Vision Screening in Older Adults Admitted with a Fragility Hip Fracture: A Healthcare Quality Improvement Report.

Background: This healthcare quality improvement report focussed on the effectiveness of an orthoptic-led inpatient vision screening service at Nottingham University Hospitals for older adults admitted with a fragility hip fracture. The service was developed in response to national guidance, which recommended a multifactorial assessment, including a vision assessment for older adults presenting following a fall. Method: Vision screening was carried out by orthoptists on eligible patients ≥65 years of age admitted to the trauma and orthopaedic wards with a hip fracture. Retrospective data for patients screened between 2015-2019 were analysed, including: patient demographics; screening eligibility and outcome; ophthalmology referrals made; ophthalmology appointment attendance; and outcome. Results: Of the 3321 patients admitted with a hip fracture between 2015-2019, 2033 (61%) were eligible for vision screening and 1532 (75%) of these were screened. Furthermore, 784 (51%) of the patients screened had an ocular abnormality requiring an ophthalmology referral, or a sight test at an optician. Only 144 of the 383 (38%) who required an ophthalmology referral via the GP were successfully referred, and only 107 of the 186 (58%) patients who were given appointments attended them. Additionally, 98 of 107 had pathology, with cataracts the most common finding (51%), and 61 of 98 (62%) patients had treatable vision impairment. Conclusions: We found a large proportion of fragility hip fracture patients with impaired vision, much of which was treatable and could be detected effectively with orthoptic-led bedside screening. The most common eye problem in those referred to ophthalmology was cataracts. An internal referral pathway to ophthalmology is proposed. There is a need to investigate reasons for disengagement with eye care services in this population.

A Mathematical Model of Aqueous Humor Production and Composition.

Purpose: We develop a mathematical model that predicts aqueous humor (AH) production rate by the ciliary processes and aqueous composition in the posterior chamber (PC), with the aim of estimating how the aqueous production rate depends on the controlling parameters and how it can be manipulated. Methods: We propose a compartmental mathematical model that considers the stromal region, ciliary epithelium, and PC. All domains contain an aqueous solution with different chemical species. We impose the concentration of all species on the stromal side and exploit the various ion channels present on the cell membrane to compute the water flux produced by osmosis, the solute concentrations in the AH and the transepithelial potential difference. Results: With a feasible set of parameters, the model predictions of water flux from the stroma to the PC and of the solute concentrations in the AH are in good agreement with measurements. Key parameters which impact the aqueous production rate are identified. A relevant role is predicted to be played by cell membrane permeability to \(\text{K}^+\) and \(\text{Cl}^-\), by the level of transport due to the Na+-H+ exchanger and to the co-transporter of Na+/K+/2Cl-; and by carbonic anhydrase. Conclusions: The mathematical model predicts the formation and composition of AH, based on the structure of the ciliary epithelium. The model provides insight into the physical processes underlying the functioning of drugs that are adopted to regulate the aqueous production. It also suggests ion channels and cell membrane properties that may be targeted to manipulate the aqueous production rate.

A Patient Perspective on Quality of Life with wAMD: A Podcast.

Podcast Video (MP4 420470 KB) Wet age-related macular degeneration (wAMD) is an advanced stage of AMD characterised by the rapid onset of acute vision loss. Vision loss limits daily activities, such as reading and driving, and therefore has a notable impact on quality of life. However, there is insufficient research focusing on the patient perspective on wAMD and its effect on quality of life. In this podcast article, a person with wAMD and an expert physician discuss the patient experience of wAMD diagnosis, disease progression and treatment, and the most important aspects of quality of life that should be preserved or improved. wAMD can progress extremely quickly, but diagnostic guidelines vary by region, so the words 'macular degeneration' are not heard by some patients until long after vision has been lost, if at all. The potential impact of wAMD on a person's life may never be explained, leading some people to rely on their own research. Therefore, patients may be unprepared for the subsequent effect on their lives and careers. The support of family is critical for maintaining quality of life. Working with a physician who understands an individual's communication preferences is also important for ensuring treatment adherence and maintaining good mental health; treatment for wAMD is typically administered via intravitreal injection, which may be alarming to patients who have not been informed well by healthcare professionals. Adapting to vision loss is key to maintaining quality of life, and magnification is especially useful for patients with wAMD. Furthermore, modern technology, such as smart phones and smart watches, greatly improves the accessibility of daily tasks. However, what is most important to patients is access to information about their disease-whether via an advocate, self-led research or a healthcare professional. Crucially, physicians must ensure that they speak to their patients in an informative but accessible manner.

