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Original Investigation | Clinical Sciences

Spectral-Domain Optical Coherence Tomography Staging and Autofluorescence Imaging in Achromatopsia

Jonathan P. Greenberg, MD1; Jerome Sherman, OD2; Sandrine A. Zweifel, MD3,4; Royce W. S. Chen, MD1; Tobias Duncker, MD1; Susanne Kohl, MSc, PhD5; Britta Baumann5; Bernd Wissinger, MSc, PhD5; Lawrence A. Yannuzzi, MD3,4; Stephen H. Tsang, MD, PhD1,6,7
[+] Author Affiliations
1Department of Ophthalmology, Columbia University, New York, New York
2Department of Clinical Sciences, State University of New York College of Optometry, New York, New York
3The Vitreous, Retina, Macula Consultants of New York, New York
4The LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York
5Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
6Bernard and Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, New York
7Department of Pathology and Cell Biology, Columbia University, New York, New York
JAMA Ophthalmol. 2014;132(4):437-445. doi:10.1001/jamaophthalmol.2013.7987.
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Importance  Evidence is mounting that achromatopsia is a progressive retinal degeneration, and treatments for this condition are on the horizon.

Objectives  To categorize achromatopsia into clinically identifiable stages using spectral-domain optical coherence tomography and to describe fundus autofluorescence imaging in this condition.

Design, Setting, and Participants  A prospective observational study was performed between 2010 and 2012 at the Edward S. Harkness Eye Institute, New York-Presbyterian Hospital. Participants included 17 patients (aged 10-62 years) with full-field electroretinography-confirmed achromatopsia.

Main Outcomes and Measures  Spectral-domain optical coherence tomography features and staging system, fundus autofluorescence and near-infrared reflectance features and their correlation to optical coherence tomography, and genetic mutations served as the outcomes and measures.

Results  Achromatopsia was categorized into 5 stages on spectral-domain optical coherence tomography: stage 1 (2 patients [12%]), intact outer retina; stage 2 (2 patients [12%]), inner segment ellipsoid line disruption; stage 3 (5 patients [29%]), presence of an optically empty space; stage 4 (5 patients [29%]), optically empty space with partial retinal pigment epithelium disruption; and stage 5 (3 patients [18%]), complete retinal pigment epithelium disruption and/or loss of the outer nuclear layer. Stage 1 patients showed isolated hyperreflectivity of the external limiting membrane in the fovea, and the external limiting membrane was hyperreflective above each optically empty space. On near infrared reflectance imaging, the fovea was normal, hyporeflective, or showed both hyporeflective and hyperreflective features. All patients demonstrated autofluorescence abnormalities in the fovea and/or parafovea: 9 participants (53%) had reduced or absent autofluorescence surrounded by increased autofluorescence, 4 individuals (24%) showed only reduced or absent autofluorescence, 3 patients (18%) displayed only increased autofluorescence, and 1 individual (6%) exhibited decreased macular pigment contrast. Inner segment ellipsoid line loss generally correlated with the area of reduced autofluorescence, but hyperautofluorescence extended into this region in 2 patients (12%). Bilateral coloboma-like atrophic macular lesions were observed in 1 patient (6%). Five novel mutations were identified (4 in the CNGA3 gene and 1 in the CNGB3 gene).

Conclusions and Relevance  Achromatopsia often demonstrates hyperautofluorescence suggestive of progressive retinal degeneration. The proposed staging system facilitates classification of the disease into different phases of progression and may have therapeutic implications.

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Figure 1.
Staging System and Corresponding Fundus Autofluorescence (AF) Images

Spectral-domain optical coherence tomography (SD-OCT) stages (left) and corresponding fundus AF images (right) in patients with achromatopsia. Stage 1: A, Outer retinal structure is intact but there is flattening and subtle discontinuity of the inner segment ellipsoid (ISe) line posterior to the foveola. The cone outer segment tip (COST) layer (left arrowhead) is relatively spared, although it is thinned toward the foveal center, and the external limiting membrane is hyperreflective (right arrowhead) in this region. B, The corresponding AF image shows decreased macular pigment contrast and fine punctate hyperautofluorescent dots scattered across the macula (the dots were also visible on color fundus photography [yellow] and near-infrared reflectance imaging [hyperreflective]). Stage 2: C, The ISe line is disrupted. Note interruption of the COST layer and hyperreflectivity of the photoreceptor inner segments. D, The AF image shows centrally reduced AF with subtle hyperautofluorescence around the inferotemporal fovea (arrowhead). Stage 3: E, This case demonstrates the classic optically empty space (OES), with absent photoreceptors in the fovea, but the retinal pigment epithelium (RPE) appears intact. F, The AF image shows hyperautofluorescence resulting in a stippled foveal appearance. Stage 4: G, An OES and partial RPE disruption (choroidal hyperreflectance is indicated with arrowheads). Note the reflective material, possibly photoreceptor debris, at the roof of the OES (also seen in E). H, The AF image displays a central area of greatly reduced AF but no observable hyperautofluorescence. Stage 5: I, Complete RPE disruption and loss of the outer nuclear layer. J, The AF image demonstrates a larger lesion with a surrounding hyperautofluorescent ring and a central region of absent AF.

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Figure 2.
Multimodal Imaging

Images in patients with stage 3 (case 5), stage 4 (case 12), and stage 5 (case 15) achromatopsia are shown. Imaging modalities (top to bottom) are spectral-domain optical coherence tomography (SD-OCT), color fundus photography (color), near-infrared reflectance (NIR), and fundus autofluorescence (AF). Correlations between imaging modalities are indicated with vertical (white) and horizontal (green) lines. In stage 3, the fovea is darkened (color) and shows decreased reflectance (NIR) and reduced AF surrounded by hyperautofluorescence (AF imaging). Spectral-domain OCT demonstrates a characteristic optically empty space (OES), but the retinal pigment epithelium (RPE) appears intact. Note the reflective material within the OES and the thickened external limiting membrane. The extent of inner segment ellipsoid (ISe) line loss correlates with the hyporeflective area on NIR. The AF image reveals extension of the hyperautofluorescence into the region of ISe loss, although it is less intense than in the surrounding area. In stage 4, the fovea reveals mottled RPE changes (color), mottled hyporeflectivity and hyperreflectivity (NIR), and greatly reduced AF surrounded by a thin hyperautofluorescent rim (AF imaging). Spectral-domain OCT shows an OES and partial RPE disruption. The region of ISe loss corresponds to the lesions seen on color, NIR, and AF. In stage 5, the fovea is dark with a well-defined central area of RPE atrophy (color), is hyporeflective with a distinct highly reflective central area (NIR), and is hypoautofluorescent with a central region of greatly reduced AF and a surrounding hyperautofluorescent ring (AF imaging). Spectral-domain OCT evidences complete RPE disruption and loss of the OES. The region of ISe loss (solid vertical lines) correlates with the dark, hyporeflective, and hypoautofluorescent areas on color, NIR, and AF, respectively. The RPE disruption (interrupted vertical lines) corresponds to the atrophic, hyperreflective, and greatly hypoautofluorescent central areas on color, NIR, and AF, respectively. Note that the RPE is relatively spared outside of the disrupted zone.

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