Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry.

PURPOSE: To report the relative frequencies of childhood and early onset glaucoma subtypes and their genetic findings in a large single cohort. DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: All individuals with childhood glaucoma (diagnosed 0 to <18 years) and early onset glaucoma (diagnosed 18 to <40 years) referred to a national disease registry. METHODS: We retrospectively reviewed the referrals of all individuals with glaucoma diagnosed at <40 years of age recruited to the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Subtypes of glaucoma were determined using the Childhood Glaucoma Research Network (CGRN) classification system. DNA extracted from blood or saliva samples underwent sequencing of genes associated with glaucoma. MAIN OUTCOME MEASURES: The phenotype and genotype distribution of glaucoma diagnosed at <40 years of age. RESULTS: A total of 290 individuals (533 eyes) with childhood glaucoma and 370 individuals (686 eyes) with early onset glaucoma were referred to the ANZRAG. Primary glaucoma was the most prevalent condition in both cohorts. In the childhood cohort, 57.6% of individuals (167/290, 303 eyes) had primary congenital glaucoma (PCG), and 19.3% (56/290, 109 eyes) had juvenile open-angle glaucoma. Juvenile open-angle glaucoma constituted 73.2% of the early onset glaucoma cohort (271/370, 513 eyes). Genetic testing in probands resulted in a diagnostic yield of 24.7% (125/506) and a reclassification of glaucoma subtype in 10.4% of probands (13/125). The highest molecular diagnostic rate was achieved in probands with glaucoma associated with nonacquired ocular anomalies (56.5%). Biallelic variants in CYP1B1 (n = 29, 23.2%) and heterozygous variants in MYOC (n = 24, 19.2%) and FOXC1 (n = 21, 16.8%) were most commonly reported among probands with a molecular diagnosis. Biallelic CYP1B1 variants were reported in twice as many female individuals as male individuals with PCG (66.7% vs. 33.3%, P = 0.02). CONCLUSIONS: We report on the largest cohort of individuals with childhood and early onset glaucoma from Australasia using the CGRN classification. Primary glaucoma was most prevalent. Genetic diagnoses ascertained in 24.7% of probands supported clinical diagnoses and genetic counseling. International collaborative efforts are required to identify further genes because the majority of individuals still lack a clear molecular diagnosis.

Current management of glaucoma.

Glaucoma is an irreversible progressive optic neuropathy, for which the major proven treatment is to lower the intraocular pressure (IOP). Five groups of IOP-lowering eye drops have varying mechanisms of action. Some drops, such as ß-blockers and α-2 agonists, have potentially serious systemic side effects. Acetazolamide is the only available oral agent; it is effective at lowering IOP, but significant side effects relegate its use usually to refractory glaucoma. Two new eye drops, netarsudil and latanoprostene bunod, have recently been approved by the United States Food and Drug Administration. Both have novel IOP-lowering mechanisms and target the conventional aqueous outflow system. Selective laser trabeculoplasty is a gentle treatment that enhances conventional aqueous outflow. It may be used as an initial treatment, as a substitute for eye drops, or to delay glaucoma drainage surgery. Recent advancements in glaucoma surgery have seen an influx of minimally invasive glaucoma surgery devices, which are being used more frequently and earlier on in the treatment paradigm. As limited long term data are available, trabeculectomy remains the gold standard IOP-lowering procedure. Improvements in drug delivery are on the horizon. Drug-eluting devices and implants are able to deliver the drug closer to the receptors for an extended period of time. This will improve treatment adherence and efficacy, which are major limitations with current medical therapy.

Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies.

PURPOSE: To evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in open-angle glaucoma (OAG) at risk for progression. DESIGN: Two randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year extension (first study) and change in primary endpoint and analysis (second study). PARTICIPANTS: Patients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous progression (per prespecified criteria). METHODS: Patients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs, standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed. MAIN OUTCOME MEASURES: The predefined primary efficacy measure was glaucomatous visual field progression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field (FDT) and optic nerve damage (stereoscopic optic disc photographs). RESULTS: The proportion of patients who completed the studies was similar among groups (80%-83%). Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glaucomatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio (95% confidence interval) assessed by SAP was -0.13 (-0.40, 0.09) and -0.17 (-0.46, 0.07) for memantine 10 mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea. CONCLUSIONS: With technologies available when the studies were conducted, daily treatment with memantine over 48 months was not shown to prevent glaucomatous progression in this patient population.

