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Wei Jia Liu,1 Laura J Taylor,2,3 Robert E MacLaren,2,3 Jasleen K Jolly4 1School of Medicine and Biomedical Sciences, University of Oxford, Oxford, UK; 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 3Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 4Vision and Eye Research Institute, Anglia Ruskin University, Cambridge, UKCorrespondence: Jasleen K Jolly, Vision and Eye Research Institute, Anglia Ruskin University, Cambridge, UK, Tel/Fax +44 122 369 5034, Email jasleen.jolly@aru.ac.ukPurpose: Clinical research brings the potential of improved diagnostics, sight-saving treatments, and more accessible services to those suffering with severe sight impairment (SSI). This report investigates whether registered ophthalmology clinical studies address the leading causes of SSI in the general and working populations of the United Kingdom (UK).Methods: The latest statistics on the leading causes of SSI in the UK general and working populations were identified by searching PubMed, Cochrane Library, and TRIP databases. Clinical study registries were searched to identify registered clinical studies (on or prior to 1st December 2022) on the leading causes of SSI. The relationship between the number of clinical studies on leading causes of SSI and the percentage of SSI certifications they account for was analyzed.Results: In the UK general population, the number of registered clinical studies on the leading causes of SSI is statistically significantly correlated (Spearman’s rho = 0.86, p < 0.01) with the percentage of SSI certifications they account for. However, there is no correlation between the two in the UK working population (aged 16– 64) (Spearman’s rho = 0.15, p = 0.70). Eye conditions accounting for the most SSI certifications in individuals of working age have significantly less clinical research activity than those that cause the most SSI certifications in the general population. Out of the lead

Purpose: Comparing the effect of half-dose photodynamic therapy and high-density subthreshold micropulse laser treatment on retinal pigment epithelial detachments (PEDs) in chronic central serous chorioretinopathy. Methods: This study included data from the PLACE trial, a prospective randomized controlled trial comparing half-dose photodynamic therapy and high-density subthreshold micropulse laser treatment in chronic central serous chorioretinopathy. Main outcome measurements were changes in both the foveal PED and the highest PED within the macula at baseline compared with first and final evaluation visit. Results: At baseline, a macular PED was detected in 76.9% of patients (123/160), and a PED within 1,500 mu m from the foveal center in 37.5% of patients (60/160). In the half-dose photodynamic therapy arm (61 patients), there was a significantly larger decrease in the highest macular PED compared with the high-density subthreshold micropulse laser treatment arm (62 patients) at both first and final evaluation visits (P < 0.001 and P = 0.012, respectively). The decrease of highest foveal PED was significant at first visit (P = 0.025). Conclusion: Half-dose photodynamic therapy is superior to high-density subthreshold micropulse laser treatment with regard to a statistically significant reduction in the height of macular PEDs in active chronic central serous chorioretinopathy. These findings may also have implications for other diseases within the pachychoroid disease spectrum that can present with PEDs.

Colm D Andrews,1,2 Aislin A Sheldon,3 Holly Bridge,3 Susan M Downes,2,4 Robert E MacLaren,2,4 Jasleen K Jolly2– 5 1Nuffield Department of Population Health, University of Oxford, Oxford, UK; 2Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 3Oxford Centre for Functional MRI of the Brain (FMRIB), Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK; 4Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 5Vision and Eye Research Institute, Anglia Ruskin University, Cambridge, UKCorrespondence: Jasleen K Jolly, Vision and Eye Research Institute, School of Medicine, Anglia Ruskin University, Young Street, Cambridge, CB1 2LZ, UK, Email jasleen.jolly@aru.ac.ukPurpose: We aimed to assess the performance of the modified-Esterman test (mET) as a rapid suprathreshold binocular quantification tool for the assessment of peripheral visual fields. The mET consists of an even spread of test points across the visual field.Materials and Methods: The mET was implemented on the Octopus 0900 perimeter using the Open Perimetry Interface (OPI) and consisted of 160 points. Patients with choroideremia, a rod-cone dystrophy, Stargardt disease, a cone-rod dystrophy, and healthy volunteers underwent both the mET and the standard Esterman tests twice. Disease severity (mild/moderate/severe) was graded on both tests independently. Voronoi tessellation was utilised to compare the tests.Results: The Voronoi visualisation was able to demonstrate that the mET was able to provide more information about the disease state at all stages of diseases. This was confirmed by the agreement statistic, which showed that the mET detected 27% more points of visual field loss compared to the Esterman test, being most useful in patients with rod-cone dystrophies.Conclusion: The mET provides a speedy quantitative measure of the peripheral visual field loss, which can be used in cli

