Retinal and Optic Nerve Degeneration in Patients with Multiple Sclerosis Followed up for 5 Years.

PURPOSE: To quantify retinal nerve fiber layer (RNFL) changes in patients with multiple sclerosis (MS) and healthy controls with a 5-year follow-up and to analyze correlations between disability progression and RNFL degeneration. DESIGN: Observational and longitudinal study. PARTICIPANTS: One hundred patients with relapsing-remitting MS and 50 healthy controls. METHODS: All participants underwent a complete ophthalmic and electrophysiologic exploration and were re-evaluated annually for 5 years. MAIN OUTCOME MEASURES: Visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (SLP), and visual evoked potentials. Expanded Disability Status Scale (EDSS) scores, disease duration, treatments, prior optic neuritis episodes, and quality of life (QOL; based on the 54-item Multiple Sclerosis Quality of Life Scale score). RESULTS: Optical coherence tomography (OCT) revealed changes in all RNFL thicknesses in both groups. In the MS group, changes were detected in average thickness and in the mean deviation using the GDx-VCC nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) and in the P100 latency of visual evoked potentials; no changes were detected in visual acuity, color vision, or visual fields. Optical coherence tomography showed greater differences in the inferior and temporal RNFL thicknesses in both groups. In MS patients only, OCT revealed a moderate correlation between the increase in EDSS and temporal and superior RNFL thinning. Temporal RNFL thinning based on OCT results was correlated moderately with decreased QOL. CONCLUSIONS: Multiple sclerosis patients exhibit a progressive axonal loss in the optic nerve fiber layer. Retinal nerve fiber layer thinning based on OCT results is a useful marker for assessing MS progression and correlates with increased disability and reduced QOL.

[The Subretinal Implant - Clinical Results]. / Das subretinale Implantat ­ klinische Ergebnisse.

Since the end of the last century, subretinal electronic chips have been used to restore vision in patients blinded by degenerative retinal diseases such as retinitis pigmentosa. Various procedures have been suggested by different international scientific groups. The promising were the retinal-based concepts, for which there are now human data. The two distinct retina-based concepts not only differ in the site of stimulation (epi- or subretinal), but in their physiological concept. Whereas in camera-based systems (epiretinal, transchoroidal), eye movements cannot be used to detect objects, this is possible with subretinal access. It is as yet unclear as to whether this is relevant to restoring some kind of useful visual perception. This and other questions can only be answered by carefully designed human studies with sufficient patient numbers. Comparison of the visual results of the different groups is neither simple nor trivial. The implantations in each project need well trained and skilled retinal surgeons.

[Future Developments in Retinal Prostheses]. / Zukünftige Entwicklungen bei implantierbaren Netzhautprothesen.

Implantable retinal prostheses for the blind are already in use. In blind subjects suffering from retinitis pigmentosa (RP), these systems are able to induce phosphenes. However, the measurable gain in vision is limited. This is due to degeneration in the retina itself and to the technology, which is used in the currently available systems. Research groups and companies are working on solutions and prototypes to improve the outcome of electrical stimulation in the visual system. One improvement will be to enlarge the electrode array in order to restore a larger visual field. A second approach is to enlarge the number of electrodes and to place them at a higher density to improve the spatial resolution of the system. A third concept is to develop a recording unit within the electrode array to analyse ganglion cell behaviour underneath the electrode. This information can than be used to optimise the stimulation pattern. Not only retinal prostheses are under development but also systems to stimulate the retina from the suprachoroidal space, to directly stimulate the optic nerve or the lateral geniculate body or even the primary visual cortex.

Optogenetics.

