High Polygenic Risk Is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open-Angle Glaucoma.

PURPOSE: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. METHODS: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment. MAIN OUTCOME MEASURES: Commencement or escalation of IOP-lowering therapy. RESULTS: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001). CONCLUSIONS: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The effect of insulin on response to intravitreal anti-VEGF injection in diabetic macular edema in type 2 diabetes mellitus.

OBJECTIVES: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus. METHODS: This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. RESULTS: The mean final BCVA and CMT improved in both the insulin (N = 137; p < 0.001; p < 0.001, respectively) and the OHA group (N = 61; p = 0.199; p < 0.001, respectively). The two treatment groups were comparable for final BCVA (p = 0.263), BCVA change (p = 0.184), final CMT (p = 0.741), CMT change (p = 0.458), and the cumulative injections received (p = 0.594). The results were comparable between the two groups when stratified by baseline vision (p > 0.05) and baseline HbA1c (p > 0.05). CONCLUSION: Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.

Quantification of localised vascular wedge-shaped defects in glaucoma.

BACKGROUND: Vascular dysfunction plays a considerable role in glaucoma pathogenesis. Previous glaucoma case studies described localised wedge-shaped vascular defects, similar to retinal nerve fibre layer (RNFL) wedge defects. This study investigates the prevalence and quantification of this vessel loss, in relation to primary open angle glaucoma (POAG) parameters. METHODS: This study included 608 eyes (351 participants): 192 PROGRESSA study participants (342 eyes) with suspect, preperimetric or early manifest POAG, observed for vascular wedge defect presence (cohort one); an additional 114 individuals (cohort two-208 eyes) with POAG at various stages of progression for wedge characterisation; and 38 controls (56 eyes). Vascular wedge defects were observed using optical coherence tomography angiography (OCTA). Wedge parameters and vessel densities were quantified using ImageJ software. RNFL and ganglion cell layer inner plexiform layer (GCLIPL) from OCT scans, and mean deviation (Humphrey visual field 24-2) were also assessed. RESULTS: Vascular wedge defects were found in 45/342 eyes (13.2%) in cohort one, in 41/208 eyes (19.7%) in cohort two and were not found in controls. Wedge defects were mostly inferotemporal (80%), and present at all disease stages. They were associated with visual field loss in the opposite hemisphere, thinner RNFL (p < 0.001), thinner GCLIPL (p = 0.003), and focal RNFL loss corresponding with the vascular defect region. CONCLUSION: Vascular wedge defects are present at all POAG stages even before functional change and are strongly concordant with focal RNFL loss. Further research is needed to explore these defects in particular their temporal relationship with clinical measures of POAG.

Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema.

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.

Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma.

PURPOSE: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma. DESIGN: Prospective, longitudinal study of preperimetric and perimetric glaucoma. PARTICIPANTS: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment. METHODS: Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients. MAIN OUTCOME MEASURES: OCT and HVF baseline status and longitudinal progression. RESULTS: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039). CONCLUSIONS: Cardiovascular disease is an important risk factor for glaucoma progression.

Effect of phacoemulsification cataract surgery on intraocular pressure in early glaucoma: A prospective multi-site study.

IMPORTANCE: Cataract and primary open-angle glaucoma (POAG) commonly co-exist, and cataract surgery is thought to reduce intraocular pressure (IOP), the major modifiable risk factor of POAG. BACKGROUND: Previous studies exploring the effect of cataract surgery on IOP are limited by retrospective design, lack of a control group, medication use and washout and loss to follow up. DESIGN: Prospective, multicentre, matched case-control Australian study. PARTICIPANTS: 171 eyes of 108 POAG patients who underwent cataract surgery, matched to 171 control eyes. METHODS: Serial longitudinal IOP measurements were compared before and after cataract surgery, and relative to the controls. A mixed-effect model was used for the longitudinal data. MAIN OUTCOME MEASURES: Change in IOP. RESULTS: The mean follow-up time was 4.8 (1.4) years. Cataract surgery reduced mean IOP by 2.22 mmHg (95% confidence interval: 1.93-2.52 mmHg, P < .001) with 59 eyes (34%) achieving at least 3 mmHg reduction. Compared to matched controls, the mean reduction in IOP was 1.75 mmHg (95% confidence interval 1.15-2.33 mmHg; P < .001). Higher preoperative IOP and being on fewer topical glaucoma medications preoperatively were strongly predictive of a larger IOP reduction in a multivariable model. Anterior chamber depth was not associated with IOP reduction. Eyes with preoperative IOP ≥24 mmHg had a mean IOP reduction of 4.03 mmHg with 81% experiencing at least 3 mmHg reduction. Sub-analysis of medication naïve and pseudoexfoliation patients showed similar results. CONCLUSIONS AND RELEVANCE: Cataract surgery has a confirmed effect in reducing IOP in a "real world" setting of early glaucoma patients.