Purpose To describe the treatment outcomes and recurrence risk of chronic central serous chorioretinopathy (cCSC) in patients who had complete resolution of subretinal fluid (SRF) after either primary half-dose photodynamic therapy (PDT) or high-density subthreshold micropulse laser (HSML) in the PLACE trial. Methods This multicentre prospective follow-up study evaluated cCSC patients at 1 year after completion of the PLACE trial. Outcomes included: complete resolution of SRF on OCT, best-corrected visual acuity (BCVA) in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, retinal sensitivity on microperimetry and a visual function questionnaire (NEI-VFQ25). Results Twenty-nine out of 37 patients who received half-dose PDT and 15 out of 17 patients who received HSML could be evaluated at final visit. At final visit, 93% of the patients treated with half-dose PDT had complete resolution of SRF, compared with 53% of HSML-treated patients (p = 0.006). At final visit, the mean estimate increase in the PDT group compared with the HSML group was + 2.1 ETDRS letters, +0.15 dB for the retinal sensitivity and + 5.1 NEI-VFQ25 points (p = 0.103, p = 0.784 and p = 0.071, respectively). The mean estimated central retinal thickness in the half-dose PDT group was -7.0 mu m compared with the HSML group (p = 0.566). The mean estimated subfoveal choroidal thickness in the half-dose PDT group was -16.6 mu m compared with the HSML group (p = 0.359). Conclusion At 20 months after treatment, cCSC patients successfully treated with half-dose PDT are less likely to have recurrences of SRF compared with those successfully treated with HSML. However, functional outcomes did not differ.

Purpose: To compare the effects of half-dose photodynamic therapy (PDT) and high-density subthreshold micropulse laser on choroidal dysfunction evaluated by degree and extent of hyperfluorescence on indocyanine green angiography (ICGA) in chronic central serous chorioretinopathy. Methods: Data from the multicenter, randomized, controlled PLACE trial were used in this study. Hyperfluorescent and hypofluorescent areas on ICGA, their association with subretinal fluid and visual function were assessed. Results: In total, 146 patients were included (72 in the PDT and 74 in the high-density subthreshold micropulse laser treatment arm). A significantly greater decrease in the size of hyperfluorescent areas on ICGA at first visit after treatment was seen after PDT compared with high-density subthreshold micropulse laser (mean, -1.41 +/- 2.40 mm(2) vs. -0.04 +/- 0.73 mm(2), respectively; P < 0.001). A reduction in the degree of hyperfluorescence on ICGA decreased the odds of having persistent subretinal fluid on optical coherence tomography at first visit after treatment (B = 0.295; P = 0.019). There were no significant differences in best-corrected visual acuity and retinal sensitivity between the subgroup with novel hypofluorescence (n = 20, 28%) on ICGA at first visit post PDT, compared with the subgroup without novel hypofluorescence on ICGA after PDT. Conclusion: Choroidal abnormalities in chronic central serous chorioretinopathy can be effectively treated by ICGA-guided half-dose PDT but not with high-density subthreshold micropulse laser application.

Vision loss caused by inherited retinal degeneration affects millions of people worldwide, and clinical trials involving gene supplementation strategies are ongoing for select forms of the disease. When early therapeutic intervention is not possible and patients suffer complete loss of their photoreceptor cells, there is an opportunity for vision restoration techniques, including optogenetic therapy. This therapy provides expression of light-sensitive molecules to surviving cell types of the retina, enabling light perception through residual neuronal pathways. To this end, the bipolar cells make an obvious optogenetic target to enable upstream processing of visual signal in the retina. However, while AAV transduction of the bipolar cells has been described, the expression of human opsins in these cell types within a model of retinal degeneration (rd1) has been less successful. In this study, we have expanded the optogenetic toolkit and shown successful expression of human rhodopsin driven by an ON-bipolar cell promoter (Grm6) in the rd1 mouse model using modified AAV capsids (AAV2.4YF, AAV8.BP2, and AAV2.7m8) delivered via intraocular injection. We also show the first presentation of ectopic expression of human cone opsin in the bipolar cells of rd1 mice. These data provide evidence of an expansion of the optogenetic toolkit with the potential to restore useful visual function, setting the stage for future trials in human patients.

Human opsin-based photopigments have great potential as light-sensitisers, but their requirement for phototransduction cascade-specific second messenger proteins may restrict their functionality in non-native cell types. In this study, eight chimeric human opsins were generated consisting of a backbone of either a rhodopsin (RHO) or long-wavelength-sensitive (LWS) opsin and intracellular domains from G(q/11)-coupled human melanopsin. Rhodopsin/melanopsin chimeric opsins coupled to both Gi and G(q/11) pathways. Greater substitution of the intracellular surface with corresponding melanopsin domains generally showed greater G(q/11) activity with a decrease in Gi activation. Unlike melanopsin, rhodopsin and rhodopsin/melanopsin chimeras were dependent upon exogenous chromophore to function. By contrast, wild-type LWS opsin and LWS opsin/melanopsin chimeras showed only weak Gi activation in response to light, whilst G(q/11) pathway activation was not detected. Immunocytochemistry (ICC) demonstrated that chimeric opsins with more intracellular domains of melanopsin were less likely to be trafficked to the plasma membrane. This study demonstrates the importance of Ga coupling efficiency to the speed of cellular responses and created human opsins with a unique combination of properties to expand the range of customised optogenetic biotools for basic research and translational therapies.