Myocilin Predictive Genetic Testing for Primary Open-Angle Glaucoma Leads to Early Identification of At-Risk Individuals.

PURPOSE: To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). DESIGN: Retrospective clinical and molecular study. PARTICIPANTS: Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: Individuals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. MAIN OUTCOME MEASURES: Glaucoma clinical parameters and age at presentation. RESULTS: At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years; P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg; P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13; P = 0.006), and mean deviation on visual field testing (-10.0±10.3 vs. -1.2±1.2; P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. Individuals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. CONCLUSIONS: Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk individuals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.

Applications of the water drinking test in glaucoma management.

Intraocular pressure (IOP) peaks and means have been considered important factors for glaucoma onset and progression. However, peak IOP detection depends only on appropriated IOP checks at office visits, whereas the mean IOP requires longitudinal IOP data collection and may be affected by the interval between visits. Also, IOP peak assessment is necessary to verify if the peak pressure of a given patient is in target range, to evaluate glaucoma suspect risk, the efficacy of hypotensive drugs and to detect early loss of IOP control. The water-drinking test has gained significant attention in recent years as an important tool to evaluate IOP peaks and instability. The main objective of this review was to present new findings and to discuss the applicability of the water-drinking test in glaucoma management.

Emerging drugs to treat glaucoma: targeting prostaglandin F and E receptors.

INTRODUCTION: Commercially available prostaglandin analogues (PGAs) activate the prostaglandin F receptor (FP) reducing intraocular pressure (IOP), thereby stabilizing glaucomatous optic neuropathy. Poor adherence with eye drops and intolerance impact treatment success. AREAS COVERED: We review developments in drug formulation and delivery, including punctal plugs, topical ring inserts, subconjunctival injections and inserts, and intraocular inserts. We also outline research into new fixed dose combinations that include prostaglandin analogues and preservative-free versions of established agents. EXPERT OPINION: Glaucoma is a chronic, usually progressive disease that causes irreversible visual loss. As its prevalence increases exponentially with age, it has significant implications as the population ages. Health resources need to meet increased demand for glaucoma management resources, including monitoring and treating glaucoma suspects and patients and supporting those who have suffered visual disability. Several promising therapies are under investigation. Sustained-release prostaglandin analogues using alternate delivery methods are encouraging. Delivery routes may be more invasive than topical drops. Nanotechnological-release delivery of prostaglandin analogues could lower IOP effectively. Approaches like this would eliminate many of the adherence issues associated with daily topical PGA eye drop use.

Impact of age-related macular degeneration in patients with glaucoma: understanding the patients' perspective.

BACKGROUND: The aim of the study is to measure the impact of age-related macular degeneration on vision-related activity limitation and preference-based status for glaucoma patients. DESIGN: This was a cross-sectional study. PARTICIPANTS: Two-hundred glaucoma patients of whom 73 had age-related macular degeneration were included in the research. METHODS: Sociodemographic information, visual field parameters and visual acuity were collected. Age-related macular degeneration was scored using the Age-Related Eye Disease Study system. MAIN OUTCOME MEASURES: The Rasch-analysed Glaucoma Activity Limitation-9 and the Visual Function Questionnaire Utility Index measured vision-related activity limitation and preference-based status, respectively. Regression models determined factors predictive of vision-related activity limitation and preference-based status. Differential item functioning compared Glaucoma Activity Limitation-9 item difficulty for those with and without age-related macular degeneration. RESULTS: Mean age was 73.7 (±10.1) years. Lower better eye mean deviation (ß: 1.42, 95% confidence interval: 1.24-1.63, P < 0.001) and age-related macular degeneration (ß: 1.26 95% confidence interval: 1.10-1.44, P = 0.001) were independently associated with worse vision-related activity limitation. Worse eye visual acuity (ß: 0.978, 95% confidence interval: 0.961-0.996, P = 0.018), high risk age-related macular degeneration (ß: 0.981, 95% confidence interval: 0.965-0.998, P = 0.028) and severe glaucoma (ß: 0.982, 95% confidence interval: 0.966-0.998, P = 0.032) were independently associated with worse preference-based status. Glaucoma patients with age-related macular degeneration found using stairs, walking on uneven ground and judging distances of foot to step/curb significantly more difficult than those without age-related macular degeneration. CONCLUSIONS: Vision-related activity limitation and preference-based status are negatively impacted by severe glaucoma and age-related macular degeneration. Patients with both conditions perceive increased difficulty walking safely compared with patients with glaucoma alone.

