Purpose. This work is part of a feasibility assessment of a retinal prosthesis as a means to restore vision to patients with blindness caused by retinitis pigmentosa. The primary goal was to assess the concordance of the form of induced perception and the pattern of electrical stimulation of the retina, and the reproducibility of the responses. methods. Five volunteers with severe retinitis pigmentosa and one with normal vision were studied. A companion paper in this issue provides details on demographics, visual function, surgical methods, general stimulation strategy, and data analysis. Volunteers were awake during surgery while a 10-μm-thick, microfabricated electrode array was placed on the retina. The array was connected to extraocular current sources that delivered charges to 50-, 100-, and 400-μm-diameter electrodes. Negative control trials were randomly included. Perceptual quality was judged by the similarity between the form of stimulation and perception (i.e., accuracy) and the reproducibility of responses. results. Only 1 of 40 control tests yielded a false-positive result. On average, volunteers 3, 5, and 6 reported percepts that matched the stimulation pattern 48% and 32% of the time for single- and multiple-electrode trials, respectively. Two-point discrimination in the best cases may have been achieved in two blind subjects using (center-to-center) electrode separation of 600 and 1960 μm. Reproducibility was achieved 66% of the time in the blind subjects. By comparison, in the normal-sighted subject, perceptual form was reported accurately 57% of the time, with 82% reproducibility, and two-point discrimination may have been achieved in one trial with 620-μm electrode spacing and in two trials each with 1860- and 2480-μm electrode spacing. In subjects 5 and 6, perceptual size was inconsistently related to the charge, although relatively large differences in charge (median: 0.55 microcoulombs [μC]) between two trials produced differently sized percepts. Longer stimuli did not produce rounder percepts. conclusions. Single percepts induced by single-electrode stimulation were relatively small, but the form of percepts, especially after multielectrode stimulation, often did not match the stimulation pattern, even in a normal-sighted volunteer. Reproducible percepts were more easily generated than those that matched the stimulation pattern.

Importance: Anecdotal experience raised the possibility that semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA) with rapidly increasing use, is associated with nonarteritic anterior ischemic optic neuropathy (NAION).Objective: To investigate whether there is an association between semaglutide and risk of NAION.Design, Setting, and Participants: In a retrospective matched cohort study using data from a centralized data registry of patients evaluated by neuro-ophthalmologists at 1 academic institution from December 1, 2017, through November 30, 2023, a search for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code H47.01 (ischemic optic neuropathy) and text search yielded 16 827 patients with no history of NAION. Propensity matching was used to assess whether prescribed semaglutide was associated with NAION in patients with type 2 diabetes (T2D) or overweight/obesity, in each case accounting for covarying factors (sex, age, systemic hypertension, T2D, obstructive sleep apnea, obesity, hyperlipidemia, and coronary artery disease) and contraindications for use of semaglutide. The cumulative incidence of NAION was determined with the Kaplan-Meier method and a Cox proportional hazards regression model adjusted for potential confounding comorbidities. Data were analyzed from December 1, 2017, through November 30, 2023.Exposures: Prescriptions for semaglutide vs non–GLP-1 RA medications to manage either T2D or weight.Main Outcomes and Measures: Cumulative incidence and hazard ratio of NAION.Results: Among 16 827 patients, 710 had T2D (194 prescribed semaglutide; 516 prescribed non–GLP-1 RA antidiabetic medications; median [IQR] age, 59 [49-68] years; 369 [52%] female) and 979 were overweight or obese (361 prescribed semaglutide; 618 prescribed non–GLP-1 RA weight-loss medications; median [IQR] age, 47 [32-59] years; 708 [72%] female). In the population with T2D, 17 NAION events occurred in patients prescribed semaglutide vs 6 in the non–GLP-1 RA antidiabetes cohort. The cumulative incidence of NAION for the semaglutide and non–GLP-1 RA cohorts over 36 months was 8.9% (95% CI, 4.5%-13.1%) and 1.8% (95% CI, 0%-3.5%), respectively. A Cox proportional hazards regression model showed higher risk of NAION for patients receiving semaglutide (hazard ratio [HR], 4.28; 95% CI, 1.62-11.29); P < .001). In the population of patients who were overweight or obese, 20 NAION events occurred in the prescribed semaglutide cohort vs 3 in the non–GLP-1 RA cohort. The cumulative incidence of NAION for the semaglutide vs non–GLP-1 RA cohorts over 36 months was 6.7% (95% CI, 3.6%-9.7%) and 0.8% (95% CI, 0%-1.8%), respectively. A Cox proportional hazards regression model showed a higher risk of NAION for patients prescribed semaglutide (HR, 7.64; 95% CI, 2.21-26.36; P < .001).Conclusions and Relevance: This study’s findings suggest an association between semaglutide and NAION. As this was an observational study, future study is required to assess causality.

