Glaucoma Australia educational impact study: a randomized short-term clinical trial evaluating the association between glaucoma education and patient knowledge, anxiety and treatment satisfaction.

IMPORTANCE: Targeted education may impact glaucoma patients' clinical experience. BACKGROUND: The aim of this study was to measure the impact of patient-centred glaucoma-related education on knowledge, anxiety and treatment satisfaction. DESIGN: This was a multicentre Australia-wide randomized clinical trial. PARTICIPANTS: One hundred one newly diagnosed glaucoma patients were randomized 1:1 to intervention or control groups. METHODS: Those randomized to the Glaucoma Australia educational intervention received telephone-based counselling about glaucoma followed by mail-out information, in addition to usual care and information from their treating ophthalmologist. The control group received only usual care and information from their treating ophthalmologist. Surveys were administered at baseline and 4 weeks following intervention. MAIN OUTCOME MEASURES: The Auckland Glaucoma Knowledge Questionnaire measured glaucoma-related knowledge. The Hospital Anxiety and Depression Scale and Eye-Drop Satisfaction Questionnaire measured anxiety and patient treatment satisfaction, respectively. RESULTS: Mean age was 64.7 ± 11.1 years, and 52 (51.5%) were male. There was no noticeable increase in knowledge levels in the control group (mean difference: 0.04 logits, P = 0.7), compared with a 0.49-logit (P = 0.02) increase in knowledge levels in the intervention group. Between-group comparison showed a non-significant increase in knowledge (0.45 logits, P = 0.07) comparing intervention participants with controls. Intervention participants experienced a statistically significant decrease in anxiety compared to controls (-0.60 logits, P = 0.02). No between-group difference was found in Eye-Drop Satisfaction Questionnaire scores. CONCLUSIONS AND RELEVANCE: Patient-centred glaucoma-related education and support services may improve knowledge and can reduce anxiety for newly diagnosed glaucoma patients. All glaucoma patients should be adequately counselled about the nature of the disease and its management.

Disease-Related Protein Variants of the Highly Conserved Enzyme PAPSS2 Show Marginal Stability and Aggregation in Cells.

Cellular sulfation pathways rely on the activated sulfate 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In humans, PAPS is exclusively provided by the two PAPS synthases PAPSS1 and PAPSS2. Mutations found in the PAPSS2 gene result in severe disease states such as bone dysplasia, androgen excess and polycystic ovary syndrome. The APS kinase domain of PAPSS2 catalyzes the rate-limiting step in PAPS biosynthesis. In this study, we show that clinically described disease mutations located in the naturally fragile APS kinase domain are associated either with its destabilization and aggregation or its deactivation. Our findings provide novel insights into possible molecular mechanisms that could give rise to disease phenotypes associated with sulfation pathway genes.

Association between focal lamina cribrosa defects and optic disc haemorrhage in glaucoma.

BACKGROUND/AIMS: To explore the relationship between focal lamina defect (LD) size and optic disc haemorrhages (DH) in glaucomatous eyes. METHODS: Radial B-scan images at 15° intervals obtained using enhanced depth imaging (EDI) spectral-domain optical coherence tomography (OCT) were performed on a group of subjects previously assessed for DH every 3 months over a period of 5 years. EDI-OCT scans were assessed for the presence of focal lamina cribrosa defects by a single observer. RESULTS: 119 eyes from 62 subjects (44 females, 18 males) were analysed. 44 eyes (37%) were noted to have at least 1 LD, and of those, eight eyes had more than one defect. 68 eyes (57%) were observed to have at least one DH occur over the course of monitoring. 48 eyes (40%) had recurrent DH, with a mean of 5.17 haemorrhages over the 5-year period. Type 1 focal LD (p=0.0000, OR 7.17), glaucoma progression (p=0.0024, OR 0.32) and ArtDiff (p=0.0466, OR 1.04) were significantly associated as predictors of DH. No correlation between the size of the LD and DH occurrence (p=0.6449, Spearman rank correlation) was found. CONCLUSION: Focal lamina cribrosa hole-type defects were significantly associated with an increase in DH occurrence over the preceding 5 years. The lack of association between defect size and DH suggests that DH and lamina defects may have separate links to the glaucomatous process.

Recurrent Optic Disc Hemorrhage and Its Association with Visual Field Deterioration in Glaucoma.