PURPOSE OF REVIEW: In this review, we will discuss the recent developments in optogenetics and their potential applications in ophthalmology to restore vision in retinal degenerative diseases. RECENT FINDINGS: In recent years, we have seen major advances in the field of optogenetics, providing us with novel opsins for potential applications in the retina. Microbial opsins with improved light sensitivity and red-shifted action spectra allow optogenetic stimulation at light levels well below the safety threshold in the human eye. In parallel, remarkable success in the development of highly efficient viral vectors for ocular gene therapy led to new strategies of using these novel optogenetic tools for vision restoration. SUMMARY: These recent findings show that novel optogenetic tools and viral vectors for ocular gene delivery are now available providing many opportunities to develop potential optogenetic strategies for vision restoration.

Interim results from the international trial of Second Sight's visual prosthesis.

PURPOSE: This study evaluated the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) in blind subjects with severe outer retinal degeneration. DESIGN: Single-arm, prospective, multicenter clinical trial. PARTICIPANTS: Thirty subjects were enrolled in the United States and Europe between June 6, 2007, and August 11, 2009. All subjects were followed up for a minimum of 6 months and up to 2.7 years. METHODS: The electronic stimulator and antenna of the implant were sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed, and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array then was tacked to the epiretinal surface. MAIN OUTCOME MEASURES: The primary safety end points for the trial were the number, severity, and relation of adverse events. Principal performance end points were assessments of visual function as well as performance on orientation and mobility tasks. RESULTS: Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects' mean performance on orientation and mobility tasks was significantly better when the system was on versus off. Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was treated successfully in all subjects except in one, who required explantation of the device without further complications. CONCLUSIONS: The long-term safety results of Second Sight's retinal prosthesis system are acceptable, and most subjects with profound visual loss perform better on visual tasks with system than without it.

Implications of Neural Plasticity in Retinal Prosthesis.

Retinal degenerative diseases such as retinitis pigmentosa cause a progressive loss of photoreceptors that eventually prevents the affected person from perceiving visual sensations. The absence of a visual input produces a neural rewiring cascade that propagates along the visual system. This remodeling occurs first within the retina. Then, subsequent neuroplastic changes take place at higher visual centers in the brain, produced by either the abnormal neural encoding of the visual inputs delivered by the diseased retina or as the result of an adaptation to visual deprivation. While retinal implants can activate the surviving retinal neurons by delivering electric current, the unselective activation patterns of the different neural populations that exist in the retinal layers differ substantially from those in physiologic vision. Therefore, artificially induced neural patterns are being delivered to a brain that has already undergone important neural reconnections. Whether or not the modulation of this neural rewiring can improve the performance for retinal prostheses remains a critical question whose answer may be the enabler of improved functional artificial vision and more personalized neurorehabilitation strategies.

Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates.

Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 1015 photons.cm-2.s-1. Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa.

Psychosocial assessment of potential retinal prosthesis trial participants.

BACKGROUND: As the field of retinal prostheses advances, volunteers are required for device trials, and optimal participant recruitment is vital for intervention success. The aims of this study were: (i) to select tests that assess the psychosocial aspects of visual impairment and develop a psychosocial assessment protocol for persons who may be eligible for participation in retinal prostheses trials; (ii) to investigate correlations between these tests; and (iii) to determine associations between psychosocial factors and a person's interest in participating in a retinal prosthesis (bionic eye) trial. METHODS: Cross-sectional study of 72 adults with advanced retinal degeneration. Questionnaire assessments included personality, cognitive ability, social-support, self-efficacy, coping, optimism, depression, and quality of life (Impact of Vision Impairment Profile ([IVI], and Vision and Quality of Life Index [VisQoL]). Level of interest in a retinal prosthesis was also evaluated. RESULTS: All questionnaires were completed without floor or ceiling effects and with minimal respondent burden. Depression correlated with decreased quality of life (rho = -0.37 and 0.40, p < 0.001 for IVI and VisQoL, respectively). Together, depression, gender and vision-specific coping explained 35.2 per cent of variance in IVI quality of life (p < 0.001). Forty-nine per cent of participants were interested in a retinal prosthesis now and 77 per cent in the future. Although the personality trait of 'openness' was somewhat predictive of interest in retinal prostheses (odds ratio 0.78, 95% CI 0.62-0.97), neither severity of vision impairment nor any of the psychosocial measures were strong predictors. CONCLUSIONS: Several existing psychosocial questionnaires can be used for patients with advanced retinal degeneration and may be useful in exploring suitability for a retinal prosthesis or evaluating outcomes. However, the questionnaires used in this study were not good predictors of whether or not a person might be interested in a retinal prosthesis.