PURPOSE: To assess whether chronic central serous chorioretinopathy (cCSC) patients without a complete resolution of subretinal fluid (SRF) after either half-dose photodynamic therapy (PDT) or high-density subthreshold micropulse laser (HSML) treatment may benefit from crossover treatment. DESIGN: Multicenter prospective interventional case series. METHODS: cCSC patients with persistent SRF at the final visit of the PLACE trial were included. Patients received crossover treatment with either half-dose PDT or HSML. RESULTS: Thirty-two patients received PDT and 10 patients received HSML. At the first evaluation visit (6-8 weeks after treatment), 81% of patients in the PDT group had complete resolution of SRF, while none of the HSML-treated patients had complete resolution of SRF. At final visit (1 year after baseline), 78% (P = .030) and 67% (P = .109) of the patients, respectively, had a complete resolution of SRF. The mean retinal sensitivity in the PDT group increased from 21.7 dB (standard error [SE]: 0.9) to 23.4 dB (SE: 0.8) at evaluation visit 1 (P = .003), to 24.7dB (SE: 0.8) at final visit (P < .001), while there were no significant changes in the HSML group (23.7 dB [SE: 1.6] at baseline, 23.8 dB [SE: 1.4] at evaluation 1, and 23.3 dB [SE: 1.4] at final visit). The mean visual acuity and mean visual quality-of-life questionnaire score did not change significantly in both groups. CONCLUSIONS: Crossover to half-dose PDT after previous unsuccessful HSML treatment for cCSC may lead to improved anatomic and functional endpoints, while crossover to HSML after half-dose PDT does not seem to significantly affect these endpoints. (C) 2020 The Authors. Published by Elsevier Inc.

Stem cell transplantation holds great promise as a potential treatment for currently incurable retinal degenerative diseases that cause poor vision and blindness. Recently, safety data have emerged from several Phase I/II clinical trials of retinal stem cell transplantation. These clinical trials, usually run in partnership with academic institutions, are based on sound preclinical studies and are focused on patient safety. However, reports of serious adverse events arising from cell therapy in other poorly regulated centers have now emerged in the lay and scientific press. While progress in stem cell research for blindness has been greeted with great enthusiasm by patients, scientists, doctors and industry alike, these adverse events have raised concerns about the safety of retinal stem cell transplantation and whether patients are truly protected from undue harm. The aim of this review is to summarize and appraise the safety of human retinal stem cell transplantation in the context of its potential to be developed into an effective treatment for retinal degenerative diseases.

Laura J Wood,1,2,* Jasleen K Jolly,1,2,* Markus Groppe,3 Larry Benjamin,3 James F Kirwan,4 Nishal Patel,5 Mostafa A Elgohary,6 Robert E MacLaren1,2 1Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 2Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 3Stoke Mandeville Hospital, Buckingham Healthcare NHS Trust, Walton, UK; 4Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, UK; 5Kent and Canterbury Hospital, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK; 6Kingston Hospital, Kingston Hospital NHS Foundation Trust, Kingston Upon Thames, UK*These authors contributed equally to this workCorrespondence: Laura J WoodNuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UKEmail enquires@ndcn.ox.ac.ukBackground/Aim: An increasing number of pre-presbyopic patients are undergoing uniocular cataract extraction. We aim to compare the binocular status of subjects with uniocular cataracts, implanted either with a multifocal or a monofocal intraocular lens (IOL).Materials and Methods: Subjects were recruited from outpatient ophthalmology clinics and randomized to an IOL type. Corrected and uncorrected LogMAR distance visual acuity (VA) and near and intermediate VA using the Radner reading test were completed. The binocular tests included the Worth Four Dot Test, fixation disparity, TNO stereoacuity and foveal suppression assessment. In addition to the near activity vision questionnaire. The trial was closed early because the chosen multifocal lens had been superseded by newer models. We report two subjects, one receiving the multifocal IOL and a monofocal IOL control with the most comparable baseline characteristics.Results: Both subjects experienced uncomplicated cataract surgery, showing clinically significant improved corrected distance VA, 0.06 LogMAR and − 0.16 LogMAR

PURPOSE. To report the clinical and molecular findings in patients with retinal dystrophy associated with the c.783G>A variant in CDHR1. METHODS. The retinal phenotype of 10 patients with CDHR1-related retinopathy was characterized by multimodal imaging including color fundus photography, optical coherence tomography (OCT), and blue- and near-infrared fundus autofluorescence imaging. Functional testing included electroretinography, visual acuity, and visual field testing. RESULTS. Six patients homozygous for the c.783G>A variant in CDHR1 showed a retinal phenotype resembling central areolar choroidal dystrophy (CACD) on multimodal imaging. Retinal function outside an area of slowly progressive macular atrophy remained relatively preserved. In contrast, biallelic severe/truncating CDHR1 mutations result in retina-wide retinal degeneration in addition to macular atrophy, with overall severely reduced retinal function. Patients compound heterozygous for the c.783G>A mutation and a truncating mutation in CDHR1 showed an intermediate phenotype. All patients except one with biallelic severe CDHR1 mutations were asymptomatic in the first four decades of life, irrespective of their individual CDHR1 mutations. Analysis of blood RNA from patients with the c.783G>A variant revealed in-frame skipping of exon 8 in vivo, predicting a partial deletion of CDHR1 ectodomains 2 and 3. CONCLUSIONS. Patients with biallelic c.783G>A CDHR1 mutations demonstrate a retinal phenotype consistent with autosomal recessive CACD. The apparently silent dbSNP-annotated c.783G>A CDHR1 variant (rs147346345) has a relatively high minor allele frequency (0.31%), with homozygous individuals annotated in the general population, and it may therefore have been disregarded in many next-generation sequencing (NGS)-based studies. The differential diagnosis includes PRPH2-associated CACD and age-related macular degeneration.