Long-term Retinal Morphology and Functional Associations in Treated Neovascular Age-Related Macular Degeneration: Findings from the Inhibition of VEGF in Age-Related Choroidal Neovascularisation Trial.

PURPOSE: To describe the frequency of long-term morphologic features and their relationships with visual function in participants who exited the Inhibition of VEGF in Age-Related Choroidal Neovascularisation (IVAN; ISRCTN92166560) trial. DESIGN: Multicenter cohort study up to 7 years after enrollment. PARTICIPANTS: Patients enrolled in the IVAN trial, excluding participants who died or withdrew during the trial. METHODS: Multimodal fundus images, best-corrected visual acuity (BCVA), and low-luminance visual acuity (LLVA) were obtained for a subset of 199 participants who attended a research visit. Clinical sites (n = 20) also provided all visual acuity and clinical information from usual care records for 532 participants and submitted the most recent color, OCT, and other fundus images for 468 participants to a reading center. MAIN OUTCOME MEASURES: Assessed the following from the most recent images: intralesional macular atrophy (ILMA) within the footprint of the neovascular lesion; hyperreflective material (HRM); intraretinal fluid (IRF); subretinal fluid (SRF); pigment epithelial detachment (PED); and disorganized retinal outer layers (DROLs). Cross-sectional relationships between morphologic features and BCVA/LLVA were estimated. RESULTS: Intralesional macular atrophy was present in 31.8% of the study eyes at IVAN exit (mean follow-up, 1.96 years) and 89.5% at the most recent imaging visit (mean follow-up, 6.18 years). Hyperreflective material, IRF, SRF, PED, and DROLs were present in 78.8%, 47.7%, 7.6%, 94.5%, and 55% of the study eyes, respectively. In the subset with complete imaging data, in eyes without DROL, the BCVA was worst in the thinnest outer fovea tertile (thinnest minus middle and thickest tertiles, -19.7 and -19.5 letters, respectively), whereas in eyes with DROL, the BCVA was worst in the thickest (thinnest and middle tertiles minus thickest, 12.5 and 12.2, respectively). Regression models showed that the presence of ILMA and HRM was independently associated with BCVA (22 letters worse [95% confidence interval {CI}, -11.2 to -32.8; P < 0.001] and 9.8 letters worse [95% CI, -0.1 to -19.4; P = 0.047], respectively). Subretinal fluid and foveal PED were associated with better BCVA (5.9 letters [95% CI, -7.9 to 19.7; P = 0.399] and 6.4 letters [95% CI, -1.1 to 14.0; P = 0.094], respectively). The model with LLVA was similar. A sensitivity analysis involving the entire eligible cohort yielded similar estimates. CONCLUSIONS: Macular atrophy and HRM were common after 7 years of follow-up and strongly associated with visual outcomes.

Development of Macular Atrophy in Patients with Wet Age-Related Macular Degeneration Receiving Anti-VEGF Treatment.

Age-related macular degeneration (AMD) is a leading cause of blindness. Late AMD can be classified into exudative (commonly known as wet AMD [wAMD]) or dry AMD, both of which may progress to macular atrophy (MA). MA causes irreversible vision loss and currently has no approved pharmacological treatment. The standard of care for wAMD is treatment with anti-vascular endothelial growth factors (VEGFs). However, recent evidence suggests that anti-VEGF treatment may play a role in the development of MA. Therefore, it is important to identify risk factors for the development of MA in patients with wAMD. For example, excessive blockade of VEGF through intense use of anti-VEGF agents may accelerate the development of MA. Patients with type III macular neovascularization (retinal angiomatous proliferation) have a particularly high risk of MA. These patients are characterized as having a pre-existing thin choroid (age-related choroidopathy), suggesting that the choroidal circulation is unable to respond to increased VEGF expression. Evidence suggests that subretinal fluid (possibly indicative of residual VEGF activity) may play a protective role. Patients receiving anti-VEGF agents must be assessed for overall risk of MA, and there is an unmet medical need to prevent the development of MA without undertreating wAMD.

