A multinational survey of potential participant perspectives on ocular gene therapy.

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.

Perspectives of carriers of X-linked retinal diseases on genetic testing and gene therapy: A global survey.

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.

Genetic testing and gene therapy in retinal diseases: Knowledge and perceptions of optometrists in Australia and New Zealand.

With advances in gene-based therapies for heritable retinal diseases, primary eye care clinicians should be informed on ocular genetics topics. This cross-sectional survey evaluated knowledge, attitudes, and concerns regarding genetic testing and gene therapy for retinal diseases among optometrists in Australia and New Zealand. Survey data included practitioner background, attitudes and practices towards genetic testing for monogenic inherited retinal disease (IRDs) and age-related macular degeneration, and knowledge of ocular genetics and gene therapy. Responses were received from 516 optometrists between 1 April and 31 December 2022. Key perceived barriers to accessing genetic testing were lack of clarity on referral pathways (81%), cost (65%), and lack of treatment options if a genetic cause is identified (50%). Almost all respondents (98%) believed that ophthalmologists should initiate genetic testing for IRDs and fewer understood the role of genetic counsellors and clinical geneticists. This study found that optometrists in Australia and New Zealand have a high level of interest in ocular genetics topics. However, knowledge gaps include referral pathways and awareness of genetic testing and gene therapy outcomes. Addressing perceived barriers to access and promoting sharing of knowledge between interdisciplinary networks can set the foundation for genetic education agendas in primary eye care.

Functional performance of a vibrotactile sensory substitution device in people with profound vision loss.

SIGNIFICANCE: This study has shown a vibrotactile sensory substitution device (SSD) prototype, VibroSight, has the potential to improve functional outcomes (i.e., obstacle avoidance, face detection) for people with profound vision loss, even with brief familiarization (<20 minutes). PURPOSE: Mobility aids such as long canes are still the mainstay of support for most people with vision loss, but they do have limitations. Emerging technologies such as SSDs are gaining widespread interest in the low vision community. The aim of this project was to assess the efficacy of a prototype vibrotactile SSD for people with profound vision loss in the face detection and obstacle avoidance tasks. METHODS: The VibroSight device was tested in a movement laboratory setting. The first task involved obstacle avoidance, in which participants were asked to walk through an obstacle course. The second was a face detection task, in which participants were asked to step toward the first face they detected. Exit interviews were also conducted to gather user experience data. Both people with low vision (n = 7) and orientation and mobility instructors (n = 4) completed the tasks. RESULTS: In obstacle avoidance task, participants were able to use the device to detect (p<0.001) and avoid (p<0.001) the obstacles within a significantly larger range, but were slower (p<0.001), when compared with without the device. In face detection task, participants demonstrated a great level of accuracy, precision, and sensitivity when using the device. Interviews revealed a positive user experience, although participants identified that they would require a lighter and compact design for real-world use. CONCLUSIONS: Overall, the results verified the functionality of vibrotactile SSD prototype. Further research is warranted to evaluate the user performance after an extended training program and to add new features, such as object recognition software algorithms, into the device.

Survey of perspectives of people with inherited retinal diseases on ocular gene therapy in Australia.

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.

Improving population-level refractive error monitoring via mixture distributions.

INTRODUCTION: Sampling and describing the distribution of refractive error in populations is critical to understanding eye care needs, refractive differences between groups and factors affecting refractive development. We investigated the ability of mixture models to describe refractive error distributions. METHODS: We used key informants to identify raw refractive error datasets and a systematic search strategy to identify published binned datasets of community-representative refractive error. Mixture models combine various component distributions via weighting to describe an observed distribution. We modelled raw refractive error data with a single-Gaussian (normal) distribution, mixtures of two to six Gaussian distributions and an additive model of an exponential and Gaussian (ex-Gaussian) distribution. We tested the relative fitting accuracy of each method via Bayesian Information Criterion (BIC) and then compared the ability of selected models to predict the observed prevalence of refractive error across a range of cut-points for both the raw and binned refractive data. RESULTS: We obtained large raw refractive error datasets from the United States and Korea. The ability of our models to fit the data improved significantly from a single-Gaussian to a two-Gaussian-component additive model and then remained stable with ≥3-Gaussian-component mixture models. Means and standard deviations for BIC relative to 1 for the single-Gaussian model, where lower is better, were 0.89 ± 0.05, 0.88 ± 0.06, 0.89 ± 0.06, 0.89 ± 0.06 and 0.90 ± 0.06 for two-, three-, four-, five- and six-Gaussian-component models, respectively, tested across US and Korean raw data grouped by age decade. Means and standard deviations for the difference between observed and model-based estimates of refractive error prevalence across a range of cut-points for the raw data were -3.0% ± 6.3, 0.5% ± 1.9, 0.6% ± 1.5 and -1.8% ± 4.0 for one-, two- and three-Gaussian-component and ex-Gaussian models, respectively. CONCLUSIONS: Mixture models appear able to describe the population distribution of refractive error accurately, offering significant advantages over commonly quoted simple summary statistics such as mean, standard deviation and prevalence.