Macular Ganglion Cell-Inner Plexiform Layer Loss Precedes Peripapillary Retinal Nerve Fiber Layer Loss in Glaucoma with Lower Intraocular Pressure.

PURPOSE: To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL). DESIGN: Prospective, longitudinal cohort study. PARTICIPANTS: Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance. METHODS: Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis. MAIN OUTCOME MEASURES: Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL. RESULTS: Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval [CI], 2.37-5.43 mmHg; P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 µm; 95% CI, 4.38-9.77 µm; P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01). CONCLUSIONS: Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.

A novel de novo Myocilin variant in a patient with sporadic juvenile open angle glaucoma.

BACKGROUND: Glaucoma is a leading cause of irreversible blindness. Pathogenic variants in the Myocilin gene (MYOC) cause juvenile open angle glaucoma (JOAG) in 8-36% of cases, and display an autosomal dominant inheritance with high penetrance. Molecular diagnosis is important for early identification as therapies are effective in minimizing vision loss and MYOC variants can be associated to severe glaucoma. MYOC variants are usually inherited, however a fifth of carriers do not report a family history. The occurrence of de novo MYOC variants is currently unknown. CASE PRESENTATION: In this study we investigated a 14 year old male Caucasian patient diagnosed with JOAG, and no family history of glaucoma. A novel probably deleterious MYOC:p.(Pro254Leu) variant was identified in the index case. This variant was not present in the parents or the siblings. CONCLUSION: This is the second report of a de novo MYOC variant in a sporadic case of JOAG and it is currently unknown if this mechanism occurs more frequently. This finding emphasizes the importance of screening individuals with JOAG for MYOC mutations irrespective of a negative family history.

CYP1B1 copy number variation is not a major contributor to primary congenital glaucoma.

PURPOSE: To evaluate the prevalence and the diagnostic utility of testing for CYP1B1 copy number variation (CNV) in primary congenital glaucoma (PCG) cases unexplained by CYP1B1 point mutations in The Australian and New Zealand Registry of Advanced Glaucoma. METHODS: In total, 50 PCG cases either heterozygous for disease-causing variants or with no CYP1B1 sequence variants were included in the study. CYP1B1 CNV was analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: No deletions or duplications were found in any of the cases. CONCLUSION: This is the first study to report on CYP1B1 CNV in PCG cases. Our findings show that this mechanism is not a major contributor to the phenotype and is of limited diagnostic utility.

Severe intraocular pressure response to periocular or intravitreal steroid treatment in Australia and New Zealand: data from the Australian and New Zealand Ophthalmic Surveillance Unit.

