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1.  X-linked cone dystrophy and colour vision deficiency arising from a missense mutation in a hybrid L/M cone opsin gene 
Vision research  2013;80:41-50.
In this report, we describe a male subject who presents with a complex phenotype of myopia associated with cone dysfunction and a protan vision deficiency. Retinal imaging demonstrates extensive cone disruption, including the presence of non-waveguiding cones, an overall thinning of the retina, and an irregular mottled appearance of the hyper reflective band associated with the inner segment ellipsoid portion of the photoreceptor. Mutation screening revealed a novel p.Glu41Lys missense mutation in a hybrid L/M opsin gene. Spectral analysis shows that the mutant opsin fails to form a pigment in vitro and fails to be trafficked to the cell membrane in transfected Neuro2a cells. Extensive sequence and quantitative PCR analysis identifies this mutant gene as the only gene present in the affected subject’s L/M opsin gene array, yet the presence of protanopia indicates that the mutant opsin must retain some activity in vivo. To account for this apparent contradiction, we propose that a limited amount of functional pigment is formed within the normal cellular environment of the intact photoreceptor, and that this requires the presence of chaperone proteins that promote stability and normal folding of the mutant protein.
PMCID: PMC3594517  PMID: 23337435
Colour vision; visual pigments; dichromacy; opsin mutation; cone dysfunction; retinal imaging
2.  Relationship Between Foveal Cone Structure and Clinical Measures of Visual Function in Patients With Inherited Retinal Degenerations 
To study the relationship between cone spacing and density and clinical measures of visual function near the fovea.
High-resolution images of the photoreceptor mosaic were obtained with adaptive optics scanning laser ophthalmoscopy from 26 patients with inherited retinal degenerations. Cone spacing measures were made close to or at the foveal center (mean [SD] eccentricity, 0.02 [0.03] degree; maximum eccentricity, 0.13 degree) and were converted to Z-scores, fraction of cones, and percentage-of-cones-below-average compared with normal values for each location (based on 37 age-similar visually normal eyes). Z-scores and percentage of cones below average were compared with best-corrected visual acuity (VA) and foveal sensitivity.
Visual acuity was significantly correlated with cone spacing (Spearman rank correlation ρ = −0.60, P = 0.003) and was preserved (≥80 letters), despite cone density measures that were 52% below normal. Foveal sensitivity showed significant correlation with cone spacing (ρ = −0.47, P = 0.017) and remained normal (≥35 decibels), despite density measures that were approximately 52% to 62% below normal.
Cone density was reduced by up to 62% below normal at or near the fovea in eyes with VA and sensitivity that remained within normal limits. Despite a significant correlation with foveal cone spacing, VA and sensitivity are insensitive indicators of the integrity of the foveal cone mosaic. Direct, objective measures of cone structure may be more sensitive indicators of disease severity than VA or foveal sensitivity in eyes with inherited retinal degenerations. ( number, NCT00254605.)
Foveal cone structure is significantly correlated with foveal sensitivity and visual acuity in patients with inherited retinal degenerations, although 52% to 62% cone density reduction may occur before abnormal changes are observed in these clinical measures of function.
PMCID: PMC3757906  PMID: 23908179
adaptive optics; cone structure; fovea; visual acuity; cone sensitivity
3.  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
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.  High-Resolution Images of Retinal Structure in Patients with Choroideremia 
To study retinal structure in choroideremia patients and carriers using high-resolution imaging techniques.
Subjects from four families (six female carriers and five affected males) with choroideremia (CHM) were characterized with best-corrected visual acuity (BCVA), kinetic and static perimetry, full-field electroretinography, and fundus autofluorescence (FAF). High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT). Coding regions of the CHM gene were sequenced.
Molecular analysis of the CHM gene identified a deletion of exons 9 to 15 in family A, a splice site mutation at position 79+1 of exon 1 in family B, deletion of exons 6 to 8 in family C, and a substitution at position 106 causing a premature stop in family D. BCVA ranged from 20/16 to 20/63 in carriers and from 20/25 to 5/63 in affected males. FAF showed abnormalities in all subjects. SD-OCT showed outer retinal layer loss, outer retinal tubulations at the margin of outer retinal loss, and inner retinal microcysts. Patchy cone loss was present in two symptomatic carriers. In two affected males, cone mosaics were disrupted with increased cone spacing near the fovea but more normal cone spacing near the edge of atrophy.
High-resolution retinal images in CHM carriers and affected males demonstrated RPE and photoreceptor cell degeneration. As both RPE and photoreceptor cells were affected, these cell types may degenerate simultaneously in CHM. These findings provide insight into the effect of CHM mutations on macular retinal structure, with implications for the development of treatments for CHM. ( number, NCT00254605.)
High-resolution retinal images in choroideremia carriers and affected males demonstrated degeneration of retinal pigment epithelial and photoreceptor cells. The findings illustrate the effect of CHM mutations on macular cone structure, with implications for the development of treatments for CHM.
