A large animal model of RDH5-associated retinopathy recapitulates important features of the human phenotype.

Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5-/- mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.542G > T; p.Gly181Val). As with patients, affected cats have a marked delay in recovery of dark adaptation. In addition, the cats develop a degeneration of the area centralis (equivalent to the human macula). This recapitulates the development of macular atrophy that is reported in a subset of patients with RDH5 mutations and is shown in this paper in seven patients with biallelic RDH5 mutations. There is notable variability in the age at onset of the area centralis changes in the cat, with most developing changes as juveniles but some not showing changes over the first few years of age. There is similar variability in development of macular atrophy in patients and while age is a risk factor, it is hypothesized that genetic modifying loci influence disease severity, and we suspect the same is true in the cat model. This novel cat model provides opportunities to improve molecular understanding of macular atrophy and test therapeutic interventions for RDH5-associated retinopathies.

Optogenetic approaches to therapy for inherited retinal degenerations.

Inherited retinal degenerations such as retinitis pigmentosa (RP) affect around one in 4000 people and are the leading cause of blindness in working age adults in several countries. In these typically monogenic conditions, there is progressive degeneration of photoreceptors; however, inner retinal neurons such as bipolar cells and ganglion cells remain largely structurally intact, even in end-stage disease. Therapeutic approaches aiming to stimulate these residual cells, independent of the underlying genetic cause, could potentially restore visual function in patients with advanced vision loss, and benefit many more patients than therapies directed at the specific gene implicated in each disorder. One approach investigated for this purpose is that of optogenetics, a method of neuromodulation that utilises light to activate neurons engineered to ectopically express a light-sensitive protein. Using gene therapy via adeno-associated viral vectors, a range of photosensitive proteins have been expressed in remaining retinal cells in advanced retinal degeneration with in vivo studies demonstrating restoration of visual function. Developing an effective optogenetic strategy requires consideration of multiple factors, including the light-sensitive protein that is used, the vector and method for gene delivery, and the target cell for expression because these in turn may affect the quality of vision that can be restored. Currently, at least four clinical trials are ongoing to investigate optogenetic therapies in patients, with the ultimate aim of reversing visual loss in end-stage disease.

Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy.

Optogenetic strategies to restore vision in patients who are blind from end-stage retinal degenerations aim to render remaining retinal cells light sensitive once photoreceptors are lost. Here, we assessed long-term functional outcomes following subretinal delivery of the human melanopsin gene (OPN4) in the rd1 mouse model of retinal degeneration using an adeno-associated viral vector. Ectopic expression of OPN4 using a ubiquitous promoter resulted in cellular depolarization and ganglion cell action potential firing. Restoration of the pupil light reflex, behavioral light avoidance, and the ability to perform a task requiring basic image recognition were restored up to 13 mo following injection. These data suggest that melanopsin gene therapy via a subretinal route may be a viable and stable therapeutic option for the treatment of end-stage retinal degeneration in humans.

Single residue AAV capsid mutation improves transduction of photoreceptors in the Abca4-/- mouse and bipolar cells in the rd1 mouse and human retina ex vivo.

Gene therapy using adeno-associated viral (AAV) vectors for the treatment of retinal degenerations has shown safety and efficacy in clinical trials. However, very high levels of vector expression may be necessary for the treatment of conditions such as Stargardt disease where a dual vector approach is potentially needed, or in optogenetic strategies for end-stage degeneration in order to achieve maximal light sensitivity. In this study, we assessed two vectors with single capsid mutations, rAAV2/2(Y444F) and rAAV2/8(Y733F) in their ability to transduce retina in the Abca4-/- and rd1 mouse models of retinal degeneration. We noted significantly increased photoreceptor transduction using rAAV2/8(Y733F) in the Abca4-/- mouse, in contrast to previous work where vectors tested in this model have shown low levels of photoreceptor transduction. Bipolar cell transduction was achieved following subretinal delivery of both vectors in the rd1 mouse, and via intravitreal delivery of rAAV2/2(Y444F). The successful use of rAAV2/8(Y733F) to target bipolar cells was further validated on human tissue using an ex vivo culture system of retinal explants. Capsid mutant AAV vectors transduce human retinal cells and may be particularly suited to treat retinal degenerations in which high levels of transgene expression are required.

