ABSTRACT

This study presents the long-term clinical results of Argus II retinal prosthesis implantation in eyes with light perception and projection in 3 patients with end-stage retinitis pigmentosa. No conjunctival erosion, hypotony, or implant displacement was observed during postoperative follow-up. The electrical threshold values were lower in the macular region and higher close to the tack fixation region and peripherally. Optical coherence tomography scans showed fibrosis and retinoschisis formation at the retina-implant interface in two cases. This was attributed to mechanical and electrical effects on the tissue due to the active daily use of the system and the electrodes’ proximity to the retina. The patients were able to integrate the system into their daily lives and perform activities that they could not do before. Studies on retinal prostheses for the rehabilitation of hereditary retinal diseases are ongoing, so both social and clinical observations and experiences related to the implant are valuable.

Introduction

Current approaches to human retinal implants are classified as epiretinal, subretinal, suprachoroidal, and scleral (transscleral suprachoroidal).¹ The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA, USA) is an epiretinal prosthesis that is surgically implanted to provide artificial vision to patients with degenerative diseases of the outer retina.^2,3 It consists of external and internal components. The internal electrode array, which consists of 60 microelectrodes 200 µm in diameter arranged in a 6x10 grid, is 9´5.5 mm in size, provides 20° of visual field, and is attached to the retina using a retinal tack. The Argus II implant has both a CE mark and FDA approval, and was implanted in more than 350 patients in numerous countries worldwide (information provided by Second Sight).³ In May 2019, Second Sight Medical Products stopped producing the Argus II Retinal Prosthesis. Thus, no new implantations are being performed, but follow-up of implanted patients and necessary updates continue. In this study, we discuss our experiences before, during, and after implantation in a single center in our country.

Discussion

Studies have indicated that patients who underwent Argus II retinal prosthesis implantation were found to have significantly more successful orientation, mobility, letter reading, reaching for and grasping objects, real-life activities, and reproducible phosphene perception when the device was active than when it was not active, and this success continued.^8,9 The highest spatial resolution obtained with the Argus II retinal prosthesis was reported as 1.8 logMAR (Snellen 20/1262),⁶ and improvements in visual field examinations were also observed after implantation.¹⁰ The patients in our series achieved some abilities while actively using the Argus II epiretinal prosthesis system. Patient 2 was able to perceive obstacles and moving people in a room or corridor and move through without hitting them, find the door and door handle in a room, notice pictures and signs hanging on the wall, notice a plate on a table and find the spoon/fork and food on the plate, notice a contrasting drink in a glass, understand whether a glass is empty or full, and walk faster and more securely using the cane he used before. Patient 1 was able to accurately place high-contrast numbers of approximately 9 cm on a clock face, and patient 3 was able to trace a shape on a white background with her index finger marked black. The patients were able to apply some of these in their daily lives at home with the support of family members, but were mainly motivated when working with the occupational therapist.

In a large series of patients with Argus II implants, 24 adverse events were reported in 40% of patients in 5 years of follow-up, most of which occurred in the first year and consisted of conjunctival erosion, conjunctival dehiscence, hypotony, 3 cases of presumed endophthalmitis, and 1 case of rhegmatogenous retinal detachment.¹¹ With improvements in the surgical procedure, the incidence of hypotony decreased.¹² In a retrospective study of 274 patients who underwent Argus II between 2007 and 2017, conjunctival erosion was the most common adverse effect, observed in 60% of patients in the first 15 months and 85% in the first 2.5 years.¹³ No implant-related complications were observed in any of the patients in our series.

The electrical stimulus threshold can be defined as the current required for the patient to perceive a phosphene. The closer an electrode is to the retinal surface and the macula, and the more cell bodies are around it, the lower this threshold is.¹⁴ Lower thresholds are more desirable in terms of reducing electrode corrosion and enabling electrical stimulation of a large area. However, the situation seen in practice may be different. In one series of 3 cases, lower threshold values and better performance in 2 of the implanted patients were attributed to small implant-retina distance,¹⁵ whereas in another 5-case series evaluating electrical stimulation results based on implant-retina distance, it was reported that the functional relevance of this distance was patient-dependent, that complete apposition was not necessary to achieve good results, and that it could even reduce function by causing retinoschisis.¹⁶ In our study, initial threshold values were relatively higher in patient 1, who was older and had a more atrophic fovea. At 1-year follow-up, implant-retina distance was decreased as a result of reduced retinal cyst formation, and there was a decrease in the threshold values. In patient 3, however, retina-implant contact was only present at the implant margin, there was no direct contact with the electrodes, and threshold values were found to be lower.