PMCID: PMC3564452  PMID: 23299470
7.  In vivo imaging of human retinal microvasculature using adaptive optics scanning light ophthalmoscope fluorescein angiography 
Biomedical Optics Express  2013;4(8):1305-1317.
The adaptive optics scanning light ophthalmoscope (AOSLO) allows visualization of microscopic structures of the human retina in vivo. In this work, we demonstrate its application in combination with oral and intravenous (IV) fluorescein angiography (FA) to the in vivo visualization of the human retinal microvasculature. Ten healthy subjects ages 20 to 38 years were imaged using oral (7 and/or 20 mg/kg) and/or IV (500 mg) fluorescein. In agreement with current literature, there were no adverse effects among the patients receiving oral fluorescein while one patient receiving IV fluorescein experienced some nausea and heaving. We determined that all retinal capillary beds can be imaged using clinically accepted fluorescein dosages and safe light levels according to the ANSI Z136.1-2000 maximum permissible exposure. As expected, the 20 mg/kg oral dose showed higher image intensity for a longer period of time than did the 7 mg/kg oral and the 500 mg IV doses. The increased resolution of AOSLO FA, compared to conventional FA, offers great opportunity for studying physiological and pathological vascular processes.
PMCID: PMC3756583  PMID: 24009994
(110.1080) Active or adaptive optics; (330.5380) Physiology; (170.1610) Clinical applications; (170.3880) Medical and biological imaging; (170.4470) Ophthalmology
8.  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
9.  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
10.  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
12.  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
13.  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
14.  Visual Function and Cortical Organization in Carriers of Blue Cone Monochromacy 
PLoS ONE  2013;8(2):e57956.
Carriers of blue cone monochromacy have fewer cone photoreceptors than normal. Here we examine how this disruption at the level of the retina affects visual function and cortical organization in these individuals. Visual resolution and contrast sensitivity was measured at the preferred retinal locus of fixation and visual resolution was tested at two eccentric locations (2.5° and 8°) with spectacle correction only. Adaptive optics corrected resolution acuity and cone spacing were simultaneously measured at several locations within the central fovea with adaptive optics scanning laser ophthalmoscopy (AOSLO). Fixation stability was assessed by extracting eye motion data from AOSLO videos. Retinotopic mapping using fMRI was carried out to estimate the area of early cortical regions, including that of the foveal confluence. Without adaptive optics correction, BCM carriers appeared to have normal visual function, with normal contrast sensitivity and visual resolution, but with AO-correction, visual resolution was significantly worse than normal. This resolution deficit is not explained by cone loss alone and is suggestive of an associated loss of retinal ganglion cells. However, despite evidence suggesting a reduction in the number of retinal ganglion cells, retinotopic mapping showed no reduction in the cortical area of the foveal confluence. These results suggest that ganglion cell density may not govern the foveal overrepresentation in the cortex. We propose that it is not the number of afferents, but rather the content of the information relayed to the cortex from the retina across the visual field that governs cortical magnification, as under normal viewing conditions this information is similar in both BCM carriers and normal controls.
PMCID: PMC3585243  PMID: 23469117
15.  Developing a new Practice-based Research Network (PBRN): lessons learned and challenges ahead 
We recently completed a strategic planning process to better understand the development of our five-year-old PBRN and to identify gaps between our original vision and current progress. While many of our experiences are not new to the PBRN community, our reflections may be valuable for those developing or re-shaping PBRNs in a changing health care environment.
Lessons Learned
We learned about the importance of: (1) Shared vision and commitment to a unique patient population; (2) Strong leadership, mentorship, and collaboration; (3) Creative approaches to engaging busy clinicians and bridging the worlds of academia and community practice; (4) Harnessing data from electronic health records and navigating processes related to data protection, sharing, and ownership.
Challenges Ahead
We must emphasize research that is timely, relevant, and integrated into practice. One model supporting this goal involves a broader partnership than was initially envisioned for our PBRN, one which includes clinicians, researchers, information architects and quality improvement experts partnering to develop an Innovation Center. This Center could facilitate development of relevant research questions while also addressing ‘quick-turnaround’ needs.
Gaps remain between our PBRN’s initial vision and current reality. Closing these gaps may require future creativity in partnership building and nontraditional funding sources.
PMCID: PMC3582650  PMID: 22956690
practice-based research; community health; primary care; electronic health records; health care safety net
16.  Imaging the Photoreceptor Mosaic with Adaptive Optics - Beyond Counting Cones 
Recent years have seen an explosion in the development of novel ophthalmic imaging devices, delivering non-invasive views of the living retina. Adaptive optics (AO) imaging systems enable resolution of individual cells in the living retina. Analysis of these images has been limited to measures of cone density and regularity. Here we introduce a small case series where the information in the high-resolution image extends beyond these standard metrics. These images should serve as the basis for evolving discussion as to how best to interpret AO retinal images.
PMCID: PMC3325514  PMID: 22183364
17.  Variable optical activation of human cone photoreceptors visualized using a short coherence light source 
Optics letters  2009;34(24):3782-3784.
