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Female carriers of X-linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease-causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self-identified carriers worldwide. Two hundred and twenty-eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy.

Adaptive optics (AO) imaging enables direct, objective assessments of retinal cells. Applications of AO show great promise in advancing our understanding of the etiology of inherited retinal disease (IRDs) and discovering new imaging biomarkers. This scoping review systematically identifies and summarizes clinical studies evaluating AO imaging in IRDs. Ovid MEDLINE and EMBASE were searched on February 6, 2023. Studies describing AO imaging in monogenic IRDs were included. Study screening and data extraction were performed by 2 reviewers independently. This review presents (1) a broad overview of the dominant areas of research; (2) a summary of IRD characteristics revealed by AO imaging; and (3) a discussion of methodological considerations relating to AO imaging in IRDs. From 140 studies with AO outcomes, including 2 following subretinal gene therapy treatments, 75% included fewer than 10 participants with AO imaging data. Of 100 studies that included participants' genetic diagnoses, the most common IRD genes with AO outcomes are CNGA3, CNGB3, CHM, USH2A, and ABCA4. Confocal reflectance AO scanning laser ophthalmoscopy was the most reported imaging modality, followed by flood-illuminated AO and split-detector AO. The most common outcome was cone density, reported quantitatively in 56% of studies. Future research areas include guidelines to reduce variability in the reporting of AO methodology and a focus on functional AO techniques to guide the development of therapeutic interventions.

Recent advances have led to therapeutic options becoming available for people with inherited retinal disease. In particular, gene therapy has been shown to hold great promise for slowing vision loss from inherited retinal disease. Recent studies suggest that gene therapy is likely to be most effective when implemented early in the disease process, making consideration of paediatric populations important. It is therefore necessary to have a comprehensive understanding of retinal imaging in children with inherited retinal diseases, in order to monitor disease progression and to determine which early retinal biomarkers may be used as outcome measures in future clinical trials. In addition, as many optometrists will review children with an inherited retinal disease, an understanding of the expected imaging outcomes can improve clinical care. This review focuses on the most common imaging modality used in research assessment of paediatric inherited retinal diseases: optical coherence tomography. Optical coherence tomography findings can be used in both the clinical and research setting. In particular, the review discusses current knowledge of optical coherence tomography findings in eight paediatric inherited retinal diseases - Stargardt disease, Bests disease, Leber's congenital amaurosis, choroideremia, RPGR related retinitis pigmentosa, Usher syndrome, X-linked retinoschisis and, Batten disease.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss among the elderly in Western communities, with an estimated global prevalence of 10 - 20% in people older than 65 years. AMD leads to central vision loss due to degeneration of the photoreceptors, retinal pigment epithelium and the choriocapillaris. Beckman's classification for AMD, based upon color fundus photographs, divides the disease into early, intermediate, and late forms. The late, vision-threatening stage includes both neovascular AMD and geographic atrophy. Despite its high prevalence and impact on patients' quality of life, treatment options for AMD are limited. While neovascular AMD can be medically managed with anti-VEGF intravitreal injections, until very recently there has been no approved treatment options for atrophic AMD; however, in February 2023 the first treatment for geographic atrophy - pegcetacoplan - was approved by the US FDA. We describe the current landscape of potential gene and cell therapeutic strategies for late-stage AMD, with an emphasis on the therapeutic options that might become available in the next few years.

This study evaluated patient experiences with genetic testing for inherited retinal diseases (IRDs) and the association between underlying knowledge, testing outcomes, and the perceived value of the results. An online survey was distributed to adults with IRDs and parents/guardians of dependents with IRDs who had had genetic testing. Data included details of genetic testing, pre- and post- test perceptions, Decision Regret Scale, perceived value of results, and knowledge of gene therapy. Of 135 responses (85% from adults with IRDs), genetic testing was primarily conducted at no charge through public hospitals (49%) or in a research setting (30%). Key motivations for genetic testing were to confirm IRD diagnosis and to contribute towards research. Those who had received a genetic diagnosis (odds ratio: 6.71; p < 0.001) and those self-reported to have good knowledge of gene therapy (odds ratio: 2.69; p = 0.018) were more likely to have gained confidence in managing their clinical care. For over 80% of respondents, knowing the causative gene empowered them to learn more about their IRD and explore opportunities regarding clinical trials. Key genetic counselling information needs include resources for family communications, structured information provision, and ongoing genetic support, particularly in the context of emerging ocular therapies, to enhance consistency in information uptake.

Amidst rapid advancements in ocular gene therapy, understanding patient perspectives is crucial for shaping future treatment choices and research directions. This international cross-sectional survey evaluated knowledge, attitudes, and perceptions of ocular genetic therapies among potential recipients with inherited retinal diseases (IRDs). Survey instruments included the Attitudes to Gene Therapy-Eye (AGT-Eye), EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), and Patient Attitudes to Clinical Trials (PACT-22) instruments. This study included 496 participant responses (89% adults with IRDs; 11% parents/guardians/carers) from 35 countries, with most from the United States of America (USA; 69%) and the United Kingdom (11%). Most participants (90%) indicated they would likely accept gene therapy if it was available, despite only 45% agreeing that they had good knowledge of gene therapy. The main sources of information were research registries (60% of participants) and the internet (61%). Compared to data from our recently published Australian national survey of people with IRDs (n = 694), USA respondents had higher knowledge of gene therapy outcomes, and Australian respondents indicated a higher perceived value of gene therapy treatments. Addressing knowledge gaps regarding outcomes and financial implications will be central to ensuring informed consent, promoting shared decision-making, and the eventual clinical adoption of genetic therapies.

