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1.  FUCHS ENDOTHELIAL CORNEAL DYSTROPHY: SUBJECTIVE GRADING VERSUS OBJECTIVE GRADING BASED ON THE CENTRAL TO PERIPHERAL THICKNESS RATIO 
Ophthalmology  2013;120(4):687-694.
Purpose
To assess inter-observer agreement between two corneal specialists grading Fuchs dystrophy clinically, and to determine if the corneal central to peripheral thickness ratio (CPTR) might be an alternative and objective metric of disease severity.
Design
Cross-sectional study.
Participants
Forty-five eyes (26 subjects) with mild and moderate Fuchs dystrophy, 73 eyes (60 subjects) with advanced Fuchs dystrophy, and 267 eyes (142 subjects) with normal corneas.
Methods
Corneas with Fuchs dystrophy were graded by two corneal specialists based on the confluence and area of guttae, and the presence or absence of edema. Central corneal thickness (CCT) and peripheral corneal thickness at 4 mm from the center (PCT4) were measured by using scanning-slit pachymetry. CPTR4 was the quotient of CCT and PCT4.
Main Outcome Measures
Inter-observer agreement for clinical grade; CPTR4.
Results
Inter-observer agreement for clinical grading of Fuchs dystrophy was moderate (κ=0.32, 95% confidence interval, 0.19-0.45). In normal corneas, CCT was not correlated with age (r= -0.10, p=0.28, n=267), PCT4 decreased with age (r= -0.33, p<0.001, n=254), and CPTR4 increased with age (r= 0.59, p<0.001, n=254). CCT was higher in Fuchs dystrophy (652 ± 61 μm, n=118) than in normal corneas (559 ± 31 μm, n=267, p<0.001). PCT4 was higher in Fuchs dystrophy (650 ± 51 μm, n=107) than in normal corneas (643 ± 43 μm, n=254, p<0.001 after adjusting thickness for age). CPTR4 was higher in advanced Fuchs dystrophy (1.03 ± 0.07, n=65) than in mild and moderate Fuchs dystrophy (0.95 ± 0.07, n=42, age-adjusted p<0.001), which in turn was higher than in normal corneas (0.87 ± 0.05, n=254, age-adjusted p<0.001). CPTR4 was highly correlated with clinical grade of Fuchs dystrophy (r=0.77, p<0.001, n=361). CPTR4 was repeatable (median coefficient of variation, 1.3%), and provided excellent discrimination between Fuchs dystrophy and normal (area under the receiver operator characteristic curve, 0.93).
Conclusions
Agreement between corneal specialists for the subjective and morphologic clinical grading of Fuchs dystrophy is only moderate. The corneal CPTR is an objective, repeatable, and possibly functional, metric of severity of Fuchs dystrophy that warrants further investigation to determine its role in monitoring disease progression and predicting the need for keratoplasty.
doi:10.1016/j.ophtha.2012.09.022
PMCID: PMC3618600  PMID: 23369486
2.  Seasonal Changes in Visual Field Sensitivity and Intraocular Pressure in the Ocular Hypertension Treatment Study 
Ophthalmology  2013;120(4):724-730.
Purpose
Longitudinal testing plays a key role in glaucoma management. Variability between visits hampers the ability to monitor progression. It has previously been shown that average intraocular pressure (IOP) exhibits seasonal fluctuations. This study examines whether visual field sensitivity also exhibits seasonal fluctuations, and seeks to determine whether such fluctuations are correlated to seasonal IOP effects.
Design
Comparative Case Series.
Participants
33873 visits by 1636 participants enrolled in the Ocular Hypertension Treatment Study. Participants were split into six geographic zones according to the prevailing climate in their location.
Testing
At each visit, standard automated perimetry was conducted on each eye, and IOP was measured.
Main Outcome Measures
Mixed effects regression models were formed to look for sinusoidal periodic effects on the change in perimetric Mean Deviation since the last visit (ΔMD), and also on IOP, both overall and within each zone.
Results
When all the data were included, a significant seasonal effect on ΔMD was found with magnitude 0.06dB, peaking in February, (p<0.001). Five of the six geographic zones exhibited significant seasonal effects on ΔMD, peaking between January and April, with magnitudes ranging from 0.04dB (p=0.049) to 0.21dB (p<0.001). Zones with greater climactic variation showed larger seasonal effects on ΔMD. All six zones exhibited a seasonal effect on IOP, peaking in January or February, with magnitudes ranging from 0.14mmHg to 0.39mmHg (p≤0.02 in all cases). However, there was no evidence of a significant association between the magnitudes or dates of peaks of the two seasonal effects.
Conclusions
MD was significantly higher in winter than summer. There is no evidence of an association with seasonal IOP fluctuations. The cause of the seasonal effect on visual field sensitivity is unknown. These findings may help shed light on the glaucomatous disease process, as well as aid efforts to reduce test-retest variability.
doi:10.1016/j.ophtha.2012.09.056
PMCID: PMC3618610  PMID: 23357622
3.  Histologic Basis of Variations in Retinal Pigment Epithelium Autofluorescence in Eyes with Geographic Atrophy 
Ophthalmology  2013;120(4):821-828.
Purpose
Lipofuscin contained in the retinal pigment epithelium (RPE) is the main source of fundus auto-fluorescence (FAF), the target of an imaging method useful for estimating the progression of geographic atrophy (GA) in clinical trials. To establish a cellular basis for hyperfluorescent GA border zones, histologic autofluorescence (HAF) was measured at defined stages of RPE pathologic progression.
Design
Experimental study.
Participants and Controls
Ten GA donor eyes (mean age ± standard deviation, 87.1±4.0 years) and 3 age-matched control eyes (mean age ± standard deviation, 84.0±7.2 years) without GA.
Methods
Ten–micrometer-thick sections were divided into zones of RPE morphologic features according to an 8-point scale. Any HAF excited by 488 nm light was imaged by laser confocal microscopy. The HAF intensity summed along vertical lines perpendicular to Bruch’s membrane at 0.2-μm intervals served as a surrogate for FAF. Intensity profiles in 151 zones were normalized to grade 0 at a standard reference location in each eye. Cross-sectional area, mean, and sum autofluorescence for individual RPE cells were measured (cellular autofluorescence [CAF]).