Purpose. To report methods for performing epiretinal electrical stimulation with microfabricated electrode arrays and determining perceptual thresholds on awake human volunteers during acute surgical trials. methods. Four hypotheses were tested: (1) epiretinal stimulation can be performed during acute experiments without obviously damaging the retina or degrading vision or the health of the eye; (2) perception can be obtained 50% of the time in blind patients with charge densities below published safety limits; (3) the minimal charge needed to induce perception would be higher in patients with more severe retinal degeneration; and (4) threshold charge would be lower at shorter stimulus durations. Five subjects with severe blindness from retinitis pigmentosa and one with normal vision (who underwent enucleation of the eye because of orbital cancer) were studied. Electrical stimulation of the retina was performed on awake volunteers by placing a single 250-μm diameter handheld needle electrode or a 10-μm thick microfabricated array of iridium oxide electrodes (400-, 100-, or 50-μm diameter) on the retina. Current sources outside the eye delivered charge to the electrodes. Assessment of damage was made by observing the clinical appearance of the eyes, comparing pre- and postoperative visual acuity, obtaining retinal histology in one case, and comparing perceptual thresholds with published safety limits. results. No clinically visible damage to the eye or loss of vision occurred. Even at sites removed from stimulation, histology revealed swollen photoreceptor inner and outer segments, which were believed to be nonspecific findings. Percepts could not be reliably elicited with 50-μm diameter electrodes using safe charges in one blind patient. With the two larger electrodes, only the normal-sighted patient had thresholds at charge densities below 0.25 and 1.0 millicoulombs (mC)/cm² for 400- and 100-μm diameter electrodes, respectively, which is one seemingly reasonable estimate of safety derived from the product of charge per phase and charge density per phase. In blind patients, thresholds always exceeded these levels, although most were close to these limits in patient 6. The range of charge density thresholds with the 400-μm electrode in blind patients was 0.28 to 2.8 mC/cm². The normal-sighted patient had a threshold of 0.08 mC/cm² with a 400-μm electrode, roughly one quarter of the lowest threshold in the blind patients. Strength–duration curves obtained in two blind patients revealed the lowest threshold charge at the 0.25- or 1.0-ms stimulus duration. conclusions. Threshold charge densities in severely blind patients were substantially higher than that in a normal-sighted patient. Charge densities in blind patients always exceeded one seemingly reasonable estimate of safe stimulation. The potential adversity of long-term stimulation of the retina by a prosthesis has yet to be determined.

A miniaturized, hermetically encased, wirelessly operated retinal prosthesis has been developed for preclinical studies in the Yucatan minipig, and includes several design improvements over our previously reported device. The prosthesis attaches conformally to the outside of the eye and electrically drives a microfabricated thin-film polyimide array of sputtered iridium oxide film electrodes. This array is implanted into the subretinal space using a customized ab externo surgical technique. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete circuit components. Feedthroughs in the case connect the stimulator chip to secondary power and data receiving coils on the eye and to the electrode array under the retina. Long-term in vitro pulse testing of the electrodes projected a lifetime consistent with typical devices in industry. The final assembly was tested in vitro to verify wireless operation of the system in physiological saline using a custom RF transmitter and primary coils. Stimulation pulse strength, duration, and frequency were programmed wirelessly from a Peripheral Component Interconnect eXtensions for Instrumentation (PXI) computer. Operation of the retinal implant has been verified in two pigs for up to five and a half months by detecting stimulus artifacts generated by the implanted device.

The field of retinal prosthetic research, now more than 20 years old, has produced many high-quality technical options that have the potential to restore vision to patients with acquired disease of the outer retina. Five companies have performed Phase I clinical trials demonstrating that blind patients can reliably report basic elements of visual percepts induced by electrical stimulation. However, at present patients and observers generally do not consider the results to be useful enough in the performance of tasks of daily living to justify the risks of surgery and chronic implantation or the costs. Having developed a wireless device implanted in the subretinal space, the Boston Retinal Implant Project has focused its efforts on developing scalable technologies to create a hermetic device that can deliver individually controlled pulses of electrical stimulation to each of hundreds of electrodes. An advanced device with such attributes will be needed to justify the risks of implantation. An assessment of long-term biocompatibility for all devices remains to be done.