PURPOSE: Female carriers of X-linked inherited retinal diseases (IRDs) can show highly variable phenotypes and disease progression. Vascular reactivity, a potential disease biomarker, has not been investigated in female IRD carriers. In this study, functional optical coherence tomography angiography (OCT-A) was used to dynamically assess the retinal microvasculature of X-linked IRD carriers. METHODS: Genetically confirmed female carriers of IRDs (choroideremia or X-linked retinitis pigmentosa), and healthy women were recruited. Macular angiograms (3x3mm, Zeiss Plex Elite 9000) were obtained in 36 eyes of 15 X-linked IRD female carriers and 21 age-matched control women. Two tests were applied to test vascular reactivity: (i) mild hypoxia and (ii) handgrip test, to induce a vasodilatory or vasoconstrictive response, respectively. Changes to vessel density (VD) and vessel length density (VLD) were independently evaluated during each of the tests for both the superficial and deep capillary plexuses. RESULTS: In the control group, the superficial and deep VD decreased during the handgrip test (p<0.001 and p=0.037, respectively). Mean superficial VLD also decreased during the handgrip test (p=0.025), while the deep plexus did not change significantly (p=0.108). During hypoxia, VD and VLD increased in the deep plexus (p=0.027 and p=0.052, respectively) but not in the superficial plexus. In carriers, the physiologic vascular responses seen in controls were not observed in either plexus during either test, with no difference in VD or VLD noted (all p>0.05). CONCLUSIONS: Functional OCT-A is a useful tool to assess dynamic retinal microvascular changes. Subclinical impairment of the physiological vascular responses seen in carriers of X-linked IRDs may serve as a valuable clinical biomarker.

PURPOSE: To describe visual function and retinal features of female carriers of choroideremia (CHM), using multimodal imaging and microperimetry. DESIGN: Cross-sectional cohort study. PARTICIPANTS AND CONTROLS: Choroideremia carriers seen in Australia (Melbourne or Perth) or the United Kingdom (Oxford or Cambridge) between 2012 and 2023. Healthy age-matched controls seen in Melbourne, Australia, between 2022 and 2023. METHODS: Participants had visual acuity, fundus-tracked microperimetry, OCT, and fundus autofluorescence imaging performed. Choroideremia carriers were either genetically or clinically confirmed (i.e., obligate carriers). Choroideremia carriers were grouped according to their retinal phenotype and compared with healthy controls. Statistical analyses were performed on StataBE (v18.0). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), average retinal sensitivity, volume of macular hill of vision (HoV), inner retinal thickness, and photoreceptor complex (PRC) thickness. RESULTS: Eighty-six eyes of 43 CHM carriers and 60 eyes of 30 healthy controls were examined using multimodal imaging and microperimetry. Median age was 54 and 48.5 years for CHM carriers and controls, respectively (P = 0.18). Most CHM carriers (86%) were genetically confirmed. Choroideremia carriers and controls had strong intereye correlation between eyes for BCVA and average retinal sensitivity (P < 0.001). Low-luminance visual acuity and macular HoV tests were sensitive tests to detect changes in CHM carriers with mild phenotypes (i.e., fine and coarse). Choroideremia carriers with geographic or male-pattern phenotypes had reduced BCVA, LLVA, retinal sensitivity, and retinal thinning, compared with healthy controls. Retinal thickening of the inner retina was observed in the central 1°, despite generalized thinning of the PRC in the central 7°, indicating retinal remodeling in CHM carriers, compared with controls. There were no genotype-phen

BACKGROUND: Advancements in genetic testing have led to Usher syndrome now being diagnosed at a much earlier age than in the past, enabling the provision of early intervention and support to children and families. Despite these developments, anecdotal reports suggest there are substantial gaps in the services and supports provided to parents of children with Usher syndrome. The current study investigated the support needs of parents of children with Usher syndrome Type 1 when their child was aged 0 to 5 years. METHOD: Purposive sampling was used, and six semi-structured interviews were conducted with Australian parents of children with Usher syndrome, Type 1. Data was analysed using modified reflexive thematic analysis. RESULTS: Four key themes were identified as being central to the support needs of parents of children with Usher syndrome aged 0 to 5 years. (1) Social Needs referred to parents' need for various sources of social support, (2) Informational Needs described the lack of information parents received regarding Usher syndrome from treating professionals, (3) Practical Needs included supports needed to assist parents in managing the day-to-day tasks of caring for a child with a disability, and (4) Emotional Needs represented the emotional support (both formal and informal) that parents needed to be a positive support to their child. CONCLUSIONS: Findings provide rich information for relevant support groups, policy makers, individual healthcare professionals, and professional governing bodies regarding the education of stakeholders and the development and implementation of best-practice treatment guidelines.

Inherited retinal diseases (IRDs) are a group of heterogeneous conditions that cause progressive vision loss, typically due to monogenic mutations. Female carriers of X-linked IRDs have a single copy of the disease-causing gene, and therefore, may exhibit variable clinical signs that vary from near normal retina to severe disease and vision loss. The relationships between individual genetic mutations and disease severity in X-linked carriers requires further study. This review summarises the current literature surrounding the spectrum of disease seen in female carriers of choroideremia and X-linked retinitis pigmentosa. Various classification systems are contrasted to accurately grade retinal disease. Furthermore, genetic mechanisms at the early embryonic stage are explored to potentially explain the variability of disease seen in female carriers. Future research in this area will provide insight into the association between genotype and retinal phenotypes of female carriers, which will guide in the management of these patients. This review acknowledges the importance of identifying which patients may be at high risk of developing severe symptoms, and therefore should be considered for emerging treatments, such as retinal gene therapy.