Multifocal versus monofocal intraocular lenses after cataract extraction.

BACKGROUND: Good unaided distance visual acuity (VA) is now a realistic expectation following cataract surgery and intraocular lens (IOL) implantation. Near vision, however, still requires additional refractive power, usually in the form of reading glasses. Multiple optic (multifocal) IOLs are available which claim to allow good vision at a range of distances. It is unclear whether this benefit outweighs the optical compromises inherent in multifocal IOLs. OBJECTIVES: To assess the visual effects of multifocal IOLs in comparison with the current standard treatment of monofocal lens implantation. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016. SELECTION CRITERIA: All randomised controlled trials comparing a multifocal IOL of any type with a monofocal IOL as control were included. Both unilateral and bilateral implantation trials were included. We also considered trials comparing multifocal IOLs with "monovision" whereby one eye is corrected for distance vision and one eye corrected for near vision. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed the 'certainty' of the evidence using GRADE. MAIN RESULTS: We found 20 eligible trials that enrolled 2230 people with data available on 2061 people (3194 eyes). These trials were conducted in Europe (13), China (three), USA (one), Middle East (one), India (one) and one multicentre study in Europe and the USA. Most of these trials compared multifocal with monofocal lenses; two trials compared multifocal lenses with monovision. There was considerable variety in the make and model of lenses implanted. Overall we considered the trials at risk of performance and detection bias because it was difficult to mask participants and outcome assessors. It was also difficult to assess the role of reporting bias.There was moderate-certainty evidence that the distance acuity achieved with multifocal lenses was not different to that achieved with monofocal lenses (unaided VA worse than 6/6: pooled RR 0.96, 95% confidence interval (CI) 0.89 to 1.03; eyes = 682; studies = 8). People receiving multifocal lenses may achieve better near vision (RR for unaided near VA worse than J3/J4 was 0.20, 95% CI 0.07 to 0.58; eyes = 782; studies = 8). We judged this to be low-certainty evidence because of risk of bias in the included studies and high heterogeneity (I2 = 93%) although all included studies favoured multifocal lenses with respect to this outcome.People receiving multifocal lenses may be less spectacle dependent (RR 0.63, 95% CI 0.55 to 0.73; eyes = 1000; studies = 10). We judged this to be low-certainty evidence because of risk of bias and evidence of publication bias (skewed funnel plot). There was also high heterogeneity (I2 = 67%) but all studies favoured multifocal lenses. We did not additionally downgrade for this.Adverse subjective visual phenomena were more prevalent and more troublesome in participants with a multifocal IOL compared with monofocals (RR for glare 1.41, 95% CI 1.03 to 1.93; eyes = 544; studies = 7, low-certainty evidence and RR for haloes 3.58, 95% CI 1.99 to 6.46; eyes = 662; studies = 7; moderate-certainty evidence).Two studies compared multifocal lenses with monovision. There was no evidence for any important differences in distance VA between the groups (mean difference (MD) 0.02 logMAR, 95% CI -0.02 to 0.06; eyes = 186; studies = 1), unaided intermediate VA (MD 0.07 logMAR, 95% CI 0.04 to 0.10; eyes = 181; studies = 1) and unaided near VA (MD -0.04, 95% CI -0.08 to 0.00; eyes = 186; studies = 1) compared with people receiving monovision. People receiving multifocal lenses were less likely to be spectacle dependent (RR 0.40, 95% CI 0.30 to 0.53; eyes = 262; studies = 2) but more likely to report problems with glare (RR 1.41, 95% CI 1.14 to 1.73; eyes = 187; studies = 1) compared with people receiving monovision. In one study, the investigators noted that more people in the multifocal group underwent IOL exchange in the first year after surgery (6 participants with multifocal vs 0 participants with monovision). AUTHORS' CONCLUSIONS: Multifocal IOLs are effective at improving near vision relative to monofocal IOLs although there is uncertainty as to the size of the effect. Whether that improvement outweighs the adverse effects of multifocal IOLs, such as glare and haloes, will vary between people. Motivation to achieve spectacle independence is likely to be the deciding factor.