Clinical audit examining the impact of benzalkonium chloride-free anti-glaucoma medications on patients with symptoms of ocular surface disease.

BACKGROUND: Ocular surface disease (OSD) is relatively common in glaucoma patients. OSD symptoms could be linked to prolonged exposure to preservatives in anti-glaucoma medications, especially benzalkonium chloride (BAK). The OBSERVE clinical audit was designed to track the impact of intraocular pressure lowering medications in patients with evidence of OSD to test the hypothesis that BAK-free anti-glaucoma preparations offer clinical advantages over BAK-containing products. DESIGN: Prospective clinical audit from March 2012 to April 2013, open to ophthalmologists practising in Australia. PARTICIPANTS: There were 375 patients enrolled, with a completion rate of 64%. The cohort was predominantly female (68%) with an average age of 71 years. METHODS: Patients were screened for inclusion during a routine consultation. If eligible, they were enrolled. At the ophthalmologist's discretion, some patients were switched to BAK-free anti-glaucoma products. Data were collected via an online survey completed by the ophthalmologist during three appointments over a 16- to 30-week period for all patients. MAIN OUTCOME MEASURES: Intraocular pressure, tear-film breakup time, McMonnies Dry Eye Questionnaire score and reported lubricant use. RESULTS: Patients who switched to BAK-free preparations reported a significant fall in the use of lubricants (P = <0.001). Patients in both groups experienced a significant improvement in McMonnies Dry Eye Questionnaire score (P = <0.0001). The percentage of patients with low tear-film breakup time decreased significantly in both groups (P = 0.0001). There was no significant change in intraocular pressure from pre-study levels for either group (P = 0.105). CONCLUSIONS: BAK-free anti-glaucoma preparations were associated with a change in lubricant use, suggesting reduction in some OSD symptoms, but more research is needed.

Intraocular pressure-lowering medications and long-term outcomes of selective laser trabeculoplasty.

BACKGROUND: To investigate the effects of current intraocular pressure-lowering medications on the efficacy of selective laser trabeculoplasty. DESIGN: Retrospective chart review of records from an urban glaucoma clinic in Sydney, Australia. PARTICIPANTS: Patients who received their first selective laser trabeculoplasty between 2002 and 2005 were studied (grouped from 0 to 3 according to the number of pre-selective laser trabeculoplasty medications, and followed for 5 years). Those with previous argon laser therapy, trabeculectomy or angle-closure were excluded. METHODS: Selective laser trabeculoplasty (Ellex) used to deliver 180 or 360 degree of treatment, under the same protocol. MAIN OUTCOME MEASURES: Responders were defined by ≥20% reduction from baseline intraocular pressure. Data were censored when pressure-lowering intervention was required. The mean intraocular pressure, survivor, response rate, number and type of medications were compared. RESULTS: There were 206 patients with ocular hypertension, primary, pseudo-exfoliation, or pigmentary glaucoma who used none (n = 20), one (n = 33), two (n = 61) or three or more (n = 92) pre-selective laser trabeculoplasty topical anti-glaucoma medications. The mean baseline intraocular pressures for each group was 23.7, 22.2, 20.7 and 20.4 mmHg, respectively (P = 0.061). Post-treatment mean intraocular pressure was 17.9, 17.7, 15.5, and 15.7 mmHg; percentage reduction was similar between groups (23.6-25.6%, P = 0.20). Kaplan-Meier survival analysis showed comparable survival rates across groups (P = 0.445). At 60 months, 11.1, 17.1, 30.5 and 11.5% of responders remained in each group. Higher proportions of patients in groups 2 and 3 required further laser or surgery. CONCLUSION: The number of pre-selective laser trabeculoplasty medications did not affect the intraocular pressure-lowering effectiveness of selective laser trabeculoplasty; however, groups on more medications required more pressure-lowering interventions.

