A new association of PAX6 variation with Juvenile onset open angle glaucoma.

Mutations in the PAX6 gene are generally associated with aniridia. We describe a family with Juvenile onset open angle glaucoma (JOAG), where one of the two children had JOAG and the other Juvenile ocular hypertension. Whole exome sequencing was performed for the parents and their two affected children where the proband and her sibling were detected to have a de novo PAX6 gene variant in the absence of aniridia. All previously described gene mutations for glaucoma were looked for in the family. The potential pathogenicity of the identified variants was assessed by determining their frequency in large public exome databases; as well as using the current ACMG guidelines. The same heterozygous variant at NM_000280.6:c.1124 C > A; p. Pro375Gln in the PAX6 gene was detected in the proband and her affected brother. The variant has been described in aniridia patients before and has been shown to cause a weaker DNA binding using functional studies. This report expands the phenotypic spectrum of the PAX6 gene to include Juvenile onset open angle glaucoma.

Distribution of TGFBI variants in patients with early onset glaucoma.

Purpose: To describe a novel association of TGFBI variants with congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome, as well as among other unrelated cases of juvenile onset open-angle glaucoma (JOAG) and primary congenital glaucoma (PCG). Methods: This study of one family of GAPO with congenital glaucoma and three unrelated patients with JOAG analyzed a common link to glaucoma pathogenesis. Three girls with GAPO syndrome born to consanguineous parents in a multi-generation consanguineous family were identified. Two of the girls had congenital glaucoma in both eyes, while the elder sibling (a 10-year-old female) had features of GAPO syndrome without glaucoma. Results: A genetic evaluation using whole exome sequencing revealed a novel homozygous ANTXR1 mutation in all three affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense variant in the TGFBI gene was shared in the two siblings with congenital glaucoma and GAPO syndrome. We found three other unrelated patients with JOAG and one patient with primary congenital glaucoma with no known glaucoma causing gene mutations, but having four different missense variants in the TGFBI gene. One of these patients with JOAG had familial granular corneal dystrophy. Molecular dynamic simulations of TGFBI and 3-D structural models of three of its variants showed significant alterations that could influence TGFBI protein function. Conclusions: The possibility that variations in the TGFBI gene could have a possible role in the pathogenesis of congenital and juvenile onset open-angle glaucomas needs further evaluation.

Myopia and glaucoma progression among patients with juvenile onset open angle glaucoma: A retrospective follow up study.

OBJECTIVE: To identify the risk factors for glaucoma progression, especially the association with myopia, among treated juvenile open angle glaucoma (JOAG) patients. METHODS: Glaucomatous progression was analysed in the eyes of JOAG patients with at least 5-years of follow up in this retrospective study. Baseline variables such as age, inheritance pattern, baseline intraocular pressure (IOP), baseline central corneal thickness, visual acuity, baseline refractive error, spherical equivalent (SE) and duration of follow-up were noted. Stereoparametric global trend analysis and Moorfields Regression Analysis on confocal scanning laser ophthalmoscopy were used to detect progression. Variables associated with glaucoma progression, with respect to progressors (PG) and non-progressors (NPG) were analysed. Since both eyes of a patient were taken for analysis, a generalised estimating equation method was used to correct the bias. RESULTS: Among 74 eyes (37 subjects), glaucoma progression was noted in 11 eyes (14.9%) of 8 patients, with a median time to progression of 7.4 years (range 5-15.5 years). For myopes (SE ≤ -1.00 D), glaucoma progression was 18 times more likely than mild and no myopes (>-1DS) (p = 0.03, 95% CI: 1.14, 217.44). The prevalence of myopia in the JOAG, PG and NPG cohorts was 70.3%, 87.5%, and 65.5%, respectively. Myopia progression was noted at follow up in 70% patients. One-unit increase in baseline vertical cup disc ratio, 1 mmHg increase in IOP fluctuations and 1 dB year-1 depression of visual field were associated with 0.44, 0.06 and 0.07 D year-1 increases in the rate of myopia progression, respectively. CONCLUSIONS: JOAG progressors had a greater baseline myopic refraction and a faster myopia development over time. The development of myopia in JOAG eyes could be an indicator of glaucoma progression, and hence progressing myopic (≤-1 D) JOAG patients should be followed up more rigorously.

