The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort.

Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.

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

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

Victorian trabeculectomy audit.

IMPORTANCE: This study highlights the efficacy and safety of trabeculectomy in Victoria, Australia. BACKGROUND: Trabeculectomy is currently the gold standard in glaucoma surgery. However, its role has been increasingly questioned because of its associated risks and complications. This audit aimed to assess the efficacy and safety of trabeculectomy surgery in the state of Victoria, Australia. DESIGN: A cross-sectional, retrospective and voluntary statewide audit of trabeculectomy surgery by individual surgeons in 2012 with 24 months follow-up. PARTICIPANTS: Twenty-four surgeons in the state of Victoria submitted data on 227 trabeculectomies. METHODS: Basic preoperative and perioperative data were collected. Post-operative data collected included intra-ocular pressure measurements, glaucoma medications, associated complications and subsequent surgery up to 24 months post-trabeculectomy. MAIN OUTCOME MEASURES: The main outcome measures were post-operative intra-ocular pressure and surgical complications. RESULTS: At 12 months, the mean intra-ocular pressure was 12.6 ± 4.1 mmHg (range 3-28 mmHg). A total of 91% of eyes had an intra-ocular pressure ≤18 mmHg with or without ocular hypotensive medications. One-third of eyes that were phakic at the time of trabeculectomy underwent cataract extraction within the 24 months of follow-up. Eyes that underwent combined cataract extraction and trabeculectomy (23% of trabeculectomies) had a significantly higher mean 12-month intra-ocular pressure than eyes that underwent trabeculectomy alone (13.9 vs. 12.2 mmHg, P = 0.01). At 24 months, there were no cases of blebitis/endophthalmitis. CONCLUSIONS AND RELEVANCE: The Victorian Trabeculectomy Audit demonstrates excellent efficacy and safety results that are comparable with international standards. Combined cataract extraction and trabeculectomy tended to result in a higher mean post-operative intra-ocular pressure than trabeculectomy alone.

Understanding the causation of primary angle closure disease using the sufficient component cause model.

BACKGROUND: Several risk factors have been associated with primary angle closure disease, but their actual role in causation of an individual case is not clear. DESIGN: Concept paper. PARTICIPANTS/SAMPLES: No patient participation. METHODS: The sufficient component cause model is briefly explained in the context of primary angle closure disease. The framework is used to conceptualize the role of individual mechanisms of disease. The possibility of personalized treatment for primary angle closure disease is discussed in this context. MAIN OUTCOME MEASURES: Qualitative concepts in disease causality may refine research and treatment in primary angle closure disease. RESULTS: The minimum set of conditions that are sufficient for primary angle closure disease to occur is considered the sufficient component cause model for that individual case. Described risk factors (including genes) as well as currently unknown influences play a role in the model. There may be many such models and all complementary components in any sufficient-cause model must be present for disease to occur. Interruption of any one component in that model can be used for treatment. Pupillary block is likely a component of most such models and may currently be considered a universally necessary component of these models. CONCLUSIONS: The sufficient component cause model can be used as a framework to explain the role of individual mechanisms of causation and treatment of primary angle closure disease. It also aids understanding of the proportion of disease due to specific causes.

Management algorithms for primary angle closure disease.

In contrast to primary open angle glaucoma, preventive interventions in primary angle closure disease (PACD) can sometimes be definitive. Data from randomized, controlled trials - and where this is not available - principles grounded in known biology, biological plausibility, logic, preferred practice and personal experience have been synthesized to develop explicit clinical algorithms for management of the spectrum of PACD. The mainstay of first-line intervention is usually a laser iridotomy: a commonly necessary but sometimes insufficient manoeuvre in PACD. The crucial stepwise considerations after iridotomy are: whether the angle is open or closed; whether the IOP can be medically controlled; the extent of PAS, and the presence of visually significant cataract. Indication for subsequent interventions--which may include iridoplasty, cataract surgery, trabeculectomy or phacotrabeulectomy--are herein based on an arbitrary threshold (180 degrees) for angle opening and extent of PAS following initial treatment.

There is insufficient evidence to recommend lens extraction as a treatment for primary open-angle glaucoma: an evidence-based perspective.

Cataract extraction in primary open-angle glaucoma has not been thought to provide a clinically useful or predictable decrease in IOP. This concept has now been challenged, with the opposite belief being promulgated: namely, that lens exchange should be considered as treatment for glaucoma. This revelation could bring a significant change in the glaucoma treatment paradigm. There are no randomised controlled trials to guide the role of lens extraction in primary open-angle glaucoma. The available evidence suggests at most a modest reduction in IOP from cataract extraction - greater in the presence of pseudoexfoliation - which is likely to be of marginal benefit, and only in milder forms of open-angle glaucoma. There is currently no evidence of any quality to suggest that lens extraction routinely represents a clinically useful treatment for primary open-angle glaucoma.

