Pupillary Responses to High-Irradiance Blue Light Correlate with Glaucoma Severity.

PURPOSE: To evaluate whether a chromatic pupillometry test can be used to detect impaired function of intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with primary open-angle glaucoma (POAG) and to determine if pupillary responses correlate with optic nerve damage and visual loss. DESIGN: Cross-sectional study. PARTICIPANTS: One hundred sixty-one healthy controls recruited from a community polyclinic (55 men; 151 ethnic Chinese) and 40 POAG patients recruited from a glaucoma clinic (22 men; 35 ethnic Chinese) 50 years of age or older. METHODS: Subjects underwent monocular exposure to narrowband blue light (469 nm) or red light (631 nm) using a modified Ganzfeld dome. Each light stimulus was increased gradually over 2 minutes to activate sequentially the rods, cones, and ipRGCs that mediate the pupillary light reflex. Pupil diameter was recorded using an infrared pupillography system. MAIN OUTCOME MEASURES: Pupillary responses to blue light and red light were compared between control subjects and those with POAG by constructing dose-response curves across a wide range of corneal irradiances (7-14 log photons/cm(2) per second). In patients with POAG, pupillary responses were evaluated relative to standard automated perimetry testing (Humphrey Visual Field [HVF]; Carl Zeiss Meditec, Dublin, CA) and scanning laser ophthalmoscopy parameters (Heidelberg Retinal Tomography [HRT]; Heidelberg Engineering, Heidelberg, Germany). RESULTS: The pupillary light reflex was reduced in patients with POAG only at higher irradiance levels, corresponding to the range of activation of ipRGCs. Pupillary responses to high-irradiance blue light associated more strongly with disease severity compared with responses to red light, with a significant linear correlation observed between pupil diameter and HVF mean deviation (r = -0.44; P = 0.005) as well as HRT linear cup-to-disc ratio (r = 0.61; P < 0.001) and several other optic nerve head parameters. CONCLUSIONS: In glaucomatous eyes, reduced pupillary responses to high-irradiance blue light were associated with greater visual field loss and optic disc cupping. In POAG, a short chromatic pupillometry test that evaluates the function of ipRGCs can be used to estimate the degree of damage to retinal ganglion cells that mediate image-forming vision. This approach could prove useful in detecting glaucoma.

Myopia in asian subjects with primary angle closure: implications for glaucoma trends in East Asia.

PURPOSE: To evaluate the occurrence of myopia in Asian subjects with angle closure and to assess the ocular biometric parameters in these subjects. DESIGN: Cross-sectional study. PARTICIPANTS: We prospectively recruited 427 angle-closure subjects (143 primary angle-closure suspects, 75 patients with primary angle closure, 165 patients with primary angle-closure glaucoma, and 44 patients with acute primary angle closure) from a Singapore hospital. METHODS: Refractive status was derived from the spherical equivalent of autorefraction. A-scan biometry (Nidek Echoscan Ultrasound US-800; Nidek Co., Tokyo, Japan) was performed to obtain anterior chamber depth (ACD), axial length (AL), lens thickness, and vitreous cavity length (VL). Anterior segment optical coherence tomography was performed to measure lens vault. MAIN OUTCOME MEASURES: Refractive status was categorized as myopia (≤-0.50 diopter [D]), emmetropia (-0.50 to +0.50 D), and hyperopia (≥+0.50 D). RESULTS: The mean age ± standard deviation of study subjects was 65.6 ± 7.6 years, with most being Chinese (n = 394; 92.3%) and women (n = 275; 64.4%). Overall, myopia was present in 94 subjects (22%), hyperopia was present in 222 subjects (52%), and emmetropia was present in 111 subjects (26%). Of the 94 myopic angle-closure patients, 28 (29.8%) were categorized as having moderate myopia (≤-2.0 to -5.0 D) and 11 (11.7%) were categorized as having high myopia (≤-5.00 D). Although myopic angle-closure subjects had longer ALs (P<0.001) and VLs (P = 0.001) than their emmetropic and hyperopic counterparts, there were no significant differences in ACD (P = 0.77), lens thickness (P = 0.44), or lens vault (P = 0.053). CONCLUSIONS: Almost one quarter of angle-closure patients were myopic. Myopic angle-closure subjects had longer VLs and ALs, but there was no difference in ACD. With the increasing rate of myopia in many East Asian populations, there may be many subjects with axial myopia but shallow ACD and angle closure. The implication is that ophthalmologists should not assume that glaucoma patients who are myopic have open angles.

