Showing papers by "Moorfields Eye Hospital published in 2018"

Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration.

Abstract: Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD.

Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials.

Abstract: Importance Geographic atrophy (GA) secondary to age-related macular degeneration is a leading cause of visual disability in older individuals. A phase 2 trial suggested that lampalizumab, a selective complement factor D inhibitor, reduced the rate of GA enlargement, warranting phase 3 trials. Objective To assess the safety and efficacy of lampalizumab vs sham procedure on enlargement of GA. Design, Setting, and Participants Two identically designed phase 3 double-masked, randomized, sham-controlled clinical trials, Chroma and Spectri, enrolled participants from August 28, 2014, to October 6, 2016, at 275 sites in 23 countries. Participants were aged 50 years or older, with bilateral GA and no prior or active choroidal neovascularization in either eye and GA lesions in the study eye measuring 2.54 to 17.78 mm 2 with diffuse or banded fundus autofluorescence patterns. Interventions Participants were randomized 2:1:2:1 to receive 10 mg of intravitreous lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks, through 96 weeks. Main Outcomes and Measures Safety and efficacy assessed as mean change from baseline in GA lesion area at week 48 from centrally read fundus autofluorescence images of the lampalizumab arms vs pooled sham arms, in the intent-to-treat population and by complement factor I–profile genetic biomarker. Results A total of 906 participants (553 women and 353 men; mean [SD] age, 78.1 [8.1] years) were enrolled in Chroma and 975 participants (578 women and 397 men; mean [SD] age, 77.9 [8.1] years) were enrolled in Spectri; 1733 of the 1881 participants (92.1%) completed the studies through 48 weeks. The adjusted mean increases in GA lesion area from baseline at week 48 were 1.93 to 2.09 mm 2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were −0.02 mm 2 (95% CI, −0.21 to 0.16 mm 2 ; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm 2 (95% CI, 0.00-0.31 mm 2 ; P = .048) for lampalizumab every 4 weeks in Spectri, 0.05 mm 2 (95% CI, −0.13 to 0.24 mm 2 ; P = .59) for lampalizumab every 6 weeks in Chroma, and 0.09 mm 2 (95% CI, −0.07 to 0.24 mm 2 ; P = .27) for lampalizumab every 6 weeks in Spectri. No benefit of lampalizumab was observed across prespecified subgroups, including by complement factor I–profile biomarker. Endophthalmitis occurred after 5 of 12 447 injections (0.04%) or in 5 of 1252 treated participants (0.4%) through week 48. Conclusions and Relevance In Chroma and Spectri, the largest studies of GA conducted to date, lampalizumab did not reduce GA enlargement vs sham during 48 weeks of treatment. Results highlight the substantial and consistent enlargement of GA, at a mean of approximately 2 mm 2 per year. Trial Registration ClinicalTrials.gov Identifier:NCT02247479andNCT02247531

ISCEV guide to visual electrodiagnostic procedures.

Abstract: Clinical electrophysiological testing of the visual system incorporates a range of noninvasive tests and provides an objective indication of function relating to different locations and cell types within the visual system. This document developed by the International Society for Clinical Electrophysiology of Vision provides an introduction to standard visual electrodiagnostic procedures in widespread use including the full-field electroretinogram (ERG), the pattern electroretinogram (pattern ERG or PERG), the multifocal electroretinogram (multifocal ERG or mfERG), the electrooculogram (EOG) and the cortical-derived visual evoked potential (VEP). The guideline outlines the basic principles of testing. Common clinical presentations and symptoms are described with illustrative examples and suggested investigation strategies.

The management of retinoblastoma.