Clear lens extraction in angle closure glaucoma.

PURPOSE OF REVIEW: Clear lens extraction is being advocated for primary angle closure disease (PACD). It is important that this advocacy should be based on a sound, peer-reviewed evidence base. This review attempts to establish the extent of that evidence and provide some management guidelines. RECENT FINDINGS: There are only three reports that incorporate clear lens extraction (CLE) for angle closure: numbers are sparse and none compare modern phacoemulsification to alternative treatments for primary angle closure glaucoma or provide enough detail to guide clinical decisions. A Cochrane review in 2006 found that there was no evidence to support lens extraction as treatment for primary angle closure glaucoma (PACG). More recent randomized controlled trials have provided support for cataract extraction--although not specifically for CLE--as treatment for part of the spectrum of PACD. A recent review has attempted to provide guidelines for application of CLE in PACG by extrapolating from this evidence. SUMMARY: There are currently no randomized controlled trials supporting the use of CLE as treatment for PACG. A benefit from the procedure is biologically plausible and extrapolation from existing randomized trials to a few specific situations may be possible. Any potential benefit must be carefully weighed against the risks of intervention.

Enter the reverend: introduction to and application of Bayes' theorem in clinical ophthalmology.

BACKGROUND: Ophthalmic practice utilizes numerous diagnostic tests, some of which are used to screen for disease. Interpretation of test results and many clinical management issues are actually problems in inverse probability that can be solved using Bayes' theorem. DESIGN: Use two-by-two tables to understand Bayes' theorem and apply it to clinical examples. SAMPLES: Specific examples of the utility of Bayes' theorem in diagnosis and management. METHODS: Two-by-two tables are used to introduce concepts and understand the theorem. The application in interpretation of diagnostic tests is explained. Clinical examples demonstrate its potential use in making management decisions. MAIN OUTCOME MEASURE: Positive predictive value and conditional probability. RESULTS: The theorem demonstrates the futility of testing when prior probability of disease is low. Application to untreated ocular hypertension demonstrates that the estimate of glaucomatous optic neuropathy is similar to that obtained from the Ocular Hypertension Treatment Study. Similar calculations are used to predict the risk of acute angle closure in a primary angle closure suspect, the risk of pupillary block in a diabetic undergoing cataract surgery, and the probability that an observed decrease in intraocular pressure is due to the medication that has been started. The examples demonstrate how data required for management can at times be easily obtained from available information. CONCLUSIONS: Knowledge of Bayes' theorem helps in interpreting test results and supports the clinical teaching that testing for conditions with a low prevalence has a poor predictive value. In some clinical situations Bayes' theorem can be used to calculate vital data required for patient management.

Increasing the Spatial Resolution of Visual Field Tests Without Increasing Test Duration: An Evaluation of ARREST.

Purpose: The Australian Reduced Range Extended Spatial Test (ARREST) approach was designed to improve visual field spatial resolution while maintaining a similar test duration to clinically used testing algorithms. ARREST does not completely threshold visual field locations with sensitivity < 17 dB, and uses the presentations saved to test new locations in areas of steep gradient within the visual field. Previous assessments of ARREST's performance have used computer simulation. In this study, we cross-sectionally assessed the performance of ARREST in people with visual field loss. Methods: We tested 23 people with glaucoma (mean age: 71 ± 8 years) with established visual field loss. Three visual field procedures were performed using the Open Perimetry Interface: cZEST and ARREST on the Octopus 900 perimeter (Haag-Streit AG, Switzerland), and a reference standard (best available estimate [BAE]) on the Compass perimeter (CenterVue SpA, Italy). ARREST was compared against the cZEST and the BAE. Results: On average, ARREST added seven new locations (range = 0-15) to a visual field test. There was no significant difference in the number of stimulus presentations between procedures (mean = 259 ± 25 [ARREST] vs. 261 ± 25 [cZEST], P = 0.78). In classifying threshold values < 17 dB, ARREST performed similarly when compared against BAE. Conclusions: This study provides empirical evidence to support conclusions from previous computer simulations that ARREST can be used to increase spatial sampling in regions of interest without increasing test time. Translational Relevance: ARREST is a new approach that augments current visual field testing procedures to provide better spatial description of visual field defects without increasing test duration.