PURPOSE: To compare the outcome between high-density subthreshold micropulse laser (HSML) treatment and half-dose photodynamic therapy (PDT) in chronic central serous chorioretinopathy (cCSC) patients, subdivided based on either focal or diffuse leakage on fluorescein angiography (FA). DESIGN: Retrospective analysis of multicenter randomized controlled trial data. METHODS: Patients were treated with either half-dose PDT or HSML (both indocyanine green angiography-guided) and categorized in 2 groups, based on focal or diffuse leakage on FA. Clinical outcomes were evaluated at baseline and during follow-up. RESULTS: In the focal leakage group (63 patients), both at first evaluation and at final visit, more PDT-treated than HSML-treated patients demonstrated a resolution of subretinal fluid (evaluation visit 1: 57% in the PDT group and 17% in the HSML group, P = .007; final visit: 75% and 38%, P = .012). In the diffuse leakage group (93 patients), both at first evaluation and at final visit, more PDT-treated than HSML-treated patients showed a resolution of subretinal fluid (evaluation visit: 1:48% in the PDT group and 16% in the HSML group, P = .002; final visit: 67% and 21%, P = .002). PDT-treated patients in the focal and diffuse leakage group had a higher retinal sensitivity increase, comparing baseline and final visit (+3.1 +/- 3.1 dB vs +1.2 +/- 4.0 dB, P = .048, and +2.7 +/- 3.3 dB vs +1.0 +/- 3.8 dB, P = .036, respectively). Only in the diffuse leakage group, the increase in ETDRS letters was higher in the PDT-treated group when comparing baseline and first evaluation visit (+4.4 +/- 6.1 vs +0.9 +/- 10.0, P = .049). CONCLUSIONS: Half-dose PDT is superior to HSML treatment in cCSC patients, regardless of the presence of focal or diffuse leakage on FA. ((C) 2019 Elsevier Inc. All rights reserved.)

PurposeTo describe the characteristics and potential differences between focal and diffuse phenotypes of untreated chronic central serous chorioretinopathy (cCSC).MethodsFor this study, patients were divided in two groups. Focal leakage was defined as 1 hot spot of leakage, whereas diffuse leakage was defined as either >1 hot spot or a larger area of widespread leakage on FA. Clinical characteristics were assessed at presentation. After Bonferroni correction, P values <0.00125 were deemed statistically significant.ResultsThe focal leakage group included 68 eyes (53 males), and the diffuse leakage group included 105 eyes (88 males). Mean best-corrected visual acuity (BCVA) was 77.18.1 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in the focal group and 76.0 +/- 9.6 ETDRS letters in the diffuse group (p=0.440). In the focal group, mean age was 46.9 +/- 8.8years, whereas this was 49.7 +/- 8.3years in the diffuse group (p=0.033). Mean central foveal thickness was 107.1 +/- 21.3m in the focal group and 106.2 +/- 27.3m in the diffuse group (p=0.818). Mean choroidal thickness was 407.5 +/- 114.8m in the focal group and 419.1 +/- 113.9m in the diffuse group (p=0.578). In the focal group, subretinal fluid was present in the fellow eye in 16% of the patients, as compared to 29% in the diffuse group (p=0.067).Conclusions In untreated cCSC patients with focal or diffuse leakage on FA, no marked differences in clinical characteristics were found. Extensive choroidal abnormalities may be present in both groups, which are presumed to lie at the basis of the development of cCSC.

BACKGROUND/AIMS: To better understand the pattern of degeneration progression in cases with choroideremia.METHODS: A cohort of genotypically confirmed choroideremia cases who underwent optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging was studied. Using HEYEX review software, the foveal centre was marked on FAF images under guidance of corresponding OCT images, followed by application of an ETDRS grid. The boundaries of preserved autofluorescence (AF) were manually segmented in each individual ETDRS subfield. The regional distribution of preserved AF was assessed by comparing its area among the various subfields.RESULTS: A total of 168 eyes from 84 choroideremia cases were enrolled. There was a statistically significant difference in the amount of preserved AF area between inner subfields as determined by one-way analysis of variance (F (3,668)=9.997, p<0.001) and also between outer subfields (F (3,668)=8.348, p<0.001). A Tukey posthoc test revealed that the preserved AF area in the nasal subfields in both the inner and outer subfields was significantly smaller compared with analogue subfields.CONCLUSION: The asymmetric spatial distribution of preserved AF in choroideremia (corresponding to the stellate shaped nature of these regions) suggests that the progression of degeneration has directional preference.

