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1.  Relationship Between Foveal Cone Specialization and Pit Morphology in Albinism 
Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism.
We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured.
We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism.
Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue.
Foveal specialization (foveal cone packing, outer segment elongation, pit morphology) in albinism is highly variable and can overlap with normal foveal structure, contrary to the typical clinical picture of albinism.
PMCID: PMC4098060  PMID: 24845642
albinism; adaptive optics; foveal morphology; foveal development
2.  Microscopic Inner Retinal Hyper-Reflective Phenotypes in Retinal and Neurologic Disease 
We surveyed inner retinal microscopic features in retinal and neurologic disease using a reflectance confocal adaptive optics scanning light ophthalmoscope (AOSLO).
Inner retinal images from 101 subjects affected by one of 38 retinal or neurologic conditions and 11 subjects with no known eye disease were examined for the presence of hyper-reflective features other than vasculature, retinal nerve fiber layer, and foveal pit reflex. The hyper-reflective features in the AOSLO images were grouped based on size, location, and subjective texture. Clinical imaging, including optical coherence tomography (OCT), scanning laser ophthalmoscopy, and fundus photography was analyzed for comparison.
Seven categories of hyper-reflective inner retinal structures were identified, namely punctate reflectivity, nummular (disc-shaped) reflectivity, granular membrane, waxy membrane, vessel-associated membrane, microcysts, and striate reflectivity. Punctate and nummular reflectivity also was found commonly in normal volunteers, but the features in the remaining five categories were found only in subjects with retinal or neurologic disease. Some of the features were found to change substantially between follow up imaging months apart.
Confocal reflectance AOSLO imaging revealed a diverse spectrum of normal and pathologic hyper-reflective inner and epiretinal features, some of which were previously unreported. Notably, these features were not disease-specific, suggesting that they might correspond to common mechanisms of degeneration or repair in pathologic states. Although prospective studies with larger and better characterized populations, along with imaging of more extensive retinal areas are needed, the hyper-reflective structures reported here could be used as disease biomarkers, provided their specificity is studied further.
The human inner retina was examined with confocal adaptive optics scanning light ophthalmoscopy. Seven non–disease-specific categories of hyper-reflective structures were identified, suggesting common mechanisms of degeneration or repair in pathologic states.
PMCID: PMC4078949  PMID: 24894394
adaptive optics; inner retina; ophthalmoscopy; neuro-ophthalmology; retinal disease
3.  Rapid, Accurate, and Non-Invasive Measurement of Zebrafish Axial Length and Other Eye Dimensions Using SD-OCT Allows Longitudinal Analysis of Myopia and Emmetropization 
PLoS ONE  2014;9(10):e110699.
Refractive errors in vision can be caused by aberrant axial length of the eye, irregular corneal shape, or lens abnormalities. Causes of eye length overgrowth include multiple genetic loci, and visual parameters. We evaluate zebrafish as a potential animal model for studies of the genetic, cellular, and signaling basis of emmetropization and myopia. Axial length and other eye dimensions of zebrafish were measured using spectral domain-optical coherence tomography (SD-OCT). We used ocular lens and body metrics to normalize and compare eye size and relative refractive error (difference between observed retinal radial length and controls) in wild-type and lrp2 zebrafish. Zebrafish were dark-reared to assess effects of visual deprivation on eye size. Two relative measurements, ocular axial length to body length and axial length to lens diameter, were found to accurately normalize comparisons of eye sizes between different sized fish (R2 = 0.9548, R2 = 0.9921). Ray-traced focal lengths of wild-type zebrafish lenses were equal to their retinal radii, while lrp2 eyes had longer retinal radii than focal lengths. Both genetic mutation (lrp2) and environmental manipulation (dark-rearing) caused elongated eye axes. lrp2 mutants had relative refractive errors of −0.327 compared to wild-types, and dark-reared wild-type fish had relative refractive errors of −0.132 compared to light-reared siblings. Therefore, zebrafish eye anatomy (axial length, lens radius, retinal radius) can be rapidly and accurately measured by SD-OCT, facilitating longitudinal studies of regulated eye growth and emmetropization. Specifically, genes homologous to human myopia candidates may be modified, inactivated or overexpressed in zebrafish, and myopia-sensitizing conditions used to probe gene-environment interactions. Our studies provide foundation for such investigations into genetic contributions that control eye size and impact refractive errors.
