIHMSID: NIHMS795018  PMID: 27467379

Abstract

Purpose

To characterize outer retina structure in Best Vitelliform Macular Dystrophy (BVMD) to determine effect of macular lesions on overlying and adjacent photoreceptors.

Methods

Five individuals with BVMD were followed prospectively with spectral-domain optical coherence tomography and confocal and non-confocal split-detector adaptive optics scanning light ophthalmoscopy (AOSLO). AOSLO cone photoreceptor mosaic images were obtained within and around retinal lesions. Cone density was measured inside and outside of lesions. In two subjects, densities were compared to published measurements acquired ∼2.5 years prior. One subject was imaged 3 times over a 5-month period.

Results

AOSLO imaging demonstrated photoreceptor morphology within BVMD retinal lesions was highly variable depending on disease stage, with photoreceptor structure present even in advanced disease. AOSLO imaging was repeatable even in severe disease over short and long time intervals. Photoreceptor density was normal in retinal areas immediately adjacent to lesions and stable over ∼2.5 years. Mobile disc-like structures possibly representing subretinal macrophages were also observed.

Conclusion

Combined confocal and non-confocal split-detector AOSLO imaging reveals substantial variability within clinical lesions in all stages of BVMD. Longitudinal cellular photoreceptor imaging could prove a powerful tool for understanding disease progression and monitoring emerging therapeutic treatment response in inherited degenerations such as BVMD.

Keywords: Adaptive Optics, Genetics, Imaging, Photoreceptor, Retina

Introduction

Best Vitelliform Macular Dystrophy (BVMD), also known as Best's disease (OMIM 607854; BEST1), is an autosomal dominant macular degeneration of variable penetrance. The disorder is characterized by varying accumulation of yellowish vitelliform material that can evolve into atrophic, fibrotic appearing lesions.1, 2 Clinical vitelliform lesions of BVMD are usually restricted to the macula, although lesions have been reported at more eccentric locations.3

Mutations in the BEST1 gene located on chromosome 11q13 encoding the protein bestophin-1 are known to cause BVMD and several other retinal degenerative diseases.4, 5 Bestrophin-1 has been localized to the basolateral membrane of the retinal pigment epithelium (RPE)6 and is thought to function as a calcium sensitive chloride channel while also influencing other channel functions.7-9 Dysfunction of this channel can lead to the hallmark findings of BVMD, including an abnormal electrooculogram (EOG), an electrophysiological test that measures changes in the transepithelial potential across the RPE throughout the retina.10 EOG often shows diminished light peak (LP) response in individuals with BVMD, even when no clinical features are evident.11

Limited histological studies of BVMD have found an abnormal accumulation of lipofuscin granules in the RPE of some donor eyes12-14 with photoreceptor loss over areas of intact RPE.12, 15 These findings are in agreement with a knock-in mouse model of BVMD that also demonstrated subretinal deposits of unphagocystosed photoreceptor outer segments and lipofuscin granules.16 Some authors have hypothesized that dysfunction of the RPE leads to accumulation of toxic materials which in turn leads to degeneration of the overlying photoreceptors in BVMD.12, 15 Some studies have found structurally normal RPE in BVMD lesions, with the primary impact of BVMD appearing to be subretinal to photoreceptors themselves.17

Advanced retinal imaging techniques have given insight into the effects of BEST1 mutations on outer retinal structures in BVMD. Optical coherence tomography (OCT) studies have localized the vitelliform material in BVMD to the subretinal space, 17-21 and some have shown increased thickening of the reflective band corresponding to photoreceptor outer segments. 17, 18 Recently, Abramoff et al. demonstrated what appears to be outer segment photoreceptor elongation with light adaptation in areas of the macula outside of retinal lesions in BVMD, which suggests photoreceptor dysfunction beyond clinically apparent lesions.22 However, multifocal electroretinogram (ERG) irregularities correspond to involved lesion areas23 and quantitative fundus autofluorescence (qAF) on patients with BVMD showed normal qAF in nonlesion areas, suggesting no increased lipofuscin levels outside of observed retinal lesions.24 Previously, confocal adaptive optics scanning light ophthalmoscopy (AOSLO) indicated that some photoreceptor structure persists over areas of Best lesions, and photoreceptor density is normal in areas adjacent to clinical lesions in BVMD.21 This study employs a new imaging technique, non-confocal split-detector AOSLO, to better delineate photoreceptor structure in BVMD. Additionally, we sought to analyze changes in the photoreceptor mosaic over time.

