Advances in retinal prosthesis systems.

Retinal prosthesis systems have undergone significant advances in the past quarter century, resulting in the development of several different novel surgical and engineering approaches. Encouraging results have demonstrated partial visual restoration, with improvement in both coarse objective function and performance of everyday tasks. To date, four systems have received marketing approval for use in Europe or the United States, with numerous others undergoing preclinical and clinical evaluation, reflecting the established safety profile of these devices for chronic implantation. This progress represents the first notion that the field of visual restorative medicine could offer blind patients a hope of real and measurable benefit. However, there are numerous complex engineering and biophysical obstacles still to be overcome, to reconcile the gap that remains between artificial and natural vision. Current developments in the form of enhanced image processing algorithms and data transfer approaches, combined with emerging nanofabrication and conductive polymerization techniques, herald an exciting and innovative future for retinal prosthetics. This review provides an update of retinal prosthetic systems currently undergoing development and clinical trials while also addressing future challenges in the field, such as the assessment of functional outcomes in ultra-low vision and strategies for tackling existing hardware and software constraints.

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

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

Quantifying Retinal Area in Ultra-Widefield Imaging Using a 3-Dimensional Printed Eye Model.

PURPOSE: To study the effects of different axial lengths on ultra-widefield imaging to determine the presence of distortion in images despite software correction and calculate an enlargement factor based on angular location. DESIGN: Experimental image analysis study. STUDY OBJECTS: Three 3-dimensional printed model eyes simulating eyes with axial lengths of 22, 24, and 26 mm. Each model has a grid of rings 9° apart centered at the posterior pole. METHODS: Single-center study performed at the National Institute for Health Research Moorfields Biomedical Research Centre (London, UK). Each model was imaged using Optos 200TX (Optos, Dunfermline, UK). Two images for each model eye that were corrected using V2 Vantage Pro software (Optos) were used for analysis and the average values obtained. Each image inter-ring area was measured using ImageJ to obtain a measured image area in pixel and square millimeters. This was compared with the true calculated object inter-ring area and an enlargement factor was determined. MAIN OUTCOME MEASURES: Measured image inter-ring area in pixels and square millimeters. True calculated object inter-ring area in square millimeters. RESULTS: The enlargement factor of the rings gradually increases toward the periphery with factors of 1.4 at 45° and 1.9 at the equator. The axial lengths did not affect the enlargement factor of the rings imaged in 3 different model eyes (P = 0.9512). The anterior equator exhibits a significant distortion despite the software correction. CONCLUSION: The enlargement factor depends on angular location and not axial length. The enlargement factors can be used in clinical practice to more accurately measure area in ultra-widefield imaging.

Long-term Repeatability and Reproducibility of Phosphene Characteristics in Chronically Implanted Argus II Retinal Prosthesis Subjects.

PURPOSE: Previously published literatures of acute studies on few subjects have shown contradictory evidence on the reproducibility and characteristics of the elicited phosphenes, despite using the same stimulating parameters with epiretinal electrode arrays. In this study, we set out to investigate the long-term repeatilibity and reproducibility of phosphenes in subjects chronically implanted with the Argus II retinal prosthesis (Second Sight Medical Products, Inc., Sylmar, CA, USA). DESIGN: Retrospective interventional case series and reliability study. METHODS: Six Argus II subjects of >5 years implantation from a single site participated. The 4-electrode cluster ("quad") closest to fovea was stimulated in each subject with a fixed biphasic current. Perceived phosphenes were depicted relative to subjective visual field center. The stimulus was applied at reducing time intervals from 20 minutes to 1 second. Two sets of stimulations were performed on the same day and 2 further sets repeated on a separate visit >1 week apart. RESULTS: Each subject depicted phosphenes of consistent shapes and sizes, and reported seeing the same colors with the fixed stimulating parameters, irrespective of the interstimuli intervals. However, there is a wide intersubject variation in the phosphene characteristics. Four subjects drew phosphenes in the same visual field quadrant, as predicted by the quad-fovea location. Two subjects depicted phosphenes in the same hemifield as the expected locations. CONCLUSION: Phosphenes for each subject were consistently reproducible in all our chronically implanted subjects. This has important implications in the development of long-term pixelated prosthetic vision for future devices.

The potential of the second sight system bionic eye implant for partial sight restoration.

INTRODUCTION: Second Sight System bionic eye implant, a commercially available visual prosthesis developed by Second Sight Medical Products, has been implanted in over 125 patients with outer retinal dystrophies such as retinitis pigmentosa. The system has gained regulatory approval in both the USA and Europe, and aims to restore vision by electrical stimulation of the nerve cells of the inner retina. AREAS COVERED: In this review, we present the safety profile of this implant from the international clinical trial and discuss the nature and levels of improvement in visual function achieved by patients implanted with the system. Expert commentary: Future developments for the system will be explored following the discussion of the current usefulness of the device, its limitation as and the areas in which further development is necessary.

The Argus(®) II Retinal Prosthesis System.