Main Outcome Measures
Statistically significant differences in intensity and localization of HAF and CAF at defined stages of RPE morphologic progression for GA and control eyes.
Results
The RPE morphologic features were most abnormal (cell rounding, sloughing, and layering; grade 2) and HAF intensity profiles were highest and most variable immediately adjacent to atrophic areas. Peaks in HAF intensity frequently were associated with vertically superimposed cells. The HAF value that optimally separated reactive RPE was 0.66 standard deviations more than the mean for uninvolved RPE and was associated with a sensitivity of 75.8% and a specificity of 76.3%. When variable cell area was accounted for, neither mean nor sum CAF differed significantly among the RPE pathologic grades.
Conclusions
Areas with advanced RPE alterations are most likely to exhibit clinically recognizable patterns of elevated FAF around GA, but may not predict cells about to die, because of vertically superimposed cells and cellular fragments. These data do not support a role for lipofuscin-related cell death and call into question the rationale of treatments targeting lipofuscin.
doi:10.1016/j.ophtha.2012.10.007
PMCID: PMC3633595  PMID: 23357621
4.  Retinal Ganglion Cell Count Estimates Associated with Early Development of Visual Field Defects in Glaucoma 
Ophthalmology  2012;120(4):736-744.
Purpose
To estimate retinal ganglion cell (RGC) losses associated with the earliest development of visual field defects in glaucoma.
Design
Observational cohort study.
Participants
The study group included 53 eyes of 53 patients suspected of having glaucoma who were followed as part of the Diagnostic Innovations in Glaucoma (DIGS) study. These eyes had normal standard automated perimetry (SAP) visual fields at baseline and developed repeatable (3 consecutive) abnormal tests during a median follow-up of 6.7 years. An age-matched control group of 124 eyes of 124 healthy subjects recruited from the general population was included.
Methods
Estimates of RGC counts were obtained using a previously published model which combines estimates of RGC numbers from SAP sensitivity thresholds and retinal nerve fiber layer (RNFL) thickness measurements with spectral domain optical coherence tomography (SDOCT). For eyes converting to glaucoma, estimates of RGC counts were obtained at the time (within ± 3 months) of the first abnormal visual field, representing the time of earliest detection of visual field losses.
Main Outcome Measures
Estimates of RGC counts in eyes converting to glaucoma versus healthy eyes.
Results
The average RGC count estimate in the eyes with early visual field defects was 652057 ± 115829 cells, which was significantly lower than the average of 910584 ± 142412 cells found in healthy eyes (P<0.001). Compared to the average number of RGCs in the healthy group, glaucoma eyes had an average RGC loss of 28.4%, ranging from 6% to 57%, at the time of the earliest visual field defect on SAP. RGC counts performed significantly better than the SDOCT average RNFL thickness parameter in discriminating glaucomatous from healthy eyes with ROC curve areas of 0.95 ± 0.02 versus 0.88 ±0.03, respectively (P=0.001).
Conclusion
Glaucomatous eyes with the earliest detectable visual field loss on automated perimetry may already show substantial loss of retinal ganglion cells. Empirical estimates of RGC counts combining structural and functional tests agreed closely with previous histological reports on the number of RGCs associated with early visual fields defects on SAP.
doi:10.1016/j.ophtha.2012.09.039
PMCID: PMC3804164  PMID: 23246120
5.  Investigation of genetic variation in scavenger receptor class B, member 1 (SCARB1) and association with serum carotenoids 
Ophthalmology  2013;120(8):1632-1640.
Objective
To investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD).
Design
A cross-sectional study of healthy adults aged 20-70.
Participants
302 participants recruited following local advertisement.
Methods
MPOD was measured by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by HPLC and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and CAREDS cohorts.
Main outcome measures
Odds ratios (ORs) for macular pigment optical density area, serum lutein and zeaxanthin concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and sex.
Results
Following multiple regression analysis with adjustment for age, body mass index, sex, high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides, smoking, dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P=0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P=2×10−4), a SNP in high linkage disequilibrium with rs11057841 (r2=0.93). No significant interactions by sex were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses.
Conclusions
Our study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of AMD risk through combating the effects of oxidative stress within the retina.
doi:10.1016/j.ophtha.2013.01.030
PMCID: PMC3946979  PMID: 23562302
Age-related macular degeneration; association study; lutein; macular pigment; macular pigment optical density; SCARB1; zeaxanthin
6.  Prevalence, treatment and outcomes of coexistent ocular surface squamous neoplasia and pterygium 
Ophthalmology  2012;120(3):445-450.
Purpose
The purpose of this study was to determine the prevalence of ocular surface neoplasia (OSSN) coexistent with pterygia in South Florida and to study the treatment and related outcomes.
Design
Non-interventional retrospective study.
Participants
Two thousand and five patients with surgically excised pterygia at the Bascom Palmer Eye Institute from 2000 – 2010.
Methods
Pathology reports of patients with pterygia were reviewed for evidence of OSSN. Patients were divided into the following groups: pterygium and no OSSN (group1), clinically suspected OSSN with pterygium (group 2) and unexpected OSSN with pterygium found on histopathology (group 3). Clinical charts of patients in group 2 and 3 were reviewed.
Main outcome measures
Period prevalence, treatment and outcome.
Results
In surgically excised pterygia, we found the prevalence of coexistent OSSN to be 1.7% (n=34), of which 41% (n=14) were clinically suspected preoperatively (group 2) and 59% (n=20) were unexpectedly found on histopathology (group 3). Clinically suspected OSSN with pterygia was generally treated with wide surgical margins and cryotherapy, whereas unexpected OSSN with pterygia was treated with simple excision, followed by adjuvant interferon treatment in 30% (n=6). After a mean follow up of 2 years, there were no recurrences in the suspected OSSN group and 2 recurrences in the unexpected OSSN group. The recurrence rate in the latter group was 11% at 1 year and 24% at 2 years.