PMCID: PMC4205002  PMID: 25334040
4.  Outer Retinal Structure in Best Vitelliform Macular Dystrophy 
JAMA ophthalmology  2013;131(9):1207-1215.
To characterize outer retinal structure in Best Vitelliform Macular Dystrophy (BVMD), using spectral domain optical coherence tomography (SD-OCT) and adaptive optics scanning light ophthalmoscopy (AOSLO).
Four symptomatic members of a family with BVMD with known BEST1 gene mutation were recruited. Thickness of two outer retinal layers corresponding to photoreceptor inner and outer segments were measured using SD-OCT. Photoreceptor mosaic AOSLO images within and around visible lesions were obtained, and cone density was assessed in two subjects.
Each subject was at a different stage of BVMD, with photoreceptor disruption evident by AOSLO at all stages. When comparing SD-OCT and AOSLO images from the same location, AOSLO images allowed for direct assessment of photoreceptor structure. A variable degree of retained photoreceptors was seen within all lesions. The photoreceptor mosaic immediately adjacent to visible lesions appeared contiguous and was of normal density. Fine hyperreflective structures were visualized by AOSLO, and their anatomical orientation and size are consistent with Henle fibers.
AOSLO findings indicate substantial photoreceptor structure persists within active lesions, accounting for good visual acuity in these patients. Despite previous reports of diffuse photoreceptor outer segment abnormalities in BVMD, our data reveal normal photoreceptor structure in areas adjacent to clinical lesions.
Clinical Relevance
This study demonstrates the utility of AOSLO for understanding the spectrum of cellular changes that occur in inherited degenerations such as BVMD. Photoreceptors are often significantly affected at various stages of inherited degenerations, and these changes may not be readily apparent with current clinical imaging instrumentation.
PMCID: PMC3968428  PMID: 23765342
5.  Evaluation of normal human foveal development using optical coherence tomography and histologic examination 
Archives of ophthalmology  2012;130(10):1291-1300.
Assess outer retinal layer maturation during late gestation and early postnatal life using optical coherence tomography (OCT) and histology.
Thirty-nine subjects ranging from 32 weeks post-menstrual age (PMA) to 4 years were imaged using a hand held OCT (102 imaging sessions). Foveal images from 16 subjects (21 imaging sessions) were normal and evaluated for inner retinal excavation and presence of outer retinal reflective bands. Reflectivity profiles of central, parafoveal, and perifoveal retina were extracted and compared to age-matched histological sections.
Foveal pit morphology in infants was generally distinguishable from adults. Reflectivity profiles showed a single hyper-reflective band at the fovea in all infants less than 42 weeks PMA. Multiple bands were distinguishable in the outer retina at the perifovea by 32 weeks PMA, and at the fovea by 3 months post term. By 17 months postnatal the characteristic appearance of four hyper-reflective bands was evident across the foveal region. These features are consistent with previous results from histology. A ‘temporal divot’ was present in some infants and foveal pit morphology and extent of inner retinal excavation was variable.
Hand-held OCT imaging is a viable technique for evaluating neonatal retinas. In premature infants, who do not develop ROP, the foveal region appears to follow a developmental time course similar to in utero maturation.
Clinical Relevance
As pediatric OCT imaging becomes more common, a better understanding of normal foveal and macular development is needed. Longitudinal imaging offers the opportunity to track postnatal foveal development in preterm infants where poor visual outcomes are anticipated or to track treatment outcomes in this population.
PMCID: PMC3724218  PMID: 23044942
6.  Subclinical Macular Findings in Infants Screened for Retinopathy of Prematurity with Spectral Domain-Optical Coherence Tomography 
Ophthalmology  2013;120(8):1665-1671.
To evaluate subclinical macular findings in premature patients at risk of retinopathy of prematurity (ROP) with the use of handheld spectral domain-optical coherence tomography (SD-OCT).
Prospective, observational case series.
Forty-nine prematurely born neonates.
