Quantification of the Posterior Cornea Using Swept Source Optical Coherence Tomography.

PURPOSE: We define optical coherence tomography (OCT) measurement parameters of the corneal endothelium/Descemet's membrane (DM) complex and peripheral transition zone (TZ) and describe these measurements in an ethnically Chinese population. METHODS: OCT images of the anterior segment and iridocorneal angle were obtained from 129 healthy Chinese subjects (129 eyes), aged 40 to 81 years. The scleral spur (SS) and Schwalbe's line (SL) were identified in each image. Endothelium/DM diameter, referred to as endothelial arc length (EAL), is the SL-to-SL distance. The SS-to-SL distance encompasses the TZ and trabecular meshwork (TM). Since the TZ cannot be visualized by OCT, a ratio of TZ-to-TZ+TM width was calculated from scanning electron microscopy (SEM) images obtained from 5 cadaveric corneas. The SS-to-SL distance was multiplied by this ratio to approximate in vivo TZ width. RESULTS: From SEM measurements, the relationship TZ = 0.20*(TZ+TM) was determined. From OCT measurements, mean EAL was 12.15 ± 0.58 mm and mean TZ width was 156 ± 20 µm. For eyes with horizontal and vertical images, vertical EAL was significantly greater than horizontal EAL (P = 0.03). CONCLUSIONS: Corneal endothelium/DM diameter and TZ width can be obtained from OCT images. Although only combined TZ+TM is visualized on OCT, TZ width can be reasonably approximated. TRANSLATIONAL RELEVANCE: Emerging procedures, like endothelial cell injection and DM transplantation (DMT), require accurate measurements of endothelium/DM size for preoperative planning. Size of the TZ, which may contain progenitor cells, also could contribute to endothelial regeneration in these procedures.

Reducing the number of invalid surgical consents in the day surgery unit.

AIM: To reduce the number of invalid surgical consents in the Singapore National Eye Centre Day Surgery Unit over a period of 6 months. METHODOLOGY: A multidisciplinary team involving doctors, nurses, day surgery unit, operating theatre, listing and clinical audit staff looked into the listing process and the root causes of the high number of invalid consents. A Pareto chart detailing the top causes of invalid consents was drawn, and with a prioritisation matrix, feasible yet effective changes were identified and effected. Plan-Do-Study-Act (PDSA) cycles included moving consent checks upstream, getting invalid consents amended on the same day, sending emails to raise awareness on invalid consents and posters in clinics to emphasise the correct way to fill up consent forms. RESULT: There has been a progressive downtrend in the monthly mean percentage of invalid consents since the introduction of PDSA cycles. There was a significant reduction in the mean rate of rejected consents from the preintervention phase of 15.2% to the postintervention phase of 11.3%, shown with a Z score of 6.56 (P<0.05). Sustainability was also demonstrated with multiple consecutive points below the median of 14.5% on the postimplementation phase of the run chart, with estimated time-efficiency savings of USD$19 738.50 annually. CONCLUSION: Errors in the workplace can be reduced with a concerted effort from multiple stakeholders. It is important to have a thorough look at processes with concerned parties, so that different perspectives and skill sets can be harnessed to determine and implement feasible and effective interventions.

Determinants of posterior corneal biometric measurements in a multi-ethnic Asian population.

PURPOSE: To describe the corneal and anterior segment determinants of posterior corneal arc length (PCAL) and posterior corneal curvature (PCC). METHODS: Cross-sectional, population-based study of 1069 subjects (1069 eyes) aged 40-80 years, from three major Asian ethnic groups. All underwent anterior segment optical coherence tomography imaging and analysis with Zhongshan Angle Assessment Program. Our main outcome measures were determinants of PCAL and PCC using adjusted, multivariate linear regression analysis, adjusted for confounders to obtain the estimated marginal means (EMM) with standard error (SE). RESULTS: The overall mean (± SD) of PCC was: 6.51±0.39 mm; and PCAL was: 12.52±0.59 mm. Malays had a relatively longer PCAL (EMM = 12.74 mm, SE = 0.04 mm) than Chinese (EMM = 12.48 mm, SE = 0.03 mm, P<0.001), and Indians (EMM = 12.42 mm, SE = 0.03 mm, P<0.001). Anterior segment parameters had weak-moderate correlations with PCAL, which included: anterior chamber depth (ACD) (r = 0.55, P<0.001), PCC (r = 0.27, P<0.001), anterior corneal curvature (ACC) (r = 0.14, P<0.001) and central corneal thickness (CCT) (r = -0.07, P = 0.023). In multivariate analysis, anterior segment parameters explained only 37.6% of the variance of PCAL, with ACD being the most important determinant (partial R2  = 0.300; P<0.001). The determinants of PCC included ACC, PCAL and CCT (explaining 72.1% variation of PCC), with ACC being the most important determinant (partial R2  = 0.683; P<0.001). CONCLUSION: There was moderate correlation of PCAL with ACD, but anterior segment parameters accounted for only a small proportion of the variation in PCAL. The significant differences in PCAL and PCC amongst different Asian ethnic groups suggests that there is a need to consider this factor when planning for anterior segment surgeries such as endothelial keratoplasty.