The safety and efficacy of gene therapy treatment for monogenic retinal and optic nerve diseases: A systematic review.

PURPOSE: This study aimed to systematically review and summarize gene therapy treatment for monogenic retinal and optic nerve diseases. METHODS: This review was prospectively registered (CRD42021229812). A comprehensive literature search was performed in Ovid MEDLINE, Ovid Embase, Cochrane Central, and clinical trial registries (February 2021). Clinical studies describing DNA-based gene therapy treatments for monogenic posterior ocular diseases were eligible for inclusion. Risk of bias evaluation was performed. Data synthesis was undertaken applying Synthesis Without Meta-analysis guidelines. RESULTS: This study identified 47 full-text publications, 50 conference abstracts, and 54 clinical trial registry entries describing DNA-based ocular gene therapy treatments for 16 different genetic variants. Study summaries and visual representations of safety and efficacy outcomes are presented for 20 unique full-text publications in RPE65-mediated retinal dystrophies, choroideremia, Leber hereditary optic neuropathy, rod-cone dystrophy, achromatopsia, and X-linked retinoschisis. The most common adverse events were related to lid/ocular surface/cornea abnormalities in subretinal gene therapy trials and anterior uveitis in intravitreal gene therapy trials. CONCLUSION: There is a high degree of variability in ocular monogenic gene therapy trials with respect to study design, statistical methodology, and reporting of safety and efficacy outcomes. This review improves the accessibility and transparency in interpreting gene therapy trials to date.

Victorian evolution of inherited retinal diseases natural history registry (VENTURE study): Rationale, methodology and initial participant characteristics.

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.

Clinical audit as an educative tool for optometrists: an intervention study in age-related macular degeneration.

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 < 0.05). Aspects well-performed pre-audit that did not change included documenting: medical histories (100% at both time points, p = 0.06) and retinal imaging (77% at both time points, p = 0.97). CONCLUSIONS: Self-audit with analytical feedback improved clinical record documentation of: AMD risk factors, clinical examination, AMD severity classification and management advice. These findings support a role for audit to improve optometric clinical care of AMD, as evidenced by improved documentation of the AMD care delivered.

Rasch Analysis of the Independent Mobility Questionnaire.

PURPOSE: The Independent Mobility Questionnaire (IMQ) assesses participants' perceived ability for independent mobility. However, it has not been validated in a severely visually impaired population. The aim of this study was to explore the IMQ's psychometric properties in participants with severe visual impairment. METHODS: This was a cross-sectional study of 40 participants with retinitis pigmentosa (better eye visual acuity <20/200 and/or visual field <10%). The key psychometric properties of the IMQ were examined using Rasch analysis, including precision, targeting, and item fit. Construct validity was assessed by testing the correlation between the IMQ and the Mobility and Independence subscale of the Impact of Vision Impairment questionnaire (Pearson correlation coefficient, r). Criterion validity was also assessed. RESULTS: The IMQ had excellent precision (Person Separation Index, 3.01) with the capacity to distinguish at least four strata of participant ability, and item difficulty was well targeted to participant ability (difference between mean person and item measures, -0.21). Items 34, 35, 21, and 14 displayed misfit (infit MnSq >1.4); however, given our sample size restrictions, these items were not removed from the analysis. The IMQ had good construct validity (moderate correlation with the Impact of Vision Impairment Mobility subscale, r = 0.595, p < 0.05) but did not demonstrate criterion validity. CONCLUSIONS: The psychometric properties of the IMQ were promising. Our findings are useful for researchers evaluating the effectiveness of novel treatment technologies on mobility in a severely visually impaired population from the participant's perspective. However, further validation studies in larger samples are required to confirm our results.