Abstract: Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood, but an uncommon paediatric cancer, with a constant incidence worldwide of 1:15,000-1:20,000 live births. Despite its rarity, Rb has served as a cornerstone in the field of oncology in many of the aspects that comprise cancer management, including classification schemes, treatment modalities, genetic testing and screening. Until just over half a century ago, the major treatment for Rb was eye removal, and prognosis was poor with outcome fatal for most children. The dramatic evolution, in a short period of time across all fields of Rb management, as well as the development of specialized centres, better infrastructure and introduction of awareness campaigns, has resulted in nearly 100% survival in developed countries and allowed eye salvage in many of the cases. External beam radiotherapy was used as the main treatment choice for four decades, but replaced by chemotherapy at the turn of the century. Initially, and still in many centres, chemotherapy is administered intravenously, but recently is targeted directly into the eye by means of intra-ophthalmic artery and intravitreal chemotherapy. To date, a range of treatments is available to the Rb expert, including enucleation, but there is lack of consensus in a number of scenarios as to what to use and when. In such a rare cancer, treatment outcomes are reported usually via retrospective analyses, with few prospective randomized controlled trials. Classification schemes have also evolved following the introduction of new treatment modalities, but discrepancies exist among centres with respect to the preferred schema and its interpretation. Retinoblastoma management is a remarkable success story, but the future will require a collaborative effort in the form of multicentre randomized controlled trials in order to further improve the quality of care for this subset of young children with ocular cancer.

Understanding aneurysmal type 1 neovascularization (polypoidal choroidal vasculopathy): a lesson in the taxonomy of 'expanded spectra' - a review.

Abstract: The term aneurysmal type 1 neovascularization is derived from terminology, which is established in the literature but has fallen out of use. We believe that aneurysmal type 1 neovascularization accurately describes the lesions which define the entity known as polypoidal choroidal vasculopathy (PCV). Over the last three decades, the clinical spectrum of PCV has expanded to recognize the occurrence of the aneurysmal (polypoidal) lesions in different contexts, resulting in a complex and unwieldy taxonomy based sometimes on circumstantial findings rather than mechanistic considerations. Advances in multimodal imaging provides increasingly convincing evidence that the lesions which define various forms of PCV are indeed vascular and arise from type 1 neovascular networks. The understanding of PCV as type 1 neovascularization with aneurysms renews focus on the question as to why some patients with type 1 neovascularization develop aneurysms while others do not. Conceptual themes and potential for further study are discussed.

Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia

Abstract: Retinal gene therapy is increasingly recognized as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology1–5. Choroideremia is a chronic X-linked retinal degeneration that was first described in 18726. It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes 2 years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, versus 1.5 letter loss, P = 0.04), with 6 treated eyes gaining more than one line of vision (>5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late-stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted. The long-term follow-up results of a phase 1/2 retinal gene therapy clinical trial for choroideremia ( NCT01461213 ) support the safety and efficacy of the treatment.

Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing.

Abstract: Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.

Optical coherence tomography angiography: a review of current and future clinical applications.

Abstract: Optical coherence tomography angiography is a non-invasive imaging technique that now allows for simultaneous in vivo imaging of the morphology as well as the vasculature in the eye. In this review, we provide an update on the existing clinical applications of optical coherence tomography angiography technology from the anterior to posterior segment of the eye. We also discuss the limitations of optical coherence tomography angiography technology, as well as the caveats to the interpretation of images. As current optical coherence tomography angiography systems are optimized for the retina, most studies have focused on interpreting images from conditions such as age related macular degeneration and retinal vascular diseases. However, the interpretation of these optical coherence tomography angiography images should be taken in consideration with other multi-modal imaging to overcome the limitations of each technique. In addition, there are a growing variety of clinical applications for optical coherence tomography angiography imaging in optic nerve head evaluation for glaucoma and optic neuropathies. Further developments in anterior optical coherence tomography angiography have now allowed for evaluation of anterior segment pathology such as glaucoma, ocular surface diseases, corneal vascularisation, and abnormal iris vasculature. Future developments in software could allow for improved segmentation and image resolution with automated measurements and analysis.

Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors

Abstract: Background/aims Acanthamoeba keratitis (AK) is a chronic debilitating corneal infection principally affecting contact lens (CL) users Studies were designed to test claims that the UK incidence may have increased in 2012–2014 and to evaluate potential causes Methods Annualised incidence data were collected from January 1984 to December 2016 Case-control study subjects were recruited between 14 April 2011 and 05 June 2017 Reusable CL users with AK were recruited retrospectively and prospectively Controls were reusable CL users, recruited prospectively, with any disorder other than AK Multivariable analysis of questionnaire data measured independent risk factors for AK Results The current outbreak of AK started in 2010–2011 with an incidence threefold higher than in 2004–2009 Risk factors for AK were: Oxipol disinfection, CLs made of group IV CL materials, poor CL hygiene, deficient hand hygiene, use of CLs while swimming or bathing, being white British, and for those in social classes 4–9 Conclusion AK is a largely preventable disease The current outbreak is unlikely to be due to any one of the identified risk factors in isolation Improving CL and hand hygiene, avoiding CLs contamination with water and use of effective CL disinfection solutions, or daily disposable CLs, will reduce the incidence of AK In the longer-term, water avoidance publicity for CL users can be expected to reduce the incidence further Ongoing surveillance of AK numbers will identify changes in incidence earlier Evaluation of Acanthamoeba contamination in end-user drinking water would contribute to our understanding of regional variations in the risk of exposure

Prediction of myopia development among Chinese school-aged children using refraction data from electronic medical records: A retrospective, multicentre machine learning study.

Abstract: Background Electronic medical records provide large-scale real-world clinical data for use in developing clinical decision systems. However, sophisticated methodology and analytical skills are required to handle the large-scale datasets necessary for the optimisation of prediction accuracy. Myopia is a common cause of vision loss. Current approaches to control myopia progression are effective but have significant side effects. Therefore, identifying those at greatest risk who should undergo targeted therapy is of great clinical importance. The objective of this study was to apply big data and machine learning technology to develop an algorithm that can predict the onset of high myopia, at specific future time points, among Chinese school-aged children. Methods and findings Real-world clinical refraction data were derived from electronic medical record systems in 8 ophthalmic centres from January 1, 2005, to December 30, 2015. The variables of age, spherical equivalent (SE), and annual progression rate were used to develop an algorithm to predict SE and onset of high myopia (SE ≤ -6.0 dioptres) up to 10 years in the future. Random forest machine learning was used for algorithm training and validation. Electronic medical records from the Zhongshan Ophthalmic Centre (a major tertiary ophthalmic centre in China) were used as the training set. Ten-fold cross-validation and out-of-bag (OOB) methods were applied for internal validation. The remaining 7 independent datasets were used for external validation. Two population-based datasets, which had no participant overlap with the ophthalmic-centre-based datasets, were used for multi-resource validation testing. The main outcomes and measures were the area under the curve (AUC) values for predicting the onset of high myopia over 10 years and the presence of high myopia at 18 years of age. In total, 687,063 multiple visit records (≥3 records) of 129,242 individuals in the ophthalmic-centre-based electronic medical record databases and 17,113 follow-up records of 3,215 participants in population-based cohorts were included in the analysis. Our algorithm accurately predicted the presence of high myopia in internal validation (the AUC ranged from 0.903 to 0.986 for 3 years, 0.875 to 0.901 for 5 years, and 0.852 to 0.888 for 8 years), external validation (the AUC ranged from 0.874 to 0.976 for 3 years, 0.847 to 0.921 for 5 years, and 0.802 to 0.886 for 8 years), and multi-resource testing (the AUC ranged from 0.752 to 0.869 for 4 years). With respect to the prediction of high myopia development by 18 years of age, as a surrogate of high myopia in adulthood, the algorithm provided clinically acceptable accuracy over 3 years (the AUC ranged from 0.940 to 0.985), 5 years (the AUC ranged from 0.856 to 0.901), and even 8 years (the AUC ranged from 0.801 to 0.837). Meanwhile, our algorithm achieved clinically acceptable prediction of the actual refraction values at future time points, which is supported by the regressive performance and calibration curves. Although the algorithm achieved balanced and robust performance, concerns about the compromised quality of real-world clinical data and over-fitting issues should be cautiously considered. Conclusions To our knowledge, this study, for the first time, used large-scale data collected from electronic health records to demonstrate the contribution of big data and machine learning approaches to improved prediction of myopia prognosis in Chinese school-aged children. This work provides evidence for transforming clinical practice, health policy-making, and precise individualised interventions regarding the practical control of school-aged myopia.