The recent approval in the United States of the first adeno-associated viral (AAV) vector for the treatment of an inherited retinal degeneration validates this approach for the treatment of many other diseases. A major limiting factor continues to be the size restriction of the AAV transgene at under 5 kb. Stargardt disease is the most prevalent form of recessively inherited blindness and is caused by mutations in ABCA4, the gene that codes for ATP-binding cassette transporter protein family member 4, which has a coding sequence length of 6.8 kb. Dual vector approaches increase the capacity of AAV gene therapy, but at the cost of substantially reduced levels of target protein, which may be insufficient to achieve a therapeutic effect. Here we show that the efficacy of recombination of dual vectors is dependent on the length of DNA overlap between two transgenes. With optimized recombination, full-length ABCA4 protein is expressed in the photoreceptor outer segments of Abca4-/- mice at levels sufficient to reduce bisretinoid formation and correct the autofluorescent phenotype. These observations support a dual vector approach in future clinical trials using AAV gene therapy to treat Stargardt disease.

IMPORTANCE Co-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause. OBJECTIVE To report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons. DESIGN, SETTING, AND PARTICIPANTS This case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP. MAIN OUTCOMES AND MEASURES Results of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing. RESULTS Nine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c. 1312C>T, c. 2210G>A, c. 2492+1G>A, c. 2763C>G, and c. 3044_3050delGGAAATC) and 5 previously reported mutations in CNGB1. CONCLUSIONS AND RELEVANCE Mutations in CNGB1 may cause an autosomal recessive RP-olfactory dysfunction syndrome characterized by a slow progression of retinal degeneration and variable anosmia or hyposmia.

Purpose: To compare the anatomic and functional efficacy and safety of half-dose photodynamic therapy (PDT) versus high-density subthreshold micropulse laser (HSML) treatment in patients with chronic central serous chorioretinopathy (cCSC). Design: Open-label, multicenter, randomized controlled clinical trial. Participants: Patients with cCSC whose disease had to be confirmed by both clinical characteristics and findings on multimodal imaging. Methods: Eligible patients were randomized in a 1:1 allocation ratio. Treatment was evaluated during a follow-up visit, and the same treatment was repeated in patients who still demonstrated subretinal fluid (SRF). Main Outcome Measures: The primary end point was the complete disappearance of SRF at the first evaluation visit at 6 to 8 weeks after treatment. As a secondary outcome measure, we assessed this anatomic result at the final evaluation visit at 7 to 8 months after treatment. Other secondary outcomes covered functional improvement and included change in best-corrected visual acuity (BCVA; measured in Early Treatment Diabetic Retinopathy Study [ETDRS] letters), retinal sensitivity (measured using microperimetry), and vision-related quality of life using a validated questionnaire. Results: Between November 2013 and September 2016, 179 patients were included: 89 patients were assigned randomly to half-dose PDT, and 90 were assigned randomly to HSML treatment. At their first evaluation visit, SRF had resolved in 51.2% and 13.8% of patients, respectively (P < 0.001). At their final evaluation visit, a significantly higher percentage of PDT-treated patients demonstrated no SRF (67.2% vs. 28.8%; P < 0.001). Moreover, at the first evaluation visit, the PDT-treated patients showed a significantly higher increase in BCVA (+4.60 +/- 6.62 ETDRS letters vs. +1.39 +/- 8.99 ETDRS letters; P = 0.011), and a significantly higher increase in retinal sensitivity on microperimetry (+2.01 +/- 3.04 dB vs. +0.92 +/- 3.65 dB; P = 0.046); how

Importance:Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. Objective:To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. Design, Setting, and Participants:A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. Main Outcomes and Measures:Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. Results:There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in pa

Purpose: To describe the clinical findings and long-term outcome of patients with chronic central serous chorioretinopathy (cCSC). Materials and methods: This was a retrospective case series in 52 eyes of 36 patients with a follow-up period of at least 1 year. Extensive ophthalmic examination and a validated questionnaire concerning vision-related quality of life (National Eye Institute Visual Function Questionnaire [NEI-VFQ]-39) were analyzed. Results: Mean visual acuity showed a significant decline over time of 0.16 logarithm of minimum angle of resolution ([logMAR] range: -0.22 to 1.3; P=0.009) after a mean follow-up period of 10.6 years. Also, patients reported lower vision-related quality of life based on the NEI-VFQ-39 for almost all categories compared to healthy controls. Macular atrophy was diagnosed more often on optical coherence tomography compared to other diagnostic entities. Retinal pigment epithelium detachments in the macula were documented on optical coherence tomography in 56% of the patients. A significant thinning of foveal thickness was measured over time compared to unaffected fellow eyes (P=0.002). On long-term follow-up, 13 eyes (37%) showed an increase in number of hot spots on fluorescein angiography. Conclusion: This study indicates that cCSC is a progressive disease in many patients, causing a progressive decline in visual acuity, accompanied by lower reported vision-related quality of life. In deciding whether or not to treat, the progressive nature of cCSC should be taken into account in this relatively young and often still professionally active patient group.

