Lauren N. Ayton

First-in-Human Trial of a Novel Suprachoroidal Retinal Prosthesis

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

Intrasession Test-Retest Variability of Microperimetry in Age-Related Macular Degeneration

PURPOSE To determine the intrasession test-retest variability of microperimetry in participants with age-related macular degeneration (AMD). METHODS This study consisted of two separate groups of subjects who had not performed microperimetry previously. In group 1, 30 AMD and 14 control participants performed three microperimetry examinations of a selected eye within one session (test 1 and 2, first pair; test 2 and 3, second pair). Follow-up examination at 6 months was available in 20 AMD participants in group 1, who performed two microperimetry examinations. In group 2, 71 AMD participants performed a short practice examination, then two microperimetry examinations of the right eye (test 1 and 2, first pair) and two of the left eye (test 3 and 4, second pair). RESULTS There was a significant improvement in average point-wise sensitivity (PWS) between the first pair of examination in both groups (P < 0.001), but not in the subsequent pair (P ≥ 0.774). This improvement was not observed at the follow-up visit in the subset of AMD participants in group 1 (P = 0.433). The PWS coefficient of repeatability (CoR) for the second pair of examinations was ± 4.12 dB and ± 4.37 dB for AMD participants for group 1 and 2 respectively. CONCLUSIONS A significant increase in sensitivity between the first and second test, but not in the subsequent tests, was found for participants who had not performed microperimetry previously. Intrasession test-retest variability can therefore be minimized by discarding the first examination to avoid the influence of a learning effect.

A Wide-Field Suprachoroidal Retinal Prosthesis Is Stable and Well Tolerated Following Chronic Implantation

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.

Choroidal thickness profiles in retinitis pigmentosa.

Little quantitative information exists regarding the effect that retinitis pigmentosa (RP) has on the choroid. The aim of this study was to determine choroidal thickness profiles in patients with RP.

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.

Factors affecting perceptual thresholds in a suprachoroidal retinal prosthesis.

PURPOSE The suprachoroidal location for a retinal prosthesis provides advantages over other locations in terms of a simplified surgical procedure and a potentially more stable electrode-neural interface. The aim of this study was to assess the factors affecting perceptual thresholds, and to optimize stimulus parameters to achieve the lowest thresholds in patients implanted with a suprachoroidal retinal prosthesis. METHODS Three patients with profound vision loss from retinitis pigmentosa were implanted with a suprachoroidal array. Perceptual thresholds measured on individual electrodes were analyzed as a function of stimulus (return configuration, pulse polarity, pulse width, interphase gap, and rate), electrode (area and number of ganged electrodes), and clinical (retinal thickness and electrode-retina distance) parameters. RESULTS A total of 92.8% of 904 measurements made up to 680 days post implantation yielded thresholds (range, 44-436 nanocoulombs [nC]) below the safe charge limit. Thresholds were found to vary between individuals and to depend significantly on electrode-retina distance, negligibly on retinal thickness, and not on electrode area or the number of ganged electrodes. Lowest thresholds were achieved when using a monopolar return, anodic-first polarity, short pulse widths (100 μs) combined with long interphase gaps (500 μs), and high stimulation rates (≥400 pulses per second [pps]). CONCLUSIONS With suprachoroidal stimulation, anodic-first pulses with a monopolar return are most efficacious. To enable high rates, an appropriate combination of pulse width and interphase gap must be chosen to ensure low thresholds and electrode voltages. Electrode-retina distance needs to be monitored carefully owing to its influence on thresholds. These results inform implantable stimulator specifications for a suprachoroidal retinal prosthesis. (ClinicalTrials.gov number, NCT01603576.).

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

Current surgical techniques for retinal prosthetic implantation require long and complicated surgery, which can increase the risk of complications and adverse outcomes.