PURPOSE: To investigate the association among optic disc hemorrhage (ODH) recurrence, location, and visual field (VF) progression. DESIGN: Prospective, observational study. PARTICIPANTS: Patients with bilateral glaucoma or unilateral glaucoma with a fellow glaucoma suspect eye were enrolled. METHODS: Patients received optic disc photography every 3 months and VF testing every 4 months. The disc was partitioned into 8 sectors to match 8 visual field (VF) sectors. The frequency of ODH in each sector was quantified over an average of 64 months. Global VF progression rate was calculated using linear regression on mean deviation. Sectoral progression rate was calculated using linear regression on the sensitivity at each VF location over time and then selecting the largest and second largest significant (P < 0.05) negative slope within that sector. The association between ODH and VF progression rate globally and within a sector was calculated using linear mixed modeling. MAIN OUTCOME MEASURES: Global and sectoral VF progression, ODH frequency, and ODH recurrence (globally and sectoral) and its association with VF progression rate. RESULTS: A total of 151 eyes from 77 patients completed the study with mean follow-up of 64 months, 20 disc photographs, and 16 VF tests. With global VF analysis, eyes with ODH in 2 different sectors of the disc had worse progression rate than eyes with ODH in 1 sector (P = 0.012) and eyes with no ODH (P < 0.001). Regarding the largest sectoral VF progression, sectors with 1 ODH had a faster VF progression rate than those with no ODH (P < 0.017) and progressed at a similar rate to those with 2 to 8 ODH (P = 0.592). Sectors with >8 ODH had faster VF progression than all other groups (all P < 0.001). CONCLUSIONS: High-frequency ODH within optic disc sectors, equivalent to detecting ODH in 45% of 3 monthly eye examination visits, was associated with significantly worse VF progression than sectors with moderate or only 1 observed ODH. In addition, ODH occurring in different sectors in the same eye was more strongly associated with greater global VF progression compared with those occurring within the same sector.

Intraocular lens dystrophic calcification after trans-scleral diode laser treatment for a cyclodialysis cleft.

PURPOSE: To describe a case of intraocular lens (IOL) dystrophic calcification as a complication of trans-scleral diode laser successfully used to treat a post-trabeculectomy cyclodialysis cleft. OBSERVATIONS: A 76-year-old male with primary open angle glaucoma and pseudophakia (+19.0D Akreos M160L, Bausch & Lomb) was evaluated for vision impairment 4 months post-trabeculectomy complicated by a cyclodialysis cleft of his right eye. The patient was successfully treated with trans-scleral diode laser. After this treatment IOL opacification developed. Slit lamp examination and color photography of the anterior segment was performed prior to exchange of the opacified IOL. The explanted IOL underwent star testing, macroscopic imaging, phase contrast and scanning electron microscopy in addition to energy dispersive x-ray spectroscopy.Confluent IOL deposits developed 4 months after trans-scleral diode laser treatment requiring IOL exchange. Star optical testing of the explanted IOL showed disruption of the diffraction image. An asymmetric pattern of deposition was congruent with the laser treatment quadrant. The subsurface location and discrete nature of the deposits were seen on phase contrast and electron microscopy. Energy dispersive x-ray spectroscopy demonstrated a predominance of calcium/phosphate in the deposits. We are unaware of previous reports in the literature of IOL dystrophic calcification occurring as a complication of trans-scleral diode laser treatment for a post-trabeculectomy cyclodialysis cleft. CONCLUSION AND IMPORTANCE: Delayed postoperative IOL dystrophic calcification in our case may have been from a combination of IOL biomaterial susceptibility to diode laser energy; damaged IOL material providing a nidus for calcific nucleation; and blood ocular barrier breakdown altering aqueous composition. We suggest that pseudophakia should influence the consideration of diode laser as treatment of a cyclodialysis cleft.

The association between retinal vein pulsation pressure and optic disc haemorrhages in glaucoma.