COMPARATIVE EVALUATION OF ANTERIOR SEGMENT OPTICAL COHERENCE TOMOGRAPHY, ULTRASOUND BIOMICROSCOPY, AND INTRAOCULAR PRESSURE CHANGES AFTER PANRETINAL PHOTOCOAGULATION BY PASCAL AND CONVENTIONAL LASER.

PURPOSE: To compare intraocular pressure, anterior segment optical coherence tomography, and ultrasound biomicroscopy parameters over 3 months after panretinal photocoagulation (PRP) for proliferative diabetic retinopathy after 1 of 2 sittings by conventional laser (half PRP) and a single sitting of Pattern Scan Laser (PASCAL) PRP. METHODS: This was a prospective, randomized, interventional study. All tests were performed at baseline, and at 1, 6, and 24 hours, and 1, 4, 8, and 12 weeks after PRP. RESULTS: The intraocular pressure at 1 hour and 6 hours after PRP was significantly raised in both groups. Mean intraocular pressure was 21.17 ± 4.01 mmHg after PASCAL and 17.48 ± 3 mmHg after conventional laser at 1 hour, P < 0.001. On anterior segment optical coherence tomography, conventional laser PRP caused a more significant narrowing of angle-opening distance (AOD750) and trabecular-iris space area (TISA 500), P = 0.03 and 0.04, respectively, on Day 1. Ultrasound biomicroscopy showed a significantly narrow angle in both groups on Day 1. A significant increase in ciliary body thickness was observed in both groups, with 57.1% of PASCAL and 100% of conventionally treated eyes showing ciliary effusion on Day 1 that decreased but persisted for the next 3 months. CONCLUSION: Performing PRP in sittings, prescribing previous glaucoma medications in patients at risk, and recording intraocular pressure an hour after the PRP could decrease complications.

Case Report: Cyclodialysis Cleft in a Case of Open-globe Injury and Role of Swept-source Anterior Segment Optical Coherence Tomography in Diagnosis.

SIGNIFICANCE: Cyclodialysis clefts can potentially develop secondary to open globe injury. The swept-source anterior segment optical coherence tomography (SS-AS-OCT) may be a valuable diagnostic tool for the identification and estimation of the circumferential extent of cyclodialysis clefts. It could be considered an alternative when ultrasound biomicroscopy cannot be performed successfully. PURPOSE: The purpose of this study was to report a case of open-globe injury associated with cyclodialysis cleft and the utility of SS-AS-OCT in its diagnosis. CASE REPORT: A 12-year-old boy presented to the clinic because of penetrating ocular trauma to his left eye with a projectile stone. He was diagnosed with limbal perforation with uveal tissue prolapse and cataract. He underwent limbal repair with cataract extraction and posterior chamber intraocular lens implantation. However, even at the 6 weeks' post-operative period, he did not gain vision and had persistent hypotony with hypotonic maculopathy. Gonioscopy showed a 2-clock-hour superonasal cyclodialysis cleft. However, on SS-AS-OCT, it was discovered that the cleft extended along 5 clock hours, involving both superonasal and inferonasal quadrants. Recognizing the large extent of the cleft, endocyclopexy by modified sewing-machine technique was planned and performed. An IOP spike and improvement in vision were noted on the next post-operative day. The SS-AS-OCT confirmed cleft closure. CONCLUSIONS: Although rare, cyclodialysis can occur in cases of open globe injury. The SS-AS-OCT is a useful diagnostic tool to study the circumferential extent of cyclodialysis and may unravel detachments hidden behind intact anterior ciliary body face.

Possible role of differentially expressing novel protein markers (ligatin and fibulin-7) in human aqueous humor and trabecular meshwork tissue in glaucoma progression.