Conclusion
OSSN is uncommonly found to coexist with pterygium. The prognosis in suspected OSSN cases is excellent with no recurrences noted despite positive margins in 50% of cases. The recurrence rates of unexpected OSSN mirrors that of OSSN not associated with pterygium, and thus vigilance for recurrence is important.
doi:10.1016/j.ophtha.2012.08.010
PMCID: PMC3562397  PMID: 23107578
pterygium; OSSN; CIN; intraepithelial carcinoma; conjunctiva; tumor
7.  Associations of Anisometropia with Unilateral Amblyopia, Interocular Acuity Difference and Stereoacuity in Preschoolers 
Ophthalmology  2012;120(3):495-503.
Purpose
To evaluate the relation of anisometropia with unilateral amblyopia, interocular acuity difference (IAD) and stereoacuity, among Head Start preschoolers, using both clinical notation and vector notation analyses.
Design
Multicenter, cross-sectional study.
Participants
3- to 5-year-old participants in the Vision In Preschoolers (VIP) Study (N=4040).
Methods
Secondary analysis of VIP data from participants who had comprehensive eye examinations including monocular visual acuity (VA) testing, stereoacuity testing, and cycloplegic refraction. VA was retested with full cycloplegic correction when retest criteria were met. Unilateral amblyopia was defined as IAD ≥2 lines in logarithm of the Minimum Angle of Resolution (logMAR). Anisometropia was defined as ≥0.25 D (diopter) difference in spherical equivalent (SE) or in cylinder power, and also two approaches using power vector notation. The percentage with unilateral amblyopia, mean IAD, and mean stereoacuity were compared between anisometropic and isometropic children.
Main Outcomes Measures
The percentage with unilateral amblyopia, mean IAD, and mean stereoacuity.
Results
Compared with isometropic children, anisometropic children had a higher percentage of unilateral amblyopia (8% vs. 2%), larger mean IAD (0.07 vs. 0.05 logMAR) and worse mean stereoacuity (145 vs.117 arc sec) (all p<0.0001). Larger amounts of anisometropia were associated with higher percentages of unilateral amblyopia, larger IAD, and worse stereoacuity (trend p<0.001). Percentage of unilateral amblyopia was significantly increased with spherical equivalent (SE) anisometropia >0.5 D, cylindrical anisometropia >0.25 D, the vertical/horizontal meridian (J0) or oblique meridian (J45) >0.125 D, or vector dioptric distance (VDD) >0.35 D (all p<0.001). VDD had higher ability in detecting unilateral amblyopia than cylinder, SE, J0 and J45 (p<0.001).
Conclusions
The presence of and amount of anisometropia were associated with the presence of unilateral amblyopia, larger IAD and worse stereoacuity. The threshold level of anisometropia at which unilateral amblyopia becomes significant was lower than current guidelines. VDD is more accurate than spherical equivalent anisometropia or cylindrical anisometropia in identifying preschoolers with unilateral amblyopia.
doi:10.1016/j.ophtha.2012.08.014
PMCID: PMC3582825  PMID: 23174398
8.  Incidence of Herpes Zoster Ophthalmicus: Results from the Pacific Ocular Inflammation Study 
Ophthalmology  2012;120(3):451-456.
Purpose
To provide a population-based estimate of the incidence of herpes zoster ophthalmicus (HZO) with comparisons across racial, gender, and age groups, as well as to estimate the frequency of postherpetic neuralgia (PHN).
Design
Retrospective, population-based cohort study
Participants
All patients enrolled in the Kaiser Permanente Hawaii health plan during the study period (N=217,061).
Methods
All patient encounters between January 1, 2006 and December 31, 2007 in the electronic medical record of Kaiser Permanente Hawaii were queried for International Classification of Diseases, 9th Edition (ICD9) codes corresponding to HZO. Charts were reviewed to confirm a diagnosis of HZO and to collect information on specific ocular manifestations. Demographic data and information on PHN were collected electronically. Incidence rates were calculated per 100,000 person-years for the entire population, as well as for age-, gender-, and race-specific subgroups.
Main Outcome Measure
Clinical diagnosis of HZO during the study period.
Results
One hundred thirty-four cases of HZO were identified in this population of 217,061 people. The overall incidence was 30.9 per 100,000 person-years (95% confidence interval (CI): 25.9–36.6). The incidence rate for the population 65 years of age and over was 104.6 per 100,000 person-years (95% CI: 79.0–135.9), approximately five times the remainder of the population (p<0.001). The most common manifestation of HZO was dermatitis, followed by keratitis and conjunctivitis. The incidence of HZO for Pacific Islanders was 19.0 per 100,000 person-years (95% CI: 12.4– 28.3), which was significantly lower than the rate for non-Pacific Islanders (p=0.007). Twenty-one percent of HZO patients developed PHN. Older age and HZO with keratitis, conjunctivitis, and/or uveitis were found to be risk factors for PHN.
Conclusions
This study provides a population-based estimate of HZO and highlights differences across various age and racial groups. It also suggests that demographic characteristics may be useful in determining the risk of developing HZO.
doi:10.1016/j.ophtha.2012.09.007
PMCID: PMC3594416  PMID: 23207173
9.  Pharmacogenetics for Genes Associated with Age-Related Macular Degeneration (AMD) in the Comparison of AMD Treatments Trials (CATT) 
Ophthalmology  2013;120(3):593-599.
Purpose
To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis) or bevacizumab (Avastin) for neovascular AMD.
Design
Clinical trial.
Participants
834 (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.
Methods
Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays.
Main Outcomes Measures
Genotypic frequencies were compared to clinical measures of response to therapy at one year including mean visual acuity (VA), mean change in VA, ≥15 letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, p≤0.01 was considered statistically significant.
Results
No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomical response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size) or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; i.e., response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata (PRN) dosing.
Conclusions
Although specific alleles for CFH, ARMS2, HTRA1 and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor (VEGF) therapy.
doi:10.1016/j.ophtha.2012.11.037
PMCID: PMC3633658  PMID: 23337555
10.  Enhanced Detection of Open-angle Glaucoma with an Anatomically Accurate Optical Coherence Tomography–Derived Neuroretinal Rim Parameter 
Ophthalmology  2012;120(3):535-543.