Methods

Subjects

Research procedures followed the tenets of the Declaration of Helsinki and were approved by the institutional review board at the Children's Hospital of WI (CHW 07/77) Four previously described family members21 and one unrelated subject, all with identified mutation (p.Arg218Cys c.652C→T) in BEST125 and clinical findings consistent with BVMD, participated in this study after giving written consent. See Table 1 for further information about each subject. Axial length measurement (Zeiss IOL Master; Carl Zeiss Meditec), visual acuity testing and fundus photography were performed at the time of research imaging in all subjects.

Table 1. Subject Demographics.

Subject Age (y) Gender Lesion Type Acuity (Snellen)
KS_0325 53 M Atrophic OS, 20/80
KS_0589 61 F Atrophic OS, 20/50
KS_0599 53 F Late vitelliruptive OD, 20/30
KS_0600 18 M Early vitelliform OS, 20/20
KS_0601 20 F Vitelliform with early vitelliruptive OS, 20/20
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Y – years; M-male, F-female; OD – right eye; OS – left eye.

SD-OCT

Spectral-domain optical coherence tomography (SD-OCT) line and volumetric scans were performed using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). The location of the fovea was determined using the fovea-finder function of the Cirrus HD-OCT, and marked on the line scan ophthalmoscope (LSO) image. Additional high-density volumetric scans acquired using the Bioptigen SD-OCT (Bioptigen Inc., Morrisville, NC) nominally covering 7×7 mm (1000 A-scans/B-scan, 250 B-scans) were used to create en face OCT sections with custom software (Java, Oracle, Redwood City, CA).26 En face projections of the ellipsoid zone (EZ) were generated to display the extent of BVMD lesions (Figures 1, 2). Multiple horizontal and vertical macular B-scans nominally covering 7 mm (1000 A-scans/B-scan; Bioptigen) were registered and averaged to increase signal to noise ratio. All OCT images are displayed on logarithmic intensity scale.

Figure 1.

Figure 1

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Imaging results from subject KS_0601. A En face OCT at the level of the ellipsoid zone reveals a large ovoid retinal detachment at the location of the lesion. The area of AOSLO imaging shown below is indicated by the white square, dashed lines indicate the locations of the B-scans. B & C Horizontal and vertical B-scan OCT reveals a large vitelliform lesion just nasal to the center of the fovea. D Confocal AOSLO imaging reveals sparse photoreceptor reflectivity. E The split-detector AOSLO imaging reveals a near complete mosaic of cone photoreceptors. Cells identified in E show 1:1 correspondence to the sparse reflections seen in D with the exception of the large reflective clusters. Scale bars B, C 200 μm, D, E 50 μm.

Figure 2.

Figure 2

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Imaging results from subject KS_0325. A. En face OCT at the level of the ellipsoid zone reveals a very large BVMD lesion with irregular borders, approximately 2.3mm in diameter. The area of AOSLO imaging shown in B & C is indicated by the white square, dashed lines indicate the locations of the B-scans and dotted rectangle indicates location of Figure 5 A & B. B & C Horizontal and vertical B-scan OCT reveals a large atrophic lesion including the entire perifovea centered just inferior to the fovea. D Confocal AOSLO imaging reveals clusters of photoreceptor reflectivity. E Split-detector AOSLO reveals numerous photoreceptors in an incomplete mosaic. Most photoreceptors have abnormal morphology, and some appear to be oriented horizontally, with corresponding areas in the confocal images darker than the background (arrows). Scale bars B, C 200 μm, D, E 50 μm.

