Retrospective cohort study exploring whether an association exists between spatial distribution of cystoid spaces in cystoid macular oedema secondary to retinitis pigmentosa and response to treatment with carbonic anhydrase inhibitors

BACKGROUND: Carbonic anhydrase inhibitors (CAIs) are frequently used as an initial step to treat retinitis pigmentosa-associated cystoid macular oedema (RP-CMO). Interestingly, it has been postulated that CAIs might reduce outer nuclear layer (ONL) fluid more effectively than inner nuclear layer (INL) fluid due to better access to retinal pigment epithelium basolateral membrane than neurosensory retina. This retrospective cohort study explores if an association between spatial distribution of cystoid spaces in RP-CMO and CAI response exists. METHODS: Two independent graders reviewed pretreatment and post-treatment optical coherence tomography (OCT) images of 25 patients (43 eyes) initiated on topical and/or oral CAIs between January 2013 and December 2014. Documentation included the presence/absence of fluid (and layer(s) involved), external limiting membrane, epiretinal membrane (ERM), vitreomacular adhesion/traction, lamellar/full-thickness macular hole and central macular thickness (CMT)/volume. RESULTS: INL fluid was found in all study eyes. All 13 'responders' (at least 11% reduction of CMT after treatment) demonstrated pretreatment ONL fluid. In seven patients (four responders and three non-responders), complete clearance of ONL fluid was achieved despite persistence of INL fluid. ERM presence was similar in responders and non-responders. CONCLUSION: In this study, INL fluid was found to be the most common spatial distribution of RP-CMO. However, patients who were classed as a 'responder' to CAI treatment all demonstrated coexisting ONL fluid on their pretreatment OCT scans. This may be explained by CAIs having better access to retinal pigment epithelium basolateral membrane than neurosensory retina. Our study also suggests a minimal impact on response to CAIs by ERM

Ophthalmic statistics note 8: missing data - exploring the unknown

Medical research is conducted to answer uncertainties and to identify effective treatments for patients. Different questions are best addressed by different types of study design—but the randomised, controlled clinical trial is typically viewed as the gold standard, providing a very high level of evidence, when examining efficacy. While clinical trial methodology has advanced considerably with clear guidance provided as to how to avoid sources of bias, even the most robustly designed study can succumb to missing data. In this statistics note, we discuss strategies for dealing with missing data but what we hope emerges is a very clear message that there is no ideal solution to missing data and prevention is the best strategy

Patients With Normal Tension Glaucoma Have Relative Sparing of the Relative Afferent Pupillary Defect Compared to Those With Open Angle Glaucoma and Elevated Intraocular Pressure

PURPOSE: We determined whether there is relative sparing of pupil function in glaucoma patients with normal pressures compared to those with high pressures. METHODS: A cross-sectional study was done of 68 patients with primary open angle glaucoma (POAG): 38 had normal IOPs on all-day phasing before treatment (never >21 mm Hg), with confirmed progression of glaucomatous optic neuropathy (NTG) and 30 had glaucomatous optic neuropathy associated with elevated intraocular pressures (>25 mm Hg; HP-POAG). The relative afferent pupillary defect (RAPD) was quantified with the RAPDx device, and mean deviation of visual field loss was obtained from reliable Humphrey visual fields. Outcomes measures evaluated were difference in slope between NTG and HP-POAG when plotting: (1) RAPD score against difference in mean deviation (MD) between eyes, and (2) RAPD score against difference in RNFL thickness between eyes. RESULTS: The slopes for magnitude of RAPD versus difference in MD were -0.06 (95% confidence interval [CI], -0.076, -0.044) for patients with NTG and -0.08 (95% CI, -0.109, -0.067) for those with HP-POAG. Fitting the interaction term showed a statistically significant difference between the slopes (0.023; 95% CI [0.0017, 0.0541]; P value = 0.037; HP-POAG reference group). Thus, for difference in MD, the slope for patients with NTG was flatter than the slope for those with HP-POAG. CONCLUSIONS: Glaucoma patients with NTG have a lesser RAPD for a given level of intereye difference of HVF MD, compared to patients with high IOPs. This suggests that damage to intrinsically photosensitive retinal ganglion cells (ipRGCs) differs between the normal and high-pressure forms of open-angle glaucoma (OAG), and supports the theory that mitochondrial optic neuropathies may have a role in the group of diagnoses currently termed normal tension glaucoma