Objective
Neuroretinal rim assessment based on the clinical optic disc margin (DM) lacks a sound anatomic basis for 2 reasons: (1) The DM is not reliable as the outer border of rim tissue because of clinically and photographically invisible extensions of Bruch’s membrane (BM) inside the DM and (2) nonaccountability of rim tissue orientation in the optic nerve head (ONH). The BM opening-minimum rim width (BMO-MRW) is a parameter that quantifies the rim from its true anatomic outer border, BMO, and accounts for its variable orientation. We report the diagnostic capability of BMO-MRW.
Design
Case control.
Participants
Patients with open-angle glaucoma (n = 107) and healthy controls (n = 48).
Methods
Spectral-domain optical coherence tomography (SD-OCT) with 24 radial and 1 circumpapillary B-scans, centered on the ONH, and confocal scanning laser tomography (CSLT) were performed. The internal limiting membrane (ILM) and BMO were manually segmented in each radial B-scan. Three SD-OCT parameters were computed globally and sectorally: (1) circumpapillary retinal nerve fiber layer thickness (RNFLT); (2) BMO-horizontal rim width (BMO-HRW), the distance between BMO and ILM in the BMO reference plane; and (3) BMO-MRW, the minimum distance between BMO and ILM. Moorfields Regression Analysis (MRA) with CLST was performed globally and sectorally to yield MRA1 and MRA2, where “borderline” was classified as normal and abnormal, respectively.
Main Outcome Measures
Sensitivity, specificity, and likelihood ratios (LRs) for positive and negative test results (LR+/LR−).
Results
The median (interquartile range) age and mean deviation of patients and controls were 69.9 (64.3–76.9) and 65.0 (58.1–74.3) years and −3.92 (−7.87 to −1.62) and 0.33 (−0.32 to 0.98) dB, respectively. Globally, BMO-MRW yielded better diagnostic performance than the other parameters. At 95% specificity, the sensitivity of RNFLT, BMO-HRW, and BMO-MRW was 70%, 51%, and 81%, respectively. The corresponding LR+/LR− was 14.0/0.3, 10.2/0.5, and 16.2/0.2. Sectorally, at 95% specificity, the sensitivity of RNFLT ranged from 31% to 59%, of BMO-HRW ranged from 35% to 64%, and of BMO-MRW ranged from 54% to 79%. Globally and in all sectors, BMO-MRW performed better than MRA1 or MRA2.
Conclusions
The higher sensitivity at 95% specificity in early glaucoma of BMO-MRW compared with current BMO methods is significant, indicating a new structural marker for the detection and risk profiling of glaucoma.
doi:10.1016/j.ophtha.2012.09.055
PMCID: PMC3667974  PMID: 23265804
11.  Predicting the Onset of Glaucoma: The Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study 
Ophthalmology  2010;117(9):1674-1683.
Objective
To evaluate the predictive ability of baseline confocal scanning laser ophthalmoscopy (CSLO) Glaucoma Probability Score (GPS) for the development of primary open angle glaucoma (POAG) and to compare it to the Moorfields Regression Analysis (MRA) classification, other topographic optic disc parameters and stereophotograph- based cup-to-disc ratio.
Design
Longitudinal randomized clinical trial
Participants
857 eyes of 438 participants in the CSLO Ancillary Study to the Ocular Hypertension Treatment Study (OHTS) with good quality baseline CSLO images.
Methods
The ability of baseline GPS, MRA and optic disc parameters to predict the development of POAG was evaluated in univariate and multivariable proportional hazard ratio analyses. Likelihood ratios and positive and negative predictive values were compared
Main Outcome Measures
POAG end point as determined by repeatable changes in the visual field or optic disc.
Results
Sixty-four eyes of 50 CSLO Ancillary Study participants developed POAG. Median time to reach a POAG endpoint was 72.3 months . The 93 eyes of 388 participants not reaching endpoint were followed for a median124.9 months. Baseline GPS identified many more eyes as outside normal limits than the MRA. In multivariable analyses, all regional and global baseline GPS indices were significantly associated with the development of POAG; hazard ratios (95% confidence interval [CI]) ranged from 2.92 to 3.74 for an outside normal limit result. MRA indices were also significantly associated with the development of POAG in multivariable analyses. In addition, the predictive ability of baseline GPS, MRA and stereometric parameters were similar to the predictive ability of models using photograph-based horizontal cup-to-disc ratio.
Conclusion
These results suggest that baseline GPS, MRA and stereoparameters alone or when combined with baseline clinical and demographic factors can be used to predict the development of POAG endpoints in OHTS participants and are as effective as stereophotographs for estimating the risk of developing POAG in ocular hypertensive subjects.
doi:10.1016/j.ophtha.2010.03.044
PMCID: PMC3938159  PMID: 20633931
12.  Retinopathy of Prematurity Residency Training 
Ophthalmology  2012;119(12):2644-5.e1-2.
doi:10.1016/j.ophtha.2012.07.015
PMCID: PMC3921178  PMID: 23207022
13.  The Future of Uveitis Treatment 
Ophthalmology  2013;121(1):365-376.
doi:10.1016/j.ophtha.2013.08.029
PMCID: PMC3913649  PMID: 24169255
14.  Evaluation of Inner Retinal Layers in Patients with Multiple Sclerosis or Neuromyelitis Optica Using Optical Coherence Tomography 
Ophthalmology  2012;120(2):387-394.
Purpose
To evaluate the thickness of the inner retinal layers in the macula using frequency domain-optical coherence tomography (fd-OCT) in patients with demyelinating diseases.
Design
Cross sectional study
Participants
301 eyes of 176 subjects were evaluated. Subjects were divided in 5 different groups: controls, neuromyelitis optica (NMO), longitudinally extensive transverse myelitis (LETM), multiple sclerosis with (MS-ON) and without (MS non-ON) history of optic neuritis, respectively.