AOSLO

AOSLO imaging was performed with a custom instrument, modified to capture light multiply scattered by the retina.27 The multiply scattered light is divided spatially to two separate detectors, and the resulting images are then subtracted to form the non-confocal split-detector image, which reveals the photoreceptor inner segment mosaic.27 Confocal and split-detector images are recorded simultaneously in perfect spatial register. Photoreceptor image sequences were recorded at the fovea as well as in the periphery to approximately 10° superior and temporal to fixation. In subject KS_0589, an overlying epiretinal membrane in temporal macula obligated imaging to 10° nasal from fixation. Image sequences were corrected for sinusoidal distortion caused by the resonant scanner, then registered and averaged as previously described.27 Using a simplified Gullstrand 2 schematic eye, the predicted 291 μm per degree of visual angle was scaled linearly by the subject's axial length to determine the scale of AOSLO images. Averaged AOSLO images were aligned manually in Adobe Photoshop (Adobe Systems Inc., San Jose, CA) to create a large montage. This montage was manually aligned to the color fundus, LSO, en face OCT and to previously acquired AOSLO images21 (where available) using blood vessel shadows as landmarks. The location of the fovea was marked on the AOSLO montage, based on the subject's fixation recorded in the Cirrus HD-OCT LSO image. All AOSLO images are displayed on linear intensity scale.

To examine longitudinal changes (approximately two years elapsed) in the cone mosaic, previously identified areas of normal cone density were re-analyzed in subjects KS_0600 and KS_0601. At three locations in each subject, confocal AOSLO images from both time points were first aligned manually, then registered with rigid translations, using the Stackreg plugin from ImageJ (National Institutes of Health, Bethesda, MA) and finally cropped to the region of overlap. Cones were identified with a previously described semi-automated algorithm.28 Cone density was calculated within 80 × 80 μm regions of interest (ROI).

In order to determine the effect of retinal lesions on the photoreceptor mosaic, the cone density was measured inside and outside of macular lesions in all subjects. Since non-waveguiding or misaligned photoreceptors are not visualized by confocal AOSLO,27, 29 split-detector AOSLO images were chosen for analysis instead. 80 × 80 μm ROIs were identified and analyzed for cone density across the entire span of AOSLO imaging in each subject. A ROI was characterized as intra-lesional if any of the ROI fell within the limits of the lesion as visualized by en-face OCT segmented at the level of the EZ. Then each lesion was sampled with 5-7 ROI to evaluate for local density variations. Cell locations within the split-detector images were identified manually. The distance between each ROI and the fovea was estimated, and cone densities were compared to published normative in vivo values.30 Normative data was linearly interpolated to cover the range of measurement locations. Patient data was pooled across eccentricity for comparison, as there is no measured difference between temporal and nasal meridians across the eccentricities studied31-33 and superior and inferior retinal loci are likely to underestimate cone photoreceptor density.31, 32 Density data was evaluated using z-scores, calculated as the difference between the subject measurement and the normative mean divided by the standard deviation at that eccentricity. Z-scores of magnitude < 2.0 were considered normal, p values < 0.05 were considered significant.

Results

The subjects included in this study had the same disease causing mutation in BEST1 and demonstrate different stages of BVMD, with split-detector AOSLO providing unprecedented views of the photoreceptor pathology (Figures 1, 2, 3). Early in the disease the photoreceptor mosaic remains contiguous but with substantially decreased density (Figure 1, 3A). Later, after further cell loss has taken place, the photoreceptor packing no longer appears contiguous (Figure 2, 3 B & C). Figure 3 shows the span of photoreceptor mosaic changes across the clinically described pathology1 of subjects in this study from early vitelliform lesion to late stage atrophy and fibrosis.