Use of Gevokizumab in Patients with Behçet's Disease Uveitis: An International, Randomized, Double-Masked, Placebo-Controlled Study and Open-Label Extension Study.

Abstract: Purpose: The purpose of this article is to demonstrate the superiority of gevokizumab as compared to placebo, on top of current standard of care, in reducing the risk of Behcet’s disease uveitis (B...

An update on inflammatory choroidal neovascularization: epidemiology, multimodal imaging, and management

Abstract: Inflammatory choroidal neovascular membranes are challenging to diagnose and manage. A number of uveitic entities may be complicated by the development of choroidal neovascularization leading to a decrease in central visual acuity. In conditions such as punctate inner choroidopathy, development of choroidal neovascularization is extremely common and must be suspected in all cases. On the other hand, in patients with conditions such as serpiginous choroiditis, and multifocal choroiditis, it may be difficult to differentiate between inflammatory choroiditis lesions and choroidal neovascularization. Multimodal imaging analysis, including the recently introduced technology of optical coherence tomography angiography, greatly aid in the diagnosis and management of inflammatory choroidal neovascularization. Management of these neovascular membranes consists of anti-vascular growth factor agents, with or without concomitant anti-inflammatory and/or corticosteroid therapy.

Selective laser trabeculoplasty: past, present, and future.

Abstract: Over the past two decades, selective laser trabeculoplasty (SLT) has increasingly become an established laser treatment used to lower intraocular pressure in open-angle glaucoma and ocular hypertensive patients. In this review we trace the origins of SLT from previous argon laser trabeculoplasty and review the current role it has in clinical practice. We outline future directions of SLT research and introduce emerging technologies that are further developing this intervention in the treatment paradigm of glaucoma.

Multicenter reliability of semiautomatic retinal layer segmentation using OCT

Abstract: Objective To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans. Methods Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps. Results Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers. Conclusions Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.

Achromatopsia: clinical features, molecular genetics, animal models and therapeutic options.

Abstract: Achromatopsia is an autosomal recessive condition, characterised by reduced visual acuity, impaired colour vision, photophobia and nystagmus. The symptoms can be profoundly disabling, and there is no cure currently available. However, the recent development of gene-based interventions may lead to improved outcomes in the future. This article aims to provide a comprehensive review of the clinical features of the condition, its genetic basis and the underlying pathogenesis. We also explore the insights derived from animal models, including the implications for gene supplementation approaches. Finally, we discuss current human gene therapy trials.

Acanthamoeba keratitis in 194 patients: risk factors for bad outcomes and severe inflammatory complications.

Abstract: Background/aims To determine demographic and clinical features of patients with Acanthamoeba keratitis (AK) that are independent risk factors both for bad outcomes and for severe inflammatory complications (SIC). Methods A retrospective audit of medical records of AK cases at Moorfields Eye Hospital from July 2000 to April 2012, including 12 earlier surgical cases. Cases with a bad outcome were defined as those having one or more of the following: corneal perforation, keratoplasty, other surgery (except biopsy), duration of antiamoebic therapy (AAT) ≥10.5 months (the 75th percentile of the whole cohort) and final visual acuity ≤20/80. SICs were defined as having scleritis and/or a stromal ring infiltrate. Multivariable analysis was used to identify independent risk factors for both bad outcomes and SICs. Results Records of 194 eyes (194 patients) were included, having bad outcomes in 93 (48%). Bad outcomes were associated with the presence of SIC, aged >34 years, corticosteroids used before giving AAT and symptom duration >37 days before AAT. The development of SIC was independently associated with aged >34 years, corticosteroids used before giving AAT and herpes simplex virus (HSV) keratitis treatment before AAT. Conclusions The prompt diagnosis of AK, avoidance of a misdiagnosis of HSV keratitis and corticosteroid use before the exclusion of AK as a potential cause of keratitis are essential to the provision of a good outcome for patients and for the avoidance of SIC. Older age is an unmodifiable risk factor that may reflect differences in the immune response to AK in this patient subset.