The pathological mechanism underlying glaucoma has always been a complex aspect of this permanently blinding disease but proteomic studies have been helpful in elucidating it to a great extent in several studies. This study was designed to evaluate the expression and to get an idea about the function of two novel markers (ligatin and fibulin-7) identified in human aqueous humor (hAH) in relation to glaucomatous progression. A significant increase in the protein content of glaucomatous hAH compared to that of non-glaucomatous controls (NG-Ctrls) was observed. Ligatin, fibulin-7, and its proteolysis were revealed in hAH of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG) and NG-Ctrls. Quantification confirmed no significant difference in expression of ligatin, whereas fibulin-7 was significantly (P < 0.05) low in hAH of PACG in comparison to NG-Ctrls and POAG. Importantly the immunohistochemical assay for both indicated their possible involvement in the maintenance of the appropriate structure of TM in vivo. Since oxidative stress is a major contributor to glaucomatous pathogenesis, in vitro analysis of nuclear and cytoplasmic fractions indicated intracellular changes in localization and expression of ligatin upon oxidative insult of human trabecular meshwork (TM) cells. While no such changes were found for fibulin-7 expression. This was also corroborated with the immunocytochemical assay. Though a study with a small sample size, this is the first report which confirms the presence of ligatin and fibulin-7 in hAH, quantified their differential expression, and indicated the possibility of their involvement in the maintenance of the TM structure.

Long-term evaluation of ocular hypertension with primary angle closure and primary open angles.

PURPOSE: To evaluate the long-term course of primary angle-closure ocular hypertension and primary open-angle ocular hypertension and possible risk factors for progression to glaucoma. METHODS: A total of 109 eyes of 109 ocular hypertension (OHT) patients with a minimum follow-up period of 5 years having complete ocular/medical records were evaluated. They were classified into primary angle closure or primary open angle based on gonioscopy at baseline. Baseline and review data of Humphrey field analyser, HFA, and Heidelberg retinal tomography, HRT, were recorded. Guided progression analysis (GPA) and univariate Cox regression were used for time to event analysis in identifying progression to glaucoma. RESULTS: Over a mean follow-up of 12.18 ± 4.8 years, progression to glaucoma was 17.43% (19 eyes), out of whom 5.5% (6 eyes) showed ≥ 3 loci on GPA. Sub-classifying them, progression to primary angle-closure glaucoma was 19.72%, and that of primary open-angle glaucoma was 13.16%. The mean time to progression was 9.34 ± 3.6 years. Significant risk factors included small disc area (≤ 1.99 sq.mm on HRT), requirement of ≥ 2 drugs to maintain target IOP and those engaged in activities yielding a Valsalva effect in daily life. Coronary artery disease (CAD) and systemic use of steroids were associated with increased severity. CONCLUSION: Overall progression of OHT to glaucoma was 17.43% over a mean of 9 years, with target IOP of ≤ 18 mm Hg. Patients with smaller discs, CAD, exercising Valsalva type activities and using ≥ 2 glaucoma medications or systemic steroids should be closely monitored.

Effect of intracameral human cord blood-derived stem cells on lasered rabbit trabecular meshwork.

BACKGROUND: This study aimed to investigate the effect of intracameral human cord blood stem cells on lasered rabbit trabecular meshwork. METHODS: Immediately following diode laser application to the trabecular meshwork, human cord blood stem cells were injected intracamerally, in one eye of 12 albino rabbits. The other eye of ten rabbits was lasered controls and two eyes were normal controls. Rabbits were killed after 4, 8 and 12 weeks. RESULTS: Lasered control rabbit eyes showed significant disruption of trabecular architecture, loss and pleomorphism of trabecular endothelial cells and progressive narrowing of trabecular spaces till 12 weeks. In contrast, lasered eyes, concurrently injected with human cord blood stem cells, showed relatively preserved endothelial cellularity and structure of the trabecular meshwork, at all time points. Human CD34- and CD44-positive cells were identified in 7/8 eyes treated with stem cells, at 4 and 8 weeks, and 2 of 3 at 12 weeks. Many PKH26-labeled human cord blood cells were visible throughout the trabecular area at 4 weeks. They gradually decreased in number by 8 weeks, and at 12 weeks, they appeared to be oriented along trabecular beams. CONCLUSIONS: There was a relative preservation of cellularity and architecture of the trabecular meshwork in eyes injected with human cord blood stem cells, as compared to lasered control eyes up to 12 weeks, without significant inflammation. This suggests a probable role for such stem cells in eyes with glaucoma, having trabecular dysfunction.