Comparison of anterior segment optical tomography parameters measured using a semi-automatic software to standard clinical instruments.

OBJECTIVE: To compare anterior segment parameters measured using a semi-automatic software (Zhongshan Angle Assessment Program, ZAP) applied to anterior segment optical coherence tomography (AS-OCT) images, with commonly used instruments. METHODS: Cross-sectional study of a total of 1069 subjects (1069 eyes) from three population-based studies of adults aged 40-80 years. All subjects underwent AS-OCT imaging and ZAP software was applied to determine anterior chamber depth (ACD), central corneal thickness (CCT), anterior and keratometry (K) - readings. These were compared to auto-refraction, keratometry and ocular biometry measured using an IOLMaster, ultrasound pachymeter and auto-refractor respectively. Agreements between AS-OCT (ZAP) and clinical instrument modalities were described using Bland-Altman, 95% limits of agreement (LOA). RESULTS: The mean age of our subjects was 56.9±9.5 years and 50.9% were male. The mean AS-OCT (ZAP) parameters of our study cohort were: ACD 3.29±0.35 mm, CCT 560.75±35.07 µm; K-reading 46.79±2.72 D. There was good agreement between the measurements from ZAP analysis and each instrument and no violations in the assumptions of the LOA; albeit with a systematic bias for each comparison: AS-OCT consistently measured a deeper ACD compared to IOLMaster (95% LOA -0.24, 0.55); and a thicker CCT for the AS-OCT compared to ultrasound pachymetry (16.8±0.53 µm 95% LOA -17.3, 50.8). AS-OCT had good agreement with auto-refractor with at least 95% of the measurements within the prediction interval (P value <0.001). CONCLUSION: This study demonstrates that there is good agreement between the measurements from the AS-OCT (ZAP) and conventional tools. However, small systematic biases remain that suggest that these measurement tools may not be interchanged.

Anterior chamber dimensions and posterior corneal arc length in Malay eyes: an anterior segment optical coherence tomography study.

PURPOSE: We provided normative data of corneal and anterior segment dimensions, and a novel parameter, posterior corneal arc length (PCAL), in an adult Malay population. METHODS: The current analysis is a substudy of the Singapore Malay Eye Study (SiMES), a population-based, cross-sectional study of urban Malay adults aged 40 to 80. Subjects underwent ophthalmic and systemic examination, including imaging with anterior segment optical coherence tomography (AS-OCT). Ocular parameters subsequently were measured with the Zhongshan Assessment Program (ZAP), and included anterior chamber depth (ACD), central corneal thickness (CCT), anterior and posterior corneal curvature (ACC and PCC, respectively), and PCAL, which is a novel parameter defined as the arc-distance of the posterior corneal border between the scleral spurs. Age- and sex-adjusted analyses, and multivariate analyses were performed to determine correlations of PCAL with other ocular and systemic components. RESULTS: We studied 237 subjects, among whom the mean age was 56.6 ± 10.4 years and 50.2% were women. Ocular parameters (mean ± SD) included central ACD 2.78 ± 0.34 mm, CCT 550.23 ± 37.12 mm, ACC 7.43 ± 0.37 mm, PCC 6.75 ± 0.37 mm, and PCAL 13.95 ± 0.51 mm. There was moderate correlation between PCAL and ACD (r = 0.476, P < 0.001), but poor correlation with PCC (r = 0.243, P < 0.001), ACC (r = 0.251, P < 0.001), and systemic parameters, like age, body mass index (BMI), blood pressure, blood glucose levels, hemoglobin A1c (HbA1c), and refractive parameters. Multivariate analysis showed a significant association between PCAL and ACD (P < 0.001), PCC (P < 0.001), and height (P < 0.05). CONCLUSIONS: Our study, to our knowledge, provides the largest baseline anterior segment parameters in an adult Asian Malay population. PCAL correlated moderately with ACD. These data are applicable clinically for assessment and surgical management of patients requiring anterior segment or corneal surgery.

Anterior segment optical coherence tomography study of the cornea and anterior segment in adult ethnic South Asian Indian eyes.