Developing a Very Low Vision Orientation and Mobility Test Battery (O&M-VLV).

PURPOSE: This study aimed to determine the feasibility of an assessment of vision-related orientation and mobility (O&M) tasks in persons with severe vision loss. These tasks may be used for future low vision rehabilitation clinical assessments or as outcome measures in vision restoration trials. METHODS: Forty legally blind persons (mean visual acuity logMAR 2.3, or hand movements) with advanced retinitis pigmentosa participated in the Orientation & Mobility-Very Low Vision (O&M-VLV) subtests from the Low Vision Assessment of Daily Activities (LoVADA) protocol. Four categories of tasks were evaluated: route travel in three indoor hospital environments, a room orientation task (the "cafe"), a visual exploration task (the "gallery"), and a modified version of the Timed Up and Go (TUG) test, which assesses re-orientation and route travel. Spatial cognition was assessed using the Stuart Tactile Maps test. Visual acuity and visual fields were measured. RESULTS: A generalized linear regression model showed that a number of measures in the O&M-VLV tasks were related to residual visual function. The percentage of preferred walking speed without an aid on three travel routes was associated with visual field (p < 0.01 for all routes) whereas the number of contacts with obstacles during route travel was associated with acuity (p = 0.001). TUG-LV task time was associated with acuity (p = 0.003), as was the cafe time and distance traveled (p = 0.006 and p < 0.001, respectively). The gallery score was the only measure that was significantly associated with both residual acuity and fields (p < 0.001 and p = 0.001, respectively). CONCLUSIONS: The O&M-VLV was designed to capture key elements of O&M performance in persons with severe vision loss, which is a population not often studied previously. Performance on these tasks was associated with both binocular visual acuity and visual field. This new protocol includes assessments of orientation, which may be of benefit in vision restoration clinical trials.

Safety and efficacy of explanting or replacing suprachoroidal electrode arrays in a feline model.

BACKGROUND: A key requirement for retinal prostheses is the ability for safe removal or replacement. We examined whether suprachoroidal electrode arrays can be removed or replaced after implantation. METHODS: Suprachoroidal electrode arrays were unilaterally implanted into 13 adult felines. After 1 month, arrays were surgically explanted (n = 6), replaced (n = 5) or undisturbed (n = 2). The retina was assessed periodically using fundus photography and optical coherence tomography. Three months after the initial implantation, the function of replaced or undisturbed arrays was assessed by measuring the responses of the visual cortex to retinal electrical stimulation. The histopathology of tissues surrounding the implant was examined. RESULTS: Array explantation or replacement was successful in all cases. Fundus photography showed localized disruption to the tapetum lucidum near the implant's tip in seven subjects following implantation. Although optical coherence tomography showed localized retinal changes, there were no widespread statistically significant differences in the thickness of the retinal layers or choroid. The distance between the electrodes and retina increased after device replacement but returned to control values within eight weeks (P < 0.03). Staphylomas developed near the scleral wound in five animals after device explantation. Device replacement did not alter the cortical evoked potential threshold. Histopathology showed localized outer nuclear layer thinning, tapetal disruption and pseudo-rosette formation, but the overall retinal morphology was preserved. CONCLUSIONS: It is feasible to remove or replace conformable medical grade silicone electrode arrays implanted suprachoroidally. The scleral wound requires careful closure to minimize the risk of staphylomas.

Relationship between retinal microstructures on optical coherence tomography and microperimetry in age-related macular degeneration.

PURPOSE: To determine the relationship between structural parameters of the outer retina on spectral-domain optical coherence tomography (SD-OCT) and microperimetric retinal sensitivity in early stages of age-related macular degeneration (AMD). DESIGN: Prospective, observational study. PARTICIPANTS: Seventy-five eyes of 75 participants with early stages of AMD (drusen ≥ 125 µm, with/without pigmentary abnormalities) and 25 control participants of a similar age. METHODS: Participants underwent microperimetry testing and high-resolution SD-OCT scans. Structural parameters at 5 central points (0°, 1°, and 2.33° nasal and temporal to the fovea along the horizontal axis) corresponding to areas tested by microperimetry were compared. Structural parameters included outer segment (OS) length, thickness and elevation of the retinal pigment epithelium (RPE) band, grading of the inner-segment ellipsoid (ISe) band integrity, and presence of hyperreflective foci (HF). MAIN OUTCOME MEASURES: Relationship between structural parameters and retinal sensitivity. RESULTS: Retinal sensitivity was significantly correlated with RPE elevation (P<0.001), ISe grading (P<0.001), and presence of HF (P ≤ 0.018) at all test points, but not with OS length (P ≥ 0.093) or RPE thickness (P ≥ 0.125). However, multiple linear regression analyses revealed that only ISe grading (P ≤ 0.011) and RPE elevation (P ≤ 0.030) remained significantly associated with retinal sensitivity at all points. By using a simple linear model incorporating ISe grading and RPE elevation to predict values of retinal sensitivity, the 95% limits of agreement between the predicted and the actual value was ± 3.83 dB. CONCLUSIONS: The integrity of the ISe band and drusen-associated RPE elevation are significant independent predictors of microperimetric retinal sensitivity. Our findings imply that these 2 structural parameters may be surrogate markers of retinal function in the early stages of AMD.

