A. Bruckmann

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).

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.

Positioning of electronic subretinal implants in blind retinitis pigmentosa patients through multimodal assessment of retinal structures

PURPOSE To optimize methods for positioning subretinal visual implants, customizing their cable length, guiding them to the predetermined retinal position, and evaluating their performance. METHODS Ten eyes of 10 patients (6 male, 4 female, mean age 46.4 years) were investigated before implantation of a subretinal visual implant. The structural characteristics of the retina as well as the ocular dimensions were determined. Topographic images of the prospective implantation site were subdivided into grids of squares. Each square received a weighted score for suitability. The sum of the scores was calculated, and the region with the highest score was chosen for the implant. In each case, the implants power supply cable length was calculated by means of magnetic resonance imaging. The planned and achieved positions before and after implantation were compared. RESULTS The mean light sensitivity ratio between the area actually covered by the chip and that of the planned position was 90.8% with an SD of 11.4%. In two cases with almost perfect positioning, the computed ratio was 100%. Measurements showed that to achieve a 95% sensitivity rate the difference between the planned and achieved chip position must be less than 1.7 mm. Preoperative calculations of the intraocular cable length proved accurate in all cases. CONCLUSIONS Preoperative evaluation of retinal structures and eye morphology is useful for guiding a retinal implant to the designated area. It is a meaningful tool for planning and performing retinal chip implantation, and it optimizes personalized implantation. (ClinicalTrials.gov numbers, NCT00515814, NCT01024803.).

Peripheral refraction profiles in subjects with low foveal refractive errors.

Purpose. To study the variability of peripheral refraction in a population of 43 subjects with low foveal refractive errors. Methods. A scan of the refractive error in the vertical pupil meridian of the right eye of 43 subjects (age range, 18 to 80 years, foveal spherical equivalent, <±2.5 diopter) over the central ±45° of the visual field was performed using a recently developed angular scanning photorefractor. Refraction profiles across the visual field were fitted with four different models: (1) “flat model” (refractions about constant across the visual field), (2) “parabolic model” (refractions follow about a parabolic function), (3) “bi-linear model” (linear change of refractions with eccentricity from the fovea to the periphery), and (4) “box model” (“flat” central area with a linear change in refraction from a certain peripheral angle). Based on the minimal residuals of each fit, the subjects were classified into one of the four models. Results. The “box model” accurately described the peripheral refractions in about 50% of the subjects. Peripheral refractions in six subjects were better characterized by a “linear model,” in eight subjects by a “flat model,” and in eight by the “parabolic model.” Even after assignment to one of the models, the variability remained strikingly large, ranging from −0.75 to 6 diopter in the temporal retina at 45° eccentricity. Conclusions. The most common peripheral refraction profile (observed in nearly 50% of our population) was best described by the “box model.” The high variability among subjects may limit attempts to reduce myopia progression with a uniform lens design and may rather call for a customized approach.

Subretinal Microelectrode Arrays Allow Blind Retinitis Pigmentosa Patients to Recognize Letters and Combine them to Words

Eleven patients received subretinal implants, powered and controlled via a subdermal cable ending in a thin intraocular foil, placed transsclerally between the retinal pigment epithelium and the neuroretina. The tip of this foil carries two distinct arrays, a Multiphotodiode Array (MPDA) with 1500 electrodes, each electrode being controlled by an adjacent photodiode and an amplifier within a 3x3x0.1 mm chip, as well as a second array with 16 electrodes, for direct stimulation (DS). Subretinal multielectrode implants with currents close to recognition threshold (10 to 27 nC/electrode) produce retinotopically correct patterns that allow for the first time recognition of individual letters (8 cm high, viewed in appr. 62 cm distance) even at low luminance levels. Stripe patterns of moderate luminance can be resolved up to 0.35 cycles/deg via the subretinal chip. This clearly supports the feasibility of light sensitive subretinal multielectrode devices for restoration of useful visual percepts in blind patients.

Associating the magnitude of relative afferent pupillary defect (RAPD) with visual field indices in glaucoma patients

Purpose To identify the variable with the strongest association between the magnitude of the relative afferent pupillary defect (RAPD) and visual field indices in patients with glaucomatous optic neuropathy. Methods Seventy-nine consecutive subjects with manifest glaucomatous optic neuropathy at least in one eye were enrolled in this retrospective study. RAPD was assessed with the swinging flashlight test and quantified with a neutral density filter. Perimetry was performed using the fast thresholding strategy German Adaptive Threshold Estimation. The values of the central differential luminance sensitivity (DLS), of the MD (mean defect) and of the ‘loss volume’ (LVOL) based on the individually modelled 3D hill of vision—the latter two within the eccentricities of 10°, 20° and 30°, respectively—were entered into a linear regression model without intercept as a function of RAPD. Results An absolute value of RAPD of 0.3 log10 units or more was present in 20 out of 79 glaucoma subjects (25%). The magnitude of RAPD was most closely associated with LVOL-30° (R2=0.77), followed by MD-30° (R2=0.73), MD-20° (R2=0.71), LVOL-20° (R2=0.67), MD-10° (R2=0.58), LVOL-10° (R2=0.54) and central DLS (R2=0.04). Conclusions The prevalence of RAPD in glaucoma patients is comparatively small (25%). The magnitude of RAPD in glaucoma subjects is associated most closely with the LVOL within 30° eccentricity (which is the maximum visual field region tested in this study) and most loosely with central DLS, underscoring the impact of the entire (30°) visual field area on the afferent pupillary system.

Peripheral refraction in pseudophakic eyes measured by infrared scanning photoretinoscopy.

PURPOSE: To obtain quantitative data of peripheral refractive errors in pseudophakic eyes including measurements up to ±45 degrees on the retina. SETTING: University Eye Hospital, Tübingen, Germany. DESIGN: Population‐based cross‐sectional study. METHODS: Pseudophakic and phakic subjects were measured with a purpose‐built scanning photorefractor. The instrument was improved over previous versions. It permits measurement of semicontinuous peripheral profiles over the central 90‐degree field of the retina at a faster speed (4 s/scan). RESULTS: Twenty‐four pseudophakic and 43 phakic subjects were enrolled. The intraocular lenses (IOLs) induced a mean myopic shift of 2.00 diopters (D) at ±45 degrees of eccentricity in the vertical pupil meridian. Ray‐tracing simulations with phakic eye and pseudophakic eye models agreed well with the experimental data. They showed that changes induced by IOLs were a consequence of an increase in astigmatism with eccentricity and a myopic shift in the spherical equivalent. CONCLUSIONS: The peripheral refractions in pseudophakic eyes were more myopic than in phakic eyes as a consequence of the optical design of the IOLs. Whether a more myopic refraction of approximately 2.00 D at 45 degrees has significant effects on visual performance must be tested. Perhaps there is room for improvement in the peripheral optics of IOLs. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.