Forty-nine infants were imaged using a handheld SD-OCT. Images were acquired in non-sedated infants in the neonatal intensive care unit. Some patients were followed and re-imaged over the course of several weeks. Two hundred ninety-eight total images were acquired, and evaluated for cystoid macular edema (CME) and persistence of inner retinal layers.
Main Outcome Measures
In vivo determination of foveal retinal lamination, image analysis and clinical observation.
Two hundred forty (81%) of the images from 45 patients were usable (defined as having scans passing through the fovea with clearly identifiable retinal layers). Persistence of one or more inner retinal layers was seen in 42 patients (93%). Patients with at least one persistent layer, 16, 5, 7, 13 and 1 had a maximum ROP stage of 0, 1, 2, 3, and 4A respectively. CME was seen in 25 of the 45 patients (56%) during one or more imaging sessions. CME was present in 9, 1, 5, 9, and 1 patient with maximum ROP stage of 0, 1, 2, 3, and 4A respectively.
Our data suggests there is persistence of inner retinal layers in premature infants, regardless of maximal ROP stage. Subclinical CME is seen in premature infants; however, CME does not appear to be correlated with ROP stage. This suggests that there maybe other etiologies for the CME seen in this patient population. Hand-held SD-OCT imaging is a viable technique for evaluating subclinical macular findings in premature infants, though larger datasets are needed from multiple centers to further evaluate the generalizability of these findings.
PMCID: PMC3737379  PMID: 23672969
7.  Adaptation of the Central Retina for High Acuity Vision: Cones, the Fovea and the Avascular Zone 
Presence of a fovea centralis is directly linked to molecular specification of an avascular area in central retina, before the fovea (or `pit') begins to form. Modeling suggests that mechanical forces, generated within the eye, initiate formation of a pit within the avascular area, and its later remodeling in the postnatal period. Within the avascular area the retina is dominated by `midget' circuitry, in which signals are transferred from a single cone to a single bipolar cell, then a single ganglion cell. Thus in inner, central retina there are relatively few lateral connections between neurons. This renders the region adaptable to tangential forces, that translocate of ganglion cells laterally / centrifugally, to form the fovea. Optical coherence tomography enables live imaging of the retina, and shows that there is greater variation in the morphology of foveae in humans than previously thought. This variation is associated with differences in size of the avascular area and appears to be genetically based, but can be modified by environmental factors, including prematurity. Even when the fovea is absent (foveal hypoplasia), cones in central retina adopt an elongated and narrow morphology, enabling them to pack more densely to increase the sampling rate, and to act as more effective waveguides. Given these findings, what then is the adaptive advantage of a fovea? We suggest that the advantages of having a pit in central retina are relatively few, and minor, but together work to enhance acuity.
PMCID: PMC3658155  PMID: 23500068
fovea centralis; area centralis; foveal avascular zone; cone photoreceptors; axon guidance factors; antiangiogenic factors; Stiles-Crawford Effects; Fresnel numbers; visual acuity
8.  Relationship between the Foveal Avascular Zone and Foveal Pit Morphology 
Using a combination of in vivo retinal imaging tools, the authors found extensive variation in the size of the foveal pit and the foveal avascular zone, with larger foveal pits associated with larger foveal avascular zones.
To assess the relationship between foveal pit morphology and size of the foveal avascular zone (FAZ).
Forty-two subjects were recruited. Volumetric images of the macula were obtained using spectral domain optical coherence tomography. Images of the FAZ were obtained using either a modified fundus camera or an adaptive optics scanning light ophthalmoscope. Foveal pit metrics (depth, diameter, slope, volume, and area) were automatically extracted from retinal thickness data, whereas the FAZ was manually segmented by two observers to extract estimates of FAZ diameter and area.
Consistent with previous reports, the authors observed significant variation in foveal pit morphology. The average foveal pit volume was 0.081 mm3 (range, 0.022 to 0.190 mm3). The size of the FAZ was also highly variable between persons, with FAZ area ranging from 0.05 to 1.05 mm2 and FAZ diameter ranging from 0.20 to 1.08 mm. FAZ area was significantly correlated with foveal pit area, depth, and volume; deeper and broader foveal pits were associated with larger FAZs.