Tablet computers versus optical aids to support education and learning in children and young people with low vision: protocol for a pilot randomised controlled trial, CREATE (Children Reading with Electronic Assistance To Educate)

INTRODUCTION: Low vision and blindness adversely affect education and independence of children and young people. New 'assistive' technologies such as tablet computers can display text in enlarged font, read text out to the user, allow speech input and conversion into typed text, offer document and spreadsheet processing and give access to wide sources of information such as the internet. Research on these devices in low vision has been limited to case series. METHODS AND ANALYSIS: We will carry out a pilot randomised controlled trial (RCT) to assess the feasibility of a full RCT of assistive technologies for children/young people with low vision. We will recruit 40 students age 10-18 years in India and the UK, whom we will randomise 1:1 into two parallel groups. The active intervention will be Apple iPads; the control arm will be the local standard low-vision aid care. Primary outcomes will be acceptance/usage, accessibility of the device and trial feasibility measures (time to recruit children, lost to follow-up). Exploratory outcomes will be validated measures of vision-related quality of life for children/young people as well as validated measures of reading and educational outcomes. In addition, we will carry out semistructured interviews with the participants and their teachers. ETHICS AND DISSEMINATION: NRES reference 15/NS/0068; dissemination is planned via healthcare and education sector conferences and publications, as well as via patient support organisations. TRIAL REGISTRATION NUMBER: NCT02798848; IRAS ID 179658, UCL reference 15/0570

Evaluation of Visual Field and Imaging Outcomes for Glaucoma Clinical Trials (An American Ophthalomological Society Thesis)

PURPOSE: To evaluate the ability of various visual field (VF) analysis methods to discriminate treatment groups in glaucoma clinical trials and establish the value of time-domain optical coherence tomography (TD OCT) imaging as an additional outcome. METHODS: VFs and retinal nerve fibre layer thickness (RNFLT) measurements (acquired by TD OCT) from 373 glaucoma patients in the UK Glaucoma Treatment Study (UKGTS) at up to 11 scheduled visits over a 2 year interval formed the cohort to assess the sensitivity of progression analysis methods. Specificity was assessed in 78 glaucoma patients with up to 11 repeated VF and OCT RNFLT measurements over a 3 month interval. Growth curve models assessed the difference in VF and RNFLT rate of change between treatment groups. Incident progression was identified by 3 VF-based methods: Guided Progression Analysis (GPA), 'ANSWERS' and 'PoPLR', and one based on VFs and RNFLT: 'sANSWERS'. Sensitivity, specificity and discrimination between treatment groups were evaluated. RESULTS: The rate of VF change was significantly faster in the placebo, compared to active treatment, group (-0.29 vs +0.03 dB/year, P<.001); the rate of RNFLT change was not different (-1.7 vs -1.1 dB/year, P=.14). After 18 months and at 95% specificity, the sensitivity of ANSWERS and PoPLR was similar (35%); sANSWERS achieved a sensitivity of 70%. GPA, ANSWERS and PoPLR discriminated treatment groups with similar statistical significance; sANSWERS did not discriminate treatment groups. CONCLUSIONS: Although the VF progression-detection method including VF and RNFLT measurements is more sensitive, it does not improve discrimination between treatment arms

Soft Contact Lenses to Optimize Vision in Adults with Idiopathic Infantile Nystagmus: A Pilot Parallel Randomized Controlled Trial

