A polymorphism in the CYP1B1 promoter is functionally associated with primary congenital glaucoma.

Primary congenital glaucoma (PCG) is a childhood autosomal-recessive disorder caused by developmental defects in the trabecular meshwork and anterior chamber angle. These defects cause raised intraocular pressure (IOP) that damages the optic nerve and if left untreated, results in irreversible blindness. Mutations in CYP1B1 gene at the GLC3A locus (2p21) are associated with PCG. However, there has been very limited exploration of its promoter region. We resequenced the CYP1B1 promoter in a large cohort (n = 835) that included patients with PCG (n = 301), other primary glaucomas (primary open-angle glaucoma: n = 115 and primary angle closure glaucoma: n = 100) and unaffected controls (n = 319). We functionally characterized one associated variant by luciferase reporter assay using the trabecular meshwork (TM3) cell line. We found evidence of strong (P = 6.01 × 10(-4)) association of rs2567206 (T2805C) SNP in PCG and not in other primary glaucomas. Luciferase assay indicated a ∼90% reduction in CYP1B1 promoter activity in the risk-allele (C) compared to the other allele (T). The association of the risk allele was stronger in cases harboring homozygous CYP1B1 mutations (P = 3.42 × 10(-12)). The risk haplotype 'C-C-G' in the promoter had a strong non-random association to the previously characterized risk haplotype 'C-G-G-T-A' in the coding region. The independent effect of genotype at the promoter T2805C locus (P = 0.001), and the interaction effect of genotypes at the promoter and coding region mutations loci (P = 0.001) were significant for the presenting IOP of the worst affected eye. This is the first study that unequivocally shows the functional involvement of a CYP1B1 promoter variant in PCG.

There is insufficient evidence to recommend lens extraction as a treatment for primary open-angle glaucoma: an evidence-based perspective.

Cataract extraction in primary open-angle glaucoma has not been thought to provide a clinically useful or predictable decrease in IOP. This concept has now been challenged, with the opposite belief being promulgated: namely, that lens exchange should be considered as treatment for glaucoma. This revelation could bring a significant change in the glaucoma treatment paradigm. There are no randomised controlled trials to guide the role of lens extraction in primary open-angle glaucoma. The available evidence suggests at most a modest reduction in IOP from cataract extraction - greater in the presence of pseudoexfoliation - which is likely to be of marginal benefit, and only in milder forms of open-angle glaucoma. There is currently no evidence of any quality to suggest that lens extraction routinely represents a clinically useful treatment for primary open-angle glaucoma.

Clinical implication of recent randomized control trial in primary angle-closure disease management.

Blindness due to primary angle-closure glaucoma (PACG) can be reduced significantly if the ongoing angle-closure process is arrested at an early stage. Various treatments such as laser peripheral iridotomy (LPI), iridoplasty, and clear lens extraction (CLE) have been advocated as first-line therapy for primary angle-closure (PAC), PACG, and high-risk cases of primary angle-closure suspect (PACS). EAGLE study, propagated the effectiveness of CLE over LPI for the management of primary angle closure and have sparked controversy regarding the role of LPI as a first line procedure. Randomized controlled trials (RCT), systematic reviews, and meta-analyses of RCTs done on the same question provide us with a solid base for creating guidelines/modules for our day-to-day clinical practice. A systematic review was conducted, searching several databases, including PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov, for the last 16 years (January 2005-December 2021) for RCTs with data published related to primary angle-closure disease (PACD). The search strategy included the following terms: "Primary Angle Closure disease," "Primary Angle Closure Glaucoma," "Primary Angle Closure," "Primary Angle Closure Suspect," "clear lens extraction," "laser iridotomy," "laser peripheral iridotomy," "argon laser peripheral iridoplasty," "selective laser trabeculoplasty," "trabeculectomy," "randomized control trial," and "meta-analysis of randomized control trial." In this review, we will discuss recently published RCTs (within the last 16 years) for the management of PACD and their clinical implications in day-to-day practice.

Clear lens extraction in angle closure glaucoma.