Although these results are consistent with predictions from existing models of foveal development, more work is needed to confirm the developmental link between the size of the FAZ and the degree of foveal pit excavation. In addition, more work is needed to understand the relationship between these and other anatomic features of the human foveal region, including peak cone density, rod-free zone diameter, and Henle fiber layer.
PMCID: PMC3339921  PMID: 22323466
9.  Assessing Retinal Structure In Complete Congenital Stationary Night Blindness and Oguchi Disease 
American journal of ophthalmology  2012;154(6):987-1001.e1.
To examine retinal structure and changes in photoreceptor intensity post-dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease.
Prospective observational case series.
We recruited three patients with complete congenital stationary night blindness caused by mutations in GRM6, two brothers with Oguchi disease caused by mutations in GRK1, and one normal control. Retinal thickness was measured from optical coherence tomography (OCT) images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged five of the patients following a period of dark adaptation, and examined layer reflectivity on OCT in a patient with Oguchi disease under light- and dark-adapted conditions.
Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations, as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. Upon removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In one Oguchi patient, the outer segment layer contrast on OCT was fourfold higher under dark-adapted versus light-adapted conditions.
The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar/ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are due to changes within the rods as opposed to changes at a different retinal locus.
PMCID: PMC3498541  PMID: 22959359
10.  The Effect of Cone Opsin Mutations on Retinal Structure and the Integrity of the Photoreceptor Mosaic 
To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations.
Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array.
While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with “L/M interchange” mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (∼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic.
The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy.
Subjects with OPN1LW and OPN1MW mutations showed a spectrum of retinal phenotypes with genotype-specific differences. This has implications for restoration of visual function in these subjects and highlights high-resolution retinal imaging as a complementary tool for emerging therapeutic efforts.
PMCID: PMC3816954  PMID: 23139274
11.  Automatic cone photoreceptor segmentation using graph theory and dynamic programming 
Biomedical Optics Express  2013;4(6):924-937.
Geometrical analysis of the photoreceptor mosaic can reveal subclinical ocular pathologies. In this paper, we describe a fully automatic algorithm to identify and segment photoreceptors in adaptive optics ophthalmoscope images of the photoreceptor mosaic. This method is an extension of our previously described closed contour segmentation framework based on graph theory and dynamic programming (GTDP). We validated the performance of the proposed algorithm by comparing it to the state-of-the-art technique on a large data set consisting of over 200,000 cones and posted the results online. We found that the GTDP method achieved a higher detection rate, decreasing the cone miss rate by over a factor of five.
PMCID: PMC3675871  PMID: 23761854
(100.0100) Image processing; (170.4470) Ophthalmology; (110.1080) Active or adaptive optics
12.  The Repeatability of In Vivo Parafoveal Cone Density and Spacing Measurementsa 
Optometry and Vision Science  2012;89(5):632-643.
To assess the repeatability and measurement error associated with cone density and nearest neighbor distance (NND) estimates in images of the parafoveal cone mosaic obtained with an adaptive optics scanning light ophthalmoscope (AOSLO).
Twenty-one participants with no known ocular pathology were recruited. Four retinal locations, approximately 0.65° eccentricity from the center of fixation were imaged 10 times in randomized order with an AOSLO. Cone coordinates in each image were identified using an automated algorithm (with or without manual correction), from which cone density and NND were calculated. Owing to naturally occurring fixational instability, the 10 images recorded from a given location did not overlap entirely. We thus analyzed each image set both before and after alignment.
Automated estimates of cone density on the unaligned image sets showed a coefficient of repeatability of 11,769 cones/mm2 (17.1%). The primary reason for this variability appears to be fixational instability, as aligning the 10 images to include the exact same retinal area, results in an improved repeatability of 4,358 cones/mm2 (6.4%) using completely automated cone identification software. Repeatability improved further by manually identifying cones missed by the automated algorithm, with a coefficient of repeatability of 1,967 cones/mm2 (2.7%). NND showed improved repeatability, and was generally insensitive to the undersampling by the automated algorithm.
