Retinal prostheses: Where to from here?

Researchers have been working towards the development of retinal prostheses, so called "bionic eyes" since the 1960s in an effort to restore functional vision to severely visually impaired patients. Groups from all around the world are involved in this research but in particular, groups from the United States, Germany, France, Japan and Australia have conducted clinical trials of these devices and three of these devices have achieved either FDA HDE (U.S. Food and Drug Administration Humanitarian Device Exception) or CE mark approval for commercial production. Despite this, all three of these devices are now not in commercial production. There are many challenges to overcome to develop devices suitable to implant in human patients and then reach commercial distribution. This is an exacting process and many hurdles need to be overcome to reach this point so that leaving the market after achieving this goal is a significant decision. Ongoing research is exploring the possibility of less complicated surgery with better visual processing algorithms to provide more useful visual information for our patients to provide a commercial alternative.

ANALYSIS OF TIME TO FAILURE AFTER RETINAL DETACHMENT SURGERY.

PURPOSE: To present the distribution of time to retinal redetachment in eyes undergoing retinal detachment surgery, using a method for adjusting time to outcome in eyes with silicone oil or heavy liquid tamponade ("oil-filled eyes"). METHODS: Data from two Australian centers were used. Adjusted time to outcome was measured from the date of tamponade removal in oil-filled eyes, unless failure was diagnosed with tamponade in situ. RESULTS: 188/1257 failures were identified (15.0%). Using unadjusted time to outcome, failures in oil-filled eyes occurred later than non-oil-filled eyes (median time to failure 57 vs. 28 days, P < 0.001). After adjustment, the distribution of time to failure was similar for oil-filled and non-oil-filled eyes (median 25 vs. 28 days, P = 0.68). Larger detachments, eyes with ≥Grade B proliferative vitreoretinopathy and eyes receiving surgery for recurrent detachments were more likely to fail, but the time to failure was similar regardless of risk. CONCLUSION: Adjustment of time to outcome resulted in a similar distribution of time to failure in oil-filled and non-oil filled eyes and was similar in low- and high-risk eyes. The use of adjusted time to outcome will support consistent collection and interpretation of outcomes across different jurisdictions where time to oil removal may vary.

Fungal endophthalmitis: A 20-year experience at a tertiary referral centre.

IMPORTANCE: Fungal endophthalmitis is an uncommon and serious intraocular infection, often with poor outcomes. This study examines the trend in this disease over 20 years, to inform clinician decision-making and optimize patient outcomes. BACKGROUND: Due to infrequent presentation of fungal endophthalmitis, there is limited understanding to formulate a standardized approach to management. DESIGN: A prospective case series over the period January 1, 1999 to December 31, 2018. PARTICIPANTS: Patients with clinically diagnosed fungal endophthalmitis managed at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. METHODS: Review of the Victorian Endophthalmitis Registry for endophthalmitis episode of each patient. MAIN OUTCOME MEASURES: Patient demographics, co-morbidities, visual acuity (VA) at presentation, aetiology, treatment, microbiology results and final VA outcome. RESULTS: Eighty-four cases of fungal endophthalmitis were identified over the study period with a median age of 43.5 years [IQR 30.8-63.0]. Then, 65.5% (n = 55) of patients were male; 81.0% (n = 68) of these cases were secondary to endogenous causes, of which 55.9% were associated with intravenous drug use (IVDU). Among the exogenous causes, penetrating eye injury (56.3%) was the most common aetiological factor. Thirty-nine patients (46.4%) grew Candida species from ocular fluid specimens, all of which were sensitive to fluconazole. CONCLUSION AND RELEVANCE: Our case series provides important insights into fungal endophthalmitis-a high degree of suspicion for fungal endophthalmitis in patients with history of IVDU, and relatively good outlook for vision when Candida is the causative organism. This should allow institutions to implement a standardized management strategy based on evidence.

Gram-negative endophthalmitis: A prospective study examining the microbiology, clinical associations and visual outcomes following infection.

IMPORTANCE: This is the largest Gram-negative endophthalmitis specific series and provides important evidence to guide management. BACKGROUND: Endophthalmitis is a sight-threatening emergency. Gram-negative infections are associated with poorer visual outcomes; however, there is limited literature pertaining to this uncommon condition. DESIGN: Prospective case series. PARTICIPANTS: All patients presenting with endophthalmitis to a tertiary institution over a 20-year period. METHODS: Data were collected prospectively and entered into a registry. Patients with microbiological evidence of Gram-negative infection were included in the analysis. MAIN OUTCOMES MEASURES: Final visual acuity (VA), precipitating events, causative organisms, antibiotic sensitivity profiles and risk factors for poor visual outcomes were reported. RESULTS: One hundred Gram-negative organisms were isolated in 97 eyes. Final VA was worse than 6/60 in 65 (67.0%) eyes at follow-up and 29 (29.9%) eyes were eviscerated or enucleated. Microbial keratitis (26.8%, n = 26) and Pseudomonas aeruginosa (34.0%, n = 34) were the most common precipitating event and causative organism, respectively. Eight (8.0%) isolates were third-generation cephalosporin resistant; of which, 7 (88.0%) were sensitive to ciprofloxacin. Preceding microbial keratitis (OR = 13.16, P = .015) or P. aeruginosa infections (OR = 3.40, P = .045) were strongly associated with poorer visual outcomes (worse than 6/60). CONCLUSIONS AND RELEVANCE: Visual outcomes following Gram-negative endophthalmitis are extremely poor, with almost 30% of patients being eviscerated or enucleated. A majority of ceftazidime resistant organisms are sensitive to ciprofloxacin, providing evidence to support the empirical use of quinolones. Clinicians should be mindful that infections secondary to P. aeruginosa or microbial keratitis carry a particularly poor prognosis.