PURPOSE OF REVIEW: Clear lens extraction is being advocated for primary angle closure disease (PACD). It is important that this advocacy should be based on a sound, peer-reviewed evidence base. This review attempts to establish the extent of that evidence and provide some management guidelines. RECENT FINDINGS: There are only three reports that incorporate clear lens extraction (CLE) for angle closure: numbers are sparse and none compare modern phacoemulsification to alternative treatments for primary angle closure glaucoma or provide enough detail to guide clinical decisions. A Cochrane review in 2006 found that there was no evidence to support lens extraction as treatment for primary angle closure glaucoma (PACG). More recent randomized controlled trials have provided support for cataract extraction--although not specifically for CLE--as treatment for part of the spectrum of PACD. A recent review has attempted to provide guidelines for application of CLE in PACG by extrapolating from this evidence. SUMMARY: There are currently no randomized controlled trials supporting the use of CLE as treatment for PACG. A benefit from the procedure is biologically plausible and extrapolation from existing randomized trials to a few specific situations may be possible. Any potential benefit must be carefully weighed against the risks of intervention.

Enter the reverend: introduction to and application of Bayes' theorem in clinical ophthalmology.

BACKGROUND: Ophthalmic practice utilizes numerous diagnostic tests, some of which are used to screen for disease. Interpretation of test results and many clinical management issues are actually problems in inverse probability that can be solved using Bayes' theorem. DESIGN: Use two-by-two tables to understand Bayes' theorem and apply it to clinical examples. SAMPLES: Specific examples of the utility of Bayes' theorem in diagnosis and management. METHODS: Two-by-two tables are used to introduce concepts and understand the theorem. The application in interpretation of diagnostic tests is explained. Clinical examples demonstrate its potential use in making management decisions. MAIN OUTCOME MEASURE: Positive predictive value and conditional probability. RESULTS: The theorem demonstrates the futility of testing when prior probability of disease is low. Application to untreated ocular hypertension demonstrates that the estimate of glaucomatous optic neuropathy is similar to that obtained from the Ocular Hypertension Treatment Study. Similar calculations are used to predict the risk of acute angle closure in a primary angle closure suspect, the risk of pupillary block in a diabetic undergoing cataract surgery, and the probability that an observed decrease in intraocular pressure is due to the medication that has been started. The examples demonstrate how data required for management can at times be easily obtained from available information. CONCLUSIONS: Knowledge of Bayes' theorem helps in interpreting test results and supports the clinical teaching that testing for conditions with a low prevalence has a poor predictive value. In some clinical situations Bayes' theorem can be used to calculate vital data required for patient management.

Chemical disinfectants in ophthalmic practice.

The instrumentation used in ophthalmic clinics can be a source of epidemics in health care set up. Contact tonometry with Schiotz or Applanation tonometer is associated with nosocomial epidemic keratoconjunctivitis outbreaks. Recently identified SARS-CoV-2 (COVID -19) spreads mainly via the respiratory route and fomites and can transmit through other body fluids, including tear film. Various ophthalmic instruments can become a common source of spreading cross infections. Chemical disinfection is one of the most common methods employed to decontaminate instruments and environmental surfaces and prevent transmission of infectious pathogens to patients through medical and surgical instruments. Various chemical disinfectants are available with a varied spectrum to work on a different group of organisms. In this article, we briefly cover commonly used chemical disinfectants in ophthalmic practice like Alcohol (Ethyl Alcohol, Isopropyl Alcohol), Chlorine-based solution (mainly Sodium Hypochlorite), Glutaraldehyde, Hydrogen Peroxide, Formaldehyde, Iodophors, and Quaternary Ammonium Compounds.

Clinical measurement and categorization of optic disc in glaucoma patients.