As our data were collected in a young, healthy population, this likely represents a best-case estimate for corresponding measurements in patients with retinal disease. Similar studies need to be carried out on other imaging systems (including those using different imaging modalities, wavefront correction technology, and/or cone identification software), as repeatability would be expected to be highly sensitive to initial image quality and the performance of cone identification algorithms. Separate studies addressing inter-session repeatability and inter-observer reliability are also needed.
PMCID: PMC3348369  PMID: 22504330
retina; cones; adaptive optics; repeatability; photoreceptors
14.  Rhodopsin F45L Allele Does Not Cause Autosomal Dominant Retinitis Pigmentosa in a Large Caucasian Family 
To ascertain the potential pathogenicity of a retinitis pigmentosa (RP)-causing RHO F45L allele in a family affected by congenital achromatopsia (ACHM).
Case series/observational study that included two patients with ACHM and 24 extended family members. Molecular genetic analysis was performed to identify RHO F45L carrier status in the family and a control population. An adaptive optics scanning light ophthalmoscope (AOSLO) was used to image the photoreceptor mosaic and assess rod and cone structure. Spectral domain optical coherence tomography (SD-OCT) was used to examine retinal lamination. Comprehensive clinical testing included acuity, color vision, and dilated fundus examination. Electroretinography was used to assess rod and cone function.
Five carriers of the RHO F45L allele alone (24–80 years) and three carriers in combination with a heterozygous CNGA3 mutant allele (10–64 years) were all free of the classic symptoms and signs of RP. In heterozygous carriers of both mutations, SD-OCT showed normal retinal thickness and intact outer retinal layers; rod and cone densities were within normal limits on AOSLO. The phenotype in two individuals affected with ACHM and harboring the RHO F45L allele was indistinguishable from that previously reported for ACHM.
The RHO F45L allele is not pathogenic in this large family; hence, the two ACHM patients would unlikely develop RP in the future.
Translational Relevance
The combined approach of comprehensive molecular analysis of individual genomes and noninvasive cellular resolution retinal imaging enhances the current repertoire of clinical diagnostic tools, giving a substantial impetus to personalized medicine.
PMCID: PMC3763889  PMID: 24049715
exome sequencing; adaptive optics; rhodopsin mutations; retinitis pigmentosa; retinal degeneration
15.  Subclinical Photoreceptor Disruption in Response to Severe Head Trauma 
Archives of Ophthalmology  2012;130(3):400-402.
PMCID: PMC3329123  PMID: 22411676
Spectral-Domain Optical Coherence Tomography; Ocular Trauma; Commotio Retinae; Adaptive Optics; Photoreceptors; Retina
16.  Spectral Domain Optical Coherence Tomography and Adaptive Optics: Imaging Photoreceptor Layer Morphology to Interpret Preclinical Phenotypes 
Recent years have seen the emergence of advances in imaging technology that enable in vivo evaluation of the living retina. Two of the more promising techniques, spectral domain optical coherence tomography (SD-OCT) and adaptive optics (AO) fundus imaging provide complementary views of the retinal tissue. SD-OCT devices have high axial resolution, allowing assessment of retinal lamination, while the high lateral resolution of AO allows visualization of individual cells. The potential exists to use one modality to interpret results from the other. As a proof of concept, we examined the retina of a 32 year-old male, previously diagnosed with a red-green color vision defect. Previous AO imaging revealed numerous gaps throughout his cone mosaic, indicating that the structure of a subset of cones had been compromised. Whether the affected cells had completely degenerated or were simply morphologically deviant was not clear. Here an AO fundus camera was used to re-examine the retina (~6 years after initial exam) and SD-OCT to examine retinal lamination. The static nature of the cone mosaic disruption combined with the normal lamination on SD-OCT suggests that the affected cones are likely still present.
PMCID: PMC3444150  PMID: 20238030
17.  Retinal imaging using commercial broadband optical coherence tomography 
To examine the practical improvement in image quality afforded by a broadband light source in a clinical setting and to define image quality metrics for future use in evaluating spectral domain optical coherence tomography (SD-OCT) images.
A commercially available SD-OCT system, configured with a standard source as well as an external broadband light source, was used to acquire 4 mm horizontal line scans of the right eye of 10 normal subjects. Scans were averaged to reduce speckling and multiple retinal layers were analysed in the resulting images.