Myrte B Breukink,1,* Alexander JM Dingemans,1,* Anneke I den Hollander,1,2 Jan EE Keunen,1 Robert E MacLaren,3,4 Sascha Fauser,5 Giuseppe Querques,6 Carel B Hoyng,1 Susan M Downes,3,4 Camiel JF Boon1,7 1Department of Ophthalmology, 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 3Oxford Eye Hospital, Oxford University Hospitals NHS Trust, 4Nuffield Laboratory of Ophthalmology and NIHR Biomedical Research Centre, Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 5Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 6Department of Ophthalmology, University Paris Est Creteil, Centre Hospitalier Intercommunal de Creteil, Creteil, France; 7Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands *These authors contributed equally to this work Purpose: To describe the clinical findings and long-term outcome of patients with chronic central serous chorioretinopathy (cCSC).Materials and methods: This was a retrospective case series in 52 eyes of 36 patients with a follow-up period of at least 1 year. Extensive ophthalmic examination and a validated questionnaire concerning vision-related quality of life (National Eye Institute Visual Function Questionnaire [NEI-VFQ]-39) were analyzed.Results: Mean visual acuity showed a significant decline over time of 0.16 logarithm of minimum angle of resolution ([logMAR] range: -0.22 to 1.3; P=0.009) after a mean follow-up period of 10.6 years. Also, patients reported lower vision-related quality of life based on the NEI-VFQ-39 for almost all categories compared to healthy controls. Macular atrophy was diagnosed more often on optical coherence tomography compared to other diagnostic entities. Retinal pigment epithelium detachments in the macula were documented on optical coherence tomography in 56% of the patients. A significant thinning of foveal thickness was measured over time compared to unaffec

Background: Chronic central serous chorioretinopathy (cCSC) is an eye disease characterized by an accumulation of serous fluid under the retina. It is postulated that this fluid accumulation results from hyperpermeability and swelling of the choroid, the underlying vascular tissue of the eye, causing a dysfunction of the retinal pigment epithelium. This fluid accumulation causes neuroretinal detachment. A prolonged neuroretinal detachment in the macula can lead to permanent vision loss. Therefore, treatment is aimed primarily at achieving resolution of subretinal fluid, preferably within the first 4 months after diagnosis of the disease. A broad spectrum of treatment modalities has been investigated in cCSC, but no consensus exists on the optimal treatment of cCSC. Currently, photodynamic therapy (PDT) and high-density subthreshold micropulse laser treatment (HSML) are among the most frequently cited treatments in obtaining successful neuroretinal reattachment. Methods/Design: This is a randomized, controlled, open-label, multicenter trial comparing the efficacy of half-dose PDT to HSML in treating patients with cCSC. A total of 156 patients will be recruited, 78 patients in each treatment arm, with a maximum follow-up duration of 8 months after the first treatment. A complete ophthalmological examination with vision-related quality of life (NEI VFQ-25) and stress questionnaires, will be performed at baseline, 6 to 8 weeks after the first treatment, 6 to 8 weeks after a second treatment (if necessary), and at the final follow-up visit at 7 to 8 months after the first treatment. Treatment visits will be scheduled within 3 weeks after the baseline visit, and within 3 weeks after the first control visit, if a second treatment is required. Discussion: Both half-dose PDT and HSML may be effective treatments in cCSC, but because of the lack of prospective randomized controlled trials, which treatment should be the first choice remains unclear. The aim of this study is to

PURPOSE. To investigate the effect of ABCA4 mutation status on lipofuscin-related quantitative autofluorescence (qAF) in humans and on bisretinoid accumulation in mice. METHODS. Genotyped parents (n = 26; age 37-64 years) of patients with biallelic ABCA4-related retinopathy underwent in-depth retinal phenotyping including qAF imaging as a surrogate measure for RPE lipofuscin accumulation. In addition, bisretinoids as the main components of autofluorescent lipofuscin at the ocular fundus were quantified in Abca4(-/-), Abca4(+/-), and wild-type mice. RESULTS. Index patients showed a retinal phenotype characteristic for ABCA4-related retinopathy, including increased qAF levels. In contrast, qAF measures in carriers of only one ABCA4 mutation were not different from age-matched controls in this sample, and there was no difference between truncating and missense mutations. Also, none of these carriers presented an abnormal phenotype on conventional imaging. One parent with ABCA4-related retinopathy and increased qAF carried an additional ABCA4 mutation, explaining the phenotype under a recessive disease model (pseudodominance). Biochemical analysis in the mouse model revealed direct downstream products (A2PE-H-2, at-RALdimer-PE) of the ABCA4 substrate N-Ret-PE to be similar in wild-type and Abca4(+/-) mice. Both bisretinoids were 12- to 18-fold increased in Abca4(-/-) mice. Levels of A2E and A2PE in Abca4(+/-) mice were in between those measured in wild-type and Abca4(-/-) mice. CONCLUSIONS. This study indicates that carriers of monoallelic ABCA4 mutations are phenotypically normal. However, biochemical analysis in the Abca4-deficient mouse model suggests detectable effects of one mutation in ABCA4 on the molecular level. The findings may have implications for therapeutic approaches such as gene replacement therapy.