Phacoemulsification with posterior chamber intraocular lens versus extracapsular cataract extraction (ECCE) with posterior chamber intraocular lens for age-related cataract.

BACKGROUND: Age-related cataract is one of the leading causes of blindness worldwide. Therefore, it is important to establish the most effective surgical technique for cataract surgery. OBJECTIVES: The aim of this review is to examine the effects of two types of cataract surgery for age-related cataract: phacoemulsification and extracapsular cataract extraction (ECCE). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2013), EMBASE (January 1980 to May 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to May 2013), Web of Science Conference Proceedings Citation Index - Science (CPCI-S) (January 1970 to May 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 May 2013. SELECTION CRITERIA: We included randomised controlled trials of phacoemulsification compared to ECCE for age-related cataract. DATA COLLECTION AND ANALYSIS: Two authors independently selected and assessed all studies. We defined two primary outcomes: 'good functional vision' (presenting visual acuity of 6/12 or better) and 'poor visual outcome' (best corrected visual acuity of less than 6/60) at three and 12 months after surgery. We also collected data on intra and postoperative complications, and the cost of the procedures. MAIN RESULTS: We included 11 trials in this review with a total of 1228 participants, ranging from age 45 to 94. The studies were generally at unclear risk of bias due to poorly reported trial methods. No study reported presenting visual acuity, so we report both uncorrected (UCVA) and best corrected visual acuity (BCVA). Studies varied in visual acuity assessment methods and time frames at which outcomes were reported. Participants in the phacoemulsification group were more likely to achieve UCVA of 6/12 or more at three months (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.36 to 2.41, two studies, 492 participants) and one year (RR 1.99, 95% CI 1.45 to 2.73, one study, 439 participants). People in the phacoemulsification group were also more likely to achieve BCVA of 6/12 or more at three months (RR 1.12, 95% CI 1.03 to 1.22, four studies, 645 participants) and one year (RR 1.06, 95% CI 0.99 to 1.14, one study, 439 participants), but the difference between the two groups was smaller. No trials reported BCVA less than 6/60 but three trials reported BCVA worse than 6/9 and 6/18: there were fewer events of this outcome in the phacoemulsification group than the ECCE group at both the three-month (RR 0.33, 95% CI 0.20 to 0.55, three studies, 604 participants) and 12-month time points (RR 0.62, 95% CI 0.36 to 1.05, one study, 439 participants). Three trials reported posterior capsule rupture: this occurred more commonly in the ECCE group than the phacoemulsification group but small numbers of events mean the true effect is uncertain (Peto odds ratio (OR) 0.56, 95% CI 0.26 to 1.22, three studies, 688 participants). Iris prolapse, cystoid macular oedema and posterior capsular opacification were also higher in the ECCE group than the phacoemulsification group. Phacoemulsification surgical costs were higher than ECCE in two studies. A third study reported similar costs for phacoemulsification and ECCE up to six weeks postoperatively, but following this time point ECCE incurred additional costs due to additional visits, spectacles and laser treatment to achieve a similar outcome. AUTHORS' CONCLUSIONS: Removing cataract by phacoemulsification may result in a better visual acuity compared to ECCE, with a lower complication rate. The review is currently underpowered to detect differences for rarer outcomes, including poor visual outcome. The lower cost of ECCE may justify its use in a patient population where high-volume surgery is a priority, however, there are a lack of data comparing phacoemulsification and ECCE in lower-income settings.

Intravitreal anti-vascular endothelial growth factor injections in pregnancy and breastfeeding: a case series and systematic review of the literature.