[Development of a minimally invasive retinal implant system]. / Entwicklung eines minimal-invasiven Retinaimplantats.

PURPOSE: It was the aim of this project to develop a minimally invasive prosthetic retinal implant system for the rehabilitation of blind patients suffering from distal retinal degenerations. For this purpose, encoded image information will be transferred to surviving retinal neurons by electrical stimulation applied via intraretinal microelectrodes. METHODS: The technological concept was generated in a feasibility study of alternative approaches to minimally invasive retinal prostheses. Then two series of test implants were fabricated and applied in different in vitro- and in vivo- studies before a long-term implantation trial was initiated. RESULTS: The conceptual design process was resulting in a system with stimulating microelectrodes penetrating the sclera and choroid ab externo, and with all other implant components in episcleral position. Microelectrode penetration and surgical application techniques were successfully tested in several series of experiments. Finally, a long-term application of test devices was successfully initiated. CONCLUSION: Results so far demonstrate the conceptual feasibility, easy-to-perform surgical application, and long-term biocompatibility of the newly designed minimally invasive retinal implant system.

Functional verification of pulse frequency modulation-based image sensor for retinal prosthesis by in vitro electrophysiological experiments using frog retina.

The functioning of a 16 x 16 pixel pulse frequency modulation (PFM) image sensor for retinal prosthesis is verified through in vitro electrophysiological experiments using detached frog retinas. This image sensor is a prototype for demonstrating the application to in vitro electrophysiological experiments. Each pixel of the image sensor consists of a pulse generator (PFM photosensor), a stimulus circuit, and a stimulus electrode (Al bonding pad). The image sensor is fabricated using standard 0.6 microm CMOS technology. For in vitro electrophysiological experiments, a Pt/Au stacked electrode is formed on the Al bonding pad of each pixel and the entire sensor is fixed in epoxy resin. The PFM image sensor is confirmed experimentally to provide electrical stimulus to the retinal cells in a detached frog retina.

Long-term stimulation by active epiretinal implants in normal and RCD1 dogs.

An epiretinal prosthesis, consisting of an extraocular microelectronic stimulator and an intraocular electrode array, was implanted in one eye of three blind and three sighted dogs. Three dogs (2 blind, 1 normal) were stimulated for 120 days, and two dogs (both normal) for 60 and 103 days respectively for 8-10 h/day at levels of 0.1 mC cm(-2) and 0.05 mC cm(-2), with each stimulus level presented to half of the array. One blind dog was kept as an inactive implant control. During the study period, electroretinograms (ERG) and fundus photographs were recorded. At the end of the study period, the dogs were sacrificed and histological and morphometric evaluation was made of the retina. No inflammatory reaction, neovascularization or hemorrhage was observed during the follow-up examinations. ERGs were unchanged. Stimulus levels used were of sufficient amplitude to elicit cortical evoked potentials. Histological evaluation showed no inflammatory infiltrates or changes in retina morphometry related to electrical stimulation when compared to the unstimulated control eye. Morphometric analysis revealed no consistent differences relating to electrical stimulation. In summary, chronic electrical stimulation of the dog retina at up to 0.1 mC cm(-2) with an epiretinal prosthesis does not appear to adversely affect the retina.

Tunable retina encoders for retina implants: why and how.