PurposeTo investigate the effect of ABCA4 mutation status on lipofuscin-related quantitative autofluorescence (qAF) in humans and on bisretinoid accumulation in mice.MethodsGenotyped parents (n = 26; age 37-64 years) of patients with biallelic ABCA4-related retinopathy underwent in-depth retinal phenotyping including qAF imaging as a surrogate measure for RPE lipofuscin accumulation. In addition, bisretinoids as the main components of autofluorescent lipofuscin at the ocular fundus were quantified in Abca4-/-, Abca4+/-, and wild-type mice.ResultsIndex patients showed a retinal phenotype characteristic for ABCA4-related retinopathy, including increased qAF levels. In contrast, qAF measures in carriers of only one ABCA4 mutation were not different from age-matched controls in this sample, and there was no difference between truncating and missense mutations. Also, none of these carriers presented an abnormal phenotype on conventional imaging. One parent with ABCA4-related retinopathy and increased qAF carried an additional ABCA4 mutation, explaining the phenotype under a recessive disease model (pseudodominance). Biochemical analysis in the mouse model revealed direct downstream products (A2PE-H2, at-RALdimer-PE) of the ABCA4 substrate N-Ret-PE to be similar in wild-type and Abca4+/- mice. Both bisretinoids were 12- to 18-fold increased in Abca4-/- mice. Levels of A2E and A2PE in Abca4+/- mice were in between those measured in wild-type and Abca4-/- mice.ConclusionsThis study indicates that carriers of monoallelic ABCA4 mutations are phenotypically normal. However, biochemical analysis in the Abca4-deficient mouse model suggests detectable effects of one mutation in ABCA4 on the molecular level. The findings may have implications for therapeutic approaches such as gene replacement therapy.

Martin S Zinkernagel,1,2 Robert E MacLaren3,41Department of Ophthalmology, 2Department of Clinical Research, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland; 3Nuffield Laboratory of Ophthalmology, University of Oxford and Oxford Eye Hospital, Oxford University NHS Trust NIHR Biomedical Research Centre, Oxford, UK; 4Moorfields Eye Hospital NIHR Biomedical Research Centre, London, UKAbstract: Choroideremia is a complex and rare disease that is frequently misdiagnosed due to its similar appearance to classic retinitis pigmentosa. Recent advances in genetic testing have identified specific genetic mutations in many retinal dystrophies, and the identification of the mutation of the CHM gene on the X chromosome 25 years ago has paved the way for gene replacement therapy with the first human trials now underway. This article reviews the epidemiological and pathological features of choroideremia and new prospects in imaging to monitor disease progression, as well as potential treatment approaches for choroideremia.Keywords: choroideremia, gene replacement therapy, retinal imaging, clinical trials

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.

PurposeTo determine the role of variant L opsin haplotypes in seven families with Bornholm Eye Disease (BED), a cone dysfunction syndrome with dichromacy and myopia.MethodsAnalysis of the opsin genes within the L/M opsin array at Xq28 included cloning and sequencing of an exon 3-5 gene fragment, long range PCR to establish gene order, and quantitative PCR to establish gene copy number. In vitro expression of normal and variant opsins was performed to examine cellular trafficking and spectral sensitivity of pigments.ResultsAll except one of the BED families possessed L opsin genes that contained a rare exon 3 haplotype. The exception was a family with the deleterious Cys203Arg substitution. Two rare exon 3 haplotypes were found and, where determined, these variant opsin genes were in the first position in the array. In vitro expression in transfected cultured neuronal cells showed that the variant opsins formed functional pigments, which trafficked to the cell membranes. The variant opsins were, however, less stable than wild type.ConclusionsIt is concluded that the variant L opsin haplotypes underlie BED. The reduction in the amount of variant opsin produced in vitro compared with wild type indicates a possible disease mechanism. Alternatively, the recently identified defective splicing of exon 3 of the variant opsin transcript may be involved. Both mechanisms explain the presence of dichromacy and cone dystrophy. Abnormal pigment may also underlie the myopia that is invariably present in BED subjects.

In this report, we describe a male subject who presents with a complex phenotype of myopia associated with cone dysfunction and a protan vision deficiency. Retinal imaging demonstrates extensive cone disruption, including the presence of non-waveguiding cones, an overall thinning of the retina, and an irregular mottled appearance of the hyper-reflective band associated with the inner segment ellipsoid portion of the photoreceptor. Mutation screening revealed a novel p.Glu41Lys missense mutation in a hybrid L/M opsin gene. Spectral analysis shows that the mutant opsin fails to form a pigment in vitro and fails to be trafficked to the cell membrane in transfected Neuro2a cells. Extensive sequence and quantitative PCR analysis identifies this mutant gene as the only gene present in the affected subject's L/M opsin gene array, yet the presence of protanopia indicates that the mutant opsin must retain some activity in vivo. To account for this apparent contradiction, we propose that a limited amount of functional pigment is formed within the normal cellular environment of the intact photoreceptor, and that this requires the presence of chaperone proteins that promote stability and normal folding of the mutant protein.

