The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer ...retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP.
Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II.
Thirty participants in 10 centers in the United States and Europe.
The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina.
The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks.
Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks.
The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada.
Background
The development of a functional retinal prosthesis for acquired blindness is a great challenge. Rapid progress in the field over the last 15 years would not have been possible without ...extensive animal experimentation pertaining to device design and fabrication, biocompatibility, stimulation parameters and functional responses. This paper presents an overview of in vivo animal research related to retinal prosthetics, and aims to summarize the relevant studies.
Methods
A Pubmed search of the English language literature was performed. The key search terms were: retinal implant, retinal prosthesis, artificial vision, rat, rabbit, cat, dog, sheep, pig, minipig. In addition a manual search was performed based on references quoted in the articles retrieved through Pubmed.
Results
We identified 50 articles relevant to in vivo animal experimentation directly related to the development of a retinal implant. The highest number of publications related to the cat (
n
= 18).
Conclusion
The contribution of animal models to the development of retinal prosthetic devices has been enormous, and has led to human feasibility studies. Grey areas remain regarding long-term tissue-implant interactions, biomaterials, prosthesis design and neural adaptation. Animals will continue to play a key role in this rapidly evolving field.
Retinal prostheses are being developed to restore vision in blind patients with photoreceptor degeneration. Electrodes arrays were subretinally implanted in transgenic P23H rats with their ...photoreceptors degenerated. Electrical stability of the implants was evaluated by long-term monitoring of their impedance changes. Electrode impedances were found to increase by two log units over a three weeks period whereas no impedance increase was noted when the implants were located in the vitreous. In case of hemorrhage or major fibrous reactions, the impedance continued to increase steadily. After explantation, it recovered its initial value indicating no deterioration of the implant. Although the glial cell layer at the surface of the subretinal space was slightly larger, no major glial reaction was seen in direct contact to the implant. These results indicate that no functional testing should be considered before at least three weeks post implantation.
To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients.
This retrospective analysis ...followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing.
Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years.
Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.
To determine the viral diagnosis and factors affecting the visual outcome of eyes with acute retinal necrosis.
Nonrandomized, retrospective, interventional, noncomparative series.
A cohort of 22 ...human immunodeficiency virus-negative patients with acute retinal necrosis (ARN). There were 17 unilateral and 5 bilateral cases.
Diagnostic vitreous biopsy for polymerase chain reaction (PCR) viral DNA analysis, prophylactic barrier laser posterior to necrotic retina to try to prevent rhegmatogenous retinal detachment (RD), intravenous acyclovir in combination with oral, and vitrectomy for RD repair.
Results of PCR viral DNA analysis, relationship between prophylactic barrier argon laser photocoagulation and occurrence of RD, and visual acuities at presentation and follow-up.
Varicella-zoster virus (VZV) was detected in 66.7% (12/18) of eyes (66.7% of patients 10/15) with vitreous biopsy and herpes simplex virus (HSV) in 22.2% (4/18) of eyes (20% of patients 3/15). Epstein-Barr virus (EBV) was detected in 16.7% (3/18) of eyes (20% of patients 3/15), and all the EBV-positive eyes were also positive for VZV. Polymerase chain reaction results were identical in both eyes of bilateral cases (5 patients) and were negative in 11.1% (2/18) of eyes (13.3% of patients 2/15) biopsied. Systemic corticosteroid treatment given before ARN diagnosis did not appear to increase the risk of developing RD (P = 0.69). Rhegmatogenous RD occurred in 35.3% (6/17) of eyes given prophylactic argon laser treatment and in 80% (8/10) of eyes that could not be lasered prohylactically. Of RDs, 96.3% (13/14) occurred after the third week and up to 5 months from onset of symptoms. The VA after surgical repair of RD improved relative to the presentation acuity in 33.3% (4/12) of eyes.
Varicella-zoster virus is the leading cause of ARN. We recommend the management of ARN to include prompt diagnosis; prophylactic argon laser retinopexy, preferably within the first 2 weeks to reduce risk of RD; systemic acyclovir; and corticosteroids to control the severe inflammation associated with ARN. Despite the guarded visual prognosis, RD repair may result in improved visual outcomes.
Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 ...people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation.
The study is a multicenter, single-arm, prospective clinical trial.
There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision).
The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina.
The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests.
A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments.
The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.