Vision loss causes a significant burden on individuals and communities on a financial, emotional and social level. Common causes include age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma and retinitis pigmentosa (RP; also known as 'rod-cone dystrophy'). As the population continues to grow and age globally, an increasing number of people will experience vision loss. Hence, there is an urgent need to develop therapies that can curb early pathological events. The broccoli-derived compound, sulforaphane (SFN), is reported to have multiple health benefits and modes of action. In this review, we outline the preclinical findings on SFN in ocular diseases and discuss the future clinical testing of this compound.

BACKGROUND: Usher syndrome is the most common cause of deaf-blindness, affecting up to 1 in 6000 people. Multidisciplinary care is required to maximize outcomes for individuals and families. This study assessed awareness of Usher Syndrome amongst allied health clinicians who provide care related to the primarily affected senses of hearing and vision, ie, optometry, orthoptics and audiology. METHODS: A prospective cross-sectional online survey of clinicians working in Australian university-affiliated clinics (7 optometry, 1 orthoptics and 4 audiology) was completed between September 2021 and January 2022. Questions were asked about the cause, common symptoms, and awareness of health professions who manage Usher syndrome. RESULTS: The 27 audiologists, 40 optometrists, and 7 orthoptists who completed the survey included 53 females (71.6%), had an average age of 37 years (range 24-70), and had an average duration of clinical experience of 13 years (range 1-45 years). The majority of respondents correctly identified Usher syndrome as a genetic condition (86%), identified at least two of the affected senses (97%), and identified the progressive nature of the vision and hearing losses (>90%). Awareness of vestibular dysfunction and its characteristics was low, as was knowledge of the key treatment roles that speech pathologists, genetic counsellors and geneticists play in the management of Usher Syndrome. The majority of respondents also did not identify important aspects of care within their own discipline. CONCLUSION: This study has shown that there is a need for targeted education to be delivered to hearing and vision care allied health clinicians to raise awareness of the vestibular impacts and aspects of vision loss experienced by people with Usher syndrome. This education needs to target the broad range of clinicians who have a key role in providing multidisciplinary care (including speech pathologists, geneticists, and genetic counsellors) and to identify the key as

PURPOSE: Accurate diagnosis of macular atrophy is paramount to enable appropriate treatment when novel treatments for geographic atrophy and macular dystrophies become available. Genetic testing is useful in distinguishing between the two conditions but is not feasible for the majority of patients in real-world clinical practice. Therefore, we aimed to investigate the potential misdiagnosis of inherited macular dystrophy as age-related macular degeneration (AMD) in real-world ophthalmic practice to assist in the development of guidelines to improve diagnostic accuracy while minimizing genetic testing for targeted patients. METHODS: Retrospective review of the medical records of patients diagnosed with AMD, which included imaging, between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia. We will use a stepwise method to screen for probable cases of macular dystrophy, followed by a consensus review by an expert panel. The outcomes are (1) to determine the potential misdiagnosis rate of macular dystrophy as atrophic AMD by retinal specialists and general ophthalmologists; (2) to identify clinical imaging modalities that are most useful for differentiating macular dystrophy from atrophic AMD; and (3) to establish preliminary guidance for clinicians to improve the diagnosis of macular atrophy from AMD in practice, and thereby target cost-efficient genetic testing. DISCUSSION: Improving the diagnostic accuracy of both AMD and macular dystrophy, while ensuring cost-efficient genetic testing, will improve the targeted treatment of macular diseases when emerging treatments become available.

The relationship between externally applied force and intraocular pressure was determined using an ex-vivo porcine eye model (N=9). Eyes were indented through the sclera with a convex ophthalmodynamometry head (ODM). Intraocular pressure and ophthalmodynamometric force were simultaneously recorded to establish a calibration curve of this indenter head. A calibration coefficient of 0.140 ± 0.009 mmHg/mN was established and was shown to be highly linear (r = 0.998 ± 0.002). Repeat application of ODM resulted in a 0.010 ± 0.002 mmHg/mN increase to the calibration coefficient.Clinical Relevance- ODM has been highlighted as a potential method of non-invasively estimating intracranial pressure. This study provides relevant data for the practical performance of ODM with similar compressive devices.

Many gene therapies are in development for treating people with inherited retinal diseases (IRD). We hypothesized that potential recipients of gene therapy would have knowledge gaps regarding treatment. We aimed to assess knowledge, attitudes, and perceptions of genetic therapies among potential recipients with IRD, using a novel instrument we designed (Attitudes to Gene Therapy-Eye (AGT-Eye)) and their associations with demographic data, self-reported visual status, and tools assessing quality of life and attitudes toward clinical trials using a community-based cross-sectional survey of Australian adults with IRD. AGT-Eye, overall quality of life EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Patient Attitudes to Clinical Trials (PACT-22) instruments were administered. Six hundred and eighty-one people completed the study, 51.7% women of mean age 53.5 years (SD ± 15.8). Most participants (91.6%) indicated they would likely accept gene therapy if it was available to them or family members. However, only 28.3% agreed that they had good knowledge of gene therapy. Most obtained information about gene therapy from the internet (49.3%). Respondents with post-graduate degrees scored highest compared to other educational levels on methods (p < 0.001) and outcomes (p = 0.003) and were more likely to see economic value of treatment (p = 0.043). Knowledge gaps were present regarding methods and outcomes of gene therapy. This survey has shown high level of interest in the IRD community for gene therapies, and highlights areas for improved clinician and patient education.