Studies in the literature have examined and attempted to explain the development of retinal thickening, retinoschisis, and fibrosis at the implant-retinal interface, which we observed to a mild degree in patient 1 and more dramatically in patient 2 in our study. In a study examining the status of 18 consecutively implanted patients at 6-month follow-up, it was observed that compared to postoperative 1 month, 68.75% of the implants had rotated inferiorly and epiretinal membranes had formed at the implant-retinal interface.¹⁷ In another study of 20 eyes implanted with the Argus II retinal prosthesis and followed up with OCT, hyperreflective tissue resembling fibrosis at the implant-retina interface was observed on OCT in 10 and progression to retinoschisis in 9 of the eyes.¹⁸ In that case series, in which the mean age was 57.4 years and mean follow-up time was 36.8 months, fibrosis onset occurred at 2-33 months and retinoschisis onset occurred at 6-36 months. Retinoschisis showed no changes after development, and implant-retina distance was not associated with the development of fibrosis.¹⁸ The authors speculated that tack irritation or residual vitreous remaining after epiretinal membrane and hyaloid removal may have caused fibrosis and hyperproliferation, while retinoschisis developed secondary to fibrosis-related traction. There was no difference in the patients’ visual functioning while the device was active.¹⁸ However, patient 1 in our series complained of a decline in function, so the fitting procedure was repeated and a revision of the threshold values was needed.

In a 52-year-old patient with RP who did not undergo epiretinal membrane peeling during implantation, retinal thickening and a hyperreflective band at the implant-retinal interface were detected at postoperative 1 year.¹⁹ The highest increase in threshold values corresponding to the area with the thickest fibrosis suggests that the thick fibrosis may have prevented transmission. The authors speculated that electrical stimulation of the retina may have induced local biochemical changes and caused the rapid growth of existing epiretinal fibrosis, and that the slight continuous rotation of the implant may have caused chronic inflammation and fibrotic tissue proliferation by mechanical friction. In fact, based on a histopathological examination of fibrotic tissue surgically removed from the same patient at 2 years post-implantation, it was reported that the pathogenesis was an inflammatory process that led to sclerosis due to increased connective tissue accumulation resulting from a foreign body reaction, and the function of the implant increased after surgery.²⁰ In our series, we believe that long-term electrical stimulation and direct electro-retinal contact led to schisis-like retinal changes in patients 1 and 3, while fibrosis developing around the same time in patient 2 secondary to an excessive inflammatory response. However, postmortem histopathological examination of an eye implanted with the Argus II for 6 years revealed no additional damage in the nerve fiber region corresponding to the implant area and the total neuron count in the macular region did not differ from that in the fellow eye, while the neuron count around the retinal tack was lower compared to other perimacular areas, and fibrotic membrane formation was observed only in and around the tack insertion site.²¹ In a preclinical study of long-term electrical stimulation, hyperfluorescence due to staining in the tack area was observed on follow-up fluorescein angiography and fibrous tissue in the tack area and fibrous proliferation in the surrounding retina were observed on histopathological examination.²² In the first patient in our series, no significant capillary non-perfusion or neovascularization was detected under the implant on OCTA at 1-year follow-up.⁵

In a recent study, the IMIE 256 epiretinal prosthesis containing 256 electrodes was implanted in 5 Chinese patients, 4 with RP and 1 with Usher syndrome, and was explanted after 90 days as per protocol.²³ This implant is based on a working principle similar to that of the Argus II epiretinal prosthesis, with an electrode array 4.75x6.50 mm in size, and 4 of the patients achieved a visual acuity of 20/1200. Studies to improve the safety, feasibility, resolution, and functionality of epiretinal prostheses, especially in patients with end-stage hereditary retinal degeneration, are ongoing. The functional results, clinical findings, anatomical data, and imaging features obtained in the follow-up of patients who have an epiretinal implant and electrically active use of the device are important for establishing cause-effect relationships and directing future projects.