The Argus II 60 channel epiretinal prosthesis has been developed in order to provide partial restoration of vision to subjects blinded from outer retinal degenerative disease. To date the device has ...been implanted in 21 subjects as part of a feasibility study. In 6 month post-implantation door finding and line tracking orientation and mobility testing, subjects have shown improvements of 86% and 73%, respectively, for system on vs. system off. In high-contrast Square Localization tests using a touch screen monitor 87% of tested subjects performed significantly better with the system on compared with off. These preliminary results show that the Argus II system provides some functional vision to blind subjects.
AIM To examine epiretinal membranes of proliferative diabetic retinopathy (PDR) for the presence of selective matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs), in order to ...determine whether neovascularisation and fibrosis, characteristic of this complication of diabetes mellitus, are associated with specific anomalies of MMP or TIMP expression. METHODS The presence of selected MMPs and TIMPs was investigated in 24 fibrovascular epiretinal membranes of PDR, and the findings compared with that observed in 21 avascular epiretinal membranes of proliferative vitreoretinopathy (PVR) and five normal retinas. Specimens were examined for deposition of interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), gelatinase A (MMP-2), gelatinase B (MMP-9), and three tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, and TIMP-3). RESULTS The results showed that unlike normal retina, which constitutively expresses MMP-1 and TIMP-2, a large proportion of PDR membranes (> 62%) stained for MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, and TIMP-3. There were no differences in the expression of these molecules when compared with PVR membranes. A characteristic staining for MMP-9 was observed within the perivascular matrix of PDR membranes, and there was a significant increase in TIMP-2 expression by PDR membranes (p= 0.036) when compared with PVR membranes. CONCLUSIONS The findings that MMPs involved in degradation of fibrovascular tissue matrix, as well as TIMP-1 and TIMP-2, are found in a large proportion of PDR membranes, and that their expression does not differ from that of PVR membranes, suggest the existence of common pathways of extracellular matrix degradation in pathological processes leading to retinal neovascularisation and fibrosis.
Uveitis, or intraocular inflammation, remains an ongoing challenge to ophthalmologists and patients alike. In most patients, uveitis is limited to the anterior ocular structures and is readily ...managed with topical steroids. The inflammatory process can extend behind the lens to involve the pars plana, the vitreous cavity, the choroid and the retina. These intermediate and posterior uveitides are relatively rare but contribute disproportionately to visual morbidity and present serious diagnostic and therapeutic difficulties. Systemic steroids constitute the first line of treatment for most sight-threatening uveitides. Their long term use is limited by universal and debilitating adverse effects. Second-line, steroid-sparing agents allow a reduction in steroid dosage. Cyclosporin and azathioprine are the main steroid-sparing agents currently in use. However, these compounds are limited by a narrow therapeutic window and significant adverse effects. This paper offers a brief discussion of some of the immune mechanisms involved in the pathogenesis of uveitis and reviews categories of investigational compounds. Inhibitors of T cell function: tacrolimus (previously FK506), licensed for use in liver transplantation, and sirolimus (rapamycin) are macrolide antibiotics. Sirolimus is a functional cytokine antagonist and in vitro studies suggest it could be up to 100 times more potent than cyclosporin. Drug synergy between sirolimus and cyclosporin has been demonstrated, resulting in immunosuppression at lower drug doses and with fewer adverse effects. Nucleotide synthesis inhibitors: mycophenolate mofetil (MMF) and leflunomide. Human lymphocytes are only able to synthesise nucleic acids de novo. Having no alternative or 'salvage' pathway, they are exquisitely sensitive to interference with the de novo nucleotide synthesis enzymatic pathway. MMF is a purine synthesis inhibitor. Compared to other purine inhibitors, early data suggest that MMF is more efficacious and less toxic than azathioprine. Leflunomide is an inhibitor of pyrimidine synthesis. Monoclonal surface receptor antibodies and immunoadhesins: the IL-2 receptor is essential for clonal expansion of activated T cells; this has led to the development of anti-IL-2 receptor antibodies. Daclizumab is a genetically engineered humanised IgG1 monoclonal antibody. In conjunction with cyclosporin, it significantly reduces renal allograft rejection rates and is also showing promise in the treatment of T cell mediated autoimmune disorders. The mechanism of action of monoclonal antibodies to other pro-inflammatory cytokines such as TNFalpha and IL-12 and data from animal and human uveitis trials are also discussed. Finally, new avenues of research in immunopharmaco-modulation are mentioned.
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