The Argus(®) II Retinal Prosthesis System (Second Sight Medical Products) is the first prosthetic vision device to obtain regulatory approval in both Europe and the USA. As such it has entered the commercial market as a treatment for patients with profound vision loss from end-stage outer retinal disease, predominantly retinitis pigmentosa. To date, over 100 devices have been implanted worldwide, representing the largest group of patients currently treated with visual prostheses. The system works by direct stimulation of the relatively preserved inner retina via epiretinal microelectrodes, thereby replacing the function of the degenerated photoreceptors. Visual information from a glasses-mounted video camera is converted to a pixelated image by an external processor, before being transmitted to the microelectrode array at the macula. Elicited retinal responses are then relayed via the normal optic nerve to the cortex for interpretation. We reviewed the animal and human studies that led to the development of the Argus(®) II device. A sufficiently robust safety profile was demonstrated in the phase I/II clinical trial of 30 patients. Improvement of function in terms of orientation and mobility, target localisation, shape and object recognition, and reading of letters and short unrehearsed words have also been shown. There remains a wide variability in the functional outcomes amongst the patients and the factors contributing to these performance differences are still unclear. Future developments in terms of both software and hardware aimed at improving visual function have been proposed. Further experience in clinical outcomes is being acquired due to increasing implantation.

Punctal function in lacrimal drainage: the 'pipette sign' and functional ectropion.

BACKGROUND: The aim was to assess the movements of the inferior punctum during blinking and discuss pertinent clinical applications. METHODS: This is a prospective, non-comparative observational case-series examining the function of inferior punctum during blinking using video recordings of the blinking action at the slitlamp with slow-motion analysis and comparison. RESULTS: In all 56 eyes of 28 patents, supero-medial movement of the lower punctum toward the medial canthus, together with a medially directed protrusion of the inferior punctum was noted. It was also noted that the punctum blanched during this projectile movement compared to the rest of the lid margin. Simultaneous posterior rotation of the punctum was also observed in 48 eyes (85.7 per cent; 23 right eyes and 25 left eyes), resulting in apposition of the punctum to the lacus lacrimalis. In eight eyes (14.3 per cent; five right eyes and three left) from six patients, co-existence of medial punctal ectropion led to failure of internal rotation of the punctum during blinking, even though punctal 'pipette formation' was preserved. These six patients all suffered from epiphora in the affected eyes. The presence of 'pipette' formation was calculated to have a sensitivity of 80 per cent and specificity of 100 per cent for punctal ectropion in our series. A two-tailed Fisher exact test showed that based on our 56 eyes, these results were statistically significant (p < 0.0001). CONCLUSIONS: The inferior punctum plays an active and important role in the drainage of tears by the mechanism of supero-medial movement and medially directed protrusion ('pipetting action'), failure of which contributes to epiphora. This is a highly specific sign and should be sought in the evaluation of epiphora, even in the absence of frank ectropion. In punctual stenosis where location of the punctal orifice is proving difficult, inducing the pipette sign will help in its identification.

The use of Argus® II retinal prosthesis by blind subjects to achieve localisation and prehension of objects in 3-dimensional space.

BACKGROUND: The Argus® II retinal prosthesis system has entered mainstream treatment for patients blind from Retinitis Pigmentosa (RP). We set out to evaluate the use of this system by blind subjects to achieve object localisation and prehension in 3-dimensional space. METHODS: This is a single-centre, prospective, internally-controlled case series involving 5 blind RP subjects who received the Argus® II implant. The subjects were instructed to visually locate, reach and grasp (i.e. prehension) a small white cuboid object placed at random locations on a black worktop. A flashing LED beacon was attached to the reaching index finger (as a finger marker) to assess the effect of enhanced finger visualisation on performance. Tasks were performed with the prosthesis switched "on" or "off" and with the finger marker switched "on" or "off". Forty-eight trials were performed per subject. Trajectory of each subject's hand movement during the task was recorded by a 3D motion-capture unit (Qualysis®, see supplementary video) and analysed using a MATLAB script. RESULT: Percentage of successful prehension±standard deviation was: 71.3 ± 27.1 % with prosthesis on and finger marker on; 77.5 ± 24.5 % with prosthesis on and finger marker off; 0.0 ± 0.0 % with prosthesis off and finger marker on, and 0.00 ± 0.00 % with prosthesis off and finger marker off. The finger marker did not have a significant effect on performance (P = 0.546 and 1, Wilcoxon Signed Rank test, with prosthesis on and off respectively). With prosthesis off, none of the subjects were able to visually locate the target object and no initiation of prehension was attempted. With prosthesis on, prehension was initiated on 82.5 % (range 59-100 %) of the trials with 89.0 % (range 66.7-100 %) achieving successful prehension. CONCLUSION: Argus® II subjects were able to achieve object localisation and prehension better with their prosthesis switched on than off.

A review and update on the current status of retinal prostheses (bionic eye).

INTRODUCTION/BACKGROUND: The Argus® II is the first retinal prosthesis approved for the treatment of patients blind from retinitis pigmentosa (RP), receiving CE (Conformité Européenne) marking in March 2011 and FDA approval in February 2013. Alpha-IMS followed closely and obtained CE marking in July 2013. Other devices are being developed, some of which are currently in clinical trials. SOURCES OF DATA: A systematic literature search was conducted on PubMED, Google Scholar and IEEExplore. AREAS OF AGREEMENT: Retinal prostheses play a part in restoring vision in blind RP patients providing stable, safe and long-term retinal stimulation. AREAS OF CONTROVERSY: Objective improvement in visual function does not always translate into consistent improvement in the patient's quality of life. Controversy exists over the use of an external image-capturing device versus internally placed photodiode devices. GROWING POINTS: The alpha-IMS, a photovoltaic-based retinal prosthesis recently obtained its CE marking in July 2013. AREAS TIMELY FOR DEVELOPING RESEARCH: Improvement in retinal prosthetic vision depends on: (i) improving visual resolution, (ii) improving the visual field, (iii) developing an accurate neural code for image processing and (iv) improving the biocompatibility of the device to ensure longevity.