BACKGROUND: Increase in intraocular pressure is a recognized complication of corticosteroid treatment via intravitreal or periocular injections for treatment of a range of conditions including macular oedema and retinal neovascularization. DESIGN: This surveillance study was designed to determine the incidence and nature of severe intraocular pressure elevation as a complication of intravitreal or periocular corticosteroid injections in Australia and New Zealand. PARTICIPANTS: Seventeen cases meeting the defined criteria of severe intraocular pressure elevation, above 35 mmHg, following an intravitreal or periocular corticosteroid injection were included in the study. METHODS: Over an 18-month period, ophthalmologists were invited to report cases to the Australian and New Zealand Ophthalmic Surveillance Unit. After reporting, further demographic and clinical information was sought via a follow-up questionnaire. MAIN OUTCOME MEASURES: Intraocular pressure elevation above 35 mmHg. RESULTS: Follow-up questionnaires were received for 20 cases of 34 initially reported to the unit. Seventeen met the defined criteria. Triamcinolone acetonide was used in all 17 cases, with 16 delivered as a 4-mg intravitreal injection. There was an absence of identified underlying risk factors in the majority of cases with personal history of glaucoma in 2 of 17 cases. No cases reported a positive family history of glaucoma. Trabeculectomy was performed in 8 of 17 patients (47%) for intraocular pressure management. CONCLUSIONS: Severe intraocular pressure elevation following intravitreal or periocular corticosteroid injection can occur in the absence of risk factors such as personal and family history of glaucoma. The severe intraocular pressure elevation may ultimately require trabeculectomy.

Predictive genetic testing experience for myocilin primary open-angle glaucoma using the Australian and New Zealand Registry of Advanced Glaucoma.

PURPOSE: Predictive genetic testing of relatives of known myocilin (MYOC) gene mutation carriers is an appropriate strategy to identify individuals at risk for glaucoma. It is likely to prevent irreversible blindness in this high-risk group because this treatable condition might otherwise be diagnosed late. The Australian and New Zealand Registry of Advanced Glaucoma has established genetic testing protocols for known glaucoma genes, including MYOC. METHODS: Through the Australian and New Zealand Registry of Advanced Glaucoma, we investigated the experience of 40 unaffected individuals who had undergone predictive genetic testing for MYOC mutations through questionnaires. RESULTS: The main motivations for being tested were (i) to make appropriate interventions and (ii) to reduce uncertainty. All our respondents perceived strong benefits, either medical or emotional, in being tested. However, different concerns were raised by the respondents that need to be addressed during counseling. Greater family awareness was reported by the majority of the respondents, and the ability to provide information to children was a strong motivation for being tested. CONCLUSION: This study provides valuable information on the personal and familial impacts of having predictive genetic testing for glaucoma, which will help health professionals to better address the issues faced by patients and provide them adequate support.

Predictive factors for treatment outcomes with intravitreal anti-vascular endothelial growth factor injections in diabetic macular edema in clinical practice.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice. METHODS: This was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models. RESULTS: There was a significant improvement in BCVA (p < 0.001) and CMT (p < 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a < 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive "early functional response" (p < 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p < 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an "early anatomical response", (p < 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response. CONCLUSIONS: The study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes. TRIAL REGISTRATION: The study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 - 067).

Association Between Body Mass Index and Primary Open Angle Glaucoma in Three Cohorts.

PURPOSE: To evaluate the relationship between body mass index (BMI) and glaucoma progression. DESIGN: Multicohort observational study. METHODS: This study combined a retrospective longitudinal analysis of suspect and early manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study. RESULTS: In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (ß 0.04 dB/year/SD95% CI [0.005, 0.069]; P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (ß -0.048/SD 95% CI [-0.056, 0.96]; P < .001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI [0.84, 0.98]; P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD; 95% CI [0.91, 0.98]; P = .002). Body mass index was also positively correlated with intraocular pressure (ß 0.11/SD; 95% CI [0.06, 0.15]; P < .001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (ß -0.007/SD; 95% CI [-0.01, -0.001]; P = .023). CONCLUSIONS: Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.

Physical Activity Is Associated With Macular Thickness: A Multi-Cohort Observational Study.

