Balekudaru Shantha

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.

Anterior Chamber Angle Assessment Using Gonioscopy and Ultrasound Biomicroscopy

PurposeComparison of anterior chamber angle measurements using ultrasound biomicroscopy (UBM) and gonioscopy.MethodsFive hundred subjects were evaluated for grading of angle width by the Shaffer method. UBM was done in the same group to document angle width, angle opening distance (AOD 500), and anterior chamber depth. Biometric parameters were documented in all subjects. UBM and gonioscopic findings were compared.ResultsA study was conducted in 282 men and 218 women with a mean age of 57.32 ± 12.48 years. Gonioscopic grading was used to segregate occludable (slit-like, grades 1 and 2) from nonoccludable (grades 3 and 4) angles. Subjective assessment by gonioscopy resulted in an overestimation of angle width within the occludable group when compared with values obtained by UBM. This did not affect the segregation of occludable versus nonoccludable angles by gonioscopy. Biometric parameters in eyes with occludable angles were significantly lower in comparison with eyes with nonoccludable angles, except for lens thickness. AOD 500 correlated well with angle width.ConclusionsWe concluded that clinical segregation into occludable and nonoccludable angles by an experienced observer using gonioscopy is fairly accurate. However, UBM is required for objective quantification of angles, and AOD 500 can be a reliable and standard parameter to grade angle width. Jpn J Ophthalmol 2004;48:44–49

ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = −0.045 mm, P = 8.17×10−9). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06–1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10−9; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Change in iris parameters with physiological mydriasis.

Purpose. A pilot study to analyze the association of change in iris parameters with physiological mydriasis in angle closure eyes compared with normal control eyes among south Indian participants. Methods. Sixteen eyes diagnosed with primary angle closure and 14 age, gender-matched open-angle control eyes were selected. All participants underwent anterior segment imaging using anterior segment optical coherence tomography in dim and bright illumination. The iris area (IA), iris volume (IV), and pupillary diameter were calculated using customized image processing software. Results. The IA and IV were found to be lesser in angle closure compared with normal controls. Average IA (dim and bright) was found to be 3.4 and 3.7 mm2 in normals and 3.03 and 3.35 mm2 in angle closure, and average IV (dim and bright) was found to be 24.28 and 26.09 mm3 in normals and 21.38 and 22.6 mm3 in angle closure. The IA and IV decreased significantly with pupillary dilation in normals and in angle closures. However, decrease in the IA (slope = 0.52 and 0.42; p = 0.012) and IV (slope = 1.97 and 1.41; p = 0.014) with pupillary dilation was significantly higher in normals compared with angle closures, respectively. Conclusions. IA and IV were found to decrease as pupil dilates in normal and angle closure eyes among South Indians. Loss in the IV was found to be lower in angle closure eyes.

Outcomes of bleb excision with free autologous conjunctival patch grafting for bleb leak and hypotony after glaucoma filtering surgery.

PurposeTo determine the outcomes of bleb excision with free autologous conjunctival patch grafting for bleb leak and hypotony after glaucoma filtering surgery. Patients and MethodsRetrospective, consecutive, noncomparative case series. Outcome measures were closure of bleb leak, intraocular pressure (IOP), and best corrected visual acuity after patch grafting and complications from intervention. Complete success was defined as resolution of the bleb leak or hypotony, with IOP between 6 and 18 mm Hg. ResultsFifty-eight eyes (57 patients) were included: 51 with bleb leaks and 7 with hypotonous maculopathy without a bleb leak. Eight eyes required scleral flap resuturing and 2 required scleral patch grafts in addition to free conjunctival patch grafting. The mean postoperative follow-up period was 112.65±128.74 weeks (median 80.0 wk). At 6 weeks and final follow-up, the IOP increased from baseline of 4.41±4.61 mm Hg (median 4.00 mm Hg) to 11.98±6.25 mm Hg (median 11.50 mm Hg) (P<0.001) and 12.67±4.83 mm Hg (median 12.00) (P<0.001), respectively. Visual acuity increased from baseline of 0.87±0.95 logMAR (median 0.60) to 0.65±0.80 logMAR (median 0.48) (P=0.001) and 0.76±0.93 logMAR (median 0.48) (P=0.35) at 6 weeks and last follow–up, respectively. The complete and qualified success rates at the final follow-up were 75.8% and 79.3%, respectively. Failure events occurred in 12 (20.6%) eyes, including 2 eyes with hypotony, 5 with raised IOP, and 3 with postoperative bleb leaks. ConclusionsFree conjunctival patch grafting is a successful procedure for bleb repair and hypotony providing moderate IOP control with minimal postoperative complications in majority of patients.