Current research towards retina implants for partial restoration of vision in blind humans with retinal degenerative dysfunctions focuses on implant and stimulation experiments and technologies. In contrast, our approach takes the availability of an epiretinal multi-electrode neural interface for granted and studies the conditions for successful joint information processing of both retinal prosthesis and brain. Our proposed learning retina encoder (RE) includes information processing modules to simulate the complex mapping operation of parts of the 5-layered neural retina and to provide an iterative, perception-based dialog between RE and human subject. Alternative information processing technologies in the learning RE are being described, which allow an individual optimization of the RE mapping operation by means of iterative tuning with learning algorithms in a dialog between implant wearing subject and RE. The primate visual system is modeled by a retina module (RM) composed of spatio-temporal (ST) filters and a central visual system module (VM). RM performs a mapping 1 of an optical pattern P1 in the physical domain onto a retinal output vector R1(t) in a neural domain, whereas VM performs a mapping 2 of R1(t) in a neural domain onto a visual percept P2 in the perceptual domain. Retinal ganglion cell properties represent non-invertible ST filters in RE, which generate ambiguous output signals. VM generates visual percepts only if the corresponding R1(t) is properly encoded, contains sufficient information, and can be disambiguated. Based on the learning RE and the proposed visual system model, a novel retina encoder (RE*) is proposed, which considers both ambiguity removal and miniature eye movements during fixation. Our simulation results suggest that VM requires miniature eye movements under control of the visual system to retrieve unambiguous patterns P2 corresponding to P1. For retina implant applications, RE* can be tuned to generate optimal ganglion cell codes for epiretinal stimulation.

[Retinal implants. Patients' expectations]. / Retinaimplantate. Erwartungen aus Patientensicht.

The "Pro Retina" Society and the "Retina Implant" Foundation, two patients associations with the goal of "preventing blindness," view the "Retina Implant" project as a possibility for providing blind individuals a modicum of restored vision. Both patients associations cultivated a cooperative relationship with researchers and policy makers already during the research phase, introducing the wishes and concerns of patients into considerations and providing information and the groundwork for acceptance in society and among those who may potentially benefit from the method. An initial survey of patients, the visually impaired, and blind people revealed that recovery of sight not only represents a medical and technical problem but that it also involves numerous psychosocial implications. By adhering to ethical standards in implantations, in particular by taking patient autonomy into consideration, anxieties and fears can be reduced. It would appear from early positive results in a short-term clinical study that soon successful chronic retinal implantation can be expected. The dedication displayed by physicians, researchers, and the industry as well as the willingness of the Federal Ministry for Research to take the risk are appreciated and greatfully accepted by the patients and their relatives.

Light-controlled biphasic current stimulator IC using CMOS image sensors for high-resolution retinal prosthesis and in vitro experimental results with rd1 mouse.

Retinal prosthetic devices stimulate retinal nerve cells with electrical signals proportional to the incident light intensities. For a high-resolution retinal prosthesis, it is necessary to reduce the size of the stimulator pixels as much as possible, because the retinal nerve cells are concentrated in a small area of approximately 5 mm × 5 mm. In this paper, a miniaturized biphasic current stimulator integrated circuit is developed for subretinal stimulation and tested in vitro. The stimulator pixel is miniaturized by using a complementary metal-oxide-semiconductor (CMOS) image sensor composed of three transistors. Compared to a pixel that uses a four-transistor CMOS image sensor, this new design reduces the pixel size by 8.3%. The pixel size is further reduced by simplifying the stimulation-current generating circuit, which provides a 43.9% size reduction when compared to the design reported to be the most advanced version to date for subretinal stimulation. The proposed design is fabricated using a 0.35 µm bipolar-CMOS-DMOS process. Each pixel is designed to fit in a 50 µ m × 55 µm area, which theoretically allows implementing more than 5000 pixels in the 5 mm × 5 mm area. Experimental results show that a biphasic current in the range of 0 to 300 µA at 12 V can be generated as a function of incident light intensities. Results from in vitro experiments with rd1 mice indicate that the proposed method can be effectively used for retinal prosthesis with a high resolution.

Can subretinal microphotodiodes successfully replace degenerated photoreceptors?