Enhanced Penetration for Axial Length Measurement of Eyes with Dense Cataracts Using Swept Source Optical Coherence Tomography: A Consecutive Observational Study.

Abstract: The aim of this study was to find cases in which the axial eye length could not be measured with partial coherence interferometry (PCI) technology and to assess if it could be measured using swept source optical coherence tomography (ss-OCT) technology. All patients were measured at their pre-assessment visit 1 week prior to cataract surgery using conventional optical biometry (PCI technology, IOLMaster 500, Carl Zeiss Meditec AG, Jena, Germany). Patients in whom one or both eyes could not be measured using PCI technology were invited to participate in the study and to be measured with the ss-OCT (IOL Master 700, Carl Zeiss Meditec AG, Jena, Germany) device. Altogether, 1226 eyes of 613 patients were measured consecutively, and 78 eyes were not measured successfully with PCI technology. Among those with unsuccessfully measured eyes, 23 patients were willing to participate in the study, and two of those were also unsuccessfully measured with the ss-OCT device (8.7%, 2/23). However, 91.3% (21/23) of the eyes that were unsuccessfully scanned with PCI technology were measurable with the ss-OCT device. The estimated overall rate of unsuccessful scans with the ss-OCT device was 0.5% (6/1226) ( $$ p_{{\chi^{2} }} $$ < 0.01). ss-OCT technology significantly improves the rate of attainable axial eye length measurements, especially in eyes with posterior subcapsular cataracts, but also in eyes with dense nuclear cataracts, except for white cataracts.

XEN-45 collagen implant for the treatment of uveitic glaucoma

Abstract: IMPORTANCE The XEN-45 implant, a hydrophilic collagen implant which drains aqueous to the subconjunctival space, has not been investigated in the context of uveitic glaucoma. BACKGROUND To determine the safety and efficacy of the XEN-45 collagen implant in eyes with uveitic glaucoma. DESIGN Exploratory prospective case series. PARTICIPANTS patients with medically uncontrolled uveitic glaucoma. METHODS Twenty-four consecutive patients (mean age ± standard deviation [SD] = 45.3 ± 18.1 years) were implanted with the XEN-45 implant. MAIN OUTCOME MEASURES The primary outcome measure was intraocular pressure (IOP) reduction at 12 months as compared to baseline. Secondary outcome measures included ocular hypotensive medication use at 12 months, the requirement for further glaucoma surgery and failure. Intraoperative and postoperative complications were documented. RESULTS The baseline mean ± SD IOP was 30.5 ± 9.8 mmHg and the mean ± SD number of glaucoma medications required was 3.3 ± 0.8. In 20 eyes (83.3%) in whom conventional glaucoma surgery was originally perceived to be inevitable, further surgery was not required after XEN-45 implantation. The mean IOP was reduced by 60.2% from baseline to 12.2 ± 3.1 mmHg and mean medication usage was reduced to 0.4 ± 0.9 at 12 months (both P < 0.001). One patient had hypotony persisting beyond 2 months that required surgical revision and one patient developed blebitis. The 12-month cumulative Kaplan-Meier survival probability was 79.2%. CONCLUSIONS AND RELEVANCE The XEN-45 implant is effective for the treatment of patients with medically uncontrolled uveitic glaucoma. Potentially sight-threatening complications, including bleb-related ocular infection and persistent hypotony, may occur.