Figure 3.

Figure 3

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Parafoveal photoreceptor imaging in remaining subjects. A-C, B-scan OCT, D-F, Confocal AOSLO imaging, G-I, Split-detector AOSLO. The earliest lesion of this cohort, from KS_0600, manifests as scattered loss of waveguiding in the confocal image. The split-detector image shows a complete and normally dense mosaic of photoreceptors. The B-scan from subject KS_0589 reveals a large late vitelliruptive lesion with significant subretinal debris. The confocal AOSLO image reveals scattered waveguiding photoreceptors, with a cluster of small reflective dots on top of the large debris (E). The split-detector image reveals abnormal photoreceptor morphology and widely varying photoreceptor size over this small area. The bottom left corner of the image contains enlarged photoreceptors with local clearings. With this modality it does not appear that the debris is covered by photoreceptors as the confocal image suggests. Despite the obvious retinal atrophy and little ellipsoid zone reflectivity in subject KS_0599, the split-detector AOSLO image reveals a near complete mosaic of photoreceptors at the fovea. The confocal AOSLO image fails to identify many of the photoreceptors, likely due to their abnormal waveguiding. Scale bars 100 μm.

In all subjects, the effect of the BVMD lesion on overlying photoreceptors was assessed by comparing photoreceptor density within and outside of lesions (Figure 4). Intra-lesion cone density was significantly reduced in subjects KS_0325, KS_0589 and KS_0601 (z-scores -5.0 to -2.5). Near the fovea KS_0599 exhibited reduced density (z-scores -5.0 to -3.6), but returned to normal at the edges of the lesion (z-scores -1.5 to -0.6). Intra-lesion density in subject KS_0600 was preserved (z-scores 0.1 to 0.7). Extra-lesion cone density was near normal in all subjects (z-scores -1.6 to 1.6) with the exception of one measurement in KS_0589 (z-score -2.0). Within a lesion, the cone density and cone appearance varied considerably over short distances, with some regions having almost no photoreceptors, as shown in Figure 2.

Figure 4.

Figure 4

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Cone photoreceptor density inside and outside of lesions. Density was sampled in all subjects within (filled symbols) and outside their BVMD lesion (open symbols). Cone density is significantly reduced within the lesions, but returns to normal outside of lesions. Normative data30 is shown as mean (solid line) ± two standard deviations (shaded region).

Only KS_0600 and KS_0601 showed clear disease progression in OCT B-scan over 32 and 30 months respectively (See Figure, Supplemental Digital Content 1 which shows longitudinal OCTs for all subjects). To determine the effect of lesion enlargement on photoreceptor number, previously analyzed areas were re-counted. Three extra-lesional locations were analyzed in two subjects, at approximately 1° from the fovea and just nasal to the BVMD lesion, where cone density was previously determined to be normal.21 In KS_0601 the cone density was found to change -2.4%, -1.7% and 1.2% over a period of 30 months. In KS_0600 the cone density was found to change 0.0%, 0.5% and -2.6% over a period of 32 months. These small variations in cone density are within the 95% confidence interval for the repeatability of the method of parafoveal density measurements (2.6-2.8%),28 and are therefore consistent with no significant changes.

Split-detector AOSLO imaging within BVMD lesions is repeatable, even in subjects with advanced retinal degeneration as illustrated by the ability to track individual cells, shown in Figure 5. Here the same clusters of photoreceptors were visualized over four months follow-up. There were, however, structures that appeared and disappeared from the images over this time scale (arrows, Figure 5). These round features had a lumpy appearance, were on average 20 μm in diameter, and appeared in areas that previously contained isolated photoreceptors or apparently empty space. Structures of similar size and appearance were also found to change in appearance on much shorter time scales, as short as an hour. These features were only noted in KS_0325, the subject with the most advanced disease.

Figure 5.