Methods
The individual layers from macular fd-OCT cube scans were segmented with an automated algorithm, and then manually hand-corrected. For each scan, we determined the thickness of the retinal nerve fiber layer (RNFL), the combined retinal ganglion cell and inner plexiform layers (RGCL+), and the inner nuclear layer (INL).
Main outcome measures
Macular RNFL, RGCL+ and INL thickness
Results
The RNFL was significantly thinner than controls for all patient groups (p≤0.01). Macular RGCL+ thickness was significantly thinner than controls for the NMO, MS-ON and MS non-ON (p<0.001 for the 3 groups). The INL thickness was significantly thicker than controls for the NMO (p=0.003) and LETM (p=0.006) patients but not for MS-ON or MS non-ON. While the RNFL and RGCL+ were not significantly different between the NMO and MS-ON groups, the NMO patients had a significantly thicker INL than the MS-ON (p=0.02) patients.
Conclusion
Macular RNFL and RGCL+ demonstrate axonal and neural loss in MS, either with or without ON, and in NMO patients. In addition, the INL thickening occurs in NMO and LETM patients and study of this layer may hold promise for differentiating between NMO and MS.
doi:10.1016/j.ophtha.2012.07.066
PMCID: PMC3554837  PMID: 23084127
15.  Descemet stripping automated endothelial keratoplasty 3-year graft and endothelial cell survival compared with penetrating keratoplasty 
Ophthalmology  2012;120(2):246-251.
Purpose
To assess 3-year outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) in comparison with penetrating keratoplasty (PKP) from the Cornea Donor Study (CDS).
Design
Prospective, multicenter, nonrandomized clinical trial.
Participants
A total of 173 subjects undergoing DSAEK for a moderate risk condition (principally Fuchs’ dystrophy or pseudophakic corneal edema) compared with 1101 subjects undergoing PKP from the CDS.
Methods
The DSAEK procedures were performed by two experienced surgeons using the same donor and similar recipient criteria as for the CDS PKP procedures, performed by 68 surgeons. Graft success was assessed by Kaplan Meier survival analysis. Central endothelial cell density (ECD) was determined from baseline donor and postoperative central endothelial images by the reading center used in the CDS Specular Microscopy Ancillary Study.
Main Outcome Measures
Graft clarity and endothelial cell density
Results
The donor and recipient demographics were comparable in the DSAEK and PKP groups, except the proportion of Fuchs’ dystrophy cases was higher in the DSAEK cohort. The 3-year survival rate did not differ significantly between DSAEK and PKP procedures performed for either Fuchs’ dystrophy (96% for both, P=0.81) or non-Fuchs cases (86% vs. 84%, respectively, P=0.41). Principal causes of graft failure/regraft within 3 years after DSAEK and PKP were immunologic graft rejection (0.6% vs. 3.1%), endothelial decompensation in the absence of documented rejection (1.7% vs 2.1%), unsatisfactory visual or refractive outcome (1.7% vs. 0.5%), and infection (0% vs. 1.1%), respectively. The 3-year predicted probability of a rejection episode was 9% with DSAEK vs. 20% with PKP (P=0.0005). The median 3-year cell loss for DSAEK and PKP was 46% and 51%, respectively (P=0.33) in Fuchs’s dystrophy cases, and 59% and 61%, respectively (P=0.70), in the non-Fuchs’ cases. At 3 years, use of a smaller DSAEK insertion incision was associated with significantly higher cell loss (60% vs. 33% for 3.2- and 5.0-mm incisions, respectively, P=0.0007) but not a significant difference in graft survival (P=0.45).
Conclusions
The graft success rate and endothelial cell loss were comparable at 3 years for DSAEK and PKP procedures. A 5-mm DSAEK incision width was associated with significantly less cell loss than a 3.2-mm incision.
doi:10.1016/j.ophtha.2012.08.007
PMCID: PMC3562557  PMID: 23107581
Descemet stripping endothelial keratoplasty; posterior lamellar keratoplasty; DSAEK; DSEK endothelial cell loss
16.  Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the AREDS study 
Ophthalmology  2012;120(2):298-305.
Purpose
A previous study of Old Order Amish families has shown association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. We conducted a candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions.
Design
Candidate gene genetic association study.
Participants
2,000 participants drawn from the Age Related Eye Disease Study (AREDS) were chosen for genotyping. After quality control filtering, 1912 individuals were available for analysis.
Methods
Microarray genotyping was performed using the HumanOmni 2.5 bead array. SNPs originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction (MSE) were performed on 30 markers using linear regression models and an additive genetic risk model, while adjusting for age, sex, education, and population substructure. Post-hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P-emp) and multiple-test study-wise (P-multi) significance levels were calculated empirically through permutation.
Main outcome measures
MSE was used as a quantitative measure of ocular refraction.
Results
The mean age and ocular refraction were 68 years (SD=4.7) and +0.55 D (SD=2.14), respectively. Pointwise statistical significance was obtained for rs1939008 (P-emp=0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower-education group: 2 of these were statistically significant after multiple testing correction. The two highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P-emp<0.01 in the lower-education stratum of AREDS participants.
Conclusions
We show suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. We also provide evidence of a gene-environment interaction between previously-reported markers and education on refractive error. Variants in MMP1- MMP10 and MMP2 regions appear to affect population variation in ocular refraction in environmental conditions less favorable for myopia development.
doi:10.1016/j.ophtha.2012.07.078
PMCID: PMC3563738  PMID: 23098370
refraction; refractive error; myopia; association study; gene-environment interaction; matrix metalloproteinase; MMP; genetics
17.  A Longitudinal Analysis of Risk Factors Associated With Central Retinal Vein Occlusion 
Ophthalmology  2012;120(2):362-370.
Purpose
To identify risk factors associated with central retinal vein occlusion (CRVO) among a diverse group of patients throughout the United States
Design
Longitudinal cohort study
Participants
All beneficiaries age ≥ 55 years who were continuously enrolled in a managed care network for at least ≥2 years and who had 2 visits to an eye care provider from 2001–2009
Methods
Insurance billing codes were used to identify individuals with a newly-diagnosed CRVO. Multivariable Cox regression was performed to determine factors associated with CRVO development.