Cataract and quality of life in patients with glaucoma.

BACKGROUND: To assess the impact of cataract on quality of life (QoL) for patients with glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Two hundred forty-two patients with mild (n = 67), moderate (n = 80) or severe (n = 45) glaucoma and 50 controls (glaucoma suspects). Patients with cataract of any severity were included. METHODS: The following data were collected: sociodemographic information, phakic/pseudophakic status, cataract grade according to the Lens Opacities Classification System (LOCS) III, visual acuity and visual field test parameters. Glaucoma severity was stratified according to binocular visual field loss. Visually significant cataract was defined as: LOCS III criteria nuclear cataract ≥3/6.9, cortical cataract ≥3/5.9 or posterior subcapsular cataract ≥2/5.9. MAIN OUTCOME MEASURES: Patients' QoL was measured using Rasch-transformed scores from the Glaucoma Activity Limitation-9 (GAL-9) questionnaire. Multiple linear regression models were used to determine the association between cataract and GAL-9 (logit) score. RESULTS: Fifty-six (23.1%) patients had at least one visually significant cataract. At least one visually significant cataract (standardized coefficient [ß] 1.19, 95% confidence interval 1.04-1.34, P = 0.011) and poor visual field index (better eye) (ß 1.47, 95% confidence interval 1.36-1.88, P < 0.001) were independently associated with worse GAL-9 score. CONCLUSIONS: Cataract influences glaucoma-related QoL among glaucoma patients of all severity levels and is an important cause of potentially reversible visual impairment among glaucoma patients. The Rasch-analysed GAL-9 questionnaire is a useful metric to quantify visual disability related to cataract in glaucoma patients.

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.

Twice-daily brinzolamide/brimonidine fixed combination versus brinzolamide or brimonidine in open-angle glaucoma or ocular hypertension.

PURPOSE: To compare the intraocular pressure (IOP)-lowering efficacy and safety of brinzolamide 1% and brimonidine 0.2% fixed combination (BBFC) with that of brinzolamide 1% or brimonidine 0.2% monotherapy, all dosed 2 times per day (BID). DESIGN: Six-month, phase 3, randomized, multicenter, double-masked clinical trial. PARTICIPANTS: A total of 560 patients with primary open-angle glaucoma or ocular hypertension who had insufficient IOP reduction with their current therapeutic regimen or who were receiving ≥ 2 IOP-lowering medications. INTERVENTION: Patients received BBFC (n = 193), brinzolamide 1% (n = 192), or brimonidine 0.2% (n = 175) BID. MAIN OUTCOME MEASURES: The primary end point was mean change in diurnal IOP from baseline to month 3. Supportive end points included mean diurnal IOP change from baseline at week 2, week 6, and month 6; and mean IOP, mean IOP change from baseline, mean percentage IOP change from baseline, and percentage of patients with IOP <18 mmHg at week 2, week 6, month 3, and month 6 at each assessment time point (i.e., 9 am, 11 am, and 4 pm). Adverse events were recorded throughout the study. RESULTS: Baseline diurnal IOP was similar among groups (mean ± standard deviation: BBFC, 25.9 ± 0.19 mmHg; brinzolamide, 25.9 ± 0.20 mmHg; brimonidine, 26.0 ± 0.19 mmHg). At month 3, BBFC lowered mean diurnal IOP from baseline to a significantly greater extent than brinzolamide (least squares [LS] mean difference: -1.4 mmHg; P < 0.0001; t test) and brimonidine (LS mean difference: -1.5 mmHg; P < 0.0001). All supportive end points corroborated the results of the primary efficacy analysis. Mean percentage reductions in IOP from baseline were 26.7% to 36.0% with BBFC, 22.4% to 27.9% with brinzolamide, and 20.6% to 31.3% with brimonidine. The most common adverse drug reactions were ocular side effects, including hyperemia, blurred vision, allergic-type reactions, and discomfort. The incidence of hyperemia of the eye was slightly lower with brinzolamide than with BBFC and brimonidine, whereas blurred vision and ocular discomfort were slightly more common with BBFC than with brinzolamide or brimonidine. CONCLUSIONS: Brinzolamide 1% and brimonidine 0.2% fixed combination administered BID had a significantly greater IOP-lowering effect than either brinzolamide or brimonidine alone and displayed a safety profile consistent with its individual components.

