Tobias Peters

Subretinal electronic chips allow blind patients to read letters and combine them to words

A light-sensitive, externally powered microchip was surgically implanted subretinally near the macular region of volunteers blind from hereditary retinal dystrophy. The implant contains an array of 1500 active microphotodiodes (‘chip’), each with its own amplifier and local stimulation electrode. At the implants tip, another array of 16 wire-connected electrodes allows light-independent direct stimulation and testing of the neuron–electrode interface. Visual scenes are projected naturally through the eyes lens onto the chip under the transparent retina. The chip generates a corresponding pattern of 38 × 40 pixels, each releasing light-intensity-dependent electric stimulation pulses. Subsequently, three previously blind persons could locate bright objects on a dark table, two of whom could discern grating patterns. One of these patients was able to correctly describe and name objects like a fork or knife on a table, geometric patterns, different kinds of fruit and discern shades of grey with only 15 per cent contrast. Without a training period, the regained visual functions enabled him to localize and approach persons in a room freely and to read large letters as complete words after several years of blindness. These results demonstrate for the first time that subretinal micro-electrode arrays with 1500 photodiodes can create detailed meaningful visual perception in previously blind individuals.

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm2 chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s−1), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037 or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implants power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.

Spatial Resolution and Perception of Patterns Mediated by a Subretinal 16-Electrode Array in Patients Blinded by Hereditary Retinal Dystrophies

PURPOSE The perception of 11 persons blinded by hereditary retinal degeneration elicited by a subretinally implanted 16-electrode array used for light-independent direct stimulation of the retina is described. This device is part of the Tübingen retina implant, which also employs a light-sensitive, multiphotodiode array (MPDA). The ability to reliably recognize complex spatial percepts was investigated. METHODS Eleven blind volunteers received implants and participated in standardized psychophysical tests investigating the size and shape of perceptions elicited by single-electrode activation, multiple-electrode activation, and activation of compound patterns such as simplified letters. RESULTS Visual percepts were elicited reliably in 8 of 11 patients. On single-electrode activation, percepts were generally described as round spots of light of distinguishable localization in the visual field. On activation of a pattern of electrodes, percepts matched that pattern when electrodes were activated sequentially. Patterns such as horizontal or vertical bars were identified reliably; the most recent participant was able to recognize simplified letters presented on the 16-electrode array. The smallest distance between sites of concurrent retinal stimulation still yielding discernible spots of light was assessed to be 280 μm, corresponding to a logMAR of 1.78. CONCLUSIONS Subretinal electric stimulation can yield reliable, predictable percepts. Patterned perception is feasible, enabling blind persons to recognize shapes and discriminate different letters. Stimulation paradigms must be optimized, to further increase spatial resolution, demanding a better understanding of physical and biological effects of single versus repetitive stimulation (ClinicalTrials.gov number, NCT00515814).

Subretinal Visual Implant Alpha IMS – Clinical trial interim report

A subretinal visual implant (Alpha IMS, Retina Implant AG, Reutlingen, Germany) was implanted in 29 blind participants with outer retinal degeneration in an international multicenter clinical trial. Primary efficacy endpoints of the study protocol were a significant improvement of activities of daily living and mobility to be assessed by activities of daily living tasks, recognition tasks, mobility, or a combination thereof. Secondary efficacy endpoints were a significant improvement of visual acuity/light perception and/or object recognition (clinicaltrials.gov, NCT01024803). During up to 12 months observation time twenty-one participants (72%) reached the primary endpoints, of which thirteen participants (45%) reported restoration of visual function which they use in daily life. Additionally, detection, localization, and identification of objects were significantly better with the implant power switched on in the first 3 months. Twenty-five participants (86%) reached the secondary endpoints. Measurable grating acuity was up to 3.3 cycles per degree, visual acuities using standardized Landolt C-rings were 20/2000, 20/2000, 20/606 and 20/546. Maximal correct motion perception ranged from 3 to 35 degrees per second. These results show that subretinal implants can restore very-low-vision or low vision in blind (light perception or less) patients with end-stage hereditary retinal degenerations.

Transcorneal Electrical Stimulation for Patients with Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Exploratory Study

PURPOSE To assess the safety of transcorneal electrical stimulation (TES) and explore its efficacy in various subjective and objective parameters of visual function in patients with retinitis pigmentosa (RP). METHODS Twenty-four patients in this prospective, randomized, partially blinded, good-clinical-practice study underwent TES (5-ms biphasic pulses; 20 Hz; DTL electrodes) 30 minutes per week for 6 consecutive weeks. The patients were randomly assigned to one of three groups: sham, 66%, or 150% of individual electrical phosphene threshold (EPT). Visual acuity (VA), visual field (VF; kinetic, static), electroretinography (Ganzfeld, multifocal), dark-adaptation (DA), color discrimination, and EPTs were assessed at all visits or four times, according to the study plan. RESULTS TES using DTL electrodes was tolerated well; all patients finished the study. Two adverse (foreign body sensation), but no serious adverse events were encountered. There was a tendency for most functional parameters to improve (8/18) or to remain constant (8/18) in the 150% group. VF area and scotopic b-wave amplitude reached statistical significance (P < 0.027 and P < 0.001, respectively). Only desaturated color discrimination and VF mean sensitivity decreased. There was no obvious trend in the 66% group. CONCLUSIONS TES was found to be safe in RP patients. Positive trends were discovered, but due to the small sample size of this exploratory study, statistical significance was reached only for VF area and scotopic b-wave amplitude. Further studies with larger sample sizes and longer duration are needed to confirm the findings and to define optimal stimulation parameters. (ClinicalTrials.gov number, NCT00804102.).