PurposeTo investigate fundus autofluorescence (AF) characteristics in the Abca4(-/-) mouse, an animal model for AMD and Stargardt disease, and to correlate findings with functional, structural, and biochemical assessments.MethodsBlue (488 nm) and near-infrared (790 nm) fundus AF images were quantitatively and qualitatively analyzed in pigmented Abca4(-/-) mice and wild type (WT) controls in vivo. Functional, structural, and biochemical assessments included electroretinography (ERG), light and electron microscopic analysis, and A2E quantification. All assessments were performed across age groups.ResultsIn Abca4(-/-) mice, lipofuscin-related 488 nm AF increased early in life with a ceiling effect after 6 months. This increase was first paralleled by an accumulation of typical lipofuscin granules in the retinal pigment epithelium (RPE). Later, lipofuscin and melanin granules decreased in number, whereas melanolipofuscin granules increased. This increase in melanolipofuscin granules paralleled an increase in melanin-related 790 nm AF. Old Abca4(-/-) mice revealed a flecked fundus AF pattern at both excitation wavelengths. The amount of A2E, a major lipofuscin component, increased 10- to 12-fold in 6- to 9-month-old Abca4(-/-) mice compared with controls, while 488 nm AF intensity only increased 2-fold. Despite pronounced lipofuscin accumulation in the RPE of Abca4(-/-) mice, ERG and histology showed a slow age-related thinning of the photoreceptor layer similar to WT controls up to 12 months.ConclusionsFundus AF can be used to monitor lipofuscin accumulation and melanin-related changes in vivo in mouse models of retinal disease. High RPE lipofuscin may not adversely affect retinal structure or function over prolonged time intervals, and melanin-related changes (melanolipofuscin formation) may occur before the decline in retinal function.

Purpose To evaluate the clinical outcomes after half-dose photodynamic therapy (PDT) in chronic central serous chorioretinopathy (cCSC) patients with pre-existent fovea-involving atrophy. Methods In this retrospective study, cCSC patients who had a window defect of the retinal pigment epithelium (RPE) on fluorescein angiography (FA), compatible with RPE atrophy, prior to half-dose PDT were included. Results Thirty-four cCSC eyes with typical findings of cCSC on multimodal imaging, and fovea-involving RPE atrophy on FA, were included. At the first visit after PDT (at a median of 1.8 months after half-dose PDT), 20 eyes (59%) had a complete resolution of SRF (p < 0.001), while this was the case in 19 eyes (56%) at final visit (median of 11.3 months after half-dose PDT; p < 0.001). The mean BCVA in Early Treatment of Diabetic Retinopathy Study letters was 71. 2 +/- 15.9 at last visit before PDT, which increased to 74.1 +/- 14.1 at first visit after PDT (p = 0.093, compared with baseline), and changed to 73.0 +/- 19.1 at final visit (p = 0.392, compared with baseline). Both at first visit after PDT and at final visit, a significant decrease in subfoveal choroidal thickness was observed (p = 0.032 and p = 0.004, respectively). Conclusions Half-dose PDT in cCSC patients with pre-existing fovea-involving atrophy may lead to anatomical changes, but not to functional improvements. Ideally, cCSC should be treated with half-dose PDT before the occurrence of such atrophy.

Purpose To evaluate the clinical outcomes after half-dose photodynamic therapy (PDT) in chronic central serous chorioretinopathy (cCSC) patients with pre-existent fovea-involving atrophy. Methods In this retrospective study, cCSC patients who had a window defect of the retinal pigment epithelium (RPE) on fluorescein angiography (FA), compatible with RPE atrophy, prior to half-dose PDT were included. Results Thirty-four cCSC eyes with typical findings of cCSC on multimodal imaging, and fovea-involving RPE atrophy on FA, were included. At the first visit after PDT (at a median of 1.8 months after half-dose PDT), 20 eyes (59%) had a complete resolution of SRF (p < 0.001), while this was the case in 19 eyes (56%) at final visit (median of 11.3 months after half-dose PDT; p < 0.001). The mean BCVA in Early Treatment of Diabetic Retinopathy Study letters was 71. 2 +/- 15.9 at last visit before PDT, which increased to 74.1 +/- 14.1 at first visit after PDT (p = 0.093, compared with baseline), and changed to 73.0 +/- 19.1 at final visit (p = 0.392, compared with baseline). Both at first visit after PDT and at final visit, a significant decrease in subfoveal choroidal thickness was observed (p = 0.032 and p = 0.004, respectively). Conclusions Half-dose PDT in cCSC patients with pre-existing fovea-involving atrophy may lead to anatomical changes, but not to functional improvements. Ideally, cCSC should be treated with half-dose PDT before the occurrence of such atrophy.