Robert Wilke

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.

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).

Mutation in the Auxiliary Calcium-Channel Subunit CACNA2D4 Causes Autosomal Recessive Cone Dystrophy

Retinal signal transmission depends on the activity of high voltage-gated l-type calcium channels in photoreceptor ribbon synapses. We recently identified a truncating frameshift mutation in the Cacna2d4 gene in a spontaneous mouse mutant with profound loss of retinal signaling and an abnormal morphology of ribbon synapses in rods and cones. The Cacna2d4 gene encodes an l-type calcium-channel auxiliary subunit of the alpha (2) delta type. Mutations in its human orthologue, CACNA2D4, were not yet known to be associated with a disease. We performed mutation analyses of 34 patients who received an initial diagnosis of night blindness, and, in two affected siblings, we detected a homozygous nucleotide substitution (c.2406C-->A) in CACNA2D4. The mutation introduces a premature stop codon that truncates one-third of the corresponding open reading frame. Both patients share symptoms of slowly progressing cone dystrophy. These findings represent the first report of a mutation in the human CACNA2D4 gene and define a novel gene defect that causes autosomal recessive cone dystrophy.

Extraocular surgery for implantation of an active subretinal visual prosthesis with external connections: feasibility and outcome in seven patients

Background: Due to low energy levels in microphotodiode-based subretinal visual prostheses, an external power supply is mandatory. We report on the surgical feasibility and the functional outcome of the extraocular part of an approach to connect a subretinal prosthesis to an extracorporeal connector in the retro-auricular space via a trans-scleral, transchoroidal cable. Methods: Seven volunteers with retinitis pigmentosa received an active subretinal implant; energy was supplied by gold wires on a trans-sclerally, transchoroidally implanted polyimide foil leading to the lateral orbital rim where it was fixated and connected to a silicone cable. The cable was implanted subperiostally beneath the temporal muscle using a trocar to the retro-auricular space where it penetrated the skin for connection to a stimulator. To avoid subretinal movement of the implant, three tension relief points have been introduced. Results: All implantations were performed as planned without complications, and no serious adverse events occurred in the postoperative period. Fixation of the implants was stable throughout the entire study duration of 4 weeks; permanent skin penetration proved to be uncomplicated. Motility was minimally restricted in downgaze and ab-/adduction. Explantation was uneventful. Conclusion: The above-described procedure provides a method for stable fixation of a subretinal device with a trans-scleral, transchoroidal cable connection to an extracorporeal connector.

Mutation Analysis Identifies GUCY2D as the Major Gene Responsible for Autosomal Dominant Progressive Cone Degeneration

PURPOSE Heterozygous mutations in the GUCY2D gene, which encodes the membrane-bound retinal guanylyl cyclase-1 protein (RetGC-1), have been shown to cause autosomal dominant inherited cone degeneration and cone-rod degeneration (adCD, adCRD). The present study was a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders. METHODS Mutation analysis was performed by direct sequencing as well as PCR and subsequent restriction length polymorphism analysis (PCR/RFLP). Haplotype analysis was performed in selected patients by using microsatellite markers. RESULTS GUCY2D gene mutations were identified in 11 (40%) of 27 patients, and all mutations clustered to codon 838, including two known and one novel missense mutation: p.R838C, p.R838H, and p.R838G. Haplotype analysis showed that among the studied patients only two of the six analyzed p.R838C mutation carriers shared a common haplotype and that none of the p.R838H mutation carriers did. CONCLUSIONS GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. Haplotype analysis indicates that in most cases these mutations arise independently. Thus, codon 838 is likely to be a mutation hotspot in the GUCY2D gene.

Electric crosstalk impairs spatial resolution of multi-electrode arrays in retinal implants

Active multi-electrode arrays are used in vision prostheses, including optic nerve cuffs and cortical and retinal implants for stimulation of neural tissue. For retinal implants, arrays with up to 1500 electrodes are used in clinical trials. The ability to convey information with high spatial resolution is critical for these applications. To assess the extent to which spatial resolution is impaired by electric crosstalk, finite-element simulation of electric field distribution in a simplified passive tissue model of the retina is performed. The effects of electrode size, electrode spacing, distance to target cells, and electrode return configuration (monopolar, tripolar, hexagonal) on spatial resolution is investigated in the form of a mathematical model of electric field distribution. Results show that spatial resolution is impaired with increased distance from the electrode array to the target cells. This effect can be partly compensated by non-monopolar electrode configurations and larger electrode diameters, albeit at the expense of lower pixel densities due to larger covering areas by each stimulation electrode. In applications where multi-electrode arrays can be brought into close proximity to target cells, as presumably with epiretinal implants, smaller electrodes in monopolar configuration can provide the highest spatial resolution. However, if the implantation site is further from the target cells, as is the case in suprachoroidal approaches, hexagonally guarded electrode return configurations can convey higher spatial resolution.

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.

CERKL Mutations and Associated Phenotypes in Seven Spanish Families with Autosomal Recessive Retinitis Pigmentosa

PURPOSE Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinopathies. Up to now, 39 genes and loci have been implicated in nonsyndromic RP, yet the genetic bases of >50% of the cases, particularly of the recessive forms, remain unknown. A novel gene (CERKL) has been described as associated with RP26. It encodes a ceramide kinase that is assumed to be involved in sphingolipid-mediated apoptosis in the retina. This is a report of the phenotypes and genotypes of persons carrying disease-causing mutations in CERKL. METHODS Two hundred ten unrelated Spanish families with nonsyndromic autosomal recessive RP were analyzed for sequence variations. Seven of these families presented a mutation in CERKL. Nine affected persons of these families were clinically investigated, including visual field, electrophysiology, and fundus examination. RESULTS The mutation p.Arg257ter was identified in the homozygous state in all seven affected families. The patients with this variation in CERKL presented a common phenotype with characteristic macular and peripheral lesions. CONCLUSIONS This study presents the first genotype-phenotype correlation for persons carrying p.Arg257ter mutation and provides clues for a characteristic phenotype of these mutations among persons with autosomal recessive cases.

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.).