INTRODUCTION: Anti-vascular endothelial growth factor (anti-VEGF) agents may occasionally need to be considered for sight-threatening macular pathology in pregnant and breastfeeding women. This is controversial due to the dearth of data on systemic side effects for mother and child. We aimed to expand the evidence base to inform management. METHODS: Retrospective case series of pregnant and breastfeeding women treated with intravitreal anti-VEGF injections at Oxford Eye Hospital between January 2015 and December 2022. In addition, we conducted a systematic review and combined eligible cases in a narrative synthesis. RESULTS: We treated six pregnant women with anti-VEGF for diabetic macular oedema(DMO) (n = 5) or choroidal neovascularisation (CNV) (n = 1). Four received ranibizumab whilst two (not known to be pregnant) received aflibercept. Patients known to be pregnant underwent counselling by an obstetric physician. Five pregnancies resulted in live births. Combining our cases with those previously published, treatment of 41 pregnant women (42 pregnancies) are reported. Indications for treatment included CNV (n = 28/41,68%), DMO (n = 7/41,17%) and proliferative diabetic retinopathy (n = 6/41,15%). Bevacizumab (n = 22/41,54%) and ranibizumab (n = 17/41,41%) were given more frequently than aflibercept (n = 2/41,5%). Many (n = 16/41,40%) were unaware of their pregnancy when treated. Most pregnancies resulted in live births (n = 34/42,81%). First trimester miscarriages (n = 5/42,12%) and stillbirths (n = 3/42,7%) mostly occurred in women with significant risk factors. CONCLUSION: Intravitreal anti-VEGF injections may not necessarily compromise obstetric outcomes, although clear associations cannot be drawn due to small numbers and confounders from high rates of first trimester miscarriages in general and inherently high-risk pregnancies. It may be worth considering routinely investigating pregnancy and breastfeeding status in women of childbearing age prior to each injection, as part of anti-VEGF treatment protocols.

IMPG2-Related Maculopathy.

PURPOSE: To investigate the phenotype, variability, and penetrance of IMPG2-related maculopathy. DESIGN: Retrospective observational case series. METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling. RESULTS: A total of 25 individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. A distinct maculopathy was present in 17 individuals (median age, 52 years; range, 20-72 years), and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best-corrected visual acuity (BCVA) was ≥20/50 in the better eye (n = 15), and 5 patients were asymptomatic. Longitudinal observation (n = 8, up to 19 years) demonstrated stable maculopathy (n = 3), partial/complete resorption (n = 4) or increase (n = 1) of the subretinal material, with overall stable vision (n = 6). No manifest maculopathy was observed in 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥20/25), all were identified through segregation analysis. All 8 individuals were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. A total of 18 different variants were detected, 11 of them truncating. Molecular modeling of 5 missense variants [c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C, and c.3193G>A] supported the hypothesis that these have a loss-of-function effect. CONCLUSIONS: Mono-allelic IMPG2 variants may result in haploinsufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.

Quantification of Fundus Autofluorescence Features in a Molecularly Characterized Cohort of More Than 3000 Inherited Retinal Disease Patients from the United Kingdom.