PURPOSE: Accurate genotyping of individuals with inherited retinal diseases (IRD) is essential for patient management and identifying suitable candidates for gene therapies. This study evaluated the diagnostic yield of next generation sequencing (NGS) in IRDs. DESIGN: Systematic review and meta-analysis. METHODS: This systematic review was prospectively registered (CRD42021293619). Ovid MEDLINE and Ovid Embase were searched on 6 June 2022. Clinical studies evaluating the diagnostic yield of NGS in individuals with IRDs were eligible for inclusion. Risk of bias assessment was performed. Studies were pooled using a random...effects inverse variance model. Sources of heterogeneity were explored using stratified analysis, meta-regression, and sensitivity analysis. RESULTS: This study included 105 publications from 28 countries. Most studies (90 studies) used targeted gene panels. The diagnostic yield of NGS was 61.3% (95% confidence interval: 57.8-64.7%; 51 studies) in mixed IRD phenotypes, 58.2% (51.6-64.6%; 41 studies) in rod-cone dystrophies, 57.7% (46.8-68.3%; eight studies) in macular and cone/cone-rod dystrophies, and 47.6% (95% CI: 41.0-54.3%; four studies) in familial exudative vitreoretinopathy. For mixed IRD phenotypes, a higher diagnostic yield was achieved pooling studies published between 2018-2022 (64.2% [59.5-68.7%]), studies using exome sequencing (73.5% [58.9-86.1%]), and studies using the American College of Medical Genetics variant interpretation standards (65.6% [60.8-70.4%]). CONCLUSION: The current diagnostic yield of NGS in IRDs is between 52-74%. The certainty of the evidence was judged as low or very low. A key limitation of the current evidence is the significant heterogeneity between studies. Adoption of standardized reporting guidelines could improve confidence in future meta-analyses.

BACKGROUND: To assess the prevalence of genetic testing for inherited retinal diseases (IRDs) in a tertiary practice setting. METHODS: Single-centre retrospective analysis of patients with diagnosed or suspected IRD. RESULTS: Four hundred and sixty-four patient records were analysed. Patients had received care for different IRDs grouped as follows: panretinal pigmentary retinopathies (283, 61%), macular dystrophies (136, 29.3%), stationary diseases (23, 5%), hereditary vitreoretinopathies (14, 3%), and other IRDs (8, 1.7%). The suspected pattern of inheritance of patients' IRD was predominantly autosomal recessive (205, 44.2%). Genetic testing was performed with the corresponding results available for 44 patients (9.5%). Diagnostic yield was 65.9% for the results received. Genetic test results were available mostly for younger patients (13.1% for <45 years vs 6.2% ≥45 years of age, p = 0.01) and those who received greater than 12 months of care (16% for ≥12 months vs 4% for <12 months, p < 0.01). For patients without genetic testing results, reasons include awaiting a geneticist consultation (17.9%), awaiting test results (4.5%), or patient refusal (8.4%). Most clinical records (69.2%) did not document genetic testing status. CONCLUSION: Genetic testing is increasingly being utilised in the work-up for patients with IRD worldwide. This large Australian private practice IRD cohort shows a low uptake of testing (around 10%), reflecting historical management patterns and accessibility of genetic counselling and testing. The results show that younger patients and those with a longer duration of care were more likely to have received genetic testing. As the importance of IRD genetic testing continues to increase, we expect to see a change in patient management within the Australian private ophthalmology system and testing rates to increase. Further research is required to identify and address clinician and patient barriers to improving genetic testing rates for IRD.

PURPOSE: To assess the measurement properties of the Attitudes to Gene Therapy for the Eye (AGT-Eye) instrument among Australian adults with inherited retinal diseases (IRDs) and parents/caregivers of people with IRDs. Constructs of interest included sources of information, knowledge of treatment methods, awareness of treatment outcomes, and perceived value of gene therapy for IRDs. METHODS: A cross-sectional, self-reported, 30-item questionnaire was administered in English from January to June 2021. It was predominantly conducted online with phone and paper alternatives available. Rating scale models were generated separately for each of the four subscales to assess fit, discrimination, and differential item functioning of the items, as well as targeting, reliability, and precision of the subscales. Principal components analysis was used to assess dimensionality. RESULTS: Responses from 681 participants (87.1% online, 12.9% phone/mail) were included (ages 18-93 years; 51.7% female). Removal of two poorly performing items slightly improved subscale properties. Item reliability was high for each of the subscales; however, person reliability was suboptimal, with limited ability to stratify participants according to traits (person separation coefficient < 1.8 for each subscale). There was no evidence of differential item functioning by gender, online completion, or patient/caregiver status. Evidence of multidimensionality was detected for two subscales. CONCLUSIONS: Four subscales of the AGT-Eye will be used to analyze operational knowledge and perceived value of ocular gene therapy in Australia. Measurement properties may be improved with the generation of additional items. TRANSLATIONAL RELEVANCE: Physicians can use the AGT-Eye to assess knowledge and expectations of potential recipients of ocular gene therapy for IRDs.