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Peripheral Retinal Imaging Biomarkers for Alzheimer's Disease: A Pilot Study.

Abstract: Purpose: To examine whether ultra-widefield (UWF) retinal imaging can identify biomarkers for Alzheimer’s disease (AD) and its progression. Methods: Images were taken using a UWF scanning laser ophthalmoscope (Optos P200C AF) to determine phenotypic variations in 59 patients with AD and 48 healthy controls at baseline (BL). All living participants were invited for a follow-up (FU) after 2 years and imaged again (if still able to participate). All participants had blood taken for genotyping at BL. Images were graded for the prevalence of age-related macular degeneration-like pathologies and retinal vascular parameters. Comparison between AD patients and controls was made using the Student t test and the χ2 test. Results: Analysis at BL revealed a significantly higher prevalence of a hard drusen phenotype in the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%) [χ2 = 9.9, df = 4, p = 0.04]. A markedly increased drusen number was observed at the 2-year FU in patients with AD compared to controls. There was a significant increase in venular width gradient at BL (zone C: 8.425 × 10–3 ± 2.865 × 10–3 vs. 6.375 × 10–3 ± 1.532 × 10–3, p = 0.008; entire image: 8.235 × 10–3 ± 2.839 × 10–3 vs. 6.050 × 10–3 ± 1.414 × 10–3, p = 0.004) and a significant decrease in arterial fractal dimension in AD at BL (entire image: 1.250 ± 0.086 vs. 1.304 ± 0.089, p = 0.049) with a trend for both at FU. Conclusions: UWF retinal imaging revealed a significant association between AD and peripheral hard drusen formation and changes to the vasculature beyond the posterior pole, at BL and after clinical progression over 2 years, suggesting that monitoring pathological changes in the peripheral retina might become a valuable tool in AD monitoring.

Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases.

Abstract: Background Diagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including CNVs. This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel NGS services for IRD. Methods Three read-depth algorithms were applied to gene panel NGS data sets for 550 referred individuals, and informatics strategies used for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory. Results We confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques. Conclusion Incorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic tests for IRD, increases clarity in diagnostic reporting and expands the spectrum of known disease-causing mutations.

Treatment of patients with neurotrophic keratitis stages 2 and 3 with plasma rich in growth factors (PRGF-Endoret) eye-drops

Abstract: To provide preliminary data about efficacy and safety of plasma rich in growth factors (PRGF) eye-drops in neurotrophic keratitis (NK) and to analyze the possible influence of certain variables on treatment outcomes. This retrospective study included patients with stages 2–3 of NK treated with PRGF eye-drops. Primary endpoint was the resolution time of corneal ulcer defect. Outcome measures including percentage of ulcer closure at 4 weeks, Ocular Surface Disease Index (OSDI), Best-Corrected Visual Acuity (BCVA) and Visual Analogue Scale (VAS) were also evaluated before and after treatment with PRGF. The influence of some patients’ clinical variables on results was assessed. Safety assessment was also performed reporting all adverse events. Thirty-eight treated eyes in a total of thirty-one patients were evaluated, of which five cases had no prior response to autologous serum treatment. Most cases (97.4%) achieved the complete resolution of corneal defect/ulcer. Mean resolution time was 11.4 weeks (SD = 13.7). A statistical significant (p < 0.05) reduction in OSDI (60.9%), VAS frequency (59.9%), VAS severity (57.0%) and improvement in BCVA (52.8%) was observed. The results were stratified according to the pathology stage and to the identified potential effect modifiers variables. Only one adverse event was reported in one patient (2.6%). PRGF eye-drops could be a safe and effective therapeutic option for patients with stages 2–3 of NK, showing high rates of corneal defect/ulcer resolution in short times, either in reducing signs and symptoms of NK, and therefore preventing the progression of NK to greater ocular complications.

A clinical and molecular characterisation of CRB1-associated maculopathy.

Abstract: To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype–phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull’s-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes—intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.