PURPOSE: The optimal management of infantile nystagmus syndrome (INS) is still unclear. Contact lenses (CL) may be superior to glasses in improving visual function in INS but it is not known whether their beneficial effects are due to optical correction alone, or to an additional proprioceptive effect, and whether soft CLs would be as effective as rigid CLs. There is little data on feasibility and and the present study aimed to provide this information. METHODS: We completed a pilot Randomized Control Trial (RCT) at a single tertiary referral centre in London, UK. We enrolled 38 adults with idiopathic INS and randomised them to either plano CL (with corrective spectacles if required) or to corrective CL. CL wear was required for a minimum of 2 weeks. Primary outcome measures were feasibility and safety of CL wear in INS; secondary outcome measures were visual acuity and nystagmus waveform parameters. RESULTS: 27 completed the study (27/38,71%). 4 partcipants withdrew due to difficulty with CL insertion/removal and 7 were lost to follow up. CL tolerability was high (24/27,89%) - 2 found the CLs irritant, and 1 had an exacerbation of allergic eye disease. At two weeks, mean improvement in binocular visual acuity from baseline with plano CLs was 0.07 logMAR (95% confidence interval (CI: 0.03-0.11) and 0.06 logMAR with fully corrective CLs (95% CI:0.02-0.1). Mean improvement in the eXpanded Nystagmus Acuity Function (NAFX, a nystagmus acuity function based on eye movement recording) with plano CLs was -0.04(95% CI: -0.08-0.005) and -0.05 with fully corrective CLs(95% CI: -0.09-0.003). CONCLUSIONS: CLs are well tolerated, with a low risk profile. Whilst our study was not powered to detect significant changes in BCVA and waveform parameters between treatment arms, we observed a trend towards an improvement in visual function at two weeks from baseline with CLs

Slow-Release Dexamethasone in Proliferative Vitreoretinopathy: A Prospective, Randomized Controlled Clinical Trial

Purpose To test the hypothesis that adjunctive slow-release dexamethasone implant (Ozurdex; Allergan Inc, Irvine, CA) can improve the outcomes of vitreoretinal surgery for established proliferative vitreoretinopathy (PVR). Design A 2-year, single-center, prospective, participant- and surgeon-masked randomized controlled clinical trial (EudraCT No. 2011-004498-96). Participants A total of 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR (Grade C) were randomized to standard (control) or study treatment (adjunct) in a 1:1 allocation ratio. Methods Intraoperatively, the adjunct group received an injection of 0.7 mg of slow-release dexamethasone (Ozurdex) at the time of (1) vitrectomy surgery and (2) silicone oil removal. The control group received standard care. Main Outcome Measures Primary outcome measure was the proportion of patients with a stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months. Secondary outcomes included (1) final visual acuity (VA) (median and Early Treatment Diabetic Retinopathy Study [ETDRS] of 55 letters or better); (2) cystoid macular edema (CMO), foveal thickness, and macular volume; (3) development of overt PVR recurrence; (4) complete and posterior retinal reattachment; (5) tractional retinal detachment; (6) hypotony/increased intraocular pressure (IOP); (7) macula pucker/epiretinal membrane; (8) cataract; and (9) quality of life. Results All 140 patients were recruited within 25 months of study commencement; 138 patients had primary outcome data. Primary outcome assessment showed similar results in anatomic success between the 2 groups (49.3% vs. 46.3%, adjunct vs. control; odds ratio, 0.89; 95% confidence interval, 0.46–1.74; P = 0.733). Mean VA at 6 months was 38.3 ETDRS letters and 40.2 letters in the adjunct and control groups, respectively. Secondary anatomic outcomes (complete/posterior reattachment rates and PVR recurrence) were comparable between the 2 groups. At 6 months, fewer adjunct patients had CMO (42.7%) or a foveal thickness of >300 μm (47.6%) compared with controls (67.2% and 67.7%, respectively, P = 0.004, P = 0.023). Conclusions A slow-release dexamethasone implant did not improve the primary anatomic success rate in eyes undergoing vitrectomy surgery with silicone oil for PVR. Further clinical trials are indicated to improve anatomic and visual outcomes in these eyes, but this study suggests that there is a greater reduction in CMO observed at 6 months in vitrectomized eyes treated with slow-release dexamethasone

Dynamic Changes in Schlemm Canal and Iridocorneal Angle Morphology During Accommodation in Children With Healthy Eyes: A Cross-Sectional Cohort Study