BACKGROUND: Assessment of optic disc size is an important component of optic nerve head examination. Agreement between different methods of disc size measurements is not very good. PURPOSE: To assess the agreement between the disc size assessed by Heidelberg retina tomograph (HRT) and stereobiomicroscopy with a 90 diopter (D) lens. To report the clinical (measured by biomicroscopy) disc diameters of small, average and large optic discs categorized by HRT disc areas. SETTING AND DESIGN: Observational study of subjects examined in the glaucoma clinic of a tertiary eye institute. MATERIALS AND METHODS: Seventy-five eyes of 75 glaucoma subjects were studied. Disc diameter was measured using stereobiomicroscopy and HRT. The agreement between the two sets of measurements was assessed by intraclass correlation coefficient (ICC). Discs were classified into small (<1.6 mm(2)), average (1.6-2.6 mm(2)) and large (>2.6 mm(2)) depending on cutoffs provided by the manufacturers of HRT. The means (95% CI) of the corresponding vertical disc diameter in these groups were assessed. STATISTICAL ANALYSIS: ICC, Bland and Altman plots. RESULTS: ICC for measurements of clinical and HRT horizontal disc diameter was 0.518 and for vertical disc diameter measurement was 0.487. The mean difference between the clinical and HRT measurements as analyzed by the Bland and Altman plot was 0.17 (95% CI, 0.13- 0.47) for horizontal and 0.22 (95% CI, 0.11- 0.54) for vertical disc diameter. Of the 75 eyes, 3 eyes had small discs, 54 average and 18 large discs. The mean clinical vertical disc diameter for small discs was 1.55 mm (95% CI, 1.2-1.7), for average discs was 1.91 mm (95% CI, 1.87-1.96) and for large discs was 2.15 mm (95% CI, 2.03-2.27). CONCLUSION: The agreement between clinical and HRT disc diameter measurements is moderate. Disc diameter measurement on stereobiomicroscopy can be used to categorize discs into small, average and large discs.

The LOXL1 gene variations are not associated with primary open-angle and primary angle-closure glaucomas.

PURPOSE: Glaucoma is a complex disease involving multiple genetic factors. Recently, single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) but not in the primary glaucomas. This study was conducted to determine the possible involvement of these SNPs in cases of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). METHODS: The three associated SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were screened in 208 unrelated and clinically well-characterized glaucoma cases comprising patients with POAG (n = 112) or PACG (n = 96) along with 105 ethnically matched normal control subjects from Indian populations. Subjects with exfoliative material on the lens and radial pigmentation in the periphery of the lens that could be earlier signs of XFS were excluded. These SNPs were screened by resequencing and further confirmed by PCR-based restriction digestions. Haplotypes were generated with the three SNPs in cases and control subjects, and linkage disequilibrium (LD) and haplotype analysis were performed with the Haploview software, which uses the EM (expectation-maximization) algorithm. RESULTS: The SNPs of LOXL1 did not exhibit any significant association with POAG or PACG, unlike previous studies from Icelandic, Swedish, U.S., and Australian populations with XFS/XFG. Haplotypes generated with these intragenic SNPs did not indicate any significant risk with POAG or PACG phenotypes. The risk haplotype G-G in XFS/XFG in other populations was present in 46% of the normal control subjects in the present cohort. CONCLUSIONS: The results from the present study do not indicate the involvement of the LOXL1 SNPs in POAG and PACG.

Diagnostic capability of scanning laser polarimetry with variable cornea compensator in Indian patients with early primary open-angle glaucoma.

PURPOSE: To evaluate the diagnostic ability of scanning laser polarimetry (GDx variable corneal compensator [VCC]) for early glaucoma in Asian Indian eyes. DESIGN: Cross-sectional observational study. PARTICIPANTS: Two groups of patients (early glaucoma and normal) who satisfied the inclusion and exclusion criteria were included. Early glaucoma was diagnosed in presence of open angles, characteristic glaucomatous optic disc changes correlating with the visual field (VF) on automated perimetry (VF defect fulfilling at least 2 of 3 Anderson and Patella's criteria with mean deviation >or= -6 decibels). Normal subjects had visual acuity >or= 20/30 and intraocular pressure < 22 mmHg, with a normal optic disc and fields and no ocular abnormality. METHODS: All patients underwent complete ophthalmic evaluation, including VF examination (24-2/30-2 Swedish interactive threshold algorithm standard program) and imaging with GDx VCC. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value and negative predictive value, area under the receiving operating characteristic curve, and likelihood ratios (LRs) were calculated for various GDx VCC parameters. RESULTS: Seventy-four eyes (74 patients) with early glaucoma and 104 eyes (104 normal subjects) were enrolled. TSNIT Std Dev (temporal-superior-nasal-inferior-temporal standard deviation) had the best combination of sensitivity and specificity-61.3 and 95.2, respectively-followed by nerve fiber index score > 50 (sensitivity, 52.7%; specificity, 99%). Nerve fiber index score > 50 had positive and negative predictive values of 74.3% and 97.6%, respectively, for an assumed glaucoma prevalence of 5%. Nerve fiber index score > 50 had a positive LR (+LR) of 54.8 for early glaucoma. CONCLUSIONS: GDx VCC has moderate sensitivity, with high specificity, in the diagnosis of early glaucoma. The high +LR for the nerve fiber index score can provide valuable diagnostic information for individual patients.