Assessment of circumferential angle-closure by the iris-trabecular contact index with swept-source optical coherence tomography.

PURPOSE: To evaluate the diagnostic performance of the iris-trabecular contact (ITC) index, a measure of the degree of angle-closure, using swept-source optical coherence tomography (SSOCT, CASIA SS-1000, Tomey Corporation, Nagoya, Japan) in comparison with gonioscopy. DESIGN: Prospective observational study. PARTICIPANTS: A total of 108 normal subjects and 32 subjects with angle-closure. METHODS: The SSOCT 3-dimensional angle scans, which obtain radial scans for the entire circumference of the angle, were performed under dark conditions and analyzed using customized software by a single examiner masked to the subjects' clinical details. The ITC index was calculated as a percentage of the angle that was closed on SSOCT images. First-order agreement coefficient (AC1) statistics and area under the receiver operating characteristic curve (AUC) analyses were performed for angle-closure on the basis of the ITC index in comparison with gonioscopy. MAIN OUTCOME MEASURES: Angle-closure on gonioscopy was defined as nonvisibility of posterior trabecular meshwork for at least 2 quadrants. Agreement of the ITC index with gonioscopically defined angle-closure was assessed using the AC1 statistic. RESULTS: Study subjects were predominantly Chinese (95.7%) and female (70.7%), with a mean age of 59.2 (standard deviation, 8.9) years. The median ITC index was 15.24% for gonioscopically open-angle eyes (n = 108) and 48.5% for closed-angle eyes (n = 32) (P = 0.0001). The agreement for angle-closure based on ITC index cutoffs (>35% and ≥50%) and gonioscopic angle-closure was 0.699 and 0.718, respectively. The AUC for angle-closure detection using the ITC index was 0.83 (95% confidence interval, 0.76-0.89), with an ITC index >35% having a sensitivity of 71.9% and specificity of 84.3%. CONCLUSIONS: The ITC index is a summary measure of the circumferential extent of angle-closure as imaged with SSOCT. The index had moderate agreement and good diagnostic performance for angle-closure with gonioscopy as the reference standard.

Changes in anterior segment morphology after laser peripheral iridotomy: an anterior segment optical coherence tomography study.

PURPOSE: Novel anterior segment optical coherence tomography (ASOCT) parameters associated with angle closure include anterior chamber area (ACA), anterior chamber volume (ACV), anterior chamber width (ACW), lens vault (LV), iris thickness (IT), iris area (I-area), and iris curvature (I-curv). We aimed to investigate changes in these parameters after laser peripheral iridotomy (LPI) in a cohort of primary angle-closure suspects (PACS). DESIGN: Prospective observational study. PARTICIPANTS AND CONTROLS: A total of 176 PACS aged ≥ 50 years who underwent LPI in 1 eye. METHODS: We analyzed ASOCT images (Visante, Carl Zeiss Meditec, Dublin, CA) from all subjects using customized software before and 1 week after LPI. Multivariate linear regression analysis was performed for predictors of percentage change in mean angle opening distance (AOD750). MAIN OUTCOME MEASURES: Change in ASOCT parameters after LPI. RESULTS: The mean age of participants was 63 ± 7.3 years. The majority of subjects were Chinese (95.5%) and women (76.7%). Mean angle width (modified Shaffer grade) changed from 0.68 ± 0.54 at baseline to 1.76±0.69 after LPI (P<0.001) with a corresponding increase in mean AOD500 (0.12 vs. 0.19 mm, P<0.001), trabecular iris surface area (TISA500, 0.06 vs. 0.08 mm(2), P<0.001), and angle recess area (ARA, 0.13 vs. 0.17 mm(2), P<0.001). Mean ACA (15.0 vs. 16.0 mm(2), P<0.001) and ACV (91.6 vs. 103.0 mm(3), P<0.001) increased significantly after LPI, but there was no change in ACW, anterior chamber depth (ACD), or LV. Mean I-curv was reduced (0.375 vs. 0.18 mm, P<0.001) after LPI, but there was no significant change in IT or I-area. After multivariate analysis, mean LV (ß = 0.286, P = 0.001), mean IT at 2000 µm (IT2000, ß = 0.172, P = 0.034), and intraocular pressure (ß = 0.159, P = 0.042) at baseline were found to be associated with ΔAOD750. CONCLUSIONS: This study confirms that LPI results in a significant increase in the angle width in PACS. The ACA and ACV increased after LPI, but there was no change in ACD, ACW, LV, IT, or I-area. The increase in ACA/ACV was mainly due to decreased I-curv after LPI.