Predicting quality of life in AMD patients-insights on the new NICE classification and on a bolt-on vision dimension for the EQ-5D.

BACKGROUND/AIMS: Health-related quality of life (HRQoL) in age-related macular degeneration (AMD) is difficult to estimate as most generic tools underestimate vision. Our aim was to measure the effect of AMD on generic and visual quality of life and how it relates to handicap. We also aimed to validate the NG82 NICE AMD classification. Finally, we studied if a bolt-on visual domain increased the EQ-5D sensitivity to AMD. PATIENTS AND METHODS: Ninety-six patients with AMD participated in this observational cross-sectional study. Visual (VF-14) and generic questionnaires (EQ-5D) with VIS, and the London handicap scale (LHS) was used to quantify HRQoL and handicap. ANOVA and regression analysis were used to identify significant associations. RESULTS: Visual dysfunction in AMD has a significant effect in VF-14 (P < 0.001), LHS (p < 0.001), and EQ-5D (p = 0.015). The EQ-5D was less sensitive than the VF-14 and LHS and was not significantly correlated with the VIS bolt-on domain (p = 0.608). On the other hand, VIS was significantly associated with visual acuity (p < 0.001), AMD diagnosis (p = 0.005), VF-14 (p < 0.001), and LHS (p < 0.001). The new AMD classification was a good predictor of visual HRQoL and had an excellent association with visual acuity in the best eye. CONCLUSION: This article shows that visual impairment is associated with lower HRQoL and with an increased handicap. It also suggests that a visual dimension may increase the EQ-5D sensitivity in AMD. There was a relationship between visual impairment and handicap with the items of the new NICE AMD classification, which supports its use.

TANDEM TRIAL: a factorial randomised controlled trial of dose and review schedule of bevacizumab (Avastin) for neovascular macular degeneration in the East Midlands.

OBJECTIVE: Neovascular age-related macular degeneration (nAMD) causes damage to the macula and severe vision loss. Bevacizumab is the most cost-effective nAMD treatment. The TANDEM trial was designed to determine whether, in patients with nAMD, low-dose bevacizumab is non-inferior to the standard dose in terms of visual deterioration and whether a bimonthly regimen is non-inferior to monthly, treatment as required, regimens. METHODS: This was a multicentre, 2×2 factorial, double-masked, non-inferiority randomised trial with patients considered eligible if they met the National Institute for Health and Care Excellence criteria for nAMD treatment with ranibizumab. Participants were randomly assigned to standard (1.25 mg) or low (0.625 mg) dose bevacizumab and either monthly or bimonthly review regimen. The primary outcome was time to vision deterioration, defined as reduction of ≥15 letters (three lines) during the loading phase (visual acuity scores at visits B and C compared with the initial visit A), or ≥6 letters (one line) during the maintenance phase (visual acuity scores at subsequent visits compared with mean vision at visits A-C). RESULTS: In total 812 participants (918 eyes) were randomised into the trial. The low dose showed some evidence of being non-inferior to standard dose (HR 1.07; 95% CI 0.80 to 1.42), however, there was no strong evidence of bimonthly review being non-inferior to monthly review (HR 1.45; 95% CI 1.09 to 1.94). There was no difference in visual acuity when assessed at 9 months and no major differences in the frequency of serious adverse events or reactions between the groups. CONCLUSION: The standard dose of bevacizumab can be halved without compromising efficacy. Bimonthly review cannot be considered to be no worse than monthly review.

Fluid and solute transport across the retinal pigment epithelium: a theoretical model.

The retina is composed of two main layers-the neuroretina and the retinal pigment epithelium (RPE)-that are separated by a potential gap termed the sub-retinal space (SRS). Accumulation of fluid in the SRS may result in a retinal detachment. A key function of the RPE is to prevent fluid accumulation in the SRS by actively pumping fluid from this space to the choroid. We have developed a mathematical model of this process that incorporates the transport of seven chemical species: Na+, K+, Cl-, HCO3-, H+, CO2 and H2CO3. This allows us to estimate solute and water fluxes and to understand the role of the different membrane ion channels. We have performed a global sensitivity analysis using the extended Fourier amplitude sensitivity test to investigate the relative importance of parameters in generating the model outputs. The model predicts that flow across the RPE is driven by an osmotic gradient in the cleft gap between adjacent cells. Moreover, the model estimates how water flux is modified in response to inhibition of membrane ion channels and carbonic anhydrase (CA). It provides a possible explanation for how CA inhibitors, which are used clinically to prevent fluid accumulation in the SRS, may be acting.