Management of complications in glaucoma surgery.

Surgical option for glaucoma is considered when other modalities are not working out to keep the intraocular pressure under control. Since the surgical procedures for glaucoma disrupt the integrity of the globe, they are known to produce various complications. Some of those complications can be vision-threatening. To minimize the morbidity, it is very important that one should know how to prevent them, recognize them and treat them. The objective of this article is to provide insight into some of those complications that will help the ophthalmologists in treating glaucoma patients in their clinical practice.

Comparison of saccadic reaction time between normal and glaucoma using an eye movement perimeter

Aim: To compare the saccadic reaction time (SRT) in both the central and peripheral visual field in normal and glaucomatous eyes using eye movement perimetery (EMP). Materials and Methods: Fifty-four normal and 25 glaucoma subjects underwent EMP and visual field testing on the Humphrey Field Analyser (HFA) 24-2 program. The EMP is based on infrared tracking of the corneal reflex. Fifty-four test locations corresponding to the locations on the 24-2 HFA program were tested. SRTs at different eccentricities and for different severities of glaucoma were compared between normal and glaucoma subjects. Results: Mean SRT was calculated for both normal and glaucoma subjects. Mann-Whitney U test showed statistically significant (P < 0.001) differences in SRTs between normal and glaucoma subjects in all zones. Conclusion: SRT was prolonged in eyes with glaucoma across different eccentricities.

Correlation of Aqueous Humor Lysyl Oxidase Activity with TGF-ß Levels and LOXL1 Genotype in Pseudoexfoliation

ABSTRACT Purpose: Pseudoexfoliation (PXF) is a microfibrillopathy involving disordered elastogenesis. Abnormal extracellular matrix (ECM) production underlies the pathophysiology of PXF. The enzyme Lysyl oxidase (LOX) and its isoforms are known to cross-link the elastin and collagen. Though the etiopathogensis of PXF is not well understood, studies report on the genetic risk involving LOXL1 gene. This study aims to screen LOXL1 coding variants rs1048661 and rs3825942 in the South Indian population and the implication of the single nucleotide polymorphism (SNP) with LOX activity. The levels of transforming growth factor β (TGF-β) in aqueous humor and its correlation with the LOX activity were also examined.Methods: Blood, plasma, and aqueous aspirates were prospectively collected from PXF cases with and without glaucoma and cataract cases as controls. DNA was extracted from 48 PXF cases without glaucoma, 12 PXF cases with glaucoma, and 40 age-matched cataract-alone controls without PXF/glaucoma for analyzing LOX SNPs. LOX activity was measured in aqueous humor and plasma of 30 PXF cases without glaucoma, 24 age-matched cataract-alone controls without PXF/glaucoma, and 14 PXF cases with glaucoma. Protein levels of LOX, LOXL1, LOXL2, and total TGF-β were estimated in plasma and aqueous humor by ELISA.Results: The specific activity of LOX in aqueous humor was found to be significantly lowered in PXF cases compared with cataract-alone controls (p = 0.014). This decrease in LOX activity in PXF cases was associated with high-risk GG haplotype. However, this was not statistically significant and a larger sample size is warranted. TGF-β1 and TGF-β2 negatively correlated with LOX activity in aqueous humor (p = 0.028; p = 0.046, respectively).Conclusions: The LOXL1 SNPs, rs1048661 and rs3825942, are associated with PXF in the South Indian population correlating with lowered LOX activity in the aqueous humor. The increased level of total TGF-β in the aqueous humor of PXF cases is possibly associated with LOX regulation which needs further investigation.