Practical approach to medical management of glaucoma.

Primary open angle glaucoma (POAG) is usually a chronic, slowly progressive disease. At present, all resources are directed towards reduction of intraocular pressure (IOP), the only known causal and treatable risk factor for glaucoma, and medical management is frequently the first choice in most cases. With the introduction of innovative tools for early diagnosis and newer medications for treatment, decision-making in diagnosis and treatment of glaucoma has become more complex. The philosophy of glaucoma management is to preserve the visual function and quality of life (QOL) of the individual with minimum effects on QOL in terms of cost, side effects, treatment regime, follow-up schedules as well as socioeconomic burden. Our aim should be not to treat just the IOP, optic disc or visual field, but to treat the patient as a whole so as to provide maximum benefit with minimal side effects. In this article, we describe the scientific approach to medical management, mainly of POAG.

Glaucoma-associated CYP1B1 mutations share similar haplotype backgrounds in POAG and PACG phenotypes.

PURPOSE: To understand the involvement of the CYP1B1 gene in cases of primary open-angle (POAG) and primary angle-closure (PACG) glaucomas and obtain the haplotype background of these mutations. METHODS: The entire coding region of CYP1B1 was screened by resequencing in 224 unrelated cases of POAG (n = 134) and PACG (n = 90) and 200 ethnically matched normal control subjects from Indian populations. Six intragenic single nucleotide polymorphisms (SNPs) in CYP1B1 (-13T>C, R48G, A119S, V432L, D449D, and N453S) were used to generate haplotype data for the cases and controls and linkage disequilibrium (LD) and haplotype analysis were performed with Haploview software, which uses the EM (expectation-maximization) algorithm. RESULTS: The frequency of CYP1B1 mutations was higher among POAG (18.6%; 95% CI, 12.9-26.1) than PACG (11.1%; 95% CI, 6.1-19.3) cases. There was a marked allelic heterogeneity, and the Arg368His was the most prevalent mutation across both the phenotypes. The spectrum of CYP1B1 mutations was largely similar across different POAG populations. Haplotypes generated with intragenic SNPs indicated the C-C-G-G-T-A to be a risk haplotype associated with CYP1B1 mutations in POAG (P = 0.006) and PACG (P = 0.043), similar to that observed in cases of primary congenital glaucoma worldwide. CONCLUSIONS: The results demonstrate an involvement of CYP1B1 in a proportion of POAG and PACG cases that should be explored further. The similar haplotype background of these mutations is indicative of their common origin across multiple glaucoma phenotypes.

Normal age-related decay of retinal nerve fiber layer thickness.