The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are emerging haematological inflammatory biomarkers. However, their significance in retinal vein occlusion (RVO) and its subtypes, branch and central RVO (BRVO and CRVO, respectively), is uncertain. This systematic review and meta-analysis aimed to clarify the association of NLR and PLR with RVO. We searched MEDLINE (Ovid), EMBASE (Ovid) and the Cochrane Library for studies investigating the association of NLR and PLR with RVO from inception to 2 December 2020. We used random-effects inverse-variance modelling to generate pooled effect measures. We used bivariate Bayesian modelling to meta-analyse the ability of NLR and PLR to differ between individuals with and without RVO and performed meta-regression and sensitivity analyses to explore inter-study heterogeneity. Eight studies published encompassing 1059 patients were included for analysis. Both NLR and PLR were significantly elevated in RVO, with pooled mean differences of 0.63 (95% confidence interval (CI) 0.31-0.95) and 21.49 (95% CI 10.03-32.95), respectively. The pooled sensitivity, specificity and area under the Bayesian summary receiver operating characteristic curve were, respectively, 0.629 (95% credible interval (CrI) 0.284-0.872), 0.731 (95% CrI 0.373-0.934) and 0.688 (95% CrI 0.358-0.872) for NLR; and 0.645 (95% CrI 0.456-0.779), 0.616 (95% CrI 0.428-0.761) and 0.621 (95% CrI 0.452-0.741) for PLR. Mean and variability of age and diabetes mellitus prevalence partially explained between-study heterogeneity. NLR and PLR are significantly elevated in RVO. Future research is needed to investigate the potential prognostic value and independence of these findings.

PURPOSE: To report the long-term observations of the electrode-tissue interface and perceptual stability in humans after chronic stimulation with a 44-channel suprachoroidal retinal implant. METHODS: Four subjects (S1-4) with end-stage retinitis pigmentosa received the implant unilaterally (NCT03406416). Electrode impedances, electrode-retina distance (measured using optical coherence tomography imaging), and perceptual thresholds were monitored up to 181 weeks after implantation as the subjects used the prosthesis in the laboratory and in daily life. Stimulation charge density was limited to 32 µC/cm2 per phase. RESULTS: Electrode impedances were stable longitudinally. The electrode-retina distances increased after surgery and then stabilized, and were well-described by an asymptotic exponential model. The stabilization of electrode-retina distances was variable between subjects, stabilizing after 45 weeks for S1, 63 weeks for S2, and 24 weeks for S3 (linear regression; Pgradient > 0.05). For S4, a statistically significant increase in electrode-retina distance persisted (P < 0.05), but by the study end point the rate of increase was clinically insignificant (exponential model: 0.33 µm/wk). Perceptual electrical thresholds were stable in one subject, decreased over time in two subjects (linear model; P < 0.05), and increased slightly in one subject but remained within the predefined charge limits (P = 0.02). CONCLUSIONS: Chronic stimulation with the suprachoroidal retinal prosthesis over 3 years resulted in stable impedances, small individual changes in perceptual electrical thresholds, and no clinically significant increase in electrode-retina distances after a period of settling after surgery. TRANSLATIONAL RELEVANCE: Chronic stimulation with the 44-channel suprachoroidal retinal implant with a charge density of up to 32 µC/cm2 per phase is suitable for long-term use in humans.

BACKGROUND: Emerging treatments are being developed for inherited retinal diseases, requiring a clear understanding of natural progression and a database of potential participants for clinical trials. This article describes the rationale, study design and methodology of the Victorian Evolution of inherited retinal diseases NaTUral history REgistry (VENTURE), including data from the first 150 participants enrolled. METHODS: VENTURE collects retrospective and prospective data from people with inherited retinal diseases. Following registration, participants are asked to attend a baseline examination using a standardised protocol to confirm their inherited retinal disease diagnosis. Examination procedures include (i) retinal function, using visual acuity and perimetry; (ii) retinal structure, using multimodal imaging and (iii) patient-reported outcomes. Participants' molecular diagnoses are obtained from their clinical records or through targeted-panel genetic testing by an independent laboratory. Phenotype and genotype data are used to enrol participants into disease-specific longitudinal cohort sub-studies. RESULTS: From 7 July 2020 to 30 December 2021, VENTURE enrolled 150 registrants (138 families) and most (63%) have a rod-cone dystrophy phenotype. From 93 participants who have received a probable molecular diagnosis, the most common affected genes are RPGR (13% of all registrants), USH2A (10%), CYP4V2 (7%), ABCA4 (5%), and CHM (5%). Most participants have early to moderate vision impairment, with over half (55%) having visual acuities of better than 6/60 (20/200) at registration. CONCLUSIONS: The VENTURE study will complement existing patient registries and help drive inherited retinal disease research in Australia, facilitating access to research opportunities for individuals with inherited retinal diseases.

The optical density of visual pigment can be measured by imaging the dark-adapted eye while bleaching with visible light. This measurement can be made for individual photoreceptor cells using adaptive optics; however, activation of the phototransduction cascade imparts rapid changes in phase that modulate the signal via optical interference. This limits utility because data must be averaged over many experimental runs. Here we used a "flood" illuminated adaptive optics system at 4000 fps, bright light to achieve rapid bleaching, and broad illumination bandwidth to mitigate interference effects. Data were super-resolved using the natural motion of the eye to overcome the reduced pixel resolution of the ultrafast camera. This approach was applied to classify the trichromatic cone photoreceptor mosaic at a single fixation locus within the foveal region of 3 healthy subjects. Subjects were dark adapted for 6 minutes to replenish cone photopigment. This was followed either directly by imaging at 555 ± 50 nm, or by first pre-adapting the retina to 700 nm light to preferentially deplete "L" cone pigment. A total of 3,252 cones were classified as either "S", "M", or "L" type based on clustering of the intensity data observed under these two conditions. Mean classification probability ranged from 99.3 to 99.8%, with individual cell probabilities exceeding 95% in 97.0 to 99.2% of cones. Accuracy of cone classification peaked when using the first 10-30 ms of data, with significant reductions in accuracy noted with the inclusion of data from later times. Our results show that rapid bleaching and data acquisition significantly improve the robustness of cell-resolved densitometry.