Purpose: To quantify relevant fundus autofluorescence (FAF) image features cross-sectionally and longitudinally in a large cohort of inherited retinal diseases (IRDs) patients. Design: Retrospective study of imaging data (55-degree blue-FAF on Heidelberg Spectralis) from patients. Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone FAF 55-degree imaging at Moorfields Eye Hospital (MEH) and the Royal Liverpool Hospital (RLH) between 2004 and 2019. Methods: Five FAF features of interest were defined: vessels, optic disc, perimacular ring of increased signal (ring), relative hypo-autofluorescence (hypo-AF) and hyper-autofluorescence (hyper-AF). Features were manually annotated by six graders in a subset of patients based on a defined grading protocol to produce segmentation masks to train an AI model, AIRDetect, which was then applied to the entire imaging dataset. Main Outcome Measures: Quantitative FAF imaging features including area in mm 2 and vessel metrics, were analysed cross-sectionally by gene and age, and longitudinally to determine rate of progression. AIRDetect feature segmentation and detection were validated with Dice score and precision/recall, respectively. Results: A total of 45,749 FAF images from 3,606 IRD patients from MEH covering 170 genes were automatically segmented using AIRDetect. Model-grader Dice scores for disc, hypo-AF, hyper-AF, ring and vessels were respectively 0.86, 0.72, 0.69, 0.68 and 0.65. The five genes with the largest hypo-AF areas were CHM , ABCC6 , ABCA4 , RDH12 , and RPE65 , with mean per-patient areas of 41.5, 30.0, 21.9, 21.4, and 15.1 mm 2 . The five genes with the largest hyper-AF areas were BEST1 , CDH23 , RDH12 , MYO7A , and NR2E3 , with mean areas of 0.49, 0.45, 0.44, 0.39, and 0.34 mm 2 respectively. The five genes with largest ring areas were CDH23 , NR2E3 , CRX , EYS and MYO7A, with mean areas of 3.63, 3.32, 2.84, 2.39, and 2.16 mm 2 . Vessel density was found to be highest in EFEMP1 , BEST1 , TIMP3 , RS1 , and PRPH2 (10.6%, 10.3%, 9.8%, 9.7%, 8.9%) and was lower in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis genes. Longitudinal analysis of decreasing ring area in four RP genes ( RPGR, USH2A, RHO, EYS ) found EYS to be the fastest progressor at -0.18 mm 2 /year. Conclusions: We have conducted the first large-scale cross-sectional and longitudinal quantitative analysis of FAF features across a diverse range of IRDs using a novel AI approach.

Manual small incision cataract surgery (MSICS) with posterior chamber intraocular lens versus phacoemulsification with posterior chamber intraocular lens for age-related cataract.

BACKGROUND: Age-related cataract is a major cause of blindness and visual morbidity worldwide. It is therefore important to establish the optimal technique of lens removal in cataract surgery. OBJECTIVES: To compare manual small incision cataract surgery (MSICS) and phacoemulsification techniques. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2013), EMBASE (January 1980 to July 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to July 2013), Web of Science Conference Proceedings Citation Index - Science (CPCI-S) (January 1970 to July 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 23 July 2013. SELECTION CRITERIA: We included randomised controlled trials (RCTs) for age-related cataract that compared MSICS and phacoemulsification. DATA COLLECTION AND ANALYSIS: Two authors independently assessed all studies. We defined two primary outcomes: 'good functional vision' (presenting visual acuity of 6/12 or better) and 'poor visual outcome' (best corrected visual acuity of less than 6/60). We collected data on these outcomes at three and 12 months after surgery. Complications such as posterior capsule rupture rates and other intra- and postoperative complications were also assessed. In addition, we examined cost effectiveness of the two techniques. Where appropriate, we pooled data using a random-effects model. MAIN RESULTS: We included eight trials in this review with a total of 1708 participants. Trials were conducted in India, Nepal and South Africa. Follow-up ranged from one day to six months, but most trials reported at six to eight weeks after surgery. Overall the trials were judged to be at risk of bias due to unclear reporting of masking and follow-up. No studies reported presenting visual acuity so data were collected on both best-corrected (BCVA) and uncorrected (UCVA) visual acuity. Most studies reported visual acuity of 6/18 or better (rather than 6/12 or better) so this was used as an indicator of good functional vision. Seven studies (1223 participants) reported BCVA of 6/18 or better at six to eight weeks (pooled risk ratio (RR) 0.99 95% confidence interval (CI) 0.98 to 1.01) indicating no difference between the MSICS and phacoemulsification groups. Three studies (767 participants) reported UCVA of 6/18 or better at six to eight weeks, with a pooled RR indicating a more favourable outcome with phacoemulsification (0.90, 95% CI 0.84 to 0.96). One trial (96 participants) reported UCVA at six months with a RR of 1.07 (95% CI 0.91 to 1.26).Regarding BCVA of less than 6/60: there were only 11/1223 events reported. The pooled Peto odds ratio was 2.48 indicating a more favourable outcome using phacoemulsification but with wide confidence intervals (0.74 to 8.28) which means that we are uncertain as to the true effect.The number of complications reported were also low for both techniques. Again this means the review is underpowered to detect a difference between the two techniques with respect to these complications. One study reported on cost which was more than four times higher using phacoemulsification than MSICS. AUTHORS' CONCLUSIONS: On the basis of this review, removing cataract by phacoemulsification may result in better UCVA in the short term (up to three months after surgery) compared to MSICS, but similar BCVA. There is a lack of data on long-term visual outcome. The review is currently underpowered to detect differences for rarer outcomes, including poor visual outcome. In view of the lower cost of MSICS, this may be a favourable technique in the patient populations examined in these studies, where high volume surgery is a priority. Further studies are required with longer-term follow-up to better assess visual outcomes and complications which may develop over time such as posterior capsule opacification.