Purpose: To assess the association between physical activity and spectral-domain optical coherence tomography (SD-OCT)-measured rates of macular thinning in an adult population with primary open-angle glaucoma. Methods: The correlation between accelerometer-measured physical activity and rates of macular ganglion cell-inner plexiform layer (GCIPL) thinning was measured in 735 eyes from 388 participants of the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study. The association between accelerometer-measured physical activity and cross-sectional SD-OCT macular thickness was then assessed in 8862 eyes from 6152 participants available for analysis in the UK Biobank who had SD-OCT, ophthalmic, comorbidity, and demographic data. Results: Greater physical activity was associated with slower rates of macular GCIPL thinning in the PROGRESSA study (beta = 0.07 µm/y/SD; 95% confidence interval [CI], 0.03-0.13; P = 0.003) after adjustment for ophthalmic, demographic and systemic predictors of macular thinning. This association persisted in subanalyses of participants characterized as glaucoma suspects (beta = 0.09 µm/y/SD; 95% CI, 0.03-0.15; P = 0.005). Participants in the upper tertile (greater than 10,524 steps/d) exhibited a 0.22-µm/y slower rate of macular GCIPL thinning than participants in the lower tertile (fewer than 6925 steps/d): -0.40 ± 0.46 µm/y versus -0.62 ± 0.55 µm/y (P = 0.003). Both time spent doing moderate/vigorous activity and mean daily active calories were positively correlated with rate of macular GCIPL thinning (moderate/vigorous activity: beta = 0.06 µm/y/SD; 95% CI, 0.01-0.105; P = 0.018; active calories: beta = 0.06 µm/y/SD; 95% CI, 0.006-0.114; P = 0.032). Analysis among 8862 eyes from the UK Biobank revealed a positive association between physical activity and cross-sectional total macular thickness (beta = 0.8 µm/SD; 95% CI, 0.47-1.14; P < 0.001). Conclusions: These results highlight the potential neuroprotective benefits of exercise on the human retina.

Quality of life in children with glaucoma: a qualitative interview study in Australia.

OBJECTIVE: Childhood glaucoma is a chronic vision-threatening condition that may significantly impact an individual's psychosocial well-being. There is a paucity of literature investigating the quality of life (QoL) in children with glaucoma. The aim of this study was to investigate and report on the QoL issues encountered by children with glaucoma. DESIGN: This is a qualitative interview study. Data were collected through semistructured interviews. NVivo V.12 software (QSR International Pty Ltd, Melbourne, Australia) was used to analyse and code data to identify QoL themes. The prominence of QoL themes was determined by the number of children who raised issues connected to the corresponding theme. SETTING: Interviews were conducted via telephone or videoconferencing between April 2020 and July 2021. PARTICIPANTS: Eighteen children with glaucoma, aged 8-17 years, who resided in Australia, were recruited from the Australian and New Zealand Registry of Advanced Glaucoma. RESULTS: Median child age was 12.1 years (IQR: 9.7-14.5 years) and 33% were female. Seven QoL themes were identified: 'coping', 'inconveniences' and 'emotional well-being' were more prominent themes than 'symptoms', 'ocular health concerns', 'social well-being' and 'autonomy'. Adaptive coping strategies included resilience throughout clinical examinations and establishing positive relationships with ophthalmologists. These minimised inconveniences related to clinic waiting times and pupillary dilatation. External to the clinical setting, children often dissociated from their glaucoma but struggled with glare symptoms and feeling misunderstood by fellow peers. Older children aged 13-17 years commonly disengaged from their glaucoma care and expressed an unwillingness to attend ophthalmic appointments. Older children further raised issues with career options, obtaining a driver's licence and family planning under the theme of autonomy. CONCLUSIONS: The psychosocial impact of childhood glaucoma extends beyond the clinical environment and was minimised using coping strategies. Older children may require additional social and ophthalmic support as they transition into adulthood.

The Caregiver Experience in Childhood Glaucoma: An Interview Study.