PURPOSE: To report the initial safety and efficacy results of a second-generation (44-channel) suprachoroidal retinal prosthesis at 56 weeks after device activation. METHODS: Four subjects, with advanced retinitis pigmentosa and bare-light perception only, enrolled in a phase II trial (NCT03406416). A 44-channel electrode array was implanted in a suprachoroidal pocket. Device stability, efficacy, and adverse events were investigated at 12-week intervals. RESULTS: All four subjects were implanted successfully and there were no device-related serious adverse events. Color fundus photography indicated a mild postoperative subretinal hemorrhage in two recipients, which cleared spontaneously within 2 weeks. Optical coherence tomography confirmed device stability and position under the macula. Screen-based localization accuracy was significantly better for all subjects with device on versus device off. Two subjects were significantly better with the device on in a motion discrimination task at 7, 15, and 30°/s and in a spatial discrimination task at 0.033 cycles per degree. All subjects were more accurate with the device on than device off at walking toward a target on a modified door task, localizing and touching tabletop objects, and detecting obstacles in an obstacle avoidance task. A positive effect of the implant on subjects' daily lives was confirmed by an orientation and mobility assessor and subject self-report. CONCLUSIONS: These interim study data demonstrate that the suprachoroidal prosthesis is safe and provides significant improvements in functional vision, activities of daily living, and observer-rated quality of life. TRANSLATIONAL RELEVANCE: A suprachoroidal prosthesis can provide clinically useful artificial vision while maintaining a safe surgical profile.

Vernier acuity measures the ability to detect a misalignment or positional offset between visual stimuli, for example between two vertical lines when reading a vernier scale. It is considered a form of visual hyperacuity due to its detectable thresholds being considerably smaller than the diameter of a foveal cone receptor, which limits the spatial resolution of classical visual acuity. Vernier acuity relies heavily on cortical processing and is minimally affected by optical media factors, making it a useful indicator of cortical visual function. Vernier acuity can be measured, usually in seconds of arc, by freely available automated online tools as well as via analysis of steady state visual-evoked potentials, which allows measurement in non- or pre-verbal subjects such as infants. Although not routinely measured in clinical practice, vernier acuity is known to be reduced in amblyopia, glaucoma and retinitis pigmentosa, and has been explored as a measure of retinal or neural visual function in the presence of optical media opacities. Current clinical utility includes a home-based vernier acuity tool, preferential hyperacuity perimetry, which is used for screening for choroidal neovascularisation in age-related macular degeneration. This review will discuss the measurement of vernier acuity, provide a current understanding of its neuro-ophthalmic mechanisms, and finally explore its utility through a clinical lens, along with our recommendations for best practice.

PURPOSE: In a clinical trial (NCT03406416) of a second-generation (44-channel) suprachoroidal retinal prosthesis implanted in subjects with late-stage retinitis pigmentosa (RP), we assessed performance in real-world functional visual tasks and emotional well-being. METHODS: The Functional Low-Vision Observer Rated Assessment (FLORA) and Impact of Vision Impairment-Very Low Vision (IVI-VLV) instruments were administered to four subjects before implantation and after device fitting. The FLORA contains 13 self-reported and 35 observer-reported items ranked for ease of conducting task (impossible-easy, central tendency given as mode). The IVI-VLV instrument quantified the impact of low vision on daily activities and emotional well-being. RESULTS: Three subjects completed the FLORA for two years after device fitting; the fourth subject ceased participation in the FLORA after fitting for reasons unrelated to the device. For all subjects at each post-fitting visit, the mode ease of task with device ON was better or equal to device OFF. Ease of task improved over the first six months with device ON, then remained stable. Subjects reported improvements in mobility, functional vision, and quality of life with device ON. The IVI-VLV suggested self-assessed vision-related quality of life was not impacted by device implantation or usage. CONCLUSIONS: Subjects demonstrated sustained improved ease of task scores with device ON compared to OFF, indicating the device has a positive impact in the real-world setting. TRANSLATIONAL RELEVANCE: Our suprachoroidal retinal prosthesis shows potential utility in everyday life, by enabling an increased environmental awareness and improving access to sensory information for people with end-stage RP.