PURPOSE: The purpose of this study was to explore changes in Schlemm canal (SC), trabecular meshwork (TM), and iridocorneal angle (ICA) morphology during accommodative effort in children and young adults. METHODS: We acquired anterior segment optical coherence tomography images (AS-OCT) of the ICA and ciliary muscle (CM) of both eyes of 50 children age 4 to 16 years with healthy eyes, at two levels of accommodation: 2.5 and 15 diopters (D). Semiautomated nasal ICA measurements were as follows: angle opening distance at 500/750 μm (AOD-500, -750), trabecular iris space area at 500/750 μm (TISA-500, -750), and trabecular iris angle at 500/750 μm (TIA-500, -750). Manual measurements were as follows: anteroposterior and radial SC diameter (SC-APD, SC-RD), cross-sectional area of SC (SC-CSA) and TM height (TMH), TM length (TML), and TM density (TMD). CM width was measured at 1, 2, and 3 mm from the scleral spur (CM-1, CM-2, CM-3). For each parameter, a three-level random-effects model was fitted to estimate differences between the two levels of accommodation. RESULTS: With accommodative effort, SC diameters and CSA increase significantly, as do TM length and iridocorneal angle parameters. With increasing age, SC dimensions reduce. Angle parameters are smaller in eyes with greater spherical equivalent (hypermetropia). CONCLUSIONS: AS-OCT can be used to visualize dynamic morphologic changes in outflow structures with physiologic accommodation. The increase in SC dimensions with accommodative effort may contribute to the regulation of IOP in children

Childhood lensectomy is associated with static and dynamic reduction in Schlemm canal size: a biomechanical hypothesis of post-lensectomy glaucoma

OBJECTIVE: To compare Schlemm canal (SC) and trabecular meshwork (TM) in children with healthy eyes and those with and without glaucoma after lensectomy. DESIGN: Cross-sectional observational study. PARTICIPANTS: Fifty children age 4 to 16 years with healthy eyes and 48 children post lensectomy (124 healthy and 72 post-lensectomy eyes). METHODS: /Interventions: Anterior segment optical coherence tomography (AS-OCT, Tomey Casia) of the nasal iridocorneal angle, at two levels of accommodative effort (2.5D, 15D). For each parameter and state of accommodation, a random-effects model was fitted to estimate differences between healthy eyes and eyes with history of lensectomy. MAIN OUTCOME MEASURES: Dimensions of SC and TM; conventional AS-OCT irido-corneal angle (ICA) measurements. RESULTS: The horizontal diameter of SC and its cross-sectional area (SC-CSA) are significantly smaller in post-lensectomy than in healthy eyes. Accommodative effort increases SC size in healthy, but not in post-lensectomy eyes. CONCLUSIONS: Lensectomy is associated with a reduction in SC size and a loss of physiological SC dilatation during accommodative effort, which may reflect a reduction in outflow facility and contribute to the development of post-lensectomy glaucoma

More frequent, more costly? Health economic modelling aspects of monitoring glaucoma patients in England

BACKGROUND: Chronic open angle glaucoma (COAG) is an age-related eye disease causing irreversible loss of visual field (VF). Health service delivery for COAG is challenging given the large number of diagnosed patients requiring lifelong periodic monitoring by hospital eye services. Yet frequent examination better determines disease worsening and speed of VF loss under treatment. We examine the cost-effectiveness of increasing frequency of VF examinations during follow-up using a health economic model. METHODS: Two different VF monitoring schemes defined as current practice (annual VF testing) and proposed practice (three VF tests per year in the first 2 years after diagnosis) were examined. A purpose written health economic Markov model is used to test the hypothesis that cost effectiveness improves by implementing proposed practice on groups of patients stratified by age and severity of COAG. Further, a new component of the model, estimating costs of visual impairment, was added. Results were derived from a simulated cohort of 10000 patients with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) used as main outcome measures. RESULTS: An ICER of £21,392 per QALY was derived for proposed practice improving to a value of £11,382 once savings for prevented visual impairment was added to the model. Proposed practice was more cost-effective in younger patients. Proposed practice for patients with advanced disease at diagnosis generated ICERs > £60,000 per QALY; these cases would likely be on the most intensive treatment pathway making clinical information on speed of VF loss redundant. Sensitivity analysis indicated results to be robust in relation to hypothetical willingness to pay threshold identified by national guidelines, although greatest uncertainty was allied to estimates of implementation and visual impairment costs. CONCLUSION: Increasing VF monitoring at the earliest stages of follow-up for COAG appears to be cost-effective depending on reasonable assumptions about implementation costs. Our health economic model highlights benefits of stratifying patients to more or less monitoring based on age and stage of disease at diagnosis; a prospective study is needed to prove these findings. Further, this works highlights gaps in knowledge about long term costs of visual impairment