Main Outcome Measure
Adjusted hazard ratios (HR) with 95% confidence intervals (CI) of being diagnosed with CRVO
Results
Of the 494,165 enrollees who met the study inclusion criteria, 1,302 (0.26%) were diagnosed with CRVO over 5.4 (±1.8) years. After adjustment for known confounders, blacks had a 57% increased risk of CRVO compared with whites (HR = 1.57 [95% CI: 1.25–1.98]) and females had a 24% decreased risk of CRVO compared with males (HR = 0.76 [95% CI: 0.67–0.85]). A diagnosis of stroke increased the hazard of CRVO by 45% (HR = 1.45 [95% CI: 1.24–1.70]) and hypercoagulable state was associated with a 146% increased CRVO risk (HR = 2.46 [95% CI: 1.41–4.29]). Individuals with end-organ damage from hypertension (HTN) or diabetes mellitus (DM) had a 90% (HR = 1.90 [95% CI: 1.50–2.41]) and 53% (HR = 1.53 [95% CI: 1.28–1.84]) increased risk of CRVO, respectively, relative to those without these conditions.
Conclusion
This study confirms that HTN and vascular diseases are important risk factors for CRVO. We also identify black race as a predictor of CRVO that was not well-appreciated previously. Furthermore, we show that compared to patients without DM, individuals with end-organ damage from DM (i.e., “complicated” cases) have a heightened risk of CRVO, while those with uncomplicated DM are not at increased risk of CRVO. This finding may provide a potential explanation for the conflicting reports in the literature on the association between CRVO and DM. Information from analyses like this can be used to create a risk calculator to identify individuals at greatest risk for CRVO.
doi:10.1016/j.ophtha.2012.07.080
PMCID: PMC3563864  PMID: 23177364
18.  Diagnosing Ocular Surface Squamous Neoplasia in East Africa 
Ophthalmology  2014;121(2):484-491.
Objective
To examine the reliability of clinical examination and in vivo confocal microscopy (IVCM) in distinguishing ocular surface squamous neoplasia (OSSN) from benign conjunctival lesions.
Design
Case-control study.
Participants
Sixty individuals with conjunctival lesions (OSSN and benign) and 60 age-matched controls with normal conjunctiva presenting to Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
Methods
Participants were examined and photographed, and IVCM was performed. Patients with conjunctival lesions were offered excisional biopsy with histopathology and a human immunodeficiency virus (HIV) test. The IVCM images were read masked to the clinical appearance and pathology results. Images were graded for several specific features and given an overall categorization (normal, benign, or malignant). A group of 8 ophthalmologists were shown photographs of conjunctival lesions and asked to independently classify as OSSN or benign.
Main Outcome Measures
Comparison of the histopathology diagnosis with the clinical and IVCM diagnosis.
Results
Fifty-two cases underwent excisional biopsy with histopathology; 34 were on the OSSN spectrum, 17 were benign, and 1 was lymphoma. The cases and controls had comparable demographic profiles. Human immunodeficiency syndrome infection was more common in OSSN compared with benign cases (58.8% vs. 5.6%; odds ratio, 24.3, 95% confidence interval [CI], 2.8–204; P = 0.003). Clinically, OSSN lesions more frequently exhibited feeder vessels and tended to have more leukoplakia and a gelatinous appearance. Overall, the ophthalmologists showed moderate agreement with the histology result (average kappa = 0.51; 95% CI, 0.36–0.64). The masked grading of IVCM images reliably distinguished normal conjunctiva. However, IVCM was unable to reliably distinguish between benign lesions and OSSN because of an overlap in their appearance (kappa = 0.44; 95% CI, 0.32–0.57). No single feature was significantly more frequent in OSSN compared with benign lesions. The sensitivity and specificity of IVCM for distinguishing OSSN from benign conjunctival lesions were 38.5% and 66.7%, respectively.
Conclusions
In East Africa, conjunctival pathology is relatively common and can present significant diagnostic challenges for the clinician. In this study, neither clinical examination nor IVCM was found to reliably distinguish OSSN from benign conjunctival pathology because of an overlap in the features of these groups. Therefore, IVCM cannot currently replace histopathology, and management decisions should continue to rely on careful clinical assessment supported by histopathology as indicated.
doi:10.1016/j.ophtha.2013.09.027
PMCID: PMC3901930  PMID: 24321141
19.  Defining real change in measures of stereoacuity 
Ophthalmology  2008;116(2):281-285.
Purpose
To establish the thresholds for “real change” in stereoacuity by defining long term test-retest variability as 95% limits of agreement for four stereoacuity tests.
Design
Retrospective cohort study.
Participants and/or Controls
We identified 36 patients (median age 17 years, range 7 to 76 years) with any type of stable strabismus who had stereoacuity measured on two consecutive visits. Stable strabismus was defined as angle of deviation within 5 prism diopters (pd) by simultaneous prism and cover test (SPCT) and prism and alternating cover test (PACT).
Methods
Stereoacuity was measured at near using the Preschool Randot and the near Frisby stereotests and at distance using the Frisby Davis Distance (FD2) and the Distance Randot stereotests. Stereoacuity was transformed to log units for analysis. 95% limits of agreement were calculated based on a 1.96 multiple of the standard deviation of differences between test and retest.
Main Outcome Measures
95% limits of agreement for change in stereoacuity thresholds at two consecutive visits.
Results
95% limits of agreement were 0.59 log arcsec for the Preschool Randot, 0.24 for the near Frisby, 0.68 for the FD2, and 0.46 for the Distance Randot. These values correspond to the following octave steps (doublings of threshold; for example, 200 to 400 arcsec): Preschool Randot 1.95, near Frisby 0.78, FD2 2.27, and Distance Randot 1.52.
Conclusions
A change of approximately two octaves of stereoacuity threshold are needed to exceed test-retest variability for most stereoacuity tests. Changes less than two octaves cannot be distinguished from test-retest variability. When used to guide patient management, caution should be taken in interpreting changes in stereoacuity of less than two octaves.
doi:10.1016/j.ophtha.2008.09.012
PMCID: PMC3903340  PMID: 19091410
20.  Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes  
Ophthalmology  2012;119(9):1874-1885.