Low-luminance visual acuity and microperimetry in age-related macular degeneration.

OBJECTIVE: To compare the effectiveness of low-luminance visual acuity (LLVA) and microperimetry as functional measures in early stages of age-related macular degeneration (AMD). DESIGN: Prospective cross-sectional study. PARTICIPANTS: One hundred seventy-nine participants with a clinical spectrum of non-neovascular AMD and 26 control participants. METHODS: Best-corrected visual acuity (BVCA), LLVA, and microperimetric retinal sensitivity were measured on 1 eye of all participants. Low-luminance deficit (LLD) was calculated as the difference between LLVA and BCVA. The functional parameters were compared between 6 clinical severity groups (from controls to non-foveal geographic atrophy [GA]), and the relationships and magnitude of these parameters were determined and compared. MAIN OUTCOME MEASURES: Visual acuity parameters (BCVA, LLVA, and LLD) and central retinal sensitivity. RESULTS: Best-corrected visual acuity, LLVA, and central retinal sensitivity were reduced significantly for all AMD clinical severity groups when compared with control participants (P ≤ 0.002), except for those with drusen between 63 and 125 µm (P ≥ 0.107). However, LLD was not significantly different from control participants in all groups (P ≥ 0.073), except in the non-foveal GA group (P = 0.008). A significant positive relationship between central retinal sensitivity and LLD (R = 0.613; P < 0.001), but not BCVA, suggests that there is a trend for LLVA to detect a greater extent of functional deficit than BCVA in eyes with increasingly poorer retinal sensitivity. However, the results of the linear regression models estimated central retinal sensitivity to be 6.1, 3.7, and 5.1 standard deviations (SDs) less than normal by the time BCVA, LLVA, and LLD, respectively, were 2 SDs less than normal. CONCLUSIONS: In early stages of AMD, LLVA did not detect a greater extent of functional deficit than BCVA when compared with control participants. Although there was a trend for LLVA to be more effective at detecting foveal deficits than BCVA in eyes with increasingly poorer retinal sensitivity, both visual acuity measures were much less sensitive compared with microperimetry.

Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization.

PURPOSE: To determine whether reticular pseudodrusen (RPD) confer an increased risk of progression to late-stage age-related macular degeneration (AMD) in fellow eyes of those recently diagnosed with unilateral choroidal neovascularization (CNV). DESIGN: Retrospective study. PARTICIPANTS: Two hundred consecutive participants with CNV secondary to AMD in 1 eye and no signs of late-stage AMD in the fellow eye. METHODS: Clinical examination and comprehensive retinal imaging, including spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and color fundus photography, at baseline and every follow-up visit. MAIN OUTCOME MEASURES: Incidence of geographic atrophy (GA) and CNV in the fellow eye. RESULTS: Mean age ± standard deviation was 77±7 years, and 61% of the cohort were female. Fifty-eight percent (n = 116) had RPD, 68% had drusen of 125 µm or more, 36% had pigmentary changes, 10% had both drusen of 125 µm or more and pigmentary changes, and 17% had only RPD in their fellow eyes. After a mean follow-up of 2.3 years, CNV developed in 36% of patients and GA developed in 14% of patients. Those with RPD demonstrated late-stage AMD (61% vs. 33.4%; P <0.001) and GA (22.4% with RPD vs. 2.4% without RPD; P <0.001) more often. The presence of reticular pseudodrusen was an independent risk factor for the development of GA (hazard ratio [HR], 4.93; P = 0.042), but not for CNV (HR, 1.19; P = 0.500), at least within the follow-up of this study. Both drusen of 125 µm or more and pigmentary changes at baseline were significant risk factors for the development of CNV and GA (HR, 1.96-11.73; P ≤0.020). CONCLUSIONS: Reticular pseudodrusen seem to confer an increased risk of progression to GA, in addition to drusen and pigmentary changes. The presence of RPD needs to be taken into account when discussing a patient's prognosis and planning management.