Association analysis of CFH, C2, BF, and HTRA1 gene polymorphisms in Chinese patients with polypoidal choroidal vasculopathy.

PURPOSE: Polypoidal choroidal vasculopathy (PCV) is a major cause of serosanguinous maculopathy in Chinese patients with age-related macular degeneration (AMD). Variants in the CFH and HTRA1/LOC387715 genes are strongly associated with AMD in Caucasians and Chinese. Variants in the C2 and BF genes have been found to confer a significantly reduced risk of AMD. This study was undertaken to determine whether these associations occur in Chinese patients with PCV. METHODS: Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV and normal control subjects were recruited from the Singapore National Eye Centre. Five single-nucleotide polymorphisms (SNPs) in the CFH gene, two each within the C2 and BF genes and two variants located in the LOC387715 and HTRA1 genes, were screened in all patients and control subjects. RESULTS: Seventy-two patients with PCV and 93 normal control subjects were studied. A significant association was noted with CFH variants rs3753394 and rs800292 among the PCV cases (P = 0.0015 and P = 0.0045, respectively). Individuals homozygous for the TT genotype of rs3753394 had a significantly higher risk (P = 0.0076) of PCV (OR = 4.29; 95% CI: 1.47-12.50) than those carrying a single copy of the T allele (P = 0.3210; OR = 1.69; 95% CI: 0.60-4.78), after adjustment for such risk factors as age and sex. The genotype frequencies of rs11200638 and rs10490924 in HTRA1 and LOC387715, respectively, were also found to be significantly different between patients with PCV and normal control subjects (P = 0.00032 and P = 0.003, respectively). The AA genotype of rs11200638 and TT genotype of rs10490924 conferred a 4.9-fold (95% CI: 1.85-12.95) and 4.89-fold (95% CI: 1.85-12.90) increased risk of PCV, respectively, after adjustment for age and sex. The Y402H variant of CFH (rs1061170) and the BF and C2 variants were not significantly different in patients and normal control subjects. CONCLUSIONS: The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV in Chinese patients.

Lack of association between interleukin-1 gene cluster polymorphisms and glaucoma in Chinese subjects.

PURPOSE: A recent study identified single nucleotide polymorphisms (SNPs) within the IL-1 gene cluster at chromosomal locus 2q13 that were associated with reduced risk for primary open-angle glaucoma (POAG) in whites. The purpose of this study was to investigate the association between IL-1 SNPs and glaucoma in Chinese patients with either POAG or primary-angle closure glaucoma (PACG). METHODS: Patients with POAG with a mean IOP without treatment that was consistently <21 mm Hg on diurnal testing were classified as having normal-tension glaucoma (NTG) and those with higher IOP were classified as having high-tension glaucoma (HTG). Subjects with PACG had at least 180 degrees of angle closure on gonioscopy. Genotypes were determined by polymerase chain reaction and restriction digest enzymes at the following loci: IL1A (-889C/T), IL1B (+3953C/T), and IL1B (-511C/T). The association of individual SNPs with glaucoma was evaluated by using chi(2) testing. Haplotype analysis was performed with the PHASE program, with haplotype frequency estimated for combined cases and controls, assuming Hardy-Weinberg equilibrium (HWE) of haplotypes. RESULTS: Of the Chinese subjects studies, 194 had POAG (94 NTG and 100 HTG), 125 had PACG, and 79 were normal control subjects. There was no significant difference in IL-1 SNP or allele frequencies for in subjects with POAG or PACG compared with control subjects, or between NTG and HTG. None of the common haplotypes showed any significant difference between the HTG, NTG, PACG, and normal control subjects. CONCLUSIONS: This study did not find an association between IL-1 gene cluster polymorphisms and glaucoma in this sample of Chinese subjects.

