View larger version (37K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Clinical presentation of the patient. Results are shown for the right eye, although all findings were seen bilaterally. A fundus photograph (A) and an autofluorescence image with asterisks indicating the locations imaged with adaptive optics shown in Figure 2 (B) demonstrate pigment irregularities throughout the macula. Visual fields (C) and multifocal electroretinography results (D) were consistent with a decrease in cone function. E and F, High-resolution spectral-domain optical coherence tomographic images using a broadband illumination with the Bioptigen spectral-domain optical coherence tomographic system (Bioptigen, Durham, North Carolina) show pronounced outer retinal disruption.

View larger version (36K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Evidence for cone photoreceptor degeneration. A, Comparison of the patient's outer nuclear layer (ONL) thickness (dashed line) with the average ONL thickness in 97 healthy control subjects reveals significant thinning. Solid lines indicate ±2 SDs from the mean. An adaptive optics image of the right eye from a normal retina at a 1° temporal location (B) and a corresponding image from the patient (C) are shown. The density of the "bubble wrap" structures is 14 917 cells/mm2. Normal cone density at this location is about 37 000 cones/mm2, based on histologic findings6 and adaptive optics data4 from other groups. D and E, Images from a 3° nasal location show heterogeneous areas of variably sized reflecting structures interleaved with 3 craterlike lowly reflecting patches (outlined in E).

High-resolution images of the macula were obtained using a Bioptigen spectral-domain (SD) OCT equipped with a 186-nm broadband light source (Bioptigen, Durham, North Carolina). Images of the cone photoreceptor mosaic were obtained using a newly developed high-speed, flood-illuminated, AO ophthalmoscope. Images were analyzed using custom Matlab programs (Mathworks, Natick, Massachusetts) and ImageJ software (National Institutes of Health, Bethesda, Maryland).

The high-resolution SD-OCT images from the patient's right eye revealed a disruption of the inner segment–outer segment layer in most parafoveal locations with preservation of cone remnants in the central fovea (Figure 1E and F). The external limiting membrane was intact, indicating the presence of remaining inner segment structures, although measurement of the outer nuclear layer revealed significant thinning compared with 97 healthy control subjects (Figure 2A).

The AO images revealed significant photoreceptor mosaic heterogeneity (Figure 2B-E). While some structures were consistent with normal cone photoreceptor appearance, these were rare. Of particular interest were patches of hexagonally packed structures with a bubble wrap appearance. The density of these structures was less than 50% of a normal cone array for this retinal location.⁴ A similar morphological appearance was reported in a patient with X-linked cone-rod dystrophy.⁴ Finally, craterlike lowly reflecting patches were seen interleaved among variably sized reflecting structures. While these changes in reflectivity may have their origins in the pigment irregularities, precise correlation was not possible owing to the low resolution of the autofluorescence image.

Comment
High-resolution imaging (SD-OCT and AO) was able to reveal cellular damage in this case of bilateral maculopathy. Specifically, the AO images greatly enhanced our understanding of the cause of this patient's condition and SD-OCT revealed significant thinning of the outer nuclear layer, confirming degeneration of the foveal cones. A challenge ahead in introducing AO as a standard clinical modality is that we need better understanding of how the various stages of cone degeneration manifest on AO imaging. Additional studies like these will help elucidate the etiology of various conditions and will also contribute to the evolving atlas of in vivo photoreceptor pathological changes. Despite there being no definitive treatment for this case, findings like these where AO is used to interpret SD-OCT demonstrate the complementary roles these modalities can play in the clinical setting.

AUTHOR INFORMATION
Correspondence: Dr Weinberg, The Eye Institute, Medical College of Wisconsin, 925 N 87th St, Milwaukee, WI 53226 (dweinber{at}mcw.edu).

Author Contributions: Dr Carroll had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This work was supported by grants EY001931 and EY017607 from the National Institutes of Health, by the Posner Foundation, Fight for Sight, the E. Matilda Ziegler Foundation for the Blind, the R. D. and Linda Peters Foundation, and Hope for Vision, and by an unrestricted grant from Research to Prevent Blindness. Dr Carroll is the recipient of a career development award from Research to Prevent Blindness.