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.

Bilateral orbital compartment syndrome in a patient with disseminated intravascular coagulation.

A 39-year-old male developed bilateral periorbital oedema and tense orbits in keeping with orbital compartment syndrome (OCS) shortly after presenting to the emergency department for uncontrollable epistaxis. Bilateral lateral canthotomy and inferior cantholysis was performed within 30 minutes of onset, with the left side further decompressed via superior cantholysis. Computed tomography demonstrated bilateral proptosis and optic nerve stretch, but no intraorbital haemorrhage or haematoma. Laboratory findings were consistent with disseminated intravascular coagulation (DIC) and sepsis of unknown origin. The right visual acuity recovered to 6/6 -2 from counting fingers, but the left eye failed to improve beyond light perception. This unique case of OCS is the first associated with DIC which had no evidence of intraorbital haemorrhage.

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.

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.

Prevalence and type of artefact with spectral domain optical coherence tomography macular ganglion cell imaging in glaucoma surveillance.

PURPOSE: The ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma. METHOD: A total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined. RESULTS: A total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes. CONCLUSION: The macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results.

Genetic Association at the 9p21 Glaucoma Locus Contributes to Sex Bias in Normal-Tension Glaucoma.

PURPOSE: Many genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at the 9p21 glaucoma locus (CDKN2B/CDKN2B-AS1) to be significantly associated with primary open-angle glaucoma (POAG), with association being stronger in normal tension glaucoma (NTG) and advanced glaucoma. We aimed to determine whether any observed differences in genetic association at the 9p21 locus are influenced by sex. METHODS: Sex was assessed as a risk factor for POAG for 2241 glaucoma participants from the Australian and New Zealand Registry of Advanced Glaucoma, the Glaucoma Inheritance Study in Tasmania, and the Flinders Medical Centre. A total of 3176 controls were drawn from the Blue Mountains Eye Study and South Australia: 1523 advanced POAG and 718 nonadvanced POAG cases were genotyped along with 3176 controls. We selected 13 SNPs at the 9p21 locus, and association results were subanalyszd by sex for high-tension glaucoma (HTG) and NTG. Odds ratios (ORs) between sexes were compared. RESULTS: A sex bias was present within advanced NTG cases (57.1% female versus 42.9% male, P = 0.0026). In all POAG cases, the strongest associated SNP at 9p21 was rs1063192 (OR, 1.43; P = 4 × 10-18). This association was stronger in females (OR, 1.5; P = 5 × 10-13) than in males (OR, 1.35; P = 7 × 10-7), with a statistically significant difference in female to male OR comparison (P = 1.0 × 10-2). An NTG to HTG subanalysis yielded statistically significant results only in females (OR, 1.63; P = 1.5 × 10-4) but not in males (OR, 1.15; P = 2.8 × 10-1), with a statistically significant difference in female to male OR comparison (P = 1.4 × 10-4). CONCLUSIONS: This study demonstrated that female sex is a risk factor for developing advanced NTG. The stronger genetic signals at the 9p21 locus among females may contribute at least in part to the observed sex bias for NTG.

Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Genetic investigation into the endophenotypic status of central corneal thickness and optic disc parameters in relation to open-angle glaucoma.

PURPOSE: To ascertain if single nucleotide polymorphisms (SNPs) involved in the determination of central corneal thickness, optic disc area, and vertical cup-to-disc ratio (VCDR) also are associated with open-angle glaucoma (OAG). DESIGN: Retrospective case-control genetic association study. METHODS: A total of 16 SNPs associated with central corneal thickness, optic disc area, and VCDR were genotyped in 876 OAG cases and 883 normal controls. To determine if the SNPs were also correlated with OAG severity, the cohort was stratified into advanced OAG (n = 326) and nonadvanced OAG (n = 550). Both the cases and controls were of European descent and were recruited from within Australia. RESULTS: Two VCDR SNPs were found to be significantly associated with OAG after correction for multiple testing. The 2 SNPs were rs10483727, found adjacent to the SIX1 gene (P = 6.2 × 10(-06); odds ratio, 1.38; 95% confidence interval, 1.20 to 1.59), and rs1063192, found within the CDKN2B gene (P = 2.2 × 10(-05); odds ratio, 0.74; 95% confidence interval, 0.64 to 0.85). The CDKN2B variant rs1063192 also was found to be associated more strongly with advanced OAG. CONCLUSIONS: The findings from this study indicate that variants influencing VCDR are also risk alleles for OAG in our Australian cohort of European descent. The identification of SIX1 and CDKN2B as susceptibility loci will assist in understanding the pathologic mechanisms involved in the development of OAG.

Challenges in non-muscle invasive bladder cancer: lessons from a regional review.

BACKGROUND: Surveillance programmes for bladder cancer are invasive and expensive. Existing guidelines are complex, and the capacity to implement these is untested. The present study examined treatment consistency, and ease of guideline implementation, for patients undergoing surveillance of non-muscle invasive bladder cancer. METHOD: Eligible cancers treated between 1 January 2005 and 30 June 2009 were identified from a prospective database in a regional South Australian Urology service. Each was analysed with respect to the timing of cystoscopic surveillance and the use of intraoperative chemotherapy. For high-risk patients, the use of urine cytology, upper tract imaging, adjuvant therapy and re-resection of T1 cancers was reviewed. RESULTS: Eight hundred and nineteen cystoscopies were performed in the surveillance of 313 cancers in 193 patients. Within each risk category, the pattern of cystoscopic surveillance varied widely. In high-risk patients, the use of cytology, upper tract imaging, adjuvant therapy and re-resection was infrequent (3-56%). An attempt was made to standardize management through the implementation of guidelines. No overall practice improvement was observed after 18 months. Difficulty incorporating new algorithms into practice and ensuring a consistent longitudinal focus in care were felt contributory. Of 78 low-risk cancer patients, 55% underwent more cystoscopies than would have been expected. In 235 cancer patients at high or intermediate risk, 43% received less follow-up than would have been recommended. CONCLUSION: Surveillance patterns were inconsistent across all risk categories. The development of consensus recommendations did not significantly alter clinical practice. Implementation of clinical guidelines for this important disease represents a significant challenge in acute hospital settings.