It has been shown that after a visible stimulus, optical oscillations of nearly all cone photoreceptors can be observed using long coherence length light and in a few cones using short coherence length light. Here, we show that after exposure to a visible stimulus, a short coherence length imaging source reveals light-evoked oscillation signals in a large number of cones. More than 80% of cones in a given retinal area are activated (modulation in the reflectance signal) after stimulation, and the pattern of their activation can be subjectively classified into one of four categories. The application of light-evoked signal detection techniques for in vivo retinal imaging may prove useful for assessing the functional status of cones in normal and diseased retinae.
PMCID: PMC3474246  PMID: 20016612
18.  Adaptive optics optical coherence tomography at 120,000 depth scans/s for non-invasive cellular phenotyping of the living human retina 
Optics express  2009;17(22):19382-19400.
This paper presents a successful combination of ultra-high speed (120,000 depth scans/s), ultra-high resolution optical coherence tomography with adaptive optics and an achromatizing lens for compensation of monochromatic and longitudinal chromatic ocular aberrations, respectively, allowing for non-invasive volumetric imaging in normal and pathologic human retinas at cellular resolution. The capability of this imaging system is demonstrated here through preliminary studies by probing cellular intraretinal structures that have not been accessible so far with in vivo, non-invasive, label-free imaging techniques, including pigment epithelial cells, micro-vasculature of the choriocapillaris, single nerve fibre bundles and collagenous plates of the lamina cribrosa in the optic nerve head. In addition, the volumetric extent of cone loss in two colour-blinds could be quantified for the first time. This novel technique provides opportunities to enhance the understanding of retinal pathogenesis and early diagnosis of retinal diseases.
PMCID: PMC3474252  PMID: 19997159
20.  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
21.  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
22.  Normality of colour vision in a compound heterozygous female carrying a protan and deutan defect 
Inherited red-green colour vision defects are quite common, affecting nearly 1 in 10 males, but are less common in women, affecting about 1 in 250. However because red-green defects are X-linked, nearly 15% of females are heterozygous carriers of red-green colour deficiency. In addition, about 1 in 150 females are “double carriers”, where both of their X chromosomes have L/M gene arrays encoding a red-green defect. If a woman carries the same type of colour vision defect on each X-chromosome, she herself will be red-green colour deficient, whereas if she carries opposing defects (protan vs. deutan) on each X chromosome she will be trichromatic, owing to the process of X-inactivation. These women are referred to as compound heterozygotes, though very few have been reported. Moreover, questions remain as to whether the colour vision capacity of these women is comparable to that of “normal” trichromats.
We examined a compound heterozygote carrier of both protanopia and deuteranomaly. We also examined male members of her family representing both forms of red-green defect carried by the female proband. Complete colour vision testing was done, including Rayleigh matches, pseudoichromatic plates, unique hue measurements, and 100-Hue tests. Flicker-photometric ERG estimates of L:M cone ratio were obtained, as were Medmont C100 settings.
Genetic analyses provided direct confirmation of compound heterozygosity. The compound heterozygote showed Schmidt’s sign, consistent with an extreme skew in her L:M cone ratio, and usually associated with protan carrier status.
Apart from Schmidt’s sign, we found the colour vision of the compound heterozygote to be indistinguishable from that of a normal trichromat.
PMCID: PMC3328350  PMID: 19473349
Color Vision; Retina; Protan; Deutan
23.  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
24.  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
25.  Spectral-Domain Optical Coherence Tomography and Adaptive Optics may Detect Hydroxychloroquine Retinal Toxicity before Symptomatic Vision Loss 
To describe spectral-domain optical coherence tomography (SD-OCT) and adaptive optics (AO) imaging in hydroxychloroquine retinal toxicity.
Two patients with long-term hydroxychloroquine use, subtle perifoveal ophthalmoscopic pigmentary changes, and bilateral perifoveal defects on automated Humphrey visual field (HVF) 10-2 perimetry were imaged using SD-OCT and AO.
SD-OCT images demonstrated loss of photoreceptor inner segment/outer segment (IS/OS) junction and a downward “sink-hole” displacement of inner retinal structures in areas of hydroxychloroquine toxicity corresponding to HVF 10-2 defects and ophthalmoscopic clinical examination findings. SD-OCT irregularities in the IS/OS junction were also seen in areas not detected on HVF 10-2. AO images showed disruption of the cone photoreceptor mosaic in areas corresponding to HVF 10-2 defects and SD-OCT IS/OS junction abnormalities. Additionally, irregularities in the cone photoreceptor density and mosaic were seen in areas with normal HVF 10-2 and SD-OCT findings.
SD-OCT and AO detected abnormalities that correlate topographically with visual field loss from hydroxychloroquine toxicity as demonstrated by HVF 10-2 and may be useful in the detection of subclinical abnormalities that precede symptoms or objective visual field loss.
PMCID: PMC2814561  PMID: 20126479

Results 1-25 (34)