Figure 5

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Short-term and long-term variability in photoreceptor layer imaging with split-detector AOSLO in KS_0325 near the fovea center. Circles indicate photoreceptor landmarks identified in both time points. Arrows indicates features that changed over long (A & B) or short (C1-2, D1-2) time scales. Images C1-2, D1-2 depict mobile features of size consistent with cells (arrows). Note how feature moves away from the stationary arrow between C1 and C2 and toward the arrow between D1 and D2. The cell in C1-2 is visible at the top edge of A (arrow), the cell in D1-2 is located approximately 200 μm temporal from A. A & B scale bar 100 μm. C1-2, D1-2 scale bar 25 μm.

Conclusions

Accurate assessment of cellular structure in inherited retinal degenerations in vivo can provide invaluable information about the pathology of these degenerations. In this study, we employed newly developed split-detector AOSLO to further assess photoreceptor structure associated with BVMD in five individuals with the same previously reported BEST1 mutation (p.Arg218Cys). Compared to confocal imaging, non-confocal split-detector AOSLO allows for a more accurate assessment of photoreceptor structure in BVMD, especially in areas of the photoreceptor mosaic overlying subretinal pathology (Figures 1-3 and Figure, Supplemental Digital Content 2, which shows split-detector and OCT imaging within and outside of vitelliform lesions.).

Cone photoreceptor packing within vitelliform lesions can range from normal appearing mosaic (Figure 3 D & G) to significant disruption (Figure 2). As highlighted in patients KS_0589 and KS_0599 (Figure 3), significant intra-lesional variability also exists with focal areas of near normal density present next to areas with severe disruption. In the fibrotic stages of BVMD as seen in KS_0325, cone photoreceptors remain, although sparsely packed and with focal areas entirely devoid of photoreceptors (Figures 2 & 5). We hypothesize this loose packing allows some photoreceptors to freely pivot so that they are oriented horizontally, allowing visualization of both inner and outer segments of the photoreceptors (Figure 2 – teardrop shaped structures in split-detector image). This irregular packing underscores the need for caution when reporting cone photoreceptor densities within areas of pathology as visualized by AOSLO, as these can vary dramatically, even if measurements are taken within 100 microns of each other.

It has been long debated whether BVMD has only focal clinically apparent fundus effects or is a true panretinal photoreceptor disorder. The results presented here show that within clinically apparent lesions, cone photoreceptor inner segments are enlarged and cone density is reduced. In agreement with previous AOSLO studies,21 immediately adjacent to the lesions both density and appearance of cone inner segments return to normal (Figure 4 and Figure, Supplemental Digital Content 2, which shows split-detector and OCT imaging within and outside of vitelliform lesions), lending support to BVMD causing focal photoreceptor lesions. Interestingly, patient KS_0325 has been followed clinically for five years with the imaged lesion exhibiting detachment of the retina from the RPE over this span. Despite this change, split-detector AOSLO confirms photoreceptors overlying these lesions still exist and as seen by stable central fixation during imaging, suggests an alternate pathway for maintenance of the photoreceptors viability than from the RPE.

Split-detector imaging also revealed mobile disc-like structures consistent in size with cells (Figure 5 C&D). Previous histologic studies have hypothesized that these cells represent subretinal macrophages,14, 34 but their lineages were not rigorously confirmed. Alternative explanations for these cells include migratory microglia35 and RPE.36 The significance of this finding is unknown, but these may represent the first in vivo images of reactive subretinal cells in a human eye.

Recent work by Milenkovic et al. suggests that the shared mutation identified in all participants in this study may affect volume-regulated anion channels in the retinal pigment epithelium differently than other BEST1 mutations.37 While the individuals imaged represent the spectrum of stages of BVMD, the clinical and subclinical phenotypes described here cannot necessarily be extended to other mutations in BEST1. Conversely, the diverse findings displayed above are more likely related to the stage of the disease rather than differential pathophysiology.

