Argus® II Retinal Prosthesis System: Clinical & Functional Outcomes

Developing artificial visual systems to restore sight in blind patients has long been the dream of scientists, clinicians and the public at large. After decades of research, the greatest success in the field has been achieved with electronic retinal prostheses. To date, 3 retinal prosthetic systems have made the transition from laboratory / clinical research to entering the commercial market for clinical use, namely the Argus® II Retinal Prosthesis System (Second Sight), the alpha-IMS system (Retinal Implant AG), and the IRIS® II (Pixium Vision). The following body of work describes the Argus® II Retinal Prosthesis system, which obtained regulatory approval in the European Economic Area in 2011 (CE marking) and later on in the USA (FDA approval in February 2013), based on the results of an international multi-centre clinical feasibility trial (Clinical Trial identifier: NCT 00407602). This thesis aims to examine the long-term clinical and functional outcomes in an early cohort of subjects chronically implanted with the Argus® II system, from the original feasibility study. A further aim is to elucidate the characteristics of the artificial vision that is perceived and its long-term repeatability and reproducibility in individual subjects. These two broad aims will assist in understanding the nature of the visual performance provided by this device, as well as to add to the current data that is defining the feasibility of constructing predictable pixelated patterns to achieve useful artificial vision in the future. Finally, we explored the feasibility of real-time imaging of visual cortex activation in response to electrical retinal stimulation with the Argus® II system, using functional near infra-red spectroscopy (fNIRS). Development of this real-time imaging tool will enable future investigations into the differences in the cortical activities in response to different stimulations and in different subjects. This may in turn help us understand the variability in their visual performance, as well as to further explore the extent and effect of cross-modal plasticity at the cortical level, in this cohort of patients who have been deprived of visual inputs for decades. Visual function was assessed in terms of: a) form recognition and b) spatial localisation under both 2-dimensional (2D) screen-based laboratory settings and 3-dimensional (3D) paradigms simulating real-life settings. A prospective study of 11 Argus® II subjects showed that the subjects could identify distinct geometric shapes presented in high contrast better with the prosthetic system switched on (median % of correct identification = 20.0%, IQR = 18.8), versus off (median = 12.5%, IQR = 5.0). The accuracy of shapes identification could be further improved by enhancing the outlines of the geometric shape (median = 33.1%, IQR = 21.6). A further prospective study from a subset of 7 subjects showed that this 2D shape identification could be translated into improved identification of 3D objects. These subjects could identify 8 common daily-life objects presented in high contrast with the prosthetic system switched on (median = 31.3%, IQR = 20.3) versus off (median = 12.5%, IQR = 12.5). Scrambling of the transmission signals within the prosthetic system in order to separate light information from form information (i.e. “scrambled mode”) hindered the identification in some but not all subjects (median = 25.0%, IQR = 12.5). The accuracy of object identification could also be improved by enhancing the edges of objects (median = 43.8%, IQR = 15.6). Previously published data showed that Argus® II subjects were able to locate and point to white squares presented on touch screens against a black background more accurately with the prosthetic system switched on versus off. We demonstrated with a prospective study of 5 subjects that they could localise an object on the table, reach out and grasp the object (prehension) with great accuracy (66.7 – 100%) when the prosthetic system was switched on, versus no object prehension (0%) with the system switched off. A prospective study of 6 Argus® II subjects illustrated that while there was a wide variation in the shape and size of the phosphenes perceived by individual subjects, the elicited phosphenes were consistently reproducible in each subject using fixed stimulating parameters, with inter-stimuli intervals ranging from 20 minutes apart, down to 1 second. The perceived location of the phosphenes grossly matched retinotopic agreement, with 4 subjects drawing phosphenes in the same visual field quadrant as predicted by the relative stimulus-fovea position, and 2 subjects depicting phosphenes in the same hemi-field as the expected locations. A retrospective study of 3 Argus® II subjects who underwent MRI brain scan (for unrelated medical reasons) showed that MRI brain scans of up to 1.5 Tesla field strength appeared to have no detrimental effect on the subjects and their implant function. The Argus® II implant produced an artefact of around 50mm x 50mm in size which would prevent visualisation of structures within the orbit, but visualisation of surrounding tissues outside this areas are unaffected. The use of functional MRI as a tool of exploring visual cortex activation in Argus® II subjects was discounted, due to concerns of signal interference from the radiofrequency telemetry of Argus® II system with that of MRI. Subsequently, we have demonstrated in a prospective study that an alternative neuro-imaging technique, functional near infra-red spectroscopy (fNIRS), was capable of capturing real-time cortical activation in 5 out of 6 Argus® II subjects, and maybe a feasible tool for future investigation into cortical function and interactions. The work in this thesis has shown that the Argus® II retinal prosthesis system could improve visual function both in terms of form recognition, as well as object localisation in 3D in situations simulating real-life settings, in a cohort of patients with end-stage retinitis pigmentosa or other outer retinal diseases such as choroideremia. The wide variation in the visual performance level observed could in part be attributable to the diversity in the phosphene features perceived by these subjects. Nevertheless, the consistency and reproducibility with which these phosphenes could be elicited, with fixed stimulating parameters within each subject, provides an encouraging basis for the construction of more complicated pixelated images. Future work to determine the underlying factors influencing the perceived phosphene characteristics, may allow for better prediction of functional outcome, which could in turn be useful for patient selection and tailored preoperative counselling. For those subjects already implanted with the Argus® II system, future work into determining the suitable stimulating parameters for each electrode / quad stimulation may be required for individual subjects, to achieve the construction of optimised and useful, pixelated prosthetic vision