Julian L Rait

Five-year incidence of open-angle glaucoma: The visual impairment project

PURPOSE To determine the incidence of open-angle glaucoma (OAG) in Melbourne, Victoria, Australia. DESIGN Population-based cohort study. PARTICIPANTS Total of 3271 participants aged 40 years and older from Melbourne, Victoria, Australia. MAIN OUTCOME MEASURES Five-year incidence of OAG. METHODS Participants were recruited through a cluster random sampling from nine urban clusters. Baseline examination was conducted from 1992 through 1994, and the follow-up data were collected from 1997 through 1999. Each participant both at baseline and follow-up underwent a standardized ophthalmic examination including intraocular pressure measurement, visual field assessment, cup-to-disc ratio measurement, and paired stereo photographs of the optic disc. Glaucoma was assessed by a consensus group of six ophthalmologists that included two glaucoma specialists. Glaucoma was diagnosed as possible, probable, or definite. RESULTS The overall incidence of definite OAG was 0.5% (95% confidence limits [CL], 0.3, 0.7); probable and definite incidence of OAG was 1.1% (95% CL, 0.8,1.4); and possible, probable, and definite OAG incidence was 2.7% (95% CL, 1.8, 3.7). The incidence of possible, probable, and definite OAG increases significantly as age increases (P < 0.001). The incidence of definite OAG increases from 0% of participants aged 40 to 49 years to 4.1% of participants aged 80 years and older. The incidence of probable and definite OAG increases from 0.2% of participants aged 40 to 49 years to 5.4% of participants aged 80 years and older. The incidence of possible, probable, and definite OAG increases from 0.5% of participants aged 40 to 49 years to 11% of participants aged 80 years and older. A nonsignificant but higher incidence of definite OAG among men was observed in this study when compared with women (odds ratio, 2.2; 95% CL, 0.9, 5.9). Fifty percent of the definite OAG participants were undiagnosed. CONCLUSIONS The incidence of OAG increases significantly with age. The undiagnosed cases suggest the need to develop novel community screening strategies for glaucoma.

Associations between glaucomatous visual field loss and participation in activities of daily living

Purpose: This study investigated the association between visual field loss and participation in daily activities in individuals with glaucoma.

Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier.

OBJECTIVE To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). DESIGN Cross-sectional genetic study. PARTICIPANTS Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. METHODS Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. CONCLUSIONS The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

Inner retinal neurons display differential responses to N-methyl-D-aspartate receptor activation.

The N‐methyl‐D‐aspartate (NMDA) responses of neurons from within the inner rabbit retina were mapped using a channel permeable cation, 1‐amino‐4‐guanidobutane (agmatine, AGB). Serial sections were subsequently probed with immunoglobulins targeting AGB, glutamate, γ‐aminobutyric acid (GABA), and glycine to visualize the NMDA responses of neurochemical subpopulations of neurons. Most inner retinal subpopulations of neurons demonstrated an NMDA concentration‐dependent increase in activation. This NMDA‐induced activation displayed a distinct pattern, with the most sensitive class to least sensitive class ranking being GC > GABA cAC > GABA/Gly cAC > Gly cAC > GABA dAC (GC, ganglion cells; AC, amacrine cells; c, conventional; d, displaced; Gly, glycine). The variable NMDA response may reflect differences in NMDA receptor subunit disposition or differences in receptor density. In addition to the variable NMDA activation pattern, we found that virtually all ganglion cells (87%) showed NMDA‐gated AGB entry, compared with only 58% of amacrine cells. We conclude that a large cohort of amacrine cells do not possess functional NMDA receptors. In addition to most ganglion cells being activated by NMDA, a large subpopulation displayed the highest sensitivity to NMDA application. The functional significance of this finding is that the ganglion cell population will be the first neuronal class to be susceptible to glutamate‐induced neurotoxicity mediated through the NMDA receptor. The addition of betaxolol significantly reduced NMDA‐mediated AGB entry into most neuronal groups (ganglion cells, GABA, and glycine amacrine cells), with the greatest effect being on ganglion cells. Betaxolol had no significant effect on NMDA‐gated entry of AGB on the GABA/Gly amacrine cell population. J. Comp. Neurol. 465:38–56, 2003.

Performance of Community-Based Glaucoma Screening Using Frequency Doubling Technology and Heidelberg Retinal Tomography

Purpose: To assess the performance of a community-based glaucoma screening algorithm in the general population. Methods: A total of 659 individuals aged 50–90 years were screened for glaucoma. Presenting visual acuity, family history of glaucoma, FDT perimetry, and HRT tests were assessed. Additional samples of participants served as control groups. Participants identified as glaucoma positive received a full ophthalmic examination. Based on this exam a consensus diagnosis was made which served as the gold standard. Results: The optimal screening strategy combining visual acuity and family history with FDT and HRT had sensitivities, specificities, positive predictive values and negative predictive values of 96.8%, 89.7%, 31.9%, and 99.8% respectively for detecting glaucoma. Conclusions: By combining assessments of presenting visual acuity and family history of glaucoma with Frequency Doubling Technology perimetry and Heidelberg Retina Tomography, we devised a community glaucoma-screening algorithm that showed a high sensitivity and specificity for detecting glaucoma in the general population.