The idea of implanting microphotodiode arrays as visual prostheses has aroused controversy on its feasibility from the moment it appeared in print. We now present results which basically support the concept of replacing damaged photoreceptors with subretinally implanted stimulation devices. Network activity in degenerated rat retinae could be modulated through local electrical stimulation in vitro. We also investigated the long term stability and biocompatibility of the subretinal implants and their impact on retinal physiology in rats. Ganzfeld electroretinograms and histology showed no significant side effect of subretinal implants on retinal function or the architecture of the inner retina.

[Subretinal microphotodiode array as replacement for degenerated photoreceptors?]. / Subretinales Mikrophotodioden-Array als Ersatz für degenerierte Photorezeptoren?

A survey is given on the status of developments, concerning a subretinal electronic microphotodiode array that aims at replacing degenerated photoreceptors. Various prototypes have been developed, tested, and implanted in various experimental animals up to 18 months. The fact that electrical responses were recorded from the visual cortex of pigs after electrical stimulation by subretinal electrodes and the fact that responses are also recorded in-vitro in degenerated rat retinae, shows the feasibility of this approach. However, there are a number of open questions concerning the biocompatibility, the long-time stability, and the type of transmitted image to be solved before application in patients can be considered.

[Histological studies of retinal degeneration and biocompatibility of subretinal implants]. / Histologische Untersuchungen zur Netzhautdegeneration und zur Gewebeverträglichkeit subretinaler Implantate.

Two basic biological premises determine the success of replacement of degenerated photoreceptors by a technical implant. First, the neuronal network in the residual retina of patients selected for implantation must still be capable of processing technically generated signals. Secondly, the implant itself must be biocompatible with tissue, i.e. it may not itself induce further degeneration. Our studies in animal models with advanced retinal degeneration and with donor retinas of retinitis pigmentosa patients have shown that even after complete destruction of the photoreceptors and long periods of blindness, the inner retina in the macular area remains for the most part histologically intact, and that all neurons are demonstrably still present and capable of successfully transmitting and processing signals. Biocompatibility of subretinal implants was studied in pigs. After 14 months of implantation, histological examination of tissue covering the implant showed that the inner retina was completely intact. There were no signs of histopathologic changes.

[Physiological functional evaluation of retinal implants in animal models]. / Physiologische Funktionsprüfungen von Retinaimplantaten an Tiermodellen.

Retinal implants can--by electrical stimulation--create visual impressions in people with certain kinds of degenerative retinal diseases (e.g. Retinitis Pigmentosa). Electrically evoked potentials in the retina must be transferred into the visual cortex in an orderly manner, a prerequisite for any kind of form- and movement-perception. In the current developmental stage the difficult investigations are performed in various animal models: isolated retinae of intact chicken and of RCS-rats (a model for Retinitis Pigmentosa), as well as in anesthetised rabbits, pigs and cats with intact retinae. Our investigations show that spatially selective ganglion-cell responses can be recorded following focal electrical stimulation, in healthy and as well in degenerated retinae. Registration of activities in area 17 of the visual cortex demonstrate that electrical retinal stimulation can indeed activate it.

The retina implant--new approach to a visual prosthesis.

Currently, no treatment is available for degenerative diseases of retinal photoreceptors. The patients are faced with a high risk of blindness. Biological approaches failed to prove efficacy. A new concept for the treatment of disorders like retinitis pigmentosa is electrical stimulation at various levels of the visual system. Therefore, devices were fabricated with stimulating electrodes contacting retinal or central neurons to elicit biological activity in these cells. It became possible to fabricate even complex devices with an external power supply encapsulated within biocompatible materials. Animal experiments showed that with implanted prototypes cortical activation could be achieved and first experiments in blind human subject also suggest that vision can be restored, however at present in a very low range of simply identifying spots of light. Further developments and also the continuation of animal experiments are necessary before the clinical application will become a standard procedure.