There is a trend for the diagnosis of glaucoma to be made at an earlier stage in 2010 compared to 2008 in Oxford, United Kingdom.

PURPOSE: New guidelines on glaucoma diagnosis and management were published by the National Institute of Clinical Excellence (NICE) in 2009. The aim of this study was to determine whether these guidelines on glaucoma referral have changed the numbers of patients diagnosed with glaucoma in Oxford and whether the severity of disease at presentation has altered between 2008 and 2010. METHODS: A retrospective study was undertaken of patients referred to a glaucoma case-finding clinic at the Oxford Eye Hospital in 2008 and 2010. Severity of glaucoma was assigned on the basis of the worse eye and defined according to mean deviation (MD) on 24-2 Humphrey visual field testing, with early glaucomatous visual field defects defined as MD less than -6 dB, moderate defects as MD between -6 and -12 dB and severe defects as MD more than -12 dB. Statistical analysis was undertaken using Chi squared and Mann Whitney tests. RESULTS: The number of referrals to this clinic increased from 521 patients in 2008, to 895 patients in 2010. 85 (16.3%) patients were diagnosed with ocular hypertension in 2008, compared to 144 (16.1%) in 2010. The number of patients diagnosed with glaucoma increased from 94 cases in 2008 to 113 cases in 2010, although the percentage of referrals diagnosed with glaucoma fell from 18.1% to 12.6%. More patients diagnosed with glaucoma in 2010 had early disease (61.9% in 2010 vs 48.8% in 2008, p = 0.03). Patients found to have glaucoma in 2010 had less severe visual field defects than in 2008: patients presented with a lower mean deviation (-6.36 dB in 2010, -7.95 dB in 2008, p = 0.03) and lower pattern standard deviation (5.44 dB in 2010, 6.64 dB in 2008, p = 0.02). However, there was no significant difference between age of presentation (65.1 years in 2010, 65.2 years in 2008, p = 0.82), and IOP (21.62 mmHg in 2010, 23.15 mmHg in 2008, p = 0.22). CONCLUSIONS: There has been a significant increase in number of referrals to the glaucoma case-finding clinic in Oxford between 2008 and 2010. The introduction of NICE referral guidelines in 2009 has had the benefit of increasing the absolute number of patients detected with glaucoma and has resulted in more patients being diagnosed with early disease. More effort needs to be made to reduce the number of false positive referrals. In addition, the guidelines on referral of individuals with ocular hypertension need to be reconsidered.

Sudden Gross Visual Deterioration: Importance of Examining the Whole Eye.