Ahmed glaucoma valve in eyes with preexisting episcleral encircling element.

Background: To describe the use of Ahmed glaucoma valve (AGV) in the management of intractable glaucoma in eyes with a preexisting episcleral encircling element. Materials and Methods: This is a retrospective, consecutive, noncomparative study. The study included 12 eyes of 12 patients with a preexisting episcleral encircling element that underwent implantation of silicone AGV to treat intractable glaucoma during January 2009 to September 2010. Results: The mean patient age was 25.6 (standard deviation 17.1) years. Five (41.6%) patients were monocular. The indications for AGV were varied. The mean duration between placement of episcleral encircling element and implantation of AGV was 30.5 (33.8) months. The mean follow-up was 37.4 (22.9) weeks. Preoperatively, the mean intraocular pressure (IOP) was 31.4 (7.9) mmHg and the mean antiglaucoma medications were 2.8. At the final postoperative follow-up, the mean IOP was 12.5 (3.5) mmHg and the mean number of antiglaucoma medications was 0.8 (P < 0.001). The complications observed over the follow-up period did include corneal graft failure in three eyes, tube erosion in two eyes and rhegmatogenous retinal detachment in one eye. Conclusion: AGV is an effective option in the management of intractable glaucoma in eyes with a preexisting episcleral encircling element keeping in mind the possibility of significant postoperative complications.

Elastin modulation and modification by homocysteine: a key factor in the pathogenesis of Pseudoexfoliation syndrome?

Background Pseudoexfoliation syndrome (PXF) is an idiopathic, elastogenesis-associated systemic disease characterised by amyloid-like material aggregates in the eye. Elevated plasma and aqueous humour (aqH) homocysteine (Hcy) is reportedly associated with PXF. This study is aimed to probe Hcy-mediated alterations in elastin expression. Methodology Lens level of Hcy (total Hcy (tHcy)), mRNA expression of Eln, CBS and MTR in lens capsule, protein expression of elastin in aqH were estimated by enzyme immunoassay, quantitative PCR and western blot, respectively in PXF, PXF with glaucoma (PXF-G) cases, in comparison with cataract-alone disease controls. Human lens epithelial cells (hLECs) were exposed to Hcy and homocysteine thiolactone (HCTL) to evaluate elastin expression in vitro. Furthermore, elastin recombinant protein was incubated with Hcy and HCTL to assess secondary and tertiary structural modifications based on circular dichroism spectroscopy, spectrophotometric and SEM studies. Results The lens tHcy was significantly high in PXF (p=0.02) and PXF-G (p=0.009). Eln expression was elevated in PXF and PXF-G (p=0.0007). Elastin level in aqH was elevated in PXF (p=0.01) and PXF-G (p=0.002). Hcy (200 µM) and HCTL (1 µM) promoted elastin expression at mRNA level by 36-fold (p=0.02) and 10-fold (p=0.05), respectively, and at protein level by nearly two-fold in cultured hLECs. Secondary structure changes in elastin protein caused by Hcy were evident from 34.11% drop in α-helix and 6.17% gain in β-sheet. Fluorescence, spectral assays and SEM analyses showed aggregation and amyloid formation of elastin with homocysteinylation. Conclusion The study reveals that lens accumulation of Hcy associated with hyperhomocysteinaemia is characteristic of PXF that augments elastin expression. Hcy causes structural changes promoting elastin aggregation, thereby contributing to defective elastin in PXF and PXF-G.