PURPOSE: To explore the potential relationship between optic disc haemorrhage, venous pulsation pressure (VPP), ocular perfusion pressures and visual field change in glaucomatous and glaucoma suspect eyes. MATERIALS AND METHODS: This prospective observational study examined 155 open angle glaucoma or glaucoma suspect eyes from 78 patients over 5 years. Patients were followed with 3 monthly non-mydriatic disc photographs, 6 monthly standard automated perimetry and annual ophthalmodynamometry. The number of disc haemorrhages in each hemidisc was counted across the study period. Visual field rate of change was calculated using linear regression on the sensitivity of each location over time, then averaged for the matching hemifield. VPP and central retinal artery diastolic pressure (CRADP) were calculated from the measured ophthalmodynanometric forces (ODF). The difference between brachial artery diastolic pressure (DiastBP) and CRADP was calculated as an index of possible flow pathology along the carotid and ophthalmic arteries. RESULTS: Mean age of the cohort was 71.9 ± 7.3 Years. 76 out of 155 eyes (49%) followed for a mean period of 64.2 months had at least 1 disc haemorrhage. 62 (81.6%) of these 76 eyes had recurrent haemorrhages, with a mean of 5.94 recurrences over 64.2 months. Using univariate analysis, rate of visual field change (P<0.0001), VPP (P = 0.0069), alternative ocular perfusion pressure (CRADP-VPP, P = 0.0036), carotid resistance index (DiastBP-CRADP, P = 0.0108) and mean brachial blood pressure (P = 0.0203) were significantly associated with the number of disc haemorrhages. Using multivariate analysis, increased baseline visual field sensitivity (P = 0.0243, coefficient = 0.0275) was significantly associated with disc haemorrhage, in conjunction with higher VPP (P = 0.0029, coefficient = 0.0631), higher mean blood pressure (P = 0.0113, coefficient = 0.0190), higher carotid resistance index (P = 0.0172, coefficient = 0.0566), and rate of visual field loss (P<0.0001, coefficient = -2.0695). CONCLUSIONS: Higher VPP was associated with disc haemorrhage and implicates the involvement of venous pathology, but the effect size is small. Additionally, a greater carotid resistance index suggests that flow pathology in the ophthalmic or carotid arteries may be associated with disc haemorrhage.

Intraocular Pressure Reduction Is Associated with Reduced Venous Pulsation Pressure.

PURPOSE: To explore whether alterations in intraocular pressure (IOP) affect vein pulsation properties using ophthalmodynamometric measures of vein pulsation pressure. PATIENTS AND METHODS: Glaucoma patients had two retinal vein pulsation pressure (VPP) measurements from upper and lower hemiveins performed by ophthalmodynamometry at least 3 months apart. All subjects had VPP and IOP recorded at two visits, with standard automated perimetry, central corneal thickness (CCT) recorded at the initial visit. Where venous pulsation was spontaneous ophthalmodynamometry could not be performed and VPP was considered equal to IOP. Change in VPP was calculated and binarized with reduction in pressure scored 1 and no change or increase scored as 0. Data analysis used a mixed logistic regression model with change in VPP as response variable and change in IOP, visual field loss (mean deviation), CCT and time interval as explanatory variables. RESULTS: 31 subjects (20 females) with mean age 60 years (sd 11) were examined with change in VPP being significantly associated with change in IOP (odds ratio 1.6/mmHg, 95% CI 1.2 to 2.1 in the glaucoma patients but not suspect patients (p = 0.0005). CONCLUSION: Change in VPP is strongly associated with change in IOP such that a reduced intraocular pressure is associated with a subsequent reduction in VPP. This indicates that reduced IOP alters some retinal vein properties however the nature and time course of these changes is not known.

Cerebrospinal fluid pressure and the eye.

Cerebrospinal fluid pressure (CSFP) interacts with intraocular pressure (IOP) and blood pressure to exert a major influence upon the eye, particularly the optic nerve head region. There is increased interest regarding the influence of CSFP upon disorders affecting this region, in particular glaucoma and idiopathic intracranial hypertension. Additionally, a high proportion of astronauts develop features similar to idiopathic intracranial hypertension that persist for years after returning to Earth. The factors that affect the CSFP influence upon the optic nerve and globe are likely to influence the outcome of various ophthalmic disorders.

PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations.

CONTEXT: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3'-phospho-adenosine-5'-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. PATIENTS AND METHODS: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. RESULTS: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. CONCLUSIONS: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

Visual field of high-pass resolution perimetry in normal subjects.

PURPOSE: To investigate the properties of the visual field of high-pass resolution perimetry in normal subjects. METHODS: Four centers collected normative data for high-pass resolution perimetry. In two of the centers the subjects were stratified by age. One eye was tested per subject using high-pass resolution perimetry (Ophthimus). We tested 640 normal subjects and describe their visual field results by test location. We also analyzed the data by concentric zone, age, and by testing center. RESULTS: The individual test location averages confirmed a reduction in resolution with eccentricity. Resolution thresholds increased with age by 0.025 dB per year (P < 0.001). The mean ring size increased by about 1 dB from age 20 to 70. Among centers there were significant differences in the means and the change in threshold with age (P = 0.009). CONCLUSION: The normal visual field of high-pass resolution perimetry is characterized by an increase in threshold with eccentricity. We found significant differences among the centers that were likely due to multiple factors including differences in subject selection criteria. Whether such differences occur with other perimetric techniques is unknown.

