Chi Pui Pang

Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma

We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10−10). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.

Comparison of macular thickness measurements between time domain and spectral domain optical coherence tomography.

PURPOSE To compare macular thickness measurements obtained from time domain optical coherence tomography (OCT) and spectral domain OCT and to evaluate their repeatability and agreement. METHODS Thirty-five healthy normal subjects were included. In one randomly selected eye in each subject, three serial macular measurements were obtained from a time domain OCT (Stratus OCT, Carl Zeiss Meditec, Dublin, CA) and a spectral domain OCT (3D OCT; Topcon, Tokyo, Japan) by an experienced technician in random order. Total and regional macular thicknesses obtained by the two OCTs were compared. Their agreement was examined with Bland-Altman plots. Repeatability (2.77 x within subject SD [Sw]), coefficient of variation (CVw; Sw/overall mean), and intraclass correlation coefficient (ICC) were calculated to evaluate repeatability. RESULTS Low variability for macular thickness measurements was found in both time domain and spectral domain OCTs. The range of the respective CVw and ICC values were 1.6% to 3.2% and 0.85 to 0.91 for Stratus OCT and 0.6% to 2.4% and 0.92 to 0.99 for 3D OCT. 3D OCT demonstrated better repeatability for total and regional macular thicknesses (all with P <or= 0.014). The foveal and total macular thicknesses measured by 3D OCT were significantly greater than those measured by Stratus OCT (both with P < 0.001). The spans of 95% limits of agreement for foveal and total macular thicknesses were 33.9 and 21.3 mum, respectively. CONCLUSIONS Although both time domain and spectral domain OCTs are reliable for macular thickness measurements, spectral domain OCT has better measurement repeatability compared with time domain OCT. Macular measurements obtained from the two OCT systems may not be used interchangeably.

Indocyanine green staining and removal of internal limiting membrane in macular hole surgery: histology and outcome

PURPOSE To report the surgical technique, outcome, and histologic findings involving indocyanine green staining and removal of internal limiting membrane in primary macular hole surgery. METHODS Prospectively, consecutive patients with idiopathic macular hole or myopic macular hole with retinal detachment were recruited. After pars plana vitrectomy and epiretinal membrane removal, the internal limiting membrane was stained and removed. The specimens were stained using hematoxylin and eosin and periodic acid-Schiff. Immunohistochemical staining was also performed for glial fibrillary acidic protein, vimentin, type I and type IV collagen, and actin. RESULTS Among 10 patients (10 eyes) in the study, nine eyes had stage 3 or 4 macular hole. Four of them had chronic macular hole. The tenth patient had retinal detachment resulting from a myopic macular hole. Postoperatively, all cases had closure of macular hole without an elevated edge and the retina was attached. Seven patients had improvement of 2 or more Snellen lines, whereas visual acuity remained the same for the other three patients. In six eyes in which complete histologic examinations were feasible, internal limiting membrane was confirmed and two eyes also had a small amount of epiretinal membrane. Myofibrocytes in internal limiting membrane, either scattered or as a single layer, were found in three cases. CONCLUSIONS Removal of indocyanine green--stained internal limiting membrane around idiopathic macular hole or myopic macular hole with retinal detachment is confirmed with histology and may contribute to macular hole closure and retinal reattachment.

Relationship between Retinal Nerve Fiber Layer Measurement and Signal Strength in Optical Coherence Tomography

PURPOSE To examine the relationship between signal strength and retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT). DESIGN Observational cross-sectional study. PARTICIPANTS Forty normal subjects were recruited. METHODS Retinal nerve fiber layer (RNFL) thickness was measured by Stratus OCT (Carl Zeiss Meditec, Dublin, CA). In each eye, the focusing knob was adjusted to obtain 6 images with different signal strengths ranging from 5 to 10. The relationships between signal strength and RNFL thickness were examined using the Spearman correlation coefficient. The differences of RNFL thicknesses were compared with repeated-measures analysis of variance. MAIN OUTCOME MEASURES Retinal nerve fiber layer thicknesses measured at different signal strengths. RESULTS Significant differences were observed between measurements obtained at signal strength of 10 and those obtained with signal strength of less than 10 at the superior, nasal, and temporal clock hours. RNFL thickness generally increased with the signal strength, with significant correlations found with the total average, superior, and nasal clock hours RNFL thicknesses. CONCLUSIONS Optical coherence tomography RNFL measurements vary significantly with signal strength. Obtaining the maximal possible signal strength is recommended for RNFL thickness measurement.

Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Repeatability and Reproducibility of Anterior Chamber Angle Measurement with Anterior Segment Optical Coherence Tomography

Aim: To evaluate the repeatability and reproducibility of anterior chamber angle measurement obtained by anterior segment optical coherence tomography. Methods: Twenty-five normal subjects were invited for anterior chamber angle imaging with an anterior segment optical coherence tomography (OCT) on one randomly selected eye in three separate visits within a week. Each eye was imaged three times under room light (light intensity = 368 lux) and three times in the dark during the first visit. In the subsequent visits, each eye was imaged once in the light and once in the dark. The angle opening distance (AOD 500) and the trabecular–iris angle (TIA 500) were measured by a single observer. Only the nasal angle was analysed. Intrasession and intersession within-subject standard deviation (Sw), precision (1.96×Sw), coefficient of variation (CVw) (100×Sw/overall mean), and intraclass correlation coefficient (ICC) were calculated to evaluate repeatability and reproducibility. Results: For intrasession repeatability, the Sw, precision, CVw and ICC of AOD/TIA were 45 &mgr;m/2.4°, 88 &mgr;m/4.7°, 5.8%/4.8% and 0.97/0.95 in the light; and 45 &mgr;m/2.1°, 88 &mgr;m/4.2°, 7.0%/5.0% and 0.98/0.97 in the dark. For intersession reproducibility, the Sw, precision, CVw and ICC of AOD/TIA were 79 &mgr;m/3.5°, 155 &mgr;m/6.8°, 10.0%/7.0%, 0.91/0.89 in the light; and 64 &mgr;m/3.4°, 124 &mgr;m/6.6°, 9.9%/7.8% and 0.95/0.92 in the dark. Conclusions: The anterior segment OCT demonstrated reliable anterior chamber angle measurement in different lighting conditions with good repeatability and reproducibility.

Anterior chamber angle measurement with anterior segment optical coherence tomography: a comparison between slit lamp OCT and Visante OCT.

PURPOSE To compare anterior chamber angle measurements obtained from two anterior segment optical coherence tomography (OCT) instruments and to evaluate their agreements and interobserver reproducibility. METHODS Forty-nine eyes from 49 healthy normal subjects were studied. The anterior chamber angle was imaged with the Visante anterior segment OCT (Carl Zeiss Meditec, Dublin, CA) and the slit lamp OCT (SLOCT, Heidelberg Engineering, GmbH, Dossenheim, Germany) on one randomly selected eye in each subject and measured by two independent observers. The angle-opening distance (AOD 500), the trabecular-iris angle (TIA 500), and the trabecular-iris space area (TISA 500) at the nasal and temporal angles were measured. The agreements between SLOCT and Visante OCT measurements and the interobserver reproducibility were evaluated. RESULTS The mean nasal/temporal anterior chamber angles measured by Visante OCT and SLOCT were 527 +/- 249/572 +/- 275 microm (AOD), 0.180 +/- 0.091/0.193 +/- 0.102 mm(2) (TISA), and 38.1 +/- 12.3/39.6 +/- 13.2 degrees (TIA); and 534 +/- 234/628 +/- 254 microm (AOD), 0.191 +/- 0.089/0.217 +/- 0.093 mm(2)(TISA), and 37.8 +/- 10.1/40.6 +/- 10.7 degrees (TIA), respectively. No significant difference was found between Visante OCT and SLOCT measurements except the temporal TISA (P = 0.034). The interobserver coefficient of variation ranged between 4.4% and 7.8% for Visante OCT and 4.9% and 7.0% for SLOCT. The spans of 95% limits of agreement of the nasal/temporal angle measurements between Visante OCT and SLOCT were 437/531 mm(2), 0.174/0.186 mm(2), and 25.3/28.0 degrees for AOD, TISA, and TIA, respectively. CONCLUSIONS Although Visante OCT and SLOCT demonstrate high interobserver reproducibility for anterior chamber angle measurements, their agreement was poor.

