High-resolution in vivo imaging in achromatopsia.
ABSTRACT To characterize the retinal changes in patients with achromatopsia using an ultrahigh-resolution (UHR) spectral-domain optical coherence tomography (OCT) to examine how human achromatopsia corresponds to its animal model.
Comparative case series.
Ultrahigh-resolution OCT (Copernicus; OPTOPOL Technology S.A., Zawiercie, Poland; 3-μm axial resolution) was used to obtain scans from 13 patients (26 eyes) with achromatopsia and from 20 controls (40 eyes).
A 3-dimensional scan program (743×75; A×B scan) sampling a 7×7-mm retinal area centered at the fovea was used to obtain tomograms of the fovea. Individual B-scans at the fovea were exported and analyzed using ImageJ (Wayne Rasband, National Institute of Health) for reflectance profiles and morphologic abnormalities.
Gross morphologic changes in OCT were characterized. Specifically, inner segment and outer segment (IS/OS) junction and cone outer segment tip (COST) disruption was noted. Using the reflectance profiles, foveal depth, thickness of the outer nuclear layer (ONL), and retinal thickness (RT) were measured.
A characteristic so-called punched out hyporeflective zone (HRZ) was noted in 7 of 13 patients; this was age-dependent (P = 0.001). The area of the HRZ was asymmetric with the nasal area being significantly greater than the temporal area (P = 0.002). In all patients, there was disruption of the IS/OS junction at the foveal or parafoveal regions, or both. Five of 13 patients also had a disrupted COST reflectivity. There was significant (P = 1.1×10(-6)) ONL thinning in the achromats compared with controls, which was age-dependent (P = 0.0002). Foveal maldevelopment was seen in 9 of 13 patients. The achromats also had a significantly reduced foveal depth (P = 7.7×10(-6)) and RT (P = 1.46×10(-9)) compared with controls.
A range of signs in achromatopsia are described that can be detected using UHR OCT. The IS/OS junction and COST reflectivity disruption and presence of HRZ and ONL thinning are signs of cone photoreceptor degeneration. The latter 2 are age-dependent, which suggests that achromatopsia is a progressive disorder. In addition, foveal maldevelopment is described; this represents a fetal developmental defect linked to cone photoreceptor degeneration.
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ABSTRACT: Purpose: Ciliary neurotrophic factor (CNTF) protects rod photoreceptors from retinal degenerative disease in multiple non-human models. Thus far, CNTF has failed to demonstrate rod protection in trials for human retinitis pigmentosa. Recently, CNTF was found to improve cone photoreceptor function in a canine CNGB3 achromatopsia model. This study explores whether this finding translates to humans with CNGB3 achromatopsia. Methods: A 5 subject open-label Phase I/II study was initiated by implanting intraocular microcapsules releasing CNTF (nominally 20 ng/day) into one eye each of CNGB3 achromat participants. Fellow eyes served as untreated controls. Subjects were followed for one year. Results: Pupil constriction in treated eyes gave evidence of intraocular CNTF release. Additionally, scotopic ERG responses were reduced, and dark adapted psychophysical absolute thresholds were increased, attributable to diminished rod or rod pathway activity. Optical coherence tomography revealed that the cone rich fovea underwent structural changes as the foveal hyporeflective zone (HRZ) became diminished in CNTF-treated eyes. No objectively measurable enhancement of cone function was found by assessments of visual acuity, mesopic increment sensitivity threshold or the photopic electroretinogram (ERG). Careful measurements of color hue discrimination showed no change. Nonetheless, subjects reported beneficial changes of visual function in the treated eyes, including reduced light sensitivity and aversion to bright light, which may trace to decreased effective ambient light from the pupillary constriction; further they noted slowed adaptation to darkness, consistent with CNTF action on rod photoreceptors. Conclusions: CNTF did not measurably enhance cone function, which reveals a species difference between human and canine CNGB3 cones in responses to CNTF.Investigative Ophthalmology & Visual Science 09/2014; · 3.66 Impact Factor
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ABSTRACT: Purpose To characterize the prevalence and features of subclinical foveal hypoplasia detected by optical coherence tomography (OCT) in children. Methods Fast macular OCT scans were performed on normal children with normal vision for the development of a normative OCT-3 database; from this data, eyes with no discernable foveal depression were identified. When possible, the ocular imaging was repeated 3 years later using both OCT-3 and spectral domain OCT (SD-OCT). SD-OCT results were compared to age-matched controls. Results Of the 286 normal children (mean age, 8.6 ± 3.1 years) scanned, 9 (mean age, 8 ± 2.9 years; 6 males) were found to have bilateral shallow foveal depression on OCT-3 imaging, including 8 of 154 white children (5.4%) and 1 child of mixed ethnicity (white/black). Children with shallow foveas (n = 9) had larger average foveal thickness (FT) compared to the cohort of controls (n = 277) with a defined fovea (FT = 231.4 ± 8.8 vs 188.8 ± 25.0, resp. [P < 0.0001]). Mean macular volume did not differ from that of controls. SD-OCT performed 3 years later on 5 of the 9 children with shallow foveal depression showed persistence of the inner macular layers over the foveal center, corresponding to grades 1 or 2 of foveal hypoplasia. The FT was increased compared to 5 age-matched controls with a defined fovea (FT = 294.5 ± 5.1 vs 219.75 ± 5.68 μm, resp. [P = 0.029]). Conclusions Up to 3% of children with clinically normal eyes had an anatomically underdeveloped foveal pit bilaterally on OCT.Journal of American Association for Pediatric Ophthalmology and Strabismus 09/2014; · 1.14 Impact Factor
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ABSTRACT: Purpose: Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, though analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM). Methods: Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of eleven subjects with ACHM and seven age-matched controls. Images were obtained, processed and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure. Results: All subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/B3-associated ACHM. Conclusions: We present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerousity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change.Investigative Ophthalmology & Visual Science 10/2014; · 3.66 Impact Factor