Nail-patella syndrome and its association with glaucoma: a review of eight families

Background: Nail-patella syndrome (NPS) is a rare autosomal dominant syndrome, characterised by dysplasia of the nails, patellae, elbows and iliac horns. Mutations in the LMX1B gene were found in four North American families in whom glaucoma cosegregated with NPS. Aims: To investigate the association of glaucoma with NPS in Australian families and to determine how common NPS is in Australia. Methods: One family with NPS and glaucoma was identified from the Glaucoma Inheritance Study in Tasmania. A further 18 index cases of NPS were identified from the genetics database for southeastern Australia. Eight of these pedigrees were available for comprehensive glaucoma examination on available family members. DNA was sequenced for mutations in LMX1B. Results: In total, 52 living cases of NPS were identified suggesting a minimum prevalence of at least 1 in 100 000. 32 subjects from eight NPS pedigrees (four familial and four sporadic cases) were examined. 14 subjects had NPS alone. 4 subjects had NPS and glaucoma or ocular hypertension. Five pedigrees with NPS had a reported family history of glaucoma, although some of these people with glaucoma did not have NPS. LMX1B mutations were identified in 5 of the 8 index cases—three sporadic and two familial. Two of the six (33%) participants over 40 years of age had developed glaucoma, showing increased risk of glaucoma in NPS. Conclusion: Patients with NPS should be examined regularly for glaucoma. However, because the families with NPS are ascertained primarily from young probands or probands who are isolated cases, the exact level of risk is unclear.

Can the specificity of the FDT for glaucoma be improved by confirming abnormal results

PurposeTo determine whether the specificity of the frequency-doubling technology (FDT) perimeter in the screening mode for glaucoma can be improved by repeating abnormal screening results. MethodsThe FDT perimeter was used in C-20-5 screening mode, and the right eye was tested first. After both eyes were tested, the screening was repeated in eyes with any abnormal visual field defects on FDT perimetry. The printouts were categorized as possible visual field abnormality (zero or one miss), probable visual field abnormality (two to four misses), and definite visual field abnormality (more than five misses). A clinical ophthalmologic examination was conducted on the day of the FDT perimetry screening. ResultsComplete data were available for 223 people. The participants ranged in age from 23 to 91 years (mean, 68.5 years; standard deviation, 13.7 years), and 119 (53%) were women. The sensitivity of the FDT perimetry screening was 100%; both cases of glaucoma showed an abnormality on FDT perimetry both times. The specificity improved moderately from the first screening to the second screening. The specificity the first time was 62% (95% confidence interval, 53.1–71.2). The specificity the second time was 68.5% (95% confidence interval, 59.8–77.1). Improvement on FDT perimetry rescreening varied by the language spoken at home. Seven of the 19 non-English speakers without glaucoma improved on rescreening, compared with none of the 23 English speakers (P = 0.002). Seven of the 25 right eyes with FDT perimetry abnormalities both times and no glaucoma had no other detectable diseases. Three of 24 left eyes with FDT perimetry abnormalities both times and no glaucoma had no other detectable diseases. Of the 85 patients who did not have glaucoma but had FDT perimetry abnormalities both times, only one did not have some other detectable disease. DiscussionIn summary, the sensitivity for glaucoma of the C-20-5 screening mode is excellent, but a paradigm for screening with the FDT perimeter to improve the overall specificity for glaucoma still must be developed.

The problem of overlapping glaucoma families in the Glaucoma Inheritance Study in Tasmania (GIST)

The Glaucoma Inheritance Study in Tasmania (GIST) is a population survey of Australias island state, Tasmania (population 450,000). Its aim is to find families with autosomal dominant, adult-onset, primary open angle glaucoma (POAG) suitable for genetic linkage analysis. POAG is relatively common, affecting around 3% of the Australian population. By finding the large families with POAG and identifying all the descendants in a captive population, it is possible that there may be overlap of different glaucoma pedigrees. Three of the first thirteen families in the study were composed of overlapping pedigrees. In one GIST family, GTas3, there has been intermarriage with other pedigrees with glaucoma on five occasions. The possibility of multiple genotypes was also reinforced by the inability to determine a single glaucoma phenotype in this family. When finding large families of POAG for linkage analysis, researchers must be aware of the risk of affected individuals inheriting their gene from the alternate parent. Thus, the alternate parents or their families must be examined, especially if the phenotype is atypical for the rest of the family.

Progression of visual field loss in open angle glaucoma in the Melbourne Visual Impairment Project

Purpose:  To quantify the progression of visual field loss in participants with open angle glaucoma.

Systemic effects of topical ophthalmic β‐adrenoceptor antagonists

Topical ophthalmic β-adrenoceptor antagonists (beta-blockers) are generally recognized as the treatment of choice in glaucoma management due to favourable efficacy, safety and tolerability. Despite topical ocular administration, beta-blockers are systemically absorbed, in relatively small amounts, through the nasolacrimal drainage system and can adversely affect cardiovascular and pulmonary function. While cardioselective beta-blockers, such as betaxolol, possibly confer an advantage with respect to clinical safety through their receptor affinity, systemic effects are also influenced by other pharmacological factors, including the rate and extent of systemic absorption and the extent of plasma protein binding. These factors are reviewed to distinguish the various ophthalmic beta-blockers and to explain the observed clinical differences in the safety profiles of these medications.