Evaluation of Retinal Nerve Fiber Layer Progression in Glaucoma: A Prospective Analysis with Neuroretinal Rim and Visual Field Progression

OBJECTIVE To evaluate the performance of progression detection and the rate of change of retinal nerve fiber layer (RNFL), neuroretinal rim, and visual field measurements in glaucoma. DESIGN Prospective study. PARTICIPANTS One hundred eight eyes of 70 glaucoma patients. METHODS Patients were followed up every 4 months for at least 2.9 years (median, 3.2 years) for measurement of RNFL thickness with the Stratus optical coherence tomograph (OCT) (Carl Zeiss Meditec, Dublin, CA), neuroretinal rim area with the Heidelberg Retinal Tomograph (HRT 3; Heidelberg Engineering, GmbH, Dossenheim, Germany), and visual field with the Humphrey Field Analyzer II (Carl Zeiss Meditec). Linear regression analyses were performed between visual field index (VFI), RNFL, and neuroretinal rim measurements and age, with progression defined when a significant negative trend was detected. The agreement among structural and functional measurements was evaluated with κ statistics. The mean rate of change was estimated with linear mixed modeling. MAIN OUTCOME MEASURES The agreement on progression detection and the rate of change of RNFL, neuroretinal rim, and VFI measurements. RESULTS A total of 1105 OCT, 1062 HRT, and 1099 visual field measurements were analyzed. The agreement of progression detection among the 3 investigations was poor (κ≤0.09). Ten eyes (9.3%; 9 patients) showed progression by average RNFL thickness, 16 (14.8%; 14 patients) by global neuroretinal rim area, and 35 (32.4%; 31 patients) by VFI. Only 1 eye (0.9%) had progression detected by all 3 methods. There were large variations in the rate of change of VFI, average RNFL thickness, and global neuroretinal rim area, with a range between -0.63% and -4.97% per year, -2.32% and -10.12% per year, and -0.61% and -8.48% per year, respectively. The respective mean rate estimates were -1.15% per year (95% confidence interval [CI], -1.56% to -0.73%), -0.70% per year (95% CI, -1.19% to -0.21%), and -1.06% per year (95% CI, -1.56% to -0.55%). CONCLUSIONS The agreement of progression detection among RNFL, neuroretinal rim, and visual field measurements was poor, and the rate of RNFL, neuroretinal rim, and visual field progression varied considerably within and between subjects. Given this variability, interpretation of RNFL, neuroretinal rim, and VFI progression always should be evaluated on an individual basis. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

The Apolipoprotein E ε4 Allele Is Unlikely to Be a Major Risk Factor of Age-Related Macular Degeneration in Chinese

Apolipoprotein E (ApoE) is a major transporter of lipids and cholesterol in the nervous system. Age-related macular degeneration (ARMD), characterized by drusen containing lipids, was reported to show a lower frequency of the ApoE ε4 allele than control subjects. We sought to examine the association of this polymorphism with ARMD in Hong Kong Chinese. Among 98 ARMD subjects, the frequency of ε4 carriers showed a trend toward a decrease compared to controls, but it was not significant (11.2 vs. 15.0%, p < 0.52). The association of ε4 with an apparent reduced risk of ARMD was reported previously in the exudative form of the disease, however among 39 exudative ARMD patients there was also no significant difference in ε4 frequency (12.8%, p < 0.93). The lack of a statistically significant effect of ε4 may be due to the lower frequency of ε4 in Chinese than Europeans. Thus we cannot exclude a possible effect of this allele on ARMD risk, but we can conclude that this allele is likely not a major factor influencing ARMD risk in the Chinese.

Long-Term In Vivo Imaging and Measurement of Dendritic Shrinkage of Retinal Ganglion Cells

PURPOSE To monitor and measure dendritic shrinkage of retinal ganglion cells (RGCs) in a strain of transgenic mice (Thy-1 YFP) that expresses yellow fluorescent proteins in neurons under the control of a Thy-1 promoter. METHODS A total of 125 RGCs from 16 eyes of Thy-1 YFP transgenic mice were serially imaged with a confocal scanning laser ophthalmoscope for 6 months after optic nerve crush. Quantitative analysis of cell body area, axon diameter, dendritic field, number of terminal branches, total dendritic branch length, branching complexity, symmetry, and distance from the optic disc was used to characterize the morphology of RGCs, describe the patterns of axonal and dendritic degeneration, identify the morphologic predictors for cell survival, and estimate the rate of dendritic shrinkage. RESULTS RGC damage was observed prospectively to begin with progressive dendritic shrinkage, followed by loss of the axon and the cell body. In a small proportion of RGCs, progressive axonal changes including fragmentation, beading, retraction, and bulb formation were also observed. RGCs with a larger dendritic field and a longer total dendritic branch length in general have a better survival probability. The rate of dendritic shrinkage was variable with a slower rate observed in cells having a larger dendritic field, a longer total dendritic branch length, and a greater distance from the optic disc. CONCLUSIONS Estimating the probability of RGC survival and measuring the rate of dendritic shrinkage could become a new paradigm for investigating neuronal degeneration and evaluating the response of neuroprotective treatment.