Clinical investigation plan for the use of interactive binocular treatment (I-BiT) for the management of anisometropic, strabismic and mixed amblyopia in children aged 3.5-12 years: a randomised controlled trial.

BACKGROUND: Amblyopia (lazy eye) affects the vision of approximately 2% of all children. Traditional treatment consists of wearing a patch over their 'good' eye for a number of hours daily, over several months. This treatment is unpopular and compliance is often low. Therefore, results can be poor. I-BiT is a system, based on stereo technology using shutter glasses, designed to treat amblyopia using dichoptic stimulation. This trial uses a redesigned system for home use and includes eye-tracking capability. METHODS/DESIGN: This is a randomised controlled trial involving three groups of 40 patients each, aged between 3.5 and 12 years, with a diagnosis of (1) anisometropic amblyopia, (2) mixed or strabismic amblyopia prior to strabismic surgery and (3) mixed or strabismic amblyopia who have just undergone strabismus surgery. They will be randomised in a 1:1 ratio between I-BiT and control and will receive treatment, at home over a 6-week period. Their visual acuity will be assessed independently at baseline, mid-treatment (week 3), at the end of treatment (week 6) and, for those receiving the active I-BiT treatment, 4 weeks after completing treatment (week 10). The primary endpoint will be the change in visual acuity from baseline to the end of treatment. Secondary endpoints will be additional visual acuity measures, patient acceptability, compliance and the incidence of adverse events. DISCUSSION: This is a randomised controlled trial using the redesigned I-BiT™ system to determine if this is a feasible treatment strategy for the management of anisometropic, strabismic and mixed amblyopia. TRIAL REGISTRATION: ISRCTN Number/Clinical trials.gov, ID: NCT02810847 . Registered on 23 June 2016.

A theory-driven qualitative study exploring issues relating to adherence to topical glaucoma medications.

PURPOSE: Investigating patients' perceptions of their illness can provide important insights into the experience and management of the illness and associated treatment, and enhance understanding of variations in adherence to prescribed medication. The Common-Sense Model of Self-Regulation (CSM) provides a theoretical framework for the study of illness cognitions, health behavior, and adherence to health recommendations. The aim of this study was to use the CSM to investigate the experience of glaucoma and its treatment from the patients' perspective, and to apply these insights to classify and clarify issues related to nonadherence with treatment. PATIENTS AND METHODS: A qualitative investigation using semi-structured interviews took place in two outpatient glaucoma clinics. Thirty-three patients with primary open-angle glaucoma using hypotensive eye drops participated in the study. Deductive content analysis was used to analyze the interview data. RESULTS: Issues relating to nonadherence with hypotensive eye drops and patients' experience with their glaucoma and treatment were identified. Treatment schedule and patient factors were classified as common barriers to adherence. Further themes include experienced symptoms of glaucoma, illness coherence, and the emotional and practical consequences of the illness. CONCLUSION: Findings provide important insights into the emotional and practical outcomes of glaucoma for patients, perceived symptoms of the illness, and insights into patient memory and cognition. These findings provide supporting evidence for the importance of conducting theoretically driven qualitative investigations of patients' experience with glaucoma and their treatment, and provide suggestions on key issues that need to be addressed in future multidimensional interventions aimed at improving adherence and patient quality of life.

Osmotic and electroosmotic fluid transport across the retinal pigment epithelium: A mathematical model.