Purpose Age‐related macular degeneration (AMD) is a major cause of vision loss. This study investigated whether performing clinical audit and receiving analytical performance feedback altered documentation of the AMD care provided by optometrists. Methods Australian optometrists were recruited and completed a survey about their demographics and confidence in AMD care, and a three‐month audit of their practice records using an AMD audit tool (termed the pre‐audit evaluation). After receiving analytical feedback, participants identified areas for improvement and re‐audited their practices after three months to analyse changes in performance (termed the post‐audit evaluation). Paired t‐tests and Wilcoxon signed‐rank tests, as appropriate, were used to compare pre‐ and post‐audit data. Results Twenty optometrists, most practising in Victoria, Australia, completed the study. Participants primarily worked in corporate practice and/or rural settings and had a range of optometric experience (2–40 years). At baseline, participants felt confident in their: knowledge of AMD risk factors (65%), advice to patients about these factors (55%) and management of earlier stages of AMD (55%). Each clinician completed (median [IQR]): 15 [IQR: 10–19] and 12 [IQR: 8–16] audits of unique patient records, pre‐ and post‐audit, respectively. Post‐audit, average record documentation (per optometrist) improved for asking about: AMD family history (94% to 100%, p = 0.03), smoking status (21% to 58%, p < 0.01), diet (11% to 29%, p < 0.01) and nutritional supplementation (20% to 51%, p < 0.01). For clinical examination, compliance with documenting pinhole visual acuity, performing an in‐office Amsler grid (upon indication) and using optical coherence tomography improved post‐audit (p < 0.05). Accuracy of severity documentation improved for earlier stages of AMD (p < 0.05). For earlier stages of AMD, documentation of counselling about modifiable risk factors significantly improved post‐audit (p < 0

Purpose: To investigate oculomotor behavior in response to dynamic stimuli in retinal implant recipients. Methods: Three suprachoroidal retinal implant recipients performed a four-alternative forced-choice motion discrimination task over six sessions longitudinally. Stimuli were a single white bar (“moving bar”) or a series of white bars (“moving grating”) sweeping left, right, up, or down across a 42′′ monitor. Performance was compared with normal video processing and scrambled video processing (randomized image-to-electrode mapping to disrupt spatiotemporal structure). Eye and head movement was monitored through-out the task. Results: Two subjects had diminished performance with scrambling, suggesting retinotopic discrimination was used in the normal condition and made smooth pursuit eye movements congruent to the moving bar stimulus direction. These two subjects also made stimulus-related eye movements resembling optokinetic reflex (OKR) for moving grating stimuli, but the movement was incongruent with stimulus direction. The third subject was less adept at the task, appeared primarily reliant on head position cues (head movements were congruent to stimulus direction), and did not exhibit retinotopic discrimination and associated eye movements. Conclusions: Our observation of smooth pursuit indicates residual functionality of corti-cal direction-selective circuits and implies a more naturalistic perception of motion than expected. A distorted OKR implies improper functionality of retinal direction-selective circuits, possibly due to retinal remodeling or the non-selective nature of the electrical stimulation. Translational Relevance: Retinal implant users can make naturalistic eye movements in response to moving stimuli, highlighting the potential for eye tracker feedback to improve perceptual localization and image stabilization in camera-based visual prosthe-ses.

Retinal prostheses are designed to restore a basic sense of sight to people with profound vision loss. They require a relatively intact posterior visual pathway (optic nerve, lateral geniculate nucleus and visual cortex). Retinal implants are options for people with severe stages of retinal degenerative disease such as retinitis pigmentosa and age-related macular degeneration. There have now been three regulatory-approved retinal prostheses. Over five hundred patients have been implanted globally over the past 15 years. Devices generally provide an improved ability to localize high-contrast objects, navigate, and perform basic orientation tasks. Adverse events have included conjunctival erosion, retinal detachment, loss of light perception, and the need for revision surgery, but are rare. There are also specific device risks, including overstimulation (which could cause damage to the retina) or delamination of implanted components, but these are very unlikely. Current challenges include how to improve visual acuity, enlarge the field-of-view, and reduce a complex visual scene to its most salient components through image processing. This review encompasses the work of over 40 individual research groups who have built devices, developed stimulation strategies, or investigated the basic physiology underpinning retinal prostheses. Current technologies are summarized, along with future challenges that face the field.

Translational research in vision prosthetics, gene therapy, optogenetics, stem cell and other forms of transplantation, and sensory substitution is creating new therapeutic options for patients with neural forms of blindness. The technical challenges faced by each of these disciplines differ considerably, but they all face the same challenge of how to assess vision in patients with ultra-low vision (ULV), who will be the earliest subjects to receive new therapies. Historically, there were few tests to assess vision in ULV patients. In the 1990s, the field of visual prosthetics expanded rapidly, and this activity led to a heightened need to develop better tests to quantify end points for clinical studies. Each group tended to develop novel tests, which made it difficult to compare outcomes across groups. The common lack of validation of the tests and the variable use of controls added to the challenge of interpreting the outcomes of these clinical studies. In 2014, at the bi-annual International "Eye and the Chip" meeting of experts in the field of visual prosthetics, a group of interested leaders agreed to work cooperatively to develop the International Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials (HOVER) Taskforce. Under this banner, more than 80 specialists across seven topic areas joined an effort to formulate guidelines for performing and reporting psychophysical tests in humans who participate in clinical trials for visual restoration. This document provides the complete version of the consensus opinions from the HOVER taskforce, which, together with its rules of governance, will be posted on the website of the Henry Ford Department of Ophthalmology (www.artificialvision.org). Research groups or companies that choose to follow these guidelines are encouraged to include a specific statement to that effect in their communications to the public. The Executive Committee of the HOVER Taskforce will maintain a list of all human psychoph