For all layers there was a significant improvement in the mean local contrast (average improvement by a factor of 1.66) when using the broadband light source. Intersession variability was shown not to be a major contributing factor to the observed improvement in image quality obtained with the broadband light source. We report the first observation of sublamination within the inner plexiform layer visible with SD-OCT.
The practical improvement with the broadband light source was significant, although it remains to be seen what the utility will be for diagnostic pathology. The approach presented here serves as a model for a more quantitative analysis of SD-OCT images, allowing for more meaningful comparisons between subjects, clinics and SD-OCT systems.
PMCID: PMC3326395  PMID: 19770161
18.  Photoreceptor Structure and Function in Patients with Congenital Achromatopsia 
Assessment of retinal structure and function in achromatopsia may be useful for the selection of patients for future therapeutic trials and for monitoring therapeutic efficacy.
To assess photoreceptor structure and function in patients with congenital achromatopsia.
Twelve patients were enrolled. All patients underwent a complete ocular examination, spectral-domain optical coherence tomography (SD-OCT), full-field electroretinographic (ERG), and color vision testing. Macular microperimetry (MP; in four patients) and adaptive optics (AO) imaging (in nine patients) were also performed. Blood was drawn for screening of disease-causing genetic mutations.
Mean (±SD) age was 30.8 (±16.6) years. Mean best-corrected visual acuity was 0.85 (±0.14) logarithm of the minimal angle of resolution (logMAR) units. Seven patients (58.3%) showed either an absent foveal reflex or nonspecific retinal pigment epithelium mottling to mild hypopigmentary changes on fundus examination. Two patients showed an atrophic-appearing macular lesion. On anomaloscopy, only 5 patients matched over the entire range from 0 to 73. SD-OCT examination showed a disruption or loss of the macular inner/outer segments (IS/OS) junction of the photoreceptors in 10 patients (83.3%). Seven of these patients showed an optically empty space at the level of the photoreceptors in the fovea. AO images of the photoreceptor mosaic were highly variable but significantly disrupted from normal. On ERG testing, 10 patients (83.3%) showed evidence of residual cone responses to a single-flash stimulus response. The macular MP testing showed that the overall mean retinal sensitivity was significantly lower than normal (12.0 vs. 16.9 dB, P < 0.0001).
The current approach of using high-resolution techniques to assess photoreceptor structure and function in patients with achromatopsia should be useful in guiding selection of patients for future therapeutic trials as well as monitoring therapeutic response in these trials.
PMCID: PMC3183969  PMID: 21778272
19.  Topographical Choroidal Thickness Change Following PDT for CSC: An OCT Case Report 
Journal of Ophthalmology  2012;2012:347206.
Purpose. To describe topographical changes in choroidal thickness as measured by optical coherence tomography following photodynamic therapy (PDT) for central serous chorioretinopathy (CSC). Methods. Case report. Results. By 1 month following PDT, mean (SD) choroidal thickness decreased from 562 microns (24) to 424 microns (27) (P < 0.01) at 3 mm temporal to fovea, 483 microns (9) to 341 microns (21) (P < 0.01) at 1.5 mm temporal to fovea, 576 microns (52) to 370 microns (81) (P < 0.01) under the fovea, 442 microns (30) to 331 microns (54) (P < 0.04) at 1.5 mm nasal to fovea, and 274 microns (39) to 171 microns (17) (P < 0.01) at 3 mm nasal to fovea. The Location of greatest choroidal thickness (648 microns) prior to treatment was at point of leakage on fluorescein angiogram (FA). This region decreased to 504 microns following treatment. Conclusion. A decrease in choroidal thickness can be seen following PDT for CSC as far as 3 mm temporal and 3 mm nasal to fovea. The Location of greatest choroidal thickness may be at point of leakage on FA.