PURPOSE: To investigate and report on the quality-of-life (QoL) issues experienced by caregivers of individuals with childhood glaucoma. DESIGN: Exploratory, qualitative study. PARTICIPANTS: Thirty-five caregivers of individuals with childhood glaucoma (defined as disease onset before 18 years of age) recruited from the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: A qualitative research methodology (interpretive phenomenology) was applied. Data were collected through semistructured in-depth interviews. NVivo-12 software (QSR International Pty Ltd) was used to analyze, code, and organize data into QoL themes inductively. MAIN OUTCOME MEASURES: Quality-of-life themes and their subthemes. RESULTS: The mean caregiver age was 50.2 ± 13.6 years, and 27 of 35 caregivers (77%) were mothers of an individual with childhood glaucoma. A total of 6 QoL themes were identified. Coping strategies and emotional well-being were the most prominent themes. Caregivers frequently adopted problem-focused adaptive coping strategies including partner or peer support, and normalization. A caregiver's psychosocial well-being was often impacted by feelings of guilt and regret regarding their child's delayed diagnosis, fear and anxiety related to medical and social support, and loss of control as their child developed medical autonomy. The effect of family planning from the perspective of the caregiver formed a novel QoL theme and was associated with normalization and parental confidence in management of the condition. CONCLUSIONS: Childhood glaucoma poses a substantial threat to a caregiver's psychosocial well-being. Strategies that promote normalization, peer support, psychotherapeutic intervention, and genetic counseling may be indicated and, indeed, critical to the caregiver as they adapt to supporting their child with glaucoma.

Quality of Life in Adults with Childhood Glaucoma: An Interview Study.

PURPOSE: To explore and report on the quality-of-life (QoL) issues encountered by adults with childhood glaucoma. DESIGN: Exploratory qualitative study. PARTICIPANTS: Forty-seven participants with childhood glaucoma (defined as disease onset <18 years) recruited from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). METHODS: A qualitative research methodology (interpretive phenomenology) was applied, and data were collected through semistructured in-depth interviews. NVivo-12 software (QSR International Pty Ltd) was used to inductively analyze and code data to identify QoL themes pertinent to the cohort studied. MAIN OUTCOME MEASURES: Quality-of-life themes and subthemes. RESULTS: Mean participant age was 40.0 ± 15.3 years, and 55% of participants were female. We identified 10 QoL themes pertinent to adults living with childhood glaucoma. Coping strategies and emotional well-being were the most prominent themes. Maladaptive coping strategies, including treatment nonadherence, were observed more commonly in individuals aged <40 years and those without a vision impairment or reviewed less regularly. Emotional well-being was affected by feelings of being misunderstood because of the rarity of the condition, being self-conscious of physical manifestations of the disease, and anxiety related to possible disease progression and vision loss. The effect of childhood glaucoma on family planning formed a novel QoL theme and included worry for their child to inherit the condition and an inability to fulfill parental duties. This often led to genetic counseling-seeking behaviors. Mobility issues were infrequently experienced. CONCLUSIONS: Childhood glaucoma poses a substantial impact to the emotional well-being of adults with the condition, which is mediated by the use of coping strategies. Genetic counseling and family planning options may be important. This study supports the development of a childhood glaucoma-specific patient-reported outcome measure for assessment of the psychosocial impact of childhood glaucoma in adults.

Attitudes Towards Polygenic Risk Testing in Individuals with Glaucoma.

PURPOSE: Glaucoma is the leading cause of irreversible blindness worldwide; however, vision loss resulting from glaucoma generally can be prevented through early identification and timely implementation of treatment. Recently, polygenic risk scores (PRSs) have shown promise in stratifying individual risk and prognostication for primary open-angle glaucoma (POAG) to reduce disease burden. Integrating PRS testing into clinical practice is becoming increasingly realistic; however, little is known about the attitudes of patients toward such testing. DESIGN: Cross-sectional, questionnaire-based study. PARTICIPANTS: Among the participants in the Australian and New Zealand Registry of Advanced Glaucoma, 2369 were invited to participate who fit the inclusion criteria of adults with a diagnosis of POAG who had not received genetic results that explain their condition, were not known to be deceased, resided in Australia, and had agreed to receive correspondence. METHODS: One thousand one hundred sixty-nine individuals (response rate, 49%) with POAG completed the survey evaluating their attitudes towards polygenic risk testing for glaucoma. MAIN OUTCOME MEASURES: Sociodemographic, health, perception, and emotional factors were examined to assess associations with interest in PRS testing. Interest in PRS testing was evaluated through assessing likelihood to take the test to predict personal risk of disease and disease severity, and whether the individual would recommend the test to family members or others. RESULTS: Our results show strong interest in the test, with 69.4% of individuals (798 of 1150) indicating a keenness in testing before diagnosis, had it been available. In particular, interest was seen in those from an urban area (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.15-2.49; P = 0.007), those who perceived their risk of developing glaucoma as higher (OR, 2.05; 95% CI, 1.28-3.29; P = 0.003), and those who were worried about developing glaucoma (OR, 2.07; 95% CI, 1.27-3.37; P = 0.004). People who were interested in testing were more likely to change their eye health-seeking intentions and to recommend testing to family members and others, as well as to undergo testing for prognostication. CONCLUSIONS: These findings will help to facilitate the clinical implementation of PRS testing for glaucoma to reduce irreversible vision loss.