PURPOSE: To determine the normal age-related loss of retinal nerve fiber layer thickness (RNFLT) as measured on Stratus optical coherence tomography (OCT 3; Carl Zeiss Meditec, Dublin, CA) in an Asian Indian population. DESIGN: Prospective, cross-sectional, observational study. PARTICIPANTS: One hundred eighty-seven eyes of 187 normal subjects (age range, 5-75 years) who satisfied the inclusion and exclusion criteria were included. The subjects were defined as normal if they had visual acuity of 20/30 or better, intraocular pressure less than 22 mmHg with normal optic disc, and no ocular abnormality. METHODS: All patients underwent complete ophthalmic evaluation including imaging with Stratus OCT 3. Simple linear regression was performed to study the effect of age on RNFLT, with age as the independent variable and RNFLT as the dependent variable. Spearman's correlation was studied between the age and RNFLT. An analysis of variance was applied to compare RNFLT between the different age groups. The chi-square test also was used to evaluate the relationship between age and RNFLT. MAIN OUTCOME MEASURE: Effect of age on RNFLT. RESULTS: One hundred eighty-seven eyes of 187 normal subjects were analyzed. Mean age+/-standard deviation was 33.0+/-19.7 years (range, 5-75). Average RNFLT and RNFLT by quadrant demonstrated the tendency of RNFLT to decrease with increasing age, especially after age 50 years. Average RNFLT demonstrated a negative slope of 0.16 microm/year (95% confidence interval [CI], -0.1 to -0.24). By quadrant, the superior average (negative slope, -0.23 microm/year; 95% CI, -0.1 to -0.34) showed a maximum tendency to decline with age, whereas in the inferior quadrant (negative slope, -0.08 microm/year; 95% CI, 0.05 to -0.24), the age-related decay was minimal. Six clock-hour RNFLT had a least negative slope of -0.022 microm/year (95% CI, -0.08 to -0.1). Chi-square test results showed a significant inverse relationship between age and average RNFLT (P = 0.01). CONCLUSIONS: Age-related retinal nerve fiber layer (RNFL) loss is not uniform in all the quadrants, with maximum loss in the superior quadrant, and seems to reach a maximum after the age of 50 years. Furthermore, it seems that inferior quadrant RNFL is more resistant to loss.

Diagnostic capability of optical coherence tomography (Stratus OCT 3) in early glaucoma.

PURPOSE: To evaluate the diagnostic capability of optical coherence tomography (Stratus OCT 3) for early glaucoma in Asian Indian eyes. DESIGN: Cross-sectional observational study. PARTICIPANTS: Two groups of patients (early glaucoma and normal) who satisfied the inclusion and exclusion criteria were included. Early glaucoma was diagnosed in presence of open angles, characteristic glaucomatous optic disc changes correlating with the visual field on automated perimetry (visual field defect fulfilling at least 2 of Anderson and Patella's 3 criteria with mean deviation > or = -6 dB). Normals had visual acuity > or =20/30, intraocular pressure <22 mmHg with normal optic disc and fields and no ocular abnormality. METHODS: All patients underwent complete ophthalmic evaluation including visual field examination (24-2/30-2 SITA standard program) and imaging with Stratus OCT 3. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values, area under the receiving operating characteristic curve and likelihood ratios were calculated for various Stratus OCT 3 parameters. RESULTS: Seventy-two eyes (72 patients) with early glaucoma and 96 eyes (96 normal subjects) were analyzed. The inferior maximum parameter had the best combination of sensitivity and specificity, 75% (95% confidence interval [CI], 70.2-79.8%) and 89.6% (95% CI, 82.6-96.6%), respectively. The 6-o'clock parameter had a sensitivity of 61.1% (95% CI, 52.3-69.9) and specificity of 99% (95% CI, 95-100); for an assumed prevalence of 5%, the positive and negative predictive values were 75% and 98%, respectively. The positive likelihood ratio for the 6-o'clock parameter (P<5%) in early glaucoma was 61. CONCLUSIONS: Optical coherence tomography has moderate sensitivity with high specificity for the diagnosis of early glaucoma and may have a potential role in screening.

Application of shape-based analysis methods to OCT retinal nerve fiber layer data in glaucoma.

PURPOSE: (1) To evaluate the performance of shape-based analysis [wavelet-Fourier analysis (WFA) and fast Fourier analysis (FFA)] applied to retinal nerve fiber layer (RNFL) thickness values obtained from the optical coherence tomograph (OCT) to discriminate healthy and glaucomatous eyes. (2) To compare the performance of the shape-based metrics to that of the standard OCT output measures (Inferior Average and Average Thickness). METHODS: RNFL values were obtained from 152 eyes of 152 individuals (83 healthy and 69 "mild"-stage perimetric glaucoma). WFA and FFA were performed on the RNFL values and linear discriminant functions for both were obtained using Fisher linear discriminant analysis. Performance was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve (ROC area). RESULTS: The ROC area of the shape-based methods [0.94 (WFA) and 0.88 (FFA)] was greater than that of OCT metrics [0.81 (Inferior Average) and 0.74 (Average Thickness)]. Specifically, WFAs performance was significantly better than both the FFA (P=0.009) and the Inferior Average (P=0.001). Inferior average performed significantly better than Average Thickness (P=0.006). CONCLUSIONS: The ability to differentiate glaucomatous from healthy eyes using stratus OCT measurements is improved by using these analysis methods that emphasize the shape of the RNFL thickness pattern.