Angiographic characteristics of acute central serous chorioretinopathy in an Asian population.

INTRODUCTION: Acute central serous chorioretinopathy (CSCR) afflicts young middle-aged males in the Western population. We aimed to analyse patient demographics and to determine the angiographic characteristics of acute CSCR in an Asian population. MATERIALS AND METHODS: This is a retrospective study of all patients presenting with acute CSCR who had fundal fluorescein angiograms performed within a 4-year period (between 1 January 1998 and 31 December 2001). RESULTS: The fluorescein angiograms of 128 patients were analysed. The majority were male (109/128) with a male-to-female ratio of 5.7:1. The age range of patients was 26 to 60 years, with a mean age of 41 years. The majority of patients (84%) were aged 30 to 50 years. With regard to racial distribution, 83% were Chinese, 6% were Malays and 11% were Indians or of other races. Unilateral disease was found in 74 patients (58%) and 52 had bilateral disease. The macula was the most common site of fluorescein leakage and was found in 97 patients (76%). Almost half the patients (44%) had more than one site of disease involvement (i.e., multifocal). The inkblot leakage pattern was found in 103 patients (80%). CONCLUSIONS: The patient demographics of acute CSCR in our population were compared to that reported in the West. The gender ratio was similar, with males being afflicted 6 to 10 times more compared to females. There was no racial predilection found for acute CSCR in the local population. We also found a significant proportion of patients with bilateral and multifocal disease compared to the West. The inkblot pattern of leakage was the most common pattern seen on angiography. There were a significant number of cases with bilateral and multifocal involvement, exceeding those reported in non-Asian populations.

A comparison of applanation tonometry using conventional reusable goldmann prisms and disposable prisms.

PURPOSE: To determine the agreement between intraocular pressure (IOP) measurements using conventional Goldmann applanation tonometry (GAT) and Tonosafe disposable prisms, and also to provide a comprehensive cost analysis of the use of both types of prisms METHODS: : In this prospective observational study, 198 eyes of 100 glaucoma patients had their IOPs measured by 5 consultant ophthalmologists. Data were analyzed using the Bland-Altman method of differences, and correlation was measured using the Pearson coefficient. An analysis of the cost incurred using the 2 methods over a 6-month period was performed. RESULTS: The majority were Chinese (82%), with a male preponderance (57%). The range of IOPs as measured by GAT was 4 to 34 mm Hg. Using the Bland-Altman method to compare GAT and disposable prisms, the bias was 0.2 mm Hg. Tonosafe overestimated the IOP by 0.2 mm Hg in the right eye and underestimated it by 0.2 mm Hg in the left eye. The Tonosafe IOP correlated well with GAT, with a Pearson coefficient of correlation(r) of 0.91 (P<0.0005) for the right eye and 0.92 (P<0.0005) for the left eye, respectively. For those with GAT IOP≥21 mm Hg (n=26), Tonosafe underestimated the IOP by 0.35 mm Hg. The cost incurred by Tonosafe prisms was approximately 8 times that of GAT, but the cost differential reverses when GAT had to be replaced after every 100 cycles of disinfection. CONCLUSIONS: We found a good correlation between Tonosafe prisms and conventional GAT in measuring the IOP. Tonosafe prisms may be of use, especially if the risk of transmission of infection is high. However, cost may limit its more widespread use.

Genotype-phenotype correlation analysis for three primary angle closure glaucoma-associated genetic polymorphisms.