Understanding androgen action in adipose tissue.

Androgens play an important role in regulation of body fat distribution in humans. They exert direct effects on adipocyte differentiation in a depot-specific manner, via the androgen receptor (AR), leading to modulation of adipocyte size and fat compartment expansion. Androgens also impact directly on key adipocyte functions including insulin signalling, lipid metabolism, fatty acid uptake and adipokine production. Androgen excess and deficiency have implications for metabolic health in both males and females, and these metabolic effects may be mediated through adipose tissue via effects on fat distribution, adipocyte function and lipolysis. Research into the field of androgen metabolism in human and animal adipose tissue has produced inconsistent results; it is important to take into account the sex-, depot- and organism-specific effects of androgens in fat. In general, studies point towards a stimulatory effect on lipolysis, with impairment of adipocyte differentiation, insulin signalling and adipokine generation. Observed effects are frequently gender-specific. Adipose tissue is an important organ of pre-receptor androgen metabolism, through which local androgen availability is rigorously controlled. Adipose androgen exposure is tightly controlled by isoenzymes of AKR1C, 5α-reductase and others, but regulation of the balance between generation and irreversible inactivation remains poorly understood. In particular, AKR1C2 and AKR1C3 are crucial in the regulation of local androgen bioavailability within adipose tissue. These isoforms control the balance between activation of androstenedione (A) to testosterone (T) by the 17ß-hydroxysteroid dehydrogenase activity (17ß-HSD) of AKR1C3, or inactivation of 5α-dihydrotestosterone (DHT) to 5α-androstane-3α,17ß-diol by the 3α-hydroxysteroid dehydrogenase (3α-HSD) activity of AKR1C2. Most studies suggest that androgen inactivation is the predominant reaction in fat, particularly in the abdominal subcutaneous (SC) depot. Modulation of local adipose androgen availability may afford future therapeutic options to improve metabolic phenotype in disorders of androgen excess and deficiency.

Photoplethysmographic measurement of various retinal vascular pulsation parameters and measurement of the venous phase delay.

PURPOSE: Retinal vein pulsation properties are altered by glaucoma, intracranial pressure (ICP) changes, and retinal venous occlusion, but measurements are limited to threshold measures or manual observation from video frames. We developed an objective retinal vessel pulsation measurement technique, assessed its repeatability, and used it to determine the phase relations between retinal arteries and veins. METHODS: Twenty-three eyes of 20 glaucoma patients had video photograph recordings from their optic nerve and peripapillary retina. A modified photoplethysmographic system using video recordings taken through an ophthalmodynamometer and timed to the cardiac cycle was used. Aligned video frames of vessel segments were analyzed for blood column light absorbance, and waveform analysis was applied. Coefficient of variation (COV) was calculated from data series using recordings taken within ±1 unit ophthalmodynamometric force of each other. The time in cardiac cycles and seconds of the peak (dilation) and trough (constriction) points of the retinal arterial and vein pulse waveforms were measured. RESULTS: Mean vein peak time COV was 3.4%, and arterial peak time COV was 4.4%. Lower vein peak occurred at 0.044 cardiac cycles (0.040 seconds) after the arterial peak (P = 0.0001), with upper vein peak an insignificant 0.019 cardiac cycles later. No difference in COV for any parameter was found between upper or lower hemiveins. Mean vein amplitude COV was 12.6%, and mean downslope COV was 17.7%. CONCLUSIONS: This technique demonstrates a small retinal venous phase lag behind arterial pulse. It is objective and applicable to any eye with clear ocular media and has moderate to high reproducibility. ( http://www.anzctr.org.au number, ACTRN12608000274370.).

Spatial modeling of visual field data for assessing glaucoma progression.

PURPOSE: In order to reduce noise and account for spatial correlation, we applied disease mapping techniques to visual field (VF) data. We compared our calculated rates of progression to other established techniques. METHODS: Conditional autoregressive (CAR) priors, weighted to account for physiologic correlations, were employed to describe spatial and spatiotemporal correlation over the VF. Our model is extended to account for several physiologic features, such as the nerve fibers serving adjacent loci on the VF not mapping to the adjacent optic disc regions, the presence of the blind spot, and large measurement fluctuation. The models were applied to VFs from 194 eyes and fitted within a Bayesian framework using Metropolis-Hastings algorithms. RESULTS: Our method (SPROG for Spatial PROGgression) showed progression in 42% of eyes. Using a clinical reference, our method had the best receiver operating characteristics compared with the point-wise linear regression methods. Because our model intrinsically accounts for the large variation of VF data, by adjusting for spatial correlation, the effects of outliers are minimized, and spurious trends are avoided. CONCLUSIONS: by using CAR priors, we have modeled the spatial correlation in the eye. combining this with physiologic information, we are able to provide a novel method for VF analysis. model diagnostics, sensitivity, and specificity show our model to be apparently superior to CURRENT POINT-wise linear regression methods. (http://www.anzctr.org.au number, ACTRN12608000274370.).