Optical coherence tomography-defined changes preceding the development of drusen-associated atrophy in age-related macular degeneration.

PURPOSE: To characterize the pathological changes preceding the development of drusen-associated atrophy in eyes with age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Longitudinal and cross-sectional retrospective observational study. PARTICIPANTS: A total of 181 participants with intermediate AMD in at least 1 eye (141 unilateral, 40 bilateral) were assessed longitudinally. A total of 230 participants with bilateral intermediate AMD (40 longitudinal participants with an additional 190 participants) were analyzed cross-sectionally. METHODS: Spectral-domain OCT, color fundus photography (CFP), near-infrared reflectance, and fundus autofluorescence imaging were performed in all participants at cross-section and every 3 months for up to 30 months in the longitudinal study. Spectral-domain OCT volume scans were examined for features that portend the development of drusen-associated atrophy, and the topography, prevalence, and risk factors of these features were determined through cross-sectional analysis. MAIN OUTCOME MEASURES: The pathological features on SD-OCT preceding the development of drusen-associated atrophy and the characteristics of these features. RESULTS: Twenty areas from 16 eyes of 16 participants developed drusen-associated atrophy after an average of 20 months (range, 8-30 months). Spectral-domain OCT features unique in these areas included: subsidence of the outer plexiform layer (OPL) and inner nuclear layer (INL), and development of a hyporeflective wedge-shaped band within the limits of the OPL. These characteristics were termed "nascent geographic atrophy" (nGA), describing features that portend the development of drusen-associated atrophy. Cross-sectional examination of participants with bilateral intermediate AMD revealed that independent risk factors for the presence of nGA included the presence of pigmentary changes (odds ratio [OR], 16.84; 95% confidence interval [CI], 2.42-117.24) and nGA in the fellow eye (OR, 4.15; 95% CI, 1.12-15.34); nGA was present in 21.9% of participants with drusen >125 µm and pigmentary changes in both eyes. CONCLUSIONS: This study identified pathological changes occurring before the development of drusen-associated atrophy using SD-OCT, which we defined as nGA. Although nGA is undetectable on CFP, it is important for determining the risk of future vision loss in AMD and could be used as an earlier surrogate end point in interventional trials targeting the early stages of AMD.

Optical coherence tomography-guided retinal prosthesis design: model of degenerated retinal curvature and thickness for patient-specific devices.

Retinitis pigmentosa affects over 1.5 million people worldwide and is a leading cause of vision loss and blindness. While retinal prostheses have shown some success in restoring basic levels of vision, only generic, "one-size-fits-all" devices are currently being implanted. In this study, we used optical coherence tomography scans of the degenerated retina from 88 patients with retinitis pigmentosa to generate models of retinal thickness and curvature for the design of customized implants. We found the average retinal thickness at the fovea to be 152.9 ± 61.3 µm, increasing to a maximum retinal thickness of 250.9 ± 57.5 µm at a nasal eccentricity of 5°. These measures could be used to assist the development of custom-made penetrating electrodes to enhance and optimize epiretinal prostheses. From the retinal thickness measurements, we determined that the optimal length of penetrating electrodes to selectively stimulate retinal ganglion cell bodies and interneuron axons in the ganglion cell layer should be 30-100 µm, and to preferentially stimulate interneurons in the inner nuclear layer, electrodes should be 100-200 µm long. Electrodes greater than 200 µm long had the potential to penetrate through the retina into the choroid, which could cause devastating complications to the eye and should be avoided. The two- and three-dimensional models of retinal thickness developed in this study can be used to design patient-specific epiretinal implants that will help with safety and to optimize the efficacy of neuronal stimulation, ensuring the best functional performance of the device for patients.

Development of a surgical procedure for implantation of a prototype suprachoroidal retinal prosthesis.

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.

Optical coherence tomography in children with inherited retinal disease.

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.

Adaptive optics imaging in inherited retinal diseases: A scoping review of the clinical literature.

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.