PURPOSE: Recently, three genetic susceptibility loci for primary angle closure glaucoma (PACG) were identified: COL11A1 rs3753841, PCMTD1-ST18 rs1015213, and PLEKHA7 rs11024102. The purpose of this study was to investigate whether these single nucleotide polymorphisms (SNPs) affect the phenotype of PACG patients. METHODS: A retrospective analysis was performed for 700 Singaporean Chinese PACG patients who had been genotyped. The associations between the three SNPs and clinical features related to severity of glaucoma were studied. For a subgroup of patients who had ≥ 5 years of follow-up and ≥ 5 reliable visual field (VF) tests, differences in glaucoma progression, as measured by the proportion of VF progression and blindness, were compared among groups with different genotypes. RESULTS: The minor allele frequencies at COL11A1 rs3753841, PCMTD1-ST18 rs1015213, and PLEKHA7 rs11024102 were 36%, 2.1%, and 41.5%, respectively. There were no significant differences in sex, diagnosis (acute primary angle closure [APAC] versus non-APAC), age at diagnosis, laterality of glaucoma, or need for filtration surgery among patients with different genotypes (all P > 0.05). We also found no significant difference between genotypes and the IOP at presentation, and other clinical characteristics at DNA collection (vertical cup-to-disc ratio, best corrected visual acuity, baseline VF mean deviation, or pattern standard deviation). For the subgroup analysis, we did not observe significant associations between VF progression and the proportion of blindness with any of the PACG susceptibility loci. CONCLUSIONS: The three genetic susceptibility loci for PACG did not underlie any major phenotypic diversity in terms of disease severity or progression.

Anterior segment optical coherence tomography parameters in subtypes of primary angle closure.

PURPOSE: To compare anterior segment parameters, assessed by anterior segment optical coherence tomography (ASOCT), in subjects categorized as primary angle closure suspect (PACS), primary angle closure (PAC), primary angle closure glaucoma (PACG), and previous acute PAC (APAC); and to identify factors associated with APAC. METHODS: This was a prospective ASOCT study of 425 subjects with angle closure (176 PACS, 66 PAC, 125 PACG, and 58 APAC). Customized software was used to measure ASOCT parameters, including angle opening distance (AOD750), trabecular-iris space area (TISA750), anterior chamber depth, width, area and volume (ACD, ACW, ACA, ACV), iris thickness (IT750), iris area (IAREA), and lens vault (LV). Mean differences in anterior segment parameters were evaluated by analysis of covariance (ANCOVA) adjusted for age, sex, and pupil diameter (PD). RESULTS: Comparison among the different subgroups showed that ACD, ACA, and ACV were smallest, and IT750 thickest in the APAC group compared with the other subgroups (P < 0.001). LV was greatest in the APAC group (1218 ± 34 µm) followed by PAC (860 ± 31 µm), PACG (845 ± 23 µm), and PACS (804 ± 19 µm), respectively (P = <0.001). While the APAC group had the narrowest angles, the PACS group had the widest (P < 0.001 for both AOD750 and TISA750). Logistic regression showed that greater LV (P = <0.001), narrower TISA750 (P = <0.001), and thicker IT750 (P = 0.007) were the major determinants of APAC. CONCLUSIONS: Eyes with APAC had the narrowest angles, smallest anterior segment dimensions, thickest iris, and largest LV compared with PACS, PAC, and PACG. LV, TISA750, and IT750 were the major determinants of APAC.

A model to measure fluid outflow in rabbit capsules post glaucoma implant surgery.