Efficacy and safety of bimatoprost as replacement for latanoprost in patients with glaucoma or ocular hypertension: a uniocular switch study.

PURPOSE: To assess the efficacy and safety of switching patients from bilateral latanoprost to bimatoprost in 1 eye while maintaining latanoprost in the fellow eye. PATIENTS AND METHODS: This prospective, open-label, multicenter, uniocular (within-eye control) study was conducted from March 2005 to February 2007; 105 patients with glaucoma or ocular hypertension were enrolled. At baseline, patients using bilateral latanoprost were switched to bimatoprost treatment in 1 eye (study eye) and continued latanoprost treatment in the fellow eye (control eye). At 12 weeks, patients were offered bilateral bimatoprost for 12 additional weeks. RESULTS: At week 12, the mean difference in intraocular pressure (IOP) from baseline was -3.0 mm Hg in study eyes and -1.6 mm Hg in control eyes, which equates to a further -1.4 mm Hg (95% confidence limits: -1.9, -0.9) reduction in IOP in study eyes compared with control eyes (P<0.0001). Overall, 27% (28/104) more study eyes had > or = -2.5 mm Hg reduction in IOP than control eyes (P<0001). At week 24, the mean difference in IOP from baseline was -2.8 mm Hg for study eyes and for control eyes that had switched to bimatoprost. Conjunctival hyperemia occurred more frequently and was more severe in bimatoprost-treated eyes at week 12 than at baseline (P<0.001). No patients withdrew from treatment because of conjunctival hyperemia. CONCLUSIONS: Clinically, these data suggest that switching patients from latanoprost to bimatoprost may result in further improvement in IOP control.

The critical role of the conjunctiva in glaucoma filtration surgery.

This review considers the critical role of the conjunctiva in determining the success or failure of glaucoma filtration surgery. Glaucoma filtration surgery can be defined as an attempt to lower intraocular pressure (IOP) by the surgical formation of an artificial drainage pathway from the anterior chamber to the subconjunctival space. Many types of glaucoma filtration surgery have been developed since the first attempts almost 180 years ago. The wide range of new techniques and devices currently under investigation is testament to the limitations of current techniques and the need for improved therapeutic outcomes. Whilst great attention has been paid to surgical techniques and devices to create the drainage pathway, relatively little attention has been given to address the question of why drainage from such artificial pathways is often problematic. This is in contrast to normal drainage pathways which last a lifetime. Furthermore, the consequences of potential changes in aqueous humour properties induced by glaucoma filtration surgery have not been sufficiently addressed. The mechanisms by which aqueous fluid is drained from the subconjunctival space after filtration surgery have also received relatively little attention. We propose that factors such as the degree of tissue damage during surgery, the surrounding tissue reaction to any surgical implant, and the degree of disruption of normal aqueous properties, are all factors which influence the successful formation of long term drainage channels from the conjunctiva, and that these channels are the key to successful filtration surgery. In recent years it has been suggested that the rate of fluid drainage from the subconjunctival space is actually the determining factor in the resultant IOP reduction. Improved knowledge of aqueous humour induced changes in such drainage pathways has the potential to significantly improve the surgical management of glaucoma. We describe for the first time a novel type of drainage surgery which attempts to minimise surgical trauma to the overlying conjunctiva. The rationale is that a healthy conjunctiva allows drainage channels to form and less opportunity for inflammation and scar tissue formation which are a frequent cause of failure in glaucoma filtration surgery. Successful drainage over extended periods of time has been demonstrated in monkey and rabbit eyes. Long lasting drainage pathways were clearly associated with the presence of lymphatic drainage pathways. A new philosophy in glaucoma drainage surgery is proposed in which minimisation of surgical trauma to the conjunctiva and the encouragement of the development of conjunctival drainage pathways, particularly lymphatic pathways, are central pillars to a successful outcome in glaucoma filtration surgery.