The retinal pigment epithelium (RPE) is the outermost cell layer of the retina. It has several important physiological functions, among which is removal of excess fluid from the sub-retinal space by pumping it isotonically towards the choroid. Failure of this pumping leads to fluid accumulation, which is closely associated with several pathological conditions, such as age-related macular degeneration, macular oedema and retinal detachment. In the present work we study mechanisms responsible for fluid transport across the RPE with the aim of understanding how fluid accumulation can be prevented. We focus on two possible mechanisms, osmosis and electroosmosis, and develop a spatially resolved mathematical model that couples fluid and ion transport across the epithelium, accounting for the presence of Na+,K+ and Cl- ions. Our model predicts spatial variability of ion concentrations and the electrical potential along the cleft gap between two adjacent cells, which osmotically drives the flow across the lateral membranes. This flow is directed from the sub-retinal space to the choroid and has a magnitude close to measured values. Electroosmosis is subdominant by three orders of magnitude to osmosis and has an opposite direction, suggesting that local osmosis is the main driving mechanism for water transport across the RPE.

Predictive Mathematical Models for the Spread and Treatment of Hyperoxia-induced Photoreceptor Degeneration in Retinitis Pigmentosa.

Purpose: To determine whether the oxygen toxicity hypothesis can explain the distinctive spatio-temporal patterns of retinal degeneration associated with human retinitis pigmentosa (RP) and to predict the effects of antioxidant and trophic factor treatments under this hypothesis. Methods: Three mathematical models were derived to describe the evolution of the retinal oxygen concentration and photoreceptor density over time. The first model considers only hyperoxia-induced degeneration, while the second and third models include mutation-induced rod and cone loss respectively. The models were formulated as systems of partial differential equations, defined on a two-dimensional domain spanning the region between the foveal center and the ora serrata, and were solved numerically using the finite element method. Results: The mathematical models recapitulate patterns of retinal degeneration which involve preferential loss of photoreceptors in the parafoveal/perifoveal and far-peripheral retina, while those which involve a preferential loss of midperipheral photoreceptors cannot be reproduced. Treatment with antioxidants or trophic factors is predicted to delay, halt, or partially reverse retinal degeneration, depending upon the strength and timing of treatment and disease severity. Conclusions: The model simulations indicate that while the oxygen toxicity hypothesis is sufficient to explain some of the patterns of retinal degeneration observed in human RP, additional mechanisms are necessary to explain the full range of behaviors. The models further suggest that antioxidant and trophic factor treatments have the potential to reduce hyperoxia-induced disease severity and that, where possible, these treatments should be targeted at retinal regions with low photoreceptor density to maximize their efficacy.

Mathematical models of retinitis pigmentosa: The oxygen toxicity hypothesis.

The group of genetically mediated diseases, known collectively as retinitis pigmentosa (RP), cause retinal degeneration and, hence, loss of vision. The most common inherited retinal degeneration, RP is currently untreatable. The retina detects light using cells known as photoreceptors, of which there are two types: rods and cones. In RP, genetic mutations cause patches of photoreceptors to degenerate and typically directly affect either rods or cones, but not both. During disease progression, degenerate patches spread and the unaffected photoreceptor type also begins to degenerate. The cause underlying these phenomena is currently unknown. The oxygen toxicity hypothesis proposes that secondary photoreceptor loss is due to hyperoxia (toxically high oxygen levels), which results from the decrease in oxygen uptake following the initial loss of photoreceptors. In this paper, we construct mathematical models, formulated as 1D systems of partial differential equations, to investigate this hypothesis. Using a combination of numerical simulations, asymptotic analysis and travelling wave analysis, we find that degeneration may spread due to hyperoxia, and generate spatio-temporal patterns of degeneration similar to those seen in vivo. We determine the conditions under which a degenerate patch will spread and show that the wave speed of degeneration is a monotone decreasing function of the local photoreceptor density. Lastly, the effects of treatment with antioxidants and trophic factors, and of capillary loss, upon the dynamics of photoreceptor loss and recovery are considered.

Use of video games for the treatment of amblyopia.

PURPOSE OF REVIEW: To review the literature up to recent for the use of videos, videogames and dichoptic stimulation as a treatment for amblyopia. RECENT FINDINGS: There have been three strategies explored. The first is to use videos and videogames monocularly with the normal eye covered. The second is dichoptic stimulation with a common background presented to both eyes and an enriched foreground to the amblyopic eye. The third are games specifically designed to generate stereopsis. Most work has focused on the second of these approaches but both of the first two approaches seem to give a similar improvement of 0.1-0.2 logMAR. One large randomized control trial (RCT) has published showing that dichoptic stimulation is not inferior to patching but no evidence that it was superior. It also showed that video games have their own compliance problems and a second smaller RCT did suggest that videogames, with a game designed by a gaming company, was superior. Most of the work done has had methodological issues and should be considered exploratory rather than definitive. SUMMARY: Dichoptic stimulation is a viable treatment option for the treatment of amblyopia. The first trial results have shown results that are not superior to patching but they are not without methodological issues. There is sufficient encouragement to justify further research in this area.