Is combined mechanism glaucoma a distinct entity?

PURPOSE: Primary adult glaucomas that have an occludable angle with peripheral anterior synechiae which are too few to account for the chronically raised IOP, or the glaucomatous optic neuropathy, do not fit the definition of either POAG or PACG and can be considered as combined mechanism glaucoma (CMG). We aimed to compare the clinical features and anatomical parameters of combined mechanism glaucoma with age, sex, and refraction-matched POAG and chronic PACG eyes. METHODS: Consecutive adult patients with definitive optic nerve head and perimetric changes of glaucoma were screened at a tertiary care center. All glaucomatous eyes having an IOP > 22 mmHg on at least three separate occasions and glaucomatous optic neuropathy consistent with moderate visual field loss in the eye were divided as POAG, PACG, and CMG. Eyes with occludable angles having < 90° of goniosynechiae were diagnosed as CMG. A detailed clinical examination, ocular biometry, and ASOCT were performed in the better eye of all individuals. RESULTS: A total of 93 patients with similar visual field index or pattern standard deviation on perimetry were evaluated: 32 POAG, 31 CMG, and 30 PACG. The mean anterior chamber depth was 3.47 ± 0.37 mm in POAG, 2.81 ± 0.32 mm in PACG, and 3.06 ± 0.26 mm in CMG (p < 0.0001). Mean lens thickness was 4.22 ± 0.27 mm in POAG, 4.53 ± 0.35 mm in PACG, and 4.44 ± 0.29 mm in CMG (p = 0.0004). Iridotrabecular contact on ASOCT was nil in POAG, a mean of 87.60 ± 12.802% in PACG eyes, and 15.23 ± 14.19% in CMG eyes, p < 0.0001. CMG was similar to PACG in terms of corneal diameters and lens thickness and had an axial length in between PACG and POAG. On ASOCT, all parameters had highest values in POAG eyes and the least in PACG eyes, with CMG eyes having values in between the other two groups, p value of < 0.0001 between each group for all parameters. CONCLUSION: This study has demonstrated significantly different anatomical parameters in eyes with CMG, in addition to the differences on gonioscopy and iridotrabecular contact, indicating that CMG is discernibly dissimilar to PACG and POAG.

Role of CYP1B1, p.E229K and p.R368H mutations among 120 families with sporadic juvenile onset open-angle glaucoma.

BACKGROUND: To determine the frequency of CYP1B1 p.E229K and p.R368H, gene mutations in a cohort of sporadic juvenile onset open-angle glaucoma (JOAG) patients and to evaluate their genotype/phenotype correlation. METHODS: Unrelated JOAG patients whose first-degree relatives had been examined and found to be unaffected were included in the study. The patients and their parents were screened for p.E229K and p.R368H mutations. The phenotypic characteristics were compared between probands carrying the mutations and those who did not carry these mutations. RESULTS: Out of 120 JOAG patients included in the study, the p.E229K mutation was seen in 9 probands (7.5%) and p.R368H in 7 (5.8%). The average age of onset of the disease (p = 0.3) and the highest untreated IOP (p = 0.4) among those carrying mutations was not significantly different from those who did not have these mutations. The proportion of probands with angle dysgenesis among those with p.E229K and p.R368H mutations was 70% (11 out of 16) in comparison to 65% (67 out of 104) of those who did not harbour these mutations (p = 0.56). Similarly, the probands with moderate to high myopia among those with p.E229K and p.R368H mutations was 20% (3 out of 16) in comparison to 18% (18 out of 104) of those who did not harbour these mutations (p = 0.59). CONCLUSION: The frequency of p.E229K and p.R368H mutations of the CYP1B1 gene is low even among sporadic JOAG patients. Moreover, there is no clinical correlation between the presence of these mutations and disease severity.

Functional evaluation of an iridotomy in primary angle closure eyes.