PURPOSE: Prior models of glaucoma filtration surgery assess bleb morphology, which does not always reflect function. Our aim is to establish a model that directly measures tissue hydraulic conductivity of postsurgical outflow in rabbit bleb capsules following experimental glaucoma filtration surgery. METHODS: Nine rabbits underwent insertion of a single-plate pediatric Molteno implant into the anterior chamber of their left eye. Right eyes were used as controls. The rabbits were then allocated to one of two groups. Group one had outflow measurements performed at 1 week after surgery (n = 5), and group two had measurements performed at 4 weeks (n = 4). Measurements were performed by cannulating the drainage tube ostium in situ with a needle attached to a pressure transducer and a fluid column at 15 mm Hg. The drop in the fluid column was measured every minute for 5 minutes. For the control eyes (n = 6), the anterior chamber of the unoperated fellow eye was cannulated. Animals were euthanized with the implant and its surrounding capsule dissected and fixed in 4% paraformaldehyde, and embedded in paraffin before 6-µm sections were cut for histologic staining. RESULTS: By 7 days after surgery, tube outflow was 0.117 ± 0.036 µL/min/mm Hg at 15 mm Hg (mean ± SEM), whereas at 28 days, it was 0.009 ± 0.003 µL/min/mm Hg. Control eyes had an outflow of 0.136 ± 0.007 µL/min/mm Hg (P = 0.004, one-way ANOVA). Hematoxylin and eosin staining demonstrated a thinner and looser arrangement of collagenous tissue in the capsules at 1 week compared with that at 4 weeks, which had thicker and more densely arranged collagen. CONCLUSIONS: We describe a new model to directly measure hydraulic conductivity in a rabbit glaucoma surgery implant model. The principal physiologic endpoint of glaucoma surgery can be reliably quantified and consistently measured with this model. At 28 days post glaucoma filtration surgery, a rabbit bleb capsule has significantly reduced tissue hydraulic conductivity, in line with loss of implant outflow facility, and increased thickness and density of fibrous encapsulation.

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.

Gundersen flaps in the management of ocular surface disease in an Asian population.

PURPOSE: To evaluate the indications, complications, and long-term outcomes with the use of a Gundersen flap for the treatment of various ocular surface conditions in an Asian population. DESIGN: Retrospective case series. STUDY SUBJECTS: Twenty-five eyes of 25 subjects who had undergone conjunctival flap surgery performed from 1999 to 2004 at the Singapore National Eye Centre. METHODS: Review of case records for indications and outcomes of patients undergoing Gundersen flap surgery. MAIN OUTCOME MEASURES: Surgical success was defined as attainment of a stable ocular surface with resolution of symptoms and no flap retraction or dehiscence resulting in reexposure of the corneal surface. Complications to be noted included infection, progression of the inflammatory or infectious disease process beneath the flap, flap loss from epithelial ingrowth, and epithelial cyst formation. RESULTS: Surgical success was achieved in all eyes. Intraoperative and postoperative complications were encountered in 6 patients (24%). One case had a buttonhole, 3 cases had partial flap retractions, and 2 had epithelial inclusion cysts. CONCLUSIONS: The Gundersen flap is still an important procedure and should be considered as a means of stabilizing globe integrity in the management of cases of severe ocular surface disease, particularly when visual potential is poor.

Population prevalence of tilted and torted optic discs among an adult Chinese population in Singapore: the Tanjong Pagar Study.

OBJECTIVE: To determine the prevalence of tilted and torted optic discs and associated risk factors among Chinese adults in Singapore. METHODS: As part of a population-based survey, optic disc stereophotographs of both eyes were obtained, and left eyes were analyzed using imaging software. A tilted optic disc was defined as an index of tilt (ratio of minimum to maximum optic disc diameter) less than 0.75. The angle of tilt was defined as the angle between the maximum and vertical optic disc diameter, and optic discs were graded as torted if the angle of tilt exceeded 15 degrees . RESULTS: Twenty-six of 739 subjects (3.5%) had tilted optic discs, and 478 (64.7%) had torted optic discs. Myopia was present in 23 of 26 eyes (88.5% [95% confidence interval, 69.9%-97.6%]) with tilted optic discs and in 211 of 661 eyes (31.9% [28.4%-35.6%]) without tilted optic discs (P < .001). On multivariate analysis, myopia (spherical equivalent) was a significant risk factor for tilted optic discs (P < .001). Index of tilt was not associated with corneal astigmatism or with cylindrical refractive error. Seventeen eyes (65.4%) with tilted optic discs had an optic disc morphologic abnormality, but none were glaucomatous. CONCLUSIONS: The prevalence of tilted optic discs among this Chinese population was 3.5%. Tilted optic discs were associated with myopia but not with glaucoma.