OBJECTIVE: One strategy to improve the effectiveness of prosthetic vision devices is to process incoming images to ensure that key information can be perceived by the user. This paper presents the first comprehensive results of vision function testing for a suprachoroidal retinal prosthetic device utilizing of 20 stimulating electrodes. Further, we investigate whether using image filtering can improve results on a light localization task for implanted participants compared to minimal vision processing. No controlled implanted participant studies have yet investigated whether vision processing methods that are not task-specific can lead to improved results. APPROACH: Three participants with profound vision loss from retinitis pigmentosa were implanted with a suprachoroidal retinal prosthesis. All three completed multiple trials of a light localization test, and one participant completed multiple trials of acuity tests. The visual representations used were: Lanczos2 (a high quality Nyquist bandlimited downsampling filter); minimal vision processing (MVP); wide view regional averaging filtering (WV); scrambled; and, system off. MAIN RESULTS: Using Lanczos2, all three participants successfully completed a light localization task and obtained a significantly higher percentage of correct responses than using MVP ([Formula: see text]) or with system off ([Formula: see text]). Further, in a preliminary result using Lanczos2, one participant successfully completed grating acuity and Landolt C tasks, and showed significantly better performance ([Formula: see text]) compared to WV, scrambled and system off on the grating acuity task. SIGNIFICANCE: Participants successfully completed vision tasks using a 20 electrode suprachoroidal retinal prosthesis. Vision processing with a Nyquist bandlimited image filter has shown an advantage for a light localization task. This result suggests that this and targeted, more advanced vision processing schemes may become important components o

Vision prostheses, or "bionic eyes", are implantable medical bionic devices with the potential to restore rudimentary sight to people with profound vision loss or blindness. In the past two decades, this field has rapidly progressed, and there are now two commercially available retinal prostheses in the US and Europe, and a number of next-generation devices in development. This review provides an update on the development of these devices and a discussion on the future directions for the field.

Since the 1950s, vision researchers have been working towards the ambitious goal of restoring a functional level of vision to the blind via electrical stimulation of the visual pathways. Groups based in Australia, USA, Germany, France and Japan report progress in the translation of retinal visual prosthetics from the experimental to clinical domains, with two retinal visual prostheses having recently received regulatory approval for clinical use. Regulatory approval for cortical visual prostheses is yet to be obtained; however, several groups report plans to conduct clinical trials in the near future, building upon the seminal clinical studies of Brindley and Dobelle. In this review, we discuss the general principles of visual prostheses employing electrical stimulation of the visual pathways, focusing on the retina and visual cortex as the two most extensively studied stimulation sites. We also discuss the surgical and functional outcomes reported to date for retinal and cortical prostheses, concluding with a brief discussion of novel developments in this field and an outlook for the future.

Retinal visual prostheses ("bionic eyes") have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration.

UNLABELLED: Retinal visual prostheses ("bionic eyes") have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration. TRIAL REGISTRATION: Clinicaltrials.gov NCT01603576.

BACKGROUND: Current surgical techniques for retinal prosthetic implantation require long and complicated surgery, which can increase the risk of complications and adverse outcomes. METHOD: The suprachoroidal position is known to be an easier location to access surgically, and so this study aimed to develop a surgical procedure for implanting a prototype suprachoroidal retinal prosthesis. The array implantation procedure was developed in 14 enucleated eyes. A full-thickness scleral incision was made parallel to the intermuscular septum and superotemporal to the lateral rectus muscle. A pocket was created in the suprachoroidal space, and the moulded electrode array was inserted. The scleral incision was closed and scleral anchor point sutured. In 9 of the 14 eyes examined, the device insertion was obstructed by the posterior ciliary neurovascular bundle. Subsequently, the position of this neurovascular bundle in 10 eyes was characterized. Implantation and lead routing procedure was then developed in six human cadavers. The array was tunnelled forward from behind the pinna to the orbit. Next, a lateral canthotomy was made. Lead fixation was established by creating an orbitotomy drilled in the frontal process of the zygomatic bone. The lateral rectus muscle was detached, and implantation was carried out. Finally, pinna to lateral canthus measurements were taken on 61 patients in order to determine optimal lead length. RESULTS: These results identified potential anatomical obstructions and informed the anatomical fitting of the suprachoroidal retinal prosthesis. CONCLUSION: As a result of this work, a straightforward surgical approach for accurate anatomical suprachoroidal array and lead placement was developed for clinical application.

PURPOSE: The safety of chronic implantation of a retinal prosthesis in the suprachoroidal space has not been established. This study aimed to determine the safety of a wide-field suprachoroidal electrode array following chronic implantation using histopathologic techniques and electroretinography. METHODS: A platinum electrode array in a wide silicone substrate was implanted unilaterally in the suprachoroidal space in adult cats (n = 7). The lead and connector were tunneled out of the orbit and positioned subcutaneously. Postsurgical recovery was assessed using fundus photography and electroretinography (ERG). Following 3 months of passive implantation, the animals were terminated and the eyes assessed for the pathologic response to implantation. RESULTS: The implant was mechanically stable in the suprachoroidal space during the course of the study. The implanted eye showed a transient increase in ERG response amplitude at 2 weeks, which returned to normal by 3 months. Pigmentary changes were observed at the distal end of the implant, near the optic disc. Histopathologic assessment revealed a largely intact retina and a thin fibrous capsule around the suprachoroidal implant cavity. The foreign body response was minimal, with sporadic presence of macrophages and no active inflammation. All implanted eyes were negative for bacterial or fungal infections. A midgrade granuloma and thick fibrous buildup surrounded the extraocular cable. Scleral closure was maintained in six of seven eyes. There were no staphylomas or choroidal incarceration. CONCLUSIONS: A wide-field retinal prosthesis was stable and well tolerated during long-term suprachoroidal implantation in a cat model. The surgical approach was reproducible and overall safe.