PURPOSE: To report normative results of anterior segment and corneal biometric parameters and their associations in ethnic South Asian Indian adults. METHODS: The Singapore Indian Eye Study is a cross-sectional, population-based study of ethnic South Asian Indians ranging in age from 40 to 80 years. Subjects underwent ophthalmic and systemic examination, including imaging with anterior segment optical coherence tomography. Parameters were derived using the Zhongshan Assessment Program: anterior chamber depth (ACD), central corneal thickness (CCT), and anterior and posterior corneal curvatures (ACC and PCC). Posterior corneal arc length (PCAL) is a novel parameter defined as the arc distance between scleral spurs on the posterior border of the cornea. The authors studied correlations between PCAL with various anterior segment parameters and systemic parameters using univariate and multivariate analyses. RESULTS: The authors studied 438 subjects whose mean age was 58.5 ± 9.9 years and of whom 50.7% were male. Parameters (mean ± SD) included central ACD 2.72 ± 0.37 mm, PCC 6.45 ± 0.35 mm, CCT 561.4 ± 34.1 µm, ACC 7.17 ± 0.35 mm, and PCAL 13.85 ± 0.54 mm. The authors found significant correlations between PCAL and ACD (r = 0.46, P < 0.001), PCC (r = 0.31, P < 0.001), and ACC (r = 0.16, P < 0.001), whereas they found poor correlations between PCAL and age, height, weight, blood pressure, and glucose levels. Multivariate analysis showed a significant association between PCAL and both ACD (P < 0.001) and PCC (P < 0.001). CONCLUSIONS: The authors have described useful baseline anterior segment parameters from this population-based study of ethnic South Indian adults. These data may be useful for corneal and anterior segment procedures such as endothelial keratoplasty and anterior chamber intraocular lens insertion.

Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models.

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 µg) and 0.12% (36 µg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 µg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma.

PURPOSE: Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties. METHODS: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. RESULTS: NCX 125 elicited cGMP formation (EC(50) = 3.8 + or - 1.0 microM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 + or - 11 microM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 + or - 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max)= -6.7 + or - 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 + or - 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 + or - 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 + or - 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. CONCLUSIONS: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.

Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV: structure-based drug design, synthesis, and biological evaluation.

A novel series of potent thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV was discovered using structure-based drug design. Synthesis, structure-activity relationship, and optimization of physicochemical properties are described. Low nanomolar potency was achieved, and selected compounds with improved thermodynamic solubility showed promising in vitro inhibition of carbonic anhydrase activity in rabbit iris ciliary body homogenate.

Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma.

Novel bi-functional compounds with a nitric oxide (NO)-releasing moiety bound to a dorzolamide scaffold were investigated. Several compounds were synthesized and their activity as selective carbonic anhydrase inhibitors (CAI) evaluated in vitro on recombinant hCA type I, II and IV enzyme isoforms where they showed different degrees of potency and selectivity to hCA II. A high resolution X-ray crystal structure for the CA II adduct with 8 confirmed the high affinity of this class of compounds for the enzyme. Compounds 4, 6, and 8 showed highly potent and efficacious NO-mediated properties as assessed by their vascular relaxant effect on methoxamine-precontracted rabbit aortic rings. Finally, compounds 4 and 6 exerted potent intraocular pressure (IOP) lowering effects in vivo in normotensive rabbits thereby anticipating their potential for the treatment of hypertensive glaucoma.

Synthesis of novel nitric oxide (NO)-releasing esters of timolol.

A novel class of timolol derivatives with nitric oxide (NO)-donating moieties achieved chemical stability yet under physiologically relevant conditions released timolol and NO. Hindered esters A were designed and synthesized, whose 'triggered' release relied on enzymatic hydrolysis of the nitrate ester in A to B, that in turn cyclized to liberate timolol.

Analysis of the posterior polymorphous corneal dystrophy 3 gene, TCF8, in late-onset Fuchs endothelial corneal dystrophy.

PURPOSE: Because the endothelial (posterior) corneal dystrophies share common pathologic features and result from primary endothelial dysfunction, it is possible that a proportion of them could be clinical manifestations of different mutations of the same gene. The aim of our study was to determine whether mutations of the TCF8 gene, recently implicated in posterior polymorphous dystrophy, may also play a role in the development of the more common Fuchs endothelial corneal dystrophy (FECD). METHODS: Genomic DNA was extracted from leukocytes of peripheral blood, and the nine exons of the TCF8 gene were PCR amplified and subjected to bidirectional sequencing and analysis. Samples from 74 unrelated Chinese patients (55 women, 19 men) with a diagnosis of late-onset FECD and 93 age- and race-matched controls were studied. RESULTS: The affected probands ranged in age from 52 to 91 years (mean age, 65.1 years); 8 had familial FECD and 66 had sporadic FECD. The authors found two mutations in the coding region of the TCF8 gene: a novel missense mutation in one patient c.2087A>G in exon 7 (Asn696Ser) and a silent mutation in exon 2 c.192T>C (D64D). CONCLUSIONS: The identification of a novel missense mutation in only one of the patients implied that TCF8 does not play a significant role in the pathogenesis of FECD in this Chinese population.