A 75-year-old caucasian female presented with sudden severe visual deterioration in one eye reduced from 6/9 to counting fingers (CF), with second eye reduction in vision from 6/9 to CF three months later. Past medical history included a background of proliferative diabetic retinopathy, uncontrolled blood pressure, and a 44-year history of poorly controlled type 1 diabetes mellitus (T1DM). Previous ocular history included bilateral pan-retinal photocoagulation for proliferative diabetic retinopathy, followed by bilateral vitrectomies, with subsequent bilateral cataract surgery with intraocular lens implants. A diagnosis of anterior ischemic optic neuropathy (AION) was thought to be the most likely diagnosis due to sudden visual loss, pale discs, and previous long-term history of diabetes and blood pressure with variable control in the absence of a raised erythrocyte sedimentation rate (ESR). However, at the time of the second eye visual loss, the inferior peripheral retina examination revealed bilateral pseudophakic intraocular lens dislocations. With spectacle correction of +11.50/-1.00 x 75 right eye and +11.50/-1.00 x 65 left eye, her visual acuities were 6/12 right eye and 6/9 left eye, and subsequent secondary intraocular lens insertion was planned. This case highlights the importance of a careful review of the whole eye to ensure that remediable causes of visual loss are not missed.

Vitreous Haemorrhage and Retinal Neovascularization Secondary to Peripheral Retinal Ischemia as the Presenting Sign of a Disseminated Melanoma.

PURPOSE: We describe a case of vitreous haemorrhage and retinal neovascularization secondary to peripheral retinal ischemia associated with disseminated melanoma. METHODS: A retrospective case report. RESULTS: A 48-year-old man presented with vitreous haemorrhage in the right eye, peripheral retinal ischemia, and retinal neovascularization in both eyes. CT and MRI scans were suggestive of disseminated malignancy and an ultrasound-guided biopsy of the abdominal mass confirmed metastatic melanoma. Immune checkpoint inhibitor therapy with ipilimumab/nivolumab was initiated. Regarding his ocular status, the vitreous haemorrhage cleared spontaneously, visual acuity improved to 6/7.5 and the patient underwent bilateral peripheral scatter laser photocoagulation to stabilize the retinopathy. The patient passed away 1 year after the initial presentation. CONCLUSION:  Our patient presented with melanoma and peripheral retinal ischaemia, leading to retinal neovascularization and vitreous haemorrhage. Therefore, melanoma should be considered as a differential diagnosis when investigating the aetiology of peripheral retinal ischaemia.

The Role of Inflammation in Age-Related Macular Degeneration-Therapeutic Landscapes in Geographic Atrophy.

Age-related macular degeneration (AMD) is the leading cause of vision loss and visual impairment in people over 50 years of age. In the current therapeutic landscape, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have been central to the management of neovascular AMD (also known as wet AMD), whereas treatments for geographic atrophy have lagged behind. Several therapeutic approaches are being developed for geographic atrophy with the goal of either slowing down disease progression or reversing sight loss. Such strategies target the inflammatory pathways, complement cascade, visual cycle or neuroprotective mechanisms to slow down the degeneration. In addition, retinal implants have been tried for vision restoration and stem cell therapies for potentially a dual purpose of slowing down the degeneration and restoring visual function. In particular, therapies focusing on the complement pathway have shown promising results with the FDA approved pegcetacoplan, a complement C3 inhibitor, and avacincaptad pegol, a complement C5 inhibitor. In this review, we discuss the mechanisms of inflammation in AMD and outline the therapeutic landscapes of atrophy AMD. Improved understanding of the various pathway components and their interplay in this complex neuroinflammatory degeneration will guide the development of current and future therapeutic options, such as optogenetic therapy.

CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History.

PURPOSE: To analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date. DESIGN: Multicenter retrospective cohort study. SUBJECTS: Forty-seven patients (37 families) with likely disease-causing CERKL variants. METHODS: Review of clinical notes, ophthalmic images, and molecular diagnosis from 2 international centers. MAIN OUTCOME MEASURES: Visual function, retinal imaging, and characteristics were evaluated and correlated. RESULTS: The mean age at the first visit was 29.6 ± 13.9 years, and the mean follow-up time was 9.1 ± 7.4 years. The most frequent initial symptom was central vision loss (40%), and the most common retinal feature was well-demarcated areas of macular atrophy (57%). Seventy-seven percent of the participants had double-null genotypes, and 64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern. Patients without double-null genotypes tended to have fewer pigment deposits and included a higher proportion of older patients with a relatively mild electrophysiological phenotype. Longitudinal analysis showed that over half of the cohort lost 15 ETDRS letters or more in ≥ 1 eye during the first 5 years of follow-up. CONCLUSIONS: The phenotype of CERKL-retinal dystrophy is broad, encompassing isolated macular disease to severe retina-wide involvement, with a range of functional phenotypes, generally not fitting in the rod-cone/cone-rod dichotomy. Disease onset is often earlier, with more severe retinal degenerative changes and photoreceptor dysfunction, in nullizygous cases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Choroidal macrovessels: multimodal imaging findings and review of the literature.