PMCID: PMC3265181  PMID: 22292111
20.  Adaptive Optics Retinal Imaging: Emerging Clinical Applications 
The human retina is a uniquely accessible tissue. Tools like scanning laser ophthalmoscopy (SLO) and spectral domain optical coherence tomography (SD-OCT) provide clinicians with remarkably clear pictures of the living retina. While the anterior optics of the eye permit such non-invasive visualization of the retina and associated pathology, these same optics induce significant aberrations that in most cases obviate cellular-resolution imaging. Adaptive optics (AO) imaging systems use active optical elements to compensate for aberrations in the optical path between the object and the camera. Applied to the human eye, AO allows direct visualization of individual rod and cone photoreceptor cells, RPE cells, and white blood cells. AO imaging has changed the way vision scientists and ophthalmologists see the retina, helping to clarify our understanding of retinal structure, function, and the etiology of various retinal pathologies. Here we review some of the advances made possible with AO imaging of the human retina, and discuss applications and future prospects for clinical imaging.
PMCID: PMC3017557  PMID: 21057346
imaging; adaptive optics; retina; pathology; photoreceptors
21.  Integrity of the Cone Photoreceptor Mosaic in Oligocone Trichromacy 
Oligocone trichromacy (OT) is an unusual cone dysfunction syndrome associated with normal or near-normal color vision. In this paper, the authors describe novel observations on the underlying structural basis of OT at the level of the cone mosaic.
Oligocone trichromacy (OT) is an unusual cone dysfunction syndrome characterized by reduced visual acuity, mild photophobia, reduced amplitude of the cone electroretinogram with normal rod responses, normal fundus appearance, and normal or near-normal color vision. It has been proposed that these patients have a reduced number of normal functioning cones (oligocone). This paper has sought to evaluate the integrity of the cone photoreceptor mosaic in four patients previously described as having OT.
Retinal images were obtained from two brothers (13 and 15 years) and two unrelated subjects, one male (47 years) and one female (24 years). High-resolution images of the cone mosaic were obtained using high-speed adaptive optics (AO) fundus cameras. Visible structures were analyzed for density using custom software. Additional retinal images were obtained using spectral domain optical coherence tomography (SD-OCT), and the four layers of the photoreceptor-retinal pigment epithelium complex (ELM, IS/OS, RPE1, RPE2) were evaluated. Cone photoreceptor length and the thickness of intraretinal layers were measured and compared to previously published normative data.
The adult male subject had infantile onset nystagmus while the three other patients did not. In the adult male patient, a normal appearing cone mosaic was observed. However, the three other subjects had a sparse mosaic of cones remaining at the fovea, with no structure visible outside the central fovea. On SD-OCT, the adult male subject had a very shallow foveal pit, with all major retinal layers being visible, and both inner segment (IS) and outer segment (OS) length were within normal limits. In the other three patients, while all four layers were visible in the central fovea and IS length was within normal limits, the OS length was significantly decreased. Peripherally the IS/OS layer decreased in intensity, and the RPE1 layer was no longer discernable, in keeping with the lack of cone structure observed on AO imaging outside the central fovea.
Findings are consistent with the visual deficits being caused by a reduced number of healthy cones in the two brothers and the adult female. In the unrelated adult subject, no structural basis for the disorder was found. These data suggest two distinct groups on the basis of structural imaging. It is proposed that the former group with evidence of a reduction in cone numbers is more in keeping with typical OT, with the latter group representing an OT-like phenotype. These two groups may be difficult to readily discern on the basis of phenotypic features alone, and high-resolution imaging may be an effective way to distinguish between these phenotypes.
PMCID: PMC3175968  PMID: 21436275
22.  Hemorrhagic Retinoschisis in Shaken Baby Syndrome Imaged with Spectral Domain Optical Coherence Tomography 
Spectral domain optical coherence tomography (SD-OCT) images from an infant victim of shaken baby syndrome who presented with vitreous hemorrhage in the left eye and bilateral, large hemorrhages over both maculae. Both RetCam and SD-OCT images were obtained, demonstrating the position of the blood beneath the internal limiting membrane of the right macula. Image registration software was used to register the photographic images with the surface projection images obtained by the SD-OCT. In the left eye, the vitreous hemorrhage was removed with vitrectomy, and the retinoschisis cavity incised to allow drainage.
PMCID: PMC3182288  PMID: 20337286
23.  Assessing Errors Inherent in OCT-Derived Macular Thickness Maps 
Journal of Ophthalmology  2011;2011:692574.