Purpose
To investigate whether the two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy (GA), segregate separately in families and to identify which genetic variants are associated with these two subtypes.
Design
Sibling correlation study and genome-wide association study (GWAS)
Participants
For the sibling correlation study, we included 209 sibling pairs with advanced AMD. For the GWAS, we included 2594 participants with advanced AMD subtypes and 4134 controls. Replication cohorts included 5383 advanced AMD participants and 15,240 controls.
Methods
Participants had AMD grade assigned based on fundus photography and/or examination. To determine heritability of advanced AMD subtypes, we performed a sibling correlation study. For the GWAS, we conducted genome-wide genotyping and imputed 6,036,699 single nucleotide polymorphism (SNPs). We then analyzed SNPs with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.
Main Outcome Measures
Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.
Results
The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P=4.2 x 10−5) meaning that siblings of probands with CNV or GA are more likely to develop CNV or GA, respectively. In the analysis comparing participants with CNV to those with GA, we observed a statistically significant association at the ARMS2/HTRA1 locus [rs10490924, odds ratio (OR)=1.47, P=4.3 ×10−9] which was confirmed in the replication samples (OR=1.38, P=7.4 x 10−14 for combined discovery and replication analysis).
Conclusions
Whether a patient with AMD develops CNV vs. GA is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations which differ for advanced AMD subtypes and deserve follow-up in additional studies.
doi:10.1016/j.ophtha.2012.03.014
PMCID: PMC3899891  PMID: 22705344
21.  Comparing outcome criteria performance in adult strabismus surgery 
Ophthalmology  2012;119(9):1930-1936.
Purpose
To evaluate the performance of motor, diplopia and health-related quality of life (HRQOL) criteria when analyzing outcomes in adult strabismus surgery.
Design
Cohort study
Participants
159 adults undergoing 171 strabismus surgeries
Methods
All patients underwent clinical assessment preoperatively and 6-weeks postoperatively, including completion of Adult Strabismus-20 (AS-20) HRQOL questionnaires. Preoperatively, strabismus was classified as either diplopic (n=117), non-diplopic (n=38) or atypical diplopic (n=16). To assess performance of motor, diplopia and HRQOL criterion, definitions of success were agreed a priori and applied separately, and in combinations. For success: 1) Motor criteria: <10 prism diopters by simultaneous prism cover test); 2) Diplopia criteria: none or only rare in primary distance and for reading; 3) HRQOL criteria: exceeding previously reported 95% limits of agreement.
Main outcome measures
Surgical success rate when applying motor, diplopia, and HRQOL criteria alone and in combinations.
Results
Overall, success rates were 90% for motor criteria, 74% for diplopia criteria and 60% for HRQOL criteria. Combining criteria, the highest success rate was for motor and diplopia criteria (67%) and the lowest success rate was when combining motor, diplopia, and HRQOL criteria (50%).
Conclusions
Applying motor criteria alone yields highest success rates when evaluating outcomes in adult strabismus surgery, but motor criteria do not fully represent the patient's postoperative status. Combining diplopia criteria with motor criteria provides a more clinically relevant standard for judging the success of adult strabismus surgery. For HRQOL criteria, exceeding 95% limits of agreement, at 6 weeks postoperatively, appears a difficult hurdle to clear for some individual patients, and evaluating change in HRQOL score may be more useful in cohort studies.
doi:10.1016/j.ophtha.2012.02.035
PMCID: PMC3895469  PMID: 22541935
22.  The Impact of Fish and Shellfish Consumption on Age-Related Macular Degeneration 
Ophthalmology  2010;117(12):2395-2401.
Purpose
To determine the relationship between fish and shellfish consumption and age-related macular degeneration (AMD) status in the Salisbury Eye Evaluation (SEE) Study participants.
Design
A cross-sectional study of dietary and ophthalmologic data.
Participants
A random sample of 2520 Salisbury, Maryland, residents aged 65 to 84 years.
Methods
A food frequency questionnaire was used to estimate weekly fish/shellfish consumption for each participant. Age-related macular degeneration status was determined from fundus photographs obtained at baseline and graded by 2 masked readers for drusen size, retinal pigment epithelium abnormalities, geographic atrophy (GA), and choroidal neovascularization (CNV). The association between weekly fish/shellfish intake and risk of AMD was investigated using logistic regression while adjusting for risk factors and correlation between eyes.
Main Outcome Measures
Status of AMD.
Results
The distribution of weekly fish/shellfish consumption was not different between specific AMD categories compared with controls (P = 0.6, 0.7, and 0.7 for large drusen, pigment abnormalities, and advanced AMD compared with controls, respectively). Those with advanced AMD (CNV or GA) were significantly less likely to consume fish/shellfish high in omega-3 fatty acids (odds ratio 0.4; confidence interval, 0.2– 0.8). There was no relationship of AMD with intake of crab and oysters combined, each of which has high levels of zinc.
Conclusions
These data support a protective effect of fish/shellfish intake against advanced AMD.
doi:10.1016/j.ophtha.2010.03.058
PMCID: PMC3894610  PMID: 20630597
23.  Comparison of the diagnostic accuracies of Spectralis, Cirrus and RTVue optical coherence tomography devices in glaucoma 
Ophthalmology  2011;118(7):10.1016/j.ophtha.2010.11.029.
Purpose
To compare the diagnostic accuracies of retinal nerve fiber layer (RNFL) thickness measurements obtained with Spectralis (Heidelberg Engineering, Dossenheim, Germany), Cirrus (Carl Zeiss Meditec, Dublin, CA) and RTVue (Optovue Inc, Fremont, CA) for the detection of glaucoma.
Design
Diagnostic, case-control study
Participants
Two hundred thirty three eyes (107 healthy, 126 glaucomatous) of 149 participants from the longitudinal Diagnostic Innovations in Glaucoma Study (DIGS) and from the African Descent and Glaucoma Evaluation Study (ADAGES).