Optic nerve head assessment: comparison of Cirrus optic coherence tomography and Heidelberg Retinal Tomograph 3.

BACKGROUND: The purpose of this study was to analyse the relationship between optic nerve head (ONH) parameters measured by spectral domain optical coherence tomography and confocal scanning laser ophthalmoscope. DESIGN: Prospective, cross-sectional study. Hospital setting. PARTICIPANTS: One hundred seventy-three subjects (85 glaucoma and 88 normal subjects). METHODS: One eye from each individual was selected randomly for ONH imaging by the spectral domain Cirrus OCT and Heidelberg Retinal Tomograph 3 (HRT3). MAIN OUTCOME MEASURES: Four ONH parameters that are measured by both technologies (average cup-to-disc ratio [CDR], rim area, disc area and cup volume) were analysed and compared for differences, agreement of the categorical classification, diagnostic sensitivities and specificities and the area under the receiver operating characteristic curves (AUC). RESULTS: ONH parameters, as determined by the two technologies were significantly different but strongly correlated. Proportional bias was demonstrated for all measurements. The agreement of categorical classification was excellent for CDR (κ = 0.94) and good for rim area and cup volume (κ = 0.63 and 0.71, respectively). The highest sensitivities at fixed specificities were achieved by Cirrus OCT. AUCs for CDR, rim area, disc area and cup volume were not significantly different between the two technologies. CONCLUSIONS: The diagnostic capability of ONH measurements by both technologies is similar. Paired ONH measurements by Cirrus OCT and HRT3 are strongly correlated but significantly different and proportionally biased. The results preclude interchangeable use of the absolute values, but categorical classification of ONH parameters may be interchangeable in clinical practice.

Effect of high myopia on glaucoma diagnostic parameters measured with optical coherence tomography.

BACKGROUND: We examined the influence of high myopia on conventional spectral-domain optical coherence tomographic parameters and assessed the macular ganglion cell complex thickness to macular outer retinal thickness ratio as a new optical coherence tomography parameter. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Sixty normal and 30 highly myopic eyes (refractive error more than -6 D). METHODS: We used the RTVue-100 to measure macular ganglion cell complex and circumpapillary retinal nerve fibre layer thickness, global loss volume, and focal loss volume and then calculated the ganglion cell complex thickness to macular outer retinal thickness ratio. MAIN OUTCOME MEASURES: Each parameter was compared between the two groups. Using the area under receiver operating characteristics curve, the classification abilities of optical coherence tomography parameters were examined in highly myopic eyes. RESULTS: Between normal and highly myopic eyes, we found significant differences in ganglion cell complex and retinal nerve fibre layer thickness, global loss volume and focal loss volume. The new ratio parameter was not significantly different between groups (55.74% vs. 54.50%). The area under receiver operating characteristics curve was 0.775 (P < 0.01) for retinal nerve fibre layer thickness, 0.721 (P < 0.01) for ganglion cell complex thickness and 0.588 (P > 0.05) for the new ratio parameter. CONCLUSIONS: Although refractive status significantly affected conventional optical coherence tomography parameters, the new ratio parameter may not be influenced by refractive error. Therefore, a normative database for healthy highly myopic eyes may not be necessary if ratio parameter is used.

Higher prevalence of myocilin mutations in advanced glaucoma in comparison with less advanced disease in an Australasian disease registry.