OBJECTIVE: To evaluate the functional efficacy of an iridotomy in primary angle closure (PAC) eyes by measuring IOP responses to provocative tests before and after iridotomy. DESIGN: Prospective cohort study. SUBJECTS: 50 consecutive adult patients, 40-60 years of age, having primary angle closure. METHODS: Clinical examination, perimetry, biometry and ultrasound biomicroscopy of the angle were done. A darkroom prone provocative test (DRPPT), a mydriatic test and a Valsalva maneuver were performed before and after the iridotomy. MAIN OUTCOME MEASURES: IOP change in response to the provocative tests before and after iridotomy, and correlation with baseline parameters. RESULTS: IOP at baseline and after iridotomy was 14.4 ± 2.7 mmHg and 14.3 ± 2.6 mmHg, respectively (p = 0.)83. There was no significant change on diurnal phasing before and after an iridotomy (p = 0.)11. The mean IOP rise was 5.9 ± 3.7 mmHg on the DRPPT, 4.3 ± 3.5 mmHg on the Mydriatic test and 9.1 ± 4.9 mmHg on the Valsalva maneuver, and was reduced significantly to 3.2 ± 2.1 mmHg, 2.3 ± 1.8 and 6.4 ± 3.5, respectively(p < 0.001 for all tests). The decrease in pupillary block component for all 50 eyes was 46.5 % for the mydriatic test, 45.8 % for the DRPPT and 29.7 % for the Valsalva maneuver. PAC eyes positive on the DRPPT and mydriatic test prior to an iridotomy became negative after laser iridotomy in 75.9 and 84.6 % eyes, respectively, but on the Valsalva maneuver, only 23.8 % became negative. After iridotomy, eyes that continued to be positive on the mydriatic test had a significantly thicker lens (p = 0.02), decreased TCPD (p = 0.014) and narrower trabecular-iris angle (p = 0.048). On the DRPPT, they had a thicker lens (p = 0.03), shorter iris thickness (p = 0.025) and TCPD (p = 0.032), and on the Valsalva maneuver, they had a narrower scleral-ciliary process angle (SCPA; p = 0.019) and shorter TCPD (p = 0.015). CONCLUSIONS: This comprehensive functional evaluation of laser iridotomy in early PAC eyes showed a significant reduction in the pupillary block component of IOP response to provocative testing, possibly decreasing IOP fluctuations over time. An iridotomy does not, however, significantly change mean IOP or diurnal phasing of IOP in PAC eyes. Eyes with a very narrow angle or a thick lens may continue to have angle closure due to other pathomechanisms for angle closure.

Long-term outcomes of glaucoma drainage devices for glaucoma post-vitreoretinal surgery with silicone oil insertion: a prospective evaluation.

PURPOSE: To evaluate long-term success of the Ahmed glaucoma valve (AGV) for refractory glaucoma after vitreoretinal surgery with silicone oil insertion. METHODS: Prospective non-comparative evaluation of patients who underwent AGV insertion for management of post-vitreoretinal surgery glaucoma, post-silicone oil removal. Intraocular pressure (IOP), visual acuity, and glaucomatous neuropathy status were evaluated preoperatively and at multiple follow-up visits postoperatively. Success, using Kaplan-Meier analysis, was determined at the 12-month follow-up visit and at the last follow-up. Factors associated with failure were analysed. RESULTS: Twenty-seven eyes of 27 patients with a mean age of 28.3 ± 15.2 years underwent a superior AGV implantation. The average follow-up after AGV implantation was 17.11 ± 8.36 months (range: 9-60 months). Kaplan-Meier survival analysis revealed a 62 % success at 12 months and 37 % at 5 years. A 48 % rate of complications was noted, 22 % of which were vision-threatening. Factors analysed, including patient age, interval between vitreoretinal surgery and silicone oil removal, interval between vitreoretinal surgery and AGV implantation, and phakic status, were not found to be associated with higher failure rates. CONCLUSION: Long-term success of AGV implantation for glaucoma after vitreoretinal surgery with silicone oil insertion is better than that reported for trabeculectomy, though complication rates remain high.