Attitudes Toward Glaucoma Genetic Risk Assessment in Unaffected Individuals.

Purpose: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an individual's risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected individuals toward PRS testing for glaucoma, and sought to identify factors associated with interest in testing. Methods: We surveyed 418 unaffected individuals including 193 with a first-degree relative with glaucoma, 117 who had a recent eye examination, and 108 general members of the community. Results: Overall, 71.3% of the individuals indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (odds ratio [OR] = 14.58, 95% confidence interval [CI] = 1.15-185.50, P = 0.039), those concerned about developing glaucoma (OR = 4.37, 95% CI = 2.32-8.25, P < 0.001), those with an intention to take appropriate measures regarding eye health (OR = 2.39, 95% CI = 1.16-4.95, P = 0.019), and those preferring to know if considered to be at-risk or not (OR = 4.52, 95% CI = 2.32-8.83, P < 0.001). Conclusions: Our results show strong interest in genetic risk assessment for glaucoma among unaffected individuals in Australia. Translational Relevance: These findings represent a valuable assessment of interest in glaucoma polygenic risk testing among potential target populations, which will be integral to the implementation and uptake of novel PRS-based tests into clinical practice.

Genetic Risk of Cardiovascular Disease Is Associated with Macular Ganglion Cell-Inner Plexiform Layer Thinning in an Early Glaucoma Cohort.

Purpose: To evaluate the association between genetic risk for cardiovascular disease and retinal thinning in early glaucoma. Design: Prospective, observational genetic association study. Participants: Multicohort study combining a cohort of patients with suspect and early manifest primary open-angle glaucoma (POAG), a cohort of patients with perimetric POAG, and an external normative control cohort. Methods: A cardiovascular disease genetic risk score was calculated for 828 participants from the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study. Participants were characterized as showing either predominantly macular ganglion cell-inner plexiform layer (GCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL) or equivalent macular GCIPL and pRNFL spectral-domain OCT thinning. The cardiovascular disease genetic risk scores for these groups were compared to an internal reference group of stable suspected glaucoma and of an external normative population. Replication was undertaken by comparing the phenotypes of participants from the Australia New Zealand Registry of Advanced Glaucoma (ANZRAG) with the normative control group. Main Outcome Measures: Spectral-domain OCT and Humphrey Visual Field (HVF) change. Results: After accounting for age, sex, and intraocular pressure (IOP), participants with predominantly macular GCIPL thinning showed a higher cardiovascular disease genetic risk score than reference participants (odds ratio [OR], 1.76/standard deviation [SD]; 95% confidence interval [CI], 1.18-2.62; P = 0.005) and than normative participants (OR, 1.32/SD; 95% CI, 1.12-1.54; P = 0.002). This finding was replicated by comparing ANZRAG participants with predominantly macular GCIPL change with the normative population (OR, 1.39/SD; 95% CI, 1.05-1.83; P = 0.022). Review of HVF data identified that participants with paracentral visual field defects also demonstrated a higher cardiovascular disease genetic risk score than reference participants (OR, 1.85/SD; 95% CI, 1.16-2.97; P = 0.010). Participants with predominantly macular GCIPL thinning exhibited a higher vertical cup-to-disc ratio genetic risk score (OR, 1.48/SD; 95% CI, 1.24-1.76; P < 0.001), but an IOP genetic risk score (OR, 1.12/SD; 95% CI, 0.95-1.33; P = 0.179) comparable with that of the normative population. Conclusions: This study highlighted the relationship between cardiovascular disease and retinal thinning in suspect and manifest glaucoma cases.