SD-OCT has become an essential tool for evaluating macular pathology; however several aspects of data collection and analysis affect the accuracy of retinal thickness measurements. Here we evaluated sampling density, scan centering, and axial length compensation as factors affecting the accuracy of macular thickness maps. Forty-three patients with various retinal pathologies and 113 normal subjects were imaged using Cirrus HD-OCT. Reduced B-scan density was associated with increased interpolation error in ETDRS macular thickness plots. Correcting for individual differences in axial length revealed modest errors in retinal thickness maps, while more pronounced errors were observed when the ETDRS plot was not positioned at the center of the fovea (which can occur as a result of errant fixation). Cumulative error can exceed hundreds of microns, even under “ideal observer” conditions. This preventable error is particularly relevant when attempting to compare macular thickness maps to normative databases or measuring the area or volume of retinal features.
PMCID: PMC3157761  PMID: 21869920
24.  Spatial and temporal variation of rod photoreceptor reflectance in the human retina 
Biomedical Optics Express  2011;2(9):2577-2589.
Using adaptive optics imaging tools to image the living retina, numerous investigators have reported temporal fluctuation in the reflectivity of individual cone photoreceptors. In addition, there is cone-to-cone (spatial) variation in reflectivity. As it has only recently become possible to image the complete rod photoreceptor mosaic in the living human retina, we sought to characterize the reflectivity of individual rods and compare their behavior to that of foveal/parafoveal cones. Across two subjects, we were able to successfully track the reflectance behavior of 1,690 rods and 1,980 cones over 12 hours. Rod and cone photoreceptors showed similar regional and temporal variability in their reflectance profiles, suggesting the presence of a common governing physiological process. Within the rod and cone mosaics, there was no sign of spatial clumping of reflectance profile behavior; that is, the arrangement of cells of a given archetypal reflectance profile within the mosaic was indistinguishable from random. These data demonstrate the ability to track the behavior of rod reflectivity over time. Finally, as these and other reflectance changes may be an indicator of photoreceptor function, a future extension of this method will be to analyze this behavior in patients with rod photoreceptor dysfunction (e.g., retinitis pigmentosa, Usher’s syndrome, and congenital stationary night blindness).
PMCID: PMC3184867  PMID: 21991550
(110.1080) Active or adaptive optics; (170.2655) Functional monitoring and imaging; (170.3880) Medical and biological imaging; (330.7331) Visual optics, receptor optics; (330.5310) Vision-photoreceptors
25.  Race- and Sex-Related Differences in Retinal Thickness and Foveal Pit Morphology 
This study provides key insight into the underlying mechanism behind the reported race- and sex-related differences in retinal thickness. Variation in foveal pit morphology is shown to underlie apparent racial differences in central retinal thickness.
To examine sex- and race-associated differences in macular thickness and foveal pit morphology by using spectral-domain optical coherence tomography (SD-OCT).
One hundred eighty eyes of 90 healthy patients (43 women, 47 men) underwent retinal imaging with spectral-domain OCT. The lateral scale of each macular volume scan was corrected for individual differences in axial length by ocular biometry. From these corrected volumes, Early Treatment Diabetic Retinopathy Study (ETDRS) grids of retinal thickness were generated and compared between the groups. Foveal morphology was measured with previously described algorithms.
Compared with the Caucasians, the Africans and African Americans had reduced central subfield thickness. Central subfield thickness was also reduced in the women compared with the men, although the women also showed significant thinning in parafoveal regions. There was no difference between the sexes in foveal pit morphology; however, the Africans/African Americans had significantly deeper and broader foveal pits than the Caucasians.
Previous studies have reported race- and sex-associated differences in macular thickness, and the inference has been that these differences represent similar anatomic features. However, the data on pit morphology collected in the present study reveal an important and significant variation. Between the sexes, the differences are due to global variability in retinal thickness, whereas the variation in thickness observed between the races appears to be driven by differences in foveal pit morphology. These differences have important implications for the use of SD-OCT in detecting and diagnosing retinal disease.
PMCID: PMC3053303  PMID: 20861480

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