Methods
All participants underwent retinal nerve fiber layer (RNFL) thickness imaging with Spectralis, Cirrus and RTVue in the same visit. Receiver operating characteristic (ROC) curves adjusted for age and race were obtained for quadrants (superior, nasal, inferior, temporal) and global RNFL thickness for all instruments. Areas under ROC (AUC) and sensitivities at fixed specificities (80% and 95%) were calculated and compared.
Main Outcome measure
Comparison of diagnostic accuracy using AUCs and sensitivities at fixed specificities of 80% and 95%.
Results
The RNFL thickness parameter with the largest AUCs was the superior quadrant for the Spectralis (0.88) and the global RNFL thickness for the Cirrus (0.88) and the RTVue (0.87). The pair-wise comparison among the ROC curves showed no statistical difference for all parameters except for the nasal quadrant, which had significantly larger AUC in Spectralis and RTVue compared to Cirrus (P<0.03 for both comparisons). There were no significant differences in sensitivities among the best parameters from each instrument (P>0.05). The superior quadrant thickness measured with Spectralis had sensitivity of 81.9% at a fixed specificity of 80% and 70% at a fixed specificity of 95%. The global thickness measured by the Cirrus had a sensitivity of 80.3% at a fixed specificity of 80% and 65.6% at a fixed specificity of 95%. For the RTVue, the global thickness had a sensitivity of 77.9% at a fixed specificity of 80% and 62.1% at a fixed specificity of 95%.
Conclusion
Although the spectral-domain OCTs have different resolution and acquisition rates, their ability to detect glaucoma was similar.
doi:10.1016/j.ophtha.2010.11.029
PMCID: PMC3881436  PMID: 21377735
24.  Characteristic Retinal Atrophy with Secondary “Inverse” Optic Atrophy Identifies Vigabatrin Toxicity in Children 
Ophthalmology  2004;111(10):10.1016/j.ophtha.2004.03.036.
Objective
To describe the clinical pattern of retinal atrophy in children caused by the anticonvulsant vigabatrin.
Design
An interventional case series report.
Participants
One hundred thirty-eight patients, mainly infants, were evaluated regularly for evidence of possible vigabatrin toxicity in the Eye and Neurology clinics at the Hospital for Sick Children, Toronto.
Method
Sequential clinical and electroretinographic (International Society for Clinical Electrophysiology of Vision standards) evaluations every 6 months.
Main Outcome Measures
Presence of recognizable retinal and optic atrophy in the presence of abnormal electroretinogram (ERG) and other clinical findings.
Results
Three children being treated for seizures with vigabatrin showed definite clinical findings of peripheral retinal nerve fiber layer atrophy, with relative sparing of the central or macular portion of the retina and relative nasal optic nerve atrophic changes. Some macular wrinkling was evident in 1 case. Progressive ERG changes showing decreased responses, especially the 30-Hz flicker response, supported the presence of decreased retinal function.
Conclusions
A recognizable and characteristic form of peripheral retinal atrophy and nasal or “inverse” optic disc atrophy can occur in a small number of children being treated with vigabatrin. The changes in superficial light reflexes of the retina in children facilitate the clinical recognition of nerve fiber layer atrophy. The macula is relatively spared, although superficial retinal light reflexes indicating wrinkling of the innermost retina suggest early macular toxicity as well. Because these changes are accompanied by electrophysiologic evidence of retinal dysfunction, discontinuation of vigabatrin should be strongly considered.
doi:10.1016/j.ophtha.2004.03.036
PMCID: PMC3880364  PMID: 15465561 CAMSID: cams3795
25.  Wide-Field Spectral-Domain Optical Coherence Tomography in Patients and Carriers of X-linked Retinoschisis 
Ophthalmology  2012;120(1):169-174.
Purpose
To evaluate macular and extramacular retinal anatomy in patients and carriers of X-linked retinoschisis (XLRS) utilizing a wide-field spectral-domain optical coherence tomography (SD-OCT) imaging technique.
Design
Case series
Participants
Six XLRS affected males and three XLRS female carriers.
Methods
The subjects prospectively underwent XLRS DNA genotyping and comprehensive ophthalmic examination including Visual acuity, 30-2 Humphrey visual field, fundus photography, and wide-field SD-OCT, a montage technique to generate SD-OCT images spanning approximately 50° horizontally and 35° vertically of the posterior pole.
Main Outcome Measures
distribution and location of schisis cavities
Results
Among affected XLRS males, asymmetric bilateral schisis was seen in all eyes imaged with montage SD-OCT (11 eyes). Wide-field OCT images demonstrated schisis cavities only in the central macula in 6 eyes (55%), throughout the macula extending to the outside of the temporal arcades in 3 eyes (27%), and throughout the macula extending nasal to the optic nerve in 2 eyes (18%). Cystoid spaces accounting for macular splitting were present in the inner nuclear layer (INL) in all 11 eyes and also in the outer nuclear layer (ONL) in 4 eyes. A few small cysts were seen parafoveally in the ganglion cell layer and/or nerve fiber layer (GCL/NFL) in 4 eyes. Subclinical extramacular schisis spaces were seen (n=5 eyes) within the INL in 1 eye, ONL in 1 eye, INL/GCL/NFL in 1 eye, ONL/GCL/NFL in 1 eye, and in the INL/ONL/GCL/NFL in 1 eye. Schisis was rarely seen nasal to the optic nerve (2 eyes). Central/paracentral visual field defects were seen in 9 eyes. Female carriers did not show schisis on exam or OCT.
Conclusions
Wide-field SD-OCT is a useful tool for evaluating complex retinal anatomy. In XLRS patients, the foveomacular schisis was seen most frequently in the INL. Subclinical extramacular schisis was seen in 45% eyes and was equally prevalent in the INL, ONL, and GCL/FNL. GCL/FNL cystoid spaces were very small and were seen near the fovea and the arcades only. Carriers were schisis-free.
doi:10.1016/j.ophtha.2012.07.051
PMCID: PMC3531562  PMID: 23009889

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