Safety and efficacy of subretinal visual implants in humans: methodological aspects

Replacing the function of visual pathway neurons by electronic implants is a novel approach presently explored by various groups in basic research and clinical trials. The novelty raises unexplored methodological aspects of clinical trial design that may require adaptation and validation.

Restoration of useful vision up to letter recognition capabilities using subretinal microphotodiodes

Our group has developed a subretinal microphotodiode array for restoration of vision. In a clinical pilot study the array has been implanted in 11 patients suffering from photoreceptor degenerations. Here we present promising results from some of those patients where the retinal tissue above the chip was functional and the implant fulfilled its expected function. A spatial resolution of approximately 0.3 cycles/degree could be achieved with fine stripe patterns. In one subject where the implant had been placed directly under the macular region of the retina a visual acuity of 20/1000 could be measured. Artificially restored visual acuity of this quality has not been reported previously. Finally, we present images illustrating an approximation of how the visual perceptions might have appeared to the subjects, based on a mathematical model and patient reports.

Implantation of ultrathin, biofunctionalized polyimide membranes into the subretinal space of rats.

Subretinal implants aim to replace the photoreceptor function in patients suffering from degenerative retinal disease by topically applying electrical stimuli in the subretinal space. Critical obstacles in the design of high-resolution subretinal implants include the proximity of stimulating electrodes to the target cells and enabling nutrient flow between the retina and the choroid. The present work evaluates the adhesion, migration and survival of retinal cells on an ultrathin (5 μm), highly porous (Ø 1 μm spaced 3 μm), gelatin-coated polyimide (PI) membrane. The biocompatibility was examined in mice indicating a good tolerance upon subcutaneous implantation with only a mild inflammatory response. In addition, organotypic cultures of rat retina evidenced that the porous membrane allowed the necessary nutrient flow for the retinal cell survival and maintenance. A transscleral implantation technique was applied to position the membrane into the subretinal space of rats. The effect on the obtained retinal integration was investigated in vivo using scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT). In 12 out of 18 rat eyes, the implant was successfully placed subretinally. SLO and OCT demonstrated complete retinal attachment and fluorescein angiography showed no retinal vascular abnormalities over and around the implant, immediately after and up to four weeks after the implantation. Histological examination of the eyes showed a close attachment of a thin fibrocyte layer to the implant, the occlusion of the pores by living cells and the survival of some photoreceptors at the implantation site.

Safety evaluation of “retina implant alpha IMS”—a prospective clinical trial

BackgroundTo restore vision in patients with retinitis pigmentosa, several types of electronic devices have been developed to stimulate neurons at different levels along the visual pathway. Subretinal stimulation of the retina with the Retina Implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) has been demonstrated to provide useful vision in daily life. Here we evaluated the safety of this device.MethodsAn interventional, prospective, multi-center, single-arm study was conducted in patients with retinitis pigmentosa with the Retina Implant Alpha IMS. The results from the first nine patients of a single center regarding safety of the device are reported. Any untoward medical occurrence related or unrelated to the tested device was documented and evaluated.ResultsNine adult subjects were included in the study at the Tübingen site. Seventy-five adverse events occurred in total, and 53 affected the eye and its adnexa. Thirty-one ocular adverse events had a relationship to the implant that was classified as “certain” while 19 had a probable or possible relationship; three had no relationship to the implant. Thirty-nine ocular adverse events resolved without sequelae, two resolved with sequelae, 11 remained unresolved, and in one the status was unknown. The intensity of ocular adverse events was mild in the majority of cases (n = 45), while six were of moderate and two of severe intensity. There was no non-ocular adverse event with certain relationship to the device. One subject lost light perception (without light localization) in her study eye.ConclusionsIn conclusion, this prospective study, “Safety and Efficacy of Subretinal Implants for Partial Restoration of Vision in Blind Patients,” shows that the Retina Implant Alpha IMS is an option for restoring vision using a subretinal stimulation device with a clinically acceptable safety profile.

The prevalence of relative afferent pupillary defects in normal subjects.

Background: Observational and pupillographic studies of small numbers of normal subjects have shown that a small (<0.3 log units) relative afferent pupil defect (RAPD) is present in a minority. We have extended the investigation of the prevalence of RAPD to a larger number of normal subjects. Methods: A total of 102 subjects were examined by observation and pupillography. The swinging flashlight test was performed using neutral density filters for quantification. During the pupillographic procedure, light-emitting diodes were placed in front of each eye, alternately flashing for 2.5 seconds with a 0.5 second break. A binocular real-time pupillometer recorded the direct and consensual pupillary responses. After artefact detection and removal, the amplitudes of pupillary response were determined and plotted against stimulus intensity. The means of the direct and the consensual responses were used for automated calculation of RAPD. Results: By observation, there was no RAPD in 87 (85%) subjects; there was an RAPD of 0.15 log units in 13 (13%), and an RAPD of 0.3 log units in 2 (2%). By pupillography, there was an RAPD of 0.07 log units in 53 (52%) subjects, an RAPD between 0.08 and 0.22 log units in 43 (42%) subjects, and an RAPD between 0.23 and 0.39 log units in 6 (6%) subjects. Conclusions: Observation and pupillographic measurements of the swinging light test in a large normal subject cohort has confirmed that an RAPD is present in a small minority but that it does not exceed 0.39 log units. The RAPD in these subjects may be explained by inaccuracy of measurement or by asymmetries in the connections between visual pathways and pretectal nuclei in the midbrain.