BACKGROUND/AIMS: To describe clinical and multimodal imaging features in a cohort of choroidal macrovessels. METHODS: Demographics and multimodal imaging features of 16 eyes of 13 patients with choroidal macrovessels were reviewed. The multimodal imaging included colour fundus photography, fundus autofluorescence (FAF), spectral domain enhanced depth imaging optical coherence tomography (OCT), en face OCT, OCT-angiography (OCT-A), B-scan ultrasonography (US), fluorescein angiography (FFA) and indocyanine green angiography (ICGA). RESULTS: Three patients had bilateral involvement. On colour fundus photography, three patterns were evident (a clearly visible orange-red vessel; a track of pigmentary changes; spots of mild pigmentary changes). Vessel orientation was horizontal (11 eyes), oblique (4 eyes) or vertical (1 eye). In 2 eyes, the vessel was extra-macular. OCT in all cases showed a hyporeflective choroidal area with posterior shadowing and elevation of the overlying retina. Subretinal fluid was present in 4 eyes. FAF (12 eyes) was normal (7 eyes) or showed a hypofluorescent/hyperfluorescent track (4 eyes) or linear hyperautofluorescence (1 eye). En-face OCT (2 eyes) revealed the course of the macrovessel at the level of choroid and choriocapillaris. On OCT-A (2 eyes) the vessel had a reflectivity similar to surrounding vessels but larger diameter. B-scan US (8 eyes) showed a nodular hypoechogenic lesion. FFA (5 eyes) showed early focal hyperfluorescence (4 eyes) not increasing in later phases, or was normal (1 eye). ICGA (6 eyes) showed early hyperfluorescence of the vessel. CONCLUSIONS: Choroidal macrovessels can mimic other entities, leading to underdiagnosis. Appreciating relevant features on different imaging modalities will aid a correct diagnosis.

The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.

Outcomes in randomised controlled trials of multifocal lenses in cataract surgery: the case for development of a core outcome set.

BACKGROUND/AIMS: To describe and summarise the outcomes reported in randomised controlled trials of multifocal versus monofocal intraocular lenses in cataract surgery. METHODS: We identified all randomised controlled trials of multifocal versus monofocal lenses in a Cochrane review (last search date June 2016). We extracted and summarised data on all outcomes reported using the framework of domain, measurement, metric and method of aggregation. RESULTS: All studies collected data on distance and near visual acuity but there was considerable variation in the measures used and whether these outcomes were unaided or best corrected. Most studies reported final value measurements, rather than change from baseline. Approximately half of the studies reported data as a continuous measure only, one-third reported both continuous and categorical measures and a minority reported categorical measures only. There was little consensus as to cut-points. Although a majority of studies included one or more patient-reported outcome measures, none of the studies reported patient involvement in the choice of outcomes. CONCLUSION: The collection and analysis of data on outcome measures in studies of multifocal intraocular lenses in cataract surgery are complicated. As a result, there is considerable heterogeneity in collection and reporting in the medical literature. This makes it difficult to synthesise such data to provide robust estimates of effect and is a potential source of research waste. Investigators in this field must produce a core outcome set that is informed by patients' views and we propose an initial set of outcomes on which these could be based.

Genetic Counseling For Predictive Retinal Imaging.

This Viewpoint discusses genetic counseling for predictive retinal imaging.