In summary, the improved resolution possible with split-detector AOSLO allows for increased understanding of cellular disease processes and could potentially be useful in monitoring therapeutic response on a cellular level in diseases such as BVMD. Future studies should be expanded to include high-resolution imaging in individuals with other mutations in BEST1 to further explore the genotype-phenotype correlations in photoreceptor morphology in BVMD.

Supplementary Material

Supplemental Data File _.doc_ .tif_ pdf_ etc.__1

Supplemental Digital Content 1. Longitudinal OCT follow-up of Best disease lesions for all patients. Time between imaging is listed in right panels in months. Scale bars 200 μm.

Supplemental Data File _.doc_ .tif_ pdf_ etc.__2

Supplemental Digital Content 2. Confocal, Split-detector and OCT imaging within and outside of vitelliform lesions. A-E, Co-registered AOSLO and OCT imaging in subject KS_0325 spanning from 0.8 to 2.4 mm retinal eccentricity, with normal AOSLO imaging for comparison. The change in photoreceptor morphology inside and outside of the lesion is highlighted in B & D. Compared to normal (A), the confocal image from KS_0325 (B) shows abnormal intra-lesion reflectivity, which returns to normal appearing near the same eccentricity the ellipsoid zone line in the OCT (C) becomes normal. The split-detector AOSLO image (D) shows that compared to normal (E), the cone density is reduced and cones are enlarged within the lesion. Outside the lesion, the number and appearance returns to normal. All scale bars 100 μm.

Acknowledgments

Research reported in this publication was supported by the National Eye Institute, the National Institute of General Medical Sciences and the National Center for Advancing Translational Sciences of the National Institutes of Health under award numbers R01EY017607, P30EY001931, T32GM007356, and UL1TR001436. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support received from the Thomas M. Aaberg Sr. Retina Research Fund, the Gene and Ruth Posner Foundation, Foundation Fighting Blindness, RD & Linda Peters Foundation, the Glaucoma Research Foundation Catalyst for a Cure Initiative and an unrestricted departmental grant from Research to Prevent Blindness (RPB). A. Dubra is the recipient of a Career Development Award from RPB. This investigation was conducted in a facility constructed with support from the Research Facilities Improvement Program, grant number C06RR016511, from the National Center for Research Resources, National Institutes of Health.

Footnotes

Presented in part at the Association for Research in Vision and Ophthalmology annual meeting 2014, Orlando, FL, poster session, May 5th, 2014.

No authors have a proprietary interest in the data presented in this manuscript.

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Associated Data

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Supplementary Materials

Supplemental Data File _.doc_ .tif_ pdf_ etc.__1

Supplemental Digital Content 1. Longitudinal OCT follow-up of Best disease lesions for all patients. Time between imaging is listed in right panels in months. Scale bars 200 μm.

NIHMS795018-supplement-Supplemental_Data_File___doc___tif__pdf__etc___1.tif (14.8MB, tif)
Supplemental Data File _.doc_ .tif_ pdf_ etc.__2

Supplemental Digital Content 2. Confocal, Split-detector and OCT imaging within and outside of vitelliform lesions. A-E, Co-registered AOSLO and OCT imaging in subject KS_0325 spanning from 0.8 to 2.4 mm retinal eccentricity, with normal AOSLO imaging for comparison. The change in photoreceptor morphology inside and outside of the lesion is highlighted in B & D. Compared to normal (A), the confocal image from KS_0325 (B) shows abnormal intra-lesion reflectivity, which returns to normal appearing near the same eccentricity the ellipsoid zone line in the OCT (C) becomes normal. The split-detector AOSLO image (D) shows that compared to normal (E), the cone density is reduced and cones are enlarged within the lesion. Outside the lesion, the number and appearance returns to normal. All scale bars 100 μm.

NIHMS795018-supplement-Supplemental_Data_File___doc___tif__pdf__etc___2.tif (17.6MB, tif)

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