Globally, CYP1B1 mutations in primary congenital glaucoma are strongly structured by geographic and haplotype backgrounds.

PURPOSE: To obtain a global perspective on the distribution and evolution of CYP1B1 mutations in primary congenital glaucoma (PCG) worldwide. METHODS: Five intragenic single-nucleotide polymorphisms in CYP1B1-R48G, A119S, V432L, D449D, and N453S-were used to generate haplotype data from 138 Indian patients with PCG and 132 ethnically matched normal controls, which were then analyzed in conjunction with data from other populations. Maximum-likelihood estimates of haplotype frequencies were estimated from the genotype data. Subsets of patients and normal control subjects were also genotyped with respect to eight short tandem repeat (STR) markers around the CYP1B1 locus (D2S305, D2S165, D2S367, D2S2259, D2S391, D2S3337, D2S23678, and D2S286), to gain evolutionary insights. RESULTS: Common mutations in CYP1B1 that are causal of PCG occurred on a uniform haplotype background among Indian patients, which is completely distinct from the modal haplotype background found among unaffected control subjects. Comparison of these data with data from other global regions reveals strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds. The two distinct modal haplotypes found among Indian patients with PCG and control subjects are both ancient with ages of similar magnitudes, as indicated by large variances in the number of repeats at eight STR loci. Together with data from chimpanzee and normal control subjects from India and other global regions, it was possible to make a parsimonious reconstruction of the evolution of these haplotypes. CONCLUSIONS: The strong association of specific haplotypes with some predominant CYP1B1 mutations underlying PCG and the observed geographical clustering, probably due to founder effects, may be useful for predictive testing.

Heidelberg Retinal Tomograph (HRT 2) parameters in primary open angle glaucoma and primary angle closure glaucoma: a comparative study in an Indian population.

AIMS: To compare the Heidelberg Retinal Tomograph (HRT 2) parameters in patients with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in an Indian population. MATERIALS AND METHODS: Two groups of patients were recruited: group I comprised 78 eyes (78 patients) with POAG and group II 58 eyes (58 patients) with PACG. Based on visual field defects detected by automated perimetry, the groups were further classified into early, moderate, and severe glaucoma. All patients underwent a complete ophthalmic examination as well as an HRT 2 examination. The HRT parameters for the two groups were compared and the sensitivity and specificity of the parameters calculated. RESULTS: All HRT parameters were similar in both groups: 85.9% (95% CI: 78.2, 93.6) of POAG and 81% (95% CI: 72.3, 89.3) of PACG had a positive F. S. Mikeleberg (FSM) discriminant function. Considering outside normal limits and borderline as abnormal, the Moorefield regression analysis had 83.3% (95% CI: 75, 91.6) sensitivity in POAG and 75.9% (95% CI: 64.9, 86.9) in PACG. In early POAG, the FSM discriminant function had a sensitivity of 74.3% (95% CI: 59.8, 88.8) compared to 58.3% (95% CI: 38.9, 77.7) for early PACG. The cup shape measure (p = 0.018) and the Moorfield regression analysis (p = 0.011) had significantly higher sensitivity for early POAG than for early PACG: cup shape measure sensitivity 62.9% (95% CI 46.9, 78.9) for early POAG versus 33.3% (95% CI: 14.4, 52.2) for early PACG and Moorefield regression analysis 74.3% (95% CI: 59.8, 88.8) versus 45.8% (95% CI: 39.9, 65.7). CONCLUSIONS: HRT has moderate sensitivity in the detection of damage leading to glaucomatous field defects. The sensitivity of HRT for early PACG appears to be less than that for early POAG. This may indicate a difference in pathophysiology.