OBJECTIVES: To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset individuals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort. DESIGN: Cross-sectional study using a national disease registry. PARTICIPANTS: One thousand sixty individuals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma. METHODS: Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation. MAIN OUTCOME MEASURES: Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in individuals with advanced and nonadvanced POAG. RESULTS: This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six individuals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers. CONCLUSIONS: The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying individuals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Relationship of change in central corneal thickness to visual field progression in eyes with glaucoma.

BACKGROUND: To assess the relationship between baseline central corneal thickness (CCT) and/or ongoing CCT change over time with subsequent visual field progression. METHODS: One hundred sixty three eyes of 163 patients with medically treated glaucoma were followed up for 6.8 ± 1.8 years. Exclusion criteria was laser or intraocular surgery. Baseline and follow up CCT, confocal scanning laser tomography and visual fields were performed. CCT and CCT change related to visual field progression using Glaucoma Progress Analysis were assessed. Multivariate logistic regression analysis for predictive factors of glaucoma progression was used to analyze data. RESULTS: Thinner baseline CCT was associated with more advanced damage at presentation, mean deviation (MD) (r=0.17, p=0.02) and neuroretinal rim area (NRR) (r=0.20, p=0.02). Progressing eyes had significantly thinner (p=0.01) baseline CCT compared to non-progressing eyes. The slope of visual field change was significantly greater (p=0.05) for thinner (<540 µm) as compared to thicker eyes. A small but significant CCT reduction (12.78 ± 13.35 µm, p<0.0001) was noted in all eyes; however, there was no significant difference (p=0.95) in the amount of change between progressing and non-progressing eyes. CCT change did not correlate with MD or NRR change. A thinner CCT (Odds ratio=1.80, p=0.02), but not CCT change (Odds ratio=1.07, p=0.69), was a significant risk factor for glaucoma progression. CONCLUSIONS: CCT correlates significantly with the amount of glaucomatous damage at presentation. Thinner corneas may be associated with increased risk of visual field progression. CCT reduced slightly over time in eyes with glaucoma; but the magnitude of this change was not related to visual field progression.

Longitudinal effect of topical antiglaucoma medications on central corneal thickness.

BACKGROUND: To determine the change in central corneal thickness over time and whether the use of long-term topical antiglaucoma medications influences central corneal thickness. DESIGN: Case control study with retrospective and prospective data collection. PARTICIPANTS: One hundred eighty-seven eyes of 187 glaucoma patients (mean follow up 6.92 ± 1.67 years) being treated with topical antiglaucoma medications (at least 3 years) with no history of surgery or laser were included and compared with 100 eyes of 100 age-matched, untreated control subjects (mean follow up 6.58 ± 1.93 years) who were glaucoma suspects with normal intraocular pressure not on any treatment. METHODS: Demographic data, central corneal thickness and intraocular pressure were collected at initial glaucoma diagnosis and at most recent visit, and findings were compared between two groups. MAIN OUTCOME MEASURES: Mean change in central corneal thickness in microns (µm). RESULTS: Central corneal thickness fell significantly (P < 0.0001) in treated eyes but not in control eyes (P = 0.18); mean central corneal thickness reduction was 12.29 ± 13.65 µm in treated eyes and 1.17 ± 8.75 µm in controls. Among treated eyes, central corneal thickness reduction was significant (P < 0.0001) in those treated with either prostaglandins or a combination of prostaglandin and beta-blockers, while no significant reduction occurred in eyes treated with only beta-blockers (P = 0.15) when compared with control eyes. CONCLUSIONS: Prostaglandins appear to be associated with a small but significant central corneal thickness reduction over time. Serial central corneal thickness measurements might be helpful in glaucoma patients, particularly those on prostaglandins.

Relationship between macular ganglion cell complex thickness and macular outer retinal thickness: a spectral-domain optical coherence tomography study.