Is the frequency of adult strabismus surgery increasing?

PURPOSE: In recent years there has been an increase in evidence for the functional and psychosocial benefits of correcting strabismus/heterotropia in adults. This study aimed to establish whether there has been an associated change in the frequency of strabismus surgery performed on adults in England since 2000. METHODS: Data on strabismus surgery performed in England between 2000 and 2014 were obtained from Hospital Episode Statistics, Health and Social Care Information Centre, England. The frequency of strabismus surgery was analysed for different age groups. Data were considered in the context of total population data for England, obtained from the Office for National Statistics. RESULTS: There was little change in the total number of strabismus operations performed in 2000-2014 (1% reduction). In the same period the number of operations performed on children aged 0-15 years decreased by 17%. In contrast, there was a 24% increase in the number of strabismus operations performed on patients aged 15 years or older. CONCLUSIONS: Although strabismus surgery is still most commonly performed on children, the data show there has been a significant increase in the number of strabismus operations performed on adults. We speculate that this increase is connected to the growing weight of evidence detailing the functional and psychosocial consequences of strabismus and the benefits of correction. These results have potential implications for the delivery of future care.

Changes in intraocular pressure in study and fellow eyes in the IVAN trial.

PURPOSE: To describe changes in intraocular pressure (IOP) in the 'alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)' trial (registered as ISRCTN92166560). DESIGN: Randomised controlled clinical trial with factorial design. PARTICIPANTS: Patients (n=610) with treatment naïve neovascular age-related macular degeneration were enrolled and randomly assigned to receive either ranibizumab or bevacizumab and to two regimens, namely monthly (continuous) or as needed (discontinuous) treatment. METHODS: At monthly visits, IOP was measured preinjection in both eyes, and postinjection in the study eye. OUTCOME MEASURES: The effects of 10 prespecified covariates on preinjection IOP, change in IOP (postinjection minus preinjection) and the difference in preinjection IOP between the two eyes were examined. RESULTS: For every month in trial, there was a statistically significant rise in both the preinjection IOP and the change in IOP postinjection during the time in the trial (estimate 0.02 mm Hg, 95% CI 0.01 to 0.03, p<0.001 and 0.03 mm Hg, 95% CI 0.01 to 0.04, p=0.002, respectively). There was also a small but significant increase during the time in trial in the difference in IOP between the two eyes (estimate 0.01 mm Hg, 95% CI 0.005 to 0.02, p<0.001). There were no differences between bevacizumab and ranibizumab for any of the three outcomes (p=0.93, p=0.22 and p=0.87, respectively). CONCLUSIONS: Anti-vascular endothelial growth factor agents induce increases in IOP of small and uncertain clinical significance. TRIAL REGISTRATION NUMBER: ISRCTN92166560.

Mathematical and computational models of the retina in health, development and disease.

The retina confers upon us the gift of vision, enabling us to perceive the world in a manner unparalleled by any other tissue. Experimental and clinical studies have provided great insight into the physiology and biochemistry of the retina; however, there are questions which cannot be answered using these methods alone. Mathematical and computational techniques can provide complementary insight into this inherently complex and nonlinear system. They allow us to characterise and predict the behaviour of the retina, as well as to test hypotheses which are experimentally intractable. In this review, we survey some of the key theoretical models of the retina in the healthy, developmental and diseased states. The main insights derived from each of these modelling studies are highlighted, as are model predictions which have yet to be tested, and data which need to be gathered to inform future modelling work. Possible directions for future research are also discussed. Whilst the present modelling studies have achieved great success in unravelling the workings of the retina, they have yet to achieve their full potential. For this to happen, greater involvement with the modelling community is required, and stronger collaborations forged between experimentalists, clinicians and theoreticians. It is hoped that, in addition to bringing the fruits of current modelling studies to the attention of the ophthalmological community, this review will encourage many such future collaborations.