Relationship Between the Second Reflective Band on Optical Coherence Tomography and Multifocal Electroretinography in Age-Related Macular Degeneration

PURPOSE The second hyper-reflective on spectral domain optical coherence tomography (SD-OCT) has been suggested to correlate with the photoreceptor inner segment ellipsoids (ISe). The purpose of our study was to determine the relationship between the intensity of the ISe band and retinal function measured by multifocal electroretinography (mfERG) in patients with early age-related macular degeneration (AMD). METHODS A high-resolution horizontal line scan through the fovea on SD-OCT and an mfERG recording were performed in one eye of 29 early AMD and 31 control participants. The relative intensity of the ISe band within 1000 μm of the fovea was quantified using ImageJ. The relationships between the relative intensity of the ISe band and the mfERG response parameters (P1 amplitude and implicit time) within the three central hexagons along the horizontal axis were determined. RESULTS In normal participants, the relative intensity of the ISe band was significantly correlated with age (r = -0.634, P < 0.001) and also exhibited a topographic variation. On average, the relative intensity of the ISe band was significantly lower in patients with early AMD (1.77 ± 0.26) compared to control subjects (1.95 ± 0.27, P < 0.001) of a similar age range. The relative intensity of the ISe band was correlated significantly with the mfERG P1 implicit time (r = -0.745, P < 0.001), but not P1 amplitude (r = 0.144, P = 0.281). CONCLUSIONS The relative intensity of the ISe band reduced with age and further in early AMD. The relative intensity was significantly correlated with mfERG P1 implicit time.

Developmental Eye Movement Test: What is it Really Measuring?

Purpose. The Developmental Eye Movement (DEM) test is commonly used as a clinical visual-verbal ocular motor assessment tool. However, while the DEM test ratio has been reported to correlate with horizontal saccadic eye movements, there have been no published comparative studies of the DEM test and objective eye movement measures. The aim of this study was to compare DEM test performance with explicit quantification of saccadic eye movements, reading performance, symptomatology and visual processing speed, to assess the validity of the DEM test in clinical practice. Methods. One hundred fifty-eight children aged 8 to 11 years completed the DEM test and a battery of eye movement tasks, recorded by a Microguide 1000 infrared eye tracker. All subjects completed a symptomatology survey. Reading performance and visual processing data was collected for 77 and 75 children, respectively. Results. One hundred twenty-nine of the 158 subjects (81.65%) passed the DEM test. There was no significant correlation between any component of DEM test performance and quantitative eye movement parameters (gain, latency, asymptotic peak velocity, and number of corrective saccades) or symptomatology. There were significant correlations between DEM test outcome and reading performance, and with visual processing speed. Conclusions. DEM test performance does not correlate with saccadic eye movement skills or symptomatology. However, it is related to reading performance and visual processing speed. This study suggests that although DEM test times may not correlate directly with eye movement parameters, they do correlate with aspects of reading performance and thus may serve a diagnostic role in clinical practice.

Fundus autofluorescence characteristics of nascent geographic atrophy in age-related macular degeneration

PURPOSE We examined the fundus autofluorescence (FAF) characteristics of nascent geographic atrophy (nGA), pathological features preceding the development of drusen-associated atrophy in eyes with age-related macular degeneration (AMD) that can be visualized using high-resolution optical coherence tomography (OCT). METHODS Spectral-domain OCT (SD-OCT) and FAF imaging were performed longitudinally in 221 eyes with intermediate AMD (having at least drusen >125 μm), and seven areas that developed drusen-associated atrophy in five eyes were examined and categorized with respect to FAF characteristics. These categories then were used to characterize 49 areas of nGA or drusen-associated atrophy on SD-OCT identified in a cross-sectional study with 230 participants with bilateral intermediate AMD. RESULTS Sequential imaging revealed that FAF characteristics in the atrophic areas could be grouped into three categories: predominantly hyperautofluorescent (hyperAF), presence of both hyper- and hypoautofluorescence (mixed AF), or predominantly hypoautofluorescent (hypoAF). In the cross-sectional study, the FAF characteristics were significantly dependent on the type of atrophic area (P = 0.002), where areas of nGA appeared most commonly as being mixed AF (63%), while areas of drusen-associated atrophy most commonly as hypoAF (86%). CONCLUSIONS Fundus autofluorescence imaging revealed that areas of nGA were most commonly characterized by both hyper- and hypoautofluorescent changes, which differs from areas of drusen-associated atrophy that most often appeared hypoautofluorescent. These findings provide important insights into the FAF characteristics of areas undergoing atrophic changes in eyes still considered to be in the early stages of AMD by current methods, and thus assist in the characterization of disease severity in these early stages.