BACKGROUND: To assess the relationship between macular ganglion cell complex and macular outer retinal thicknesses. DESIGN: Case-control study. PARTICIPANTS: Forty-two normal eyes and 91 eyes with primary open-angle glaucoma were studied. METHODS: Spectral-domain optical coherence tomography (RTVue-100) was used to measure the macular ganglion cell complex and macular outer retinal thickness. Ganglion cell complex to outer retinal thickness ratio was also calculated. MAIN OUTCOME MEASURES: The relationships between the ganglion cell complex and outer retinal thicknesses and between the ganglion cell complex to outer retinal thickness ratio and outer retinal thickness were evaluated. RESULTS: There was a positive correlation between ganglion cell complex and outer retinal thicknesses in the normal group and the glaucoma group (r = 0.53, P < 0.001 and r = 0.42, P < 0.001, respectively). In that respect, there was no correlation between ganglion cell complex to outer retinal thickness ratio and outer retinal thickness in the both groups (r = -0.07, P = 0.657, and r = 0.04, P = 0.677, respectively). The ganglion cell complex to outer retinal thickness ratio was 55.65% in the normal group, 45.07% in the glaucoma group. This difference was statistically significant. CONCLUSIONS: The ganglion cell complex thickness may be affected by outer retinal thickness, and there is individual variation in the outer retinal thickness. Therefore, when determining the ganglion cell complex, it seems necessary to consider the outer retinal thickness as well. We propose the ratio as a suitable parameter to account for individual variations in outer retinal thickness.

Retinal nerve fibre layer imaging: comparison of Cirrus optical coherence tomography and Heidelberg retinal tomograph 3.

BACKGROUND: The purpose of this study was to analyze the relationship between retinal nerve fibre layer thickness measured by spectral domain optical coherence tomography and confocal scanning laser ophthalmoscope. DESIGN: Prospective, cross-sectional study. Hospital setting. PARTICIPANTS: One hundred seventy-three subjects (85 glaucoma and 88 normal subjects). METHODS: One eye from each individual was selected randomly for imaging by the spectral domain Cirrus optical coherence tomography and Heidelberg retinal tomograph 3. MAIN OUTCOME MEASURES: Global thickness and measurements at the four quadrants around the optic disc. RESULTS: Measurements as determined by Heidelberg retinal tomograph 3 were significantly larger than measurements done by Cirrus optical coherence tomography (respectively in mm, for global thickness: 200.0 ± 87.2 and 80.7 ± 14.7; for temporal quadrant: 75.3 ± 31.9 and 59.1 ± 13.8; for superior quadrant: 223.2 ± 128.4 and 97.7 ± 20.9; for nasal quadrant: 208.0 ± 102.9 and 66.8 ± 11.8; and for inferior quadrant: 224.4 ± 116.9 and 99.1 ± 26.6, for all P < 0.01). Significant correlation was found for all measurements (P ≤ 0.009), but a pattern of proportional bias was demonstrated. The agreement of categorical classification (within normal limits, borderline or outside normal limits) ranged between poor and fair. CONCLUSIONS: The thickness easurements by the two technologies are strongly correlated but significantly different. The differences are substantial and proportional to the retinal nerve fibre layer thickness. The normative diagnostic classification of the two technologies may not agree. The results preclude interchangeable use of these measurements in clinical practice.

The gut microbiome and primary open angle glaucoma: Evidence for a 'gut-glaucoma' axis?

Glaucoma presents an epidemiological burden as the leading cause of irreversible blindness globally and the most common cause of preventable blindness. While elevated intraocular pressure is the strongest modifiable risk factor, the exact mechanisms of retinal ganglion cell damage leading to progressive vision loss are not entirely understood. Studies of other neurodegenerative diseases show a potential for human gut microbiome dysbiosis to play a pathogenic role. An investigation into whether the microbiome, a potential modifiable risk factor, has significance in glaucoma enables exploration of prophylactic or additive treatments. Elevated population levels of specific bacterial species have been noted in glaucoma patients, particularly Prevotellaceae, Enterobacteriaceae and Escherichia coli, while Megomonas is speculated to be protective. Evidence also points to systemic neuro-inflammation and disruption of autoimmune processes as a result of imbalances in both human and animal models, where heat shock proteins may contribute to pathogenesis. Further research into the influence of gut microbiome on pathogenesis offers a chance to minimise irreversible vision loss in glaucoma.