Predictors of visual outcome and the role of early vitrectomy in streptococcal endophthalmitis.

IMPORTANCE: Streptococcal endophthalmitis has devastating sequelae. This study aims to identify factors which may be targeted to optimize patient outcomes. BACKGROUND: This study investigated characteristics influencing visual outcomes and the role of early vitrectomy. DESIGN: Retrospective observational case series of consecutive patients was conducted. PARTICIPANTS: All patients with a culture-positive diagnosis of streptococcal endophthalmitis treated at a tertiary ophthalmology referral centre between July 1997 and February 2012 were included. METHODS: Patient records were reviewed and data collected on their presentation, examination, microbiology results, procedures and final outcome. MAIN OUTCOME MEASURES: Visual acuity (VA) and enucleation/evisceration were measured. RESULTS: Of the 101 patients, 35.6% presented with a VA of hand movements and 42.6% with light perception (LP). Final VA was poor (6/60 or worse) in 77.6% and 24.7% were enucleated/eviscerated. Presenting VA of LP or worse (P = 0.008), no view of fundus (P = 0.001), large number of organisms (P < 0.001), recognition of Streptococcus on Gram stain (P = 0.010), heavy growth on culture (P < 0.001) and more intravitreal injections (P = 0.038) were significantly associated with poor visual outcome (6/60 or worse). Presenting VA of LP or worse (P = 0.042) and non-viridans Streptococcus species (P = 0.002) were significantly associated with enucleation/evisceration. Fifteen patients (14.9%) had early vitrectomy within 48 h which was not associated with poor final VA or removal of the eye (P = 1.000). CONCLUSIONS AND RELEVANCE: Early vitrectomy did not influence visual outcome in this cohort. Microbiology results were useful in predicting poor outcomes, and may allow clinicians to make early treatment decisions and provide prognostic information for patients.

Recurrent glomerulonephritis after kidney transplantation: risk factors and allograft outcomes.

Recurrent glomerulonephritis after kidney transplantation is a feared complication because it is unpredictable and may have a negative impact on graft outcomes. To better understand this we collected data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry accumulated over 30 years. The incidence, risk factors, and outcomes of recurrent glomerulonephritis in transplant recipients were determined using adjusted Cox proportional hazard and competing risk modeling. A total of 6,597 recipients with biopsy-proven glomerulonephritis as the primary cause of end-stage kidney disease were followed for 51,871 person-years (median duration 7.7 years). The four most common types of glomerulonephritis were IgA nephropathy in 2501 patients, focal segmental glomerulosclerosis (FSGS) in 1403, membranous in 376, and membranoproliferative (MPGN) nephropathy in 357 patients. Among these four types, recurrence was reported in 479 of 4637 patients, and of these, 212 lost their allograft due to recurrence. Older age at transplantation (adjusted hazard ratio [per year increase] 0.96 [95% confidence interval 0.95 - 0.97]) was associated with a lower risk of recurrence. Significantly, the five-year graft survival was 30% for recipients with recurrent MPGN and 57-59% for recipients with FSGS, IgA, and membranous nephropathy. Transplant recipients with recurrent disease were twice as likely to lose their allografts compared to those without recurrence (adjusted hazard ratio 2.04 [1.81-2.31]). Thus, recurrent glomerulonephritis remains a significant cause of graft loss in transplant recipients.

Rising trends of endogenous Klebsiella pneumoniae endophthalmitis in Australia.

BACKGROUND: Endogenous Klebsiella pneumoniae endophthalmitis (EKPE) is a well-known entity in South-East Asia. We demonstrate a range of differing clinical features and outcomes of EKPE, and highlight the increasing incidence of EKPE in major centres in Sydney and Melbourne, Australia. DESIGN: Retrospective observational case study and case series in the hospital setting. PARTICIPANTS: Four cases of EKPE. METHODS: EKPE cases from 2005 to 2015 were identified through established endophthalmitis databases as well as hospital-based microbiological searches. MAIN OUTCOME MEASURES: EKPE cases were confirmed with positive K. pneumoniae intraocular samples. RESULTS: Rising trends of EKPE were noted in major centres in Australia. Six eyes of four patients with EKPE from January 2011 to December 2015 are reported. The mean age was 49 years (range 43-58 years). Two patients had bilateral involvement. There were systemic symptoms up to 10 days prior to ocular symptoms. The source of sepsis in all cases was a hepatic abscess. Two patients had diabetes mellitus. Five eyes had hypopyon panuveitis on presentation. All eyes underwent vitrectomy. The patient with the most delayed presentation underwent enucleation following globe perforation. Final best corrected visual acuity (BCVA) in one patient with bilateral EKPE was light perception (LP) only. The other three eyes had BCVA in at least one eye of 6/24 or better. CONCLUSIONS: EKPE is an emerging condition in Australia. Although rare, EKPE is a sight-threatening and potentially life-threatening emergency that can initially present to ophthalmologists. One should suspect EKPE in septic patients with a B-scan showing a vitreous or retinal abscess.

Development of a Magnetic Attachment Method for Bionic Eye Applications.

Successful visual prostheses require stable, long-term attachment. Epiretinal prostheses, in particular, require attachment methods to fix the prosthesis onto the retina. The most common method is fixation with a retinal tack; however, tacks cause retinal trauma, and surgical proficiency is important to ensure optimal placement of the prosthesis near the macula. Accordingly, alternate attachment methods are required. In this study, we detail a novel method of magnetic attachment for an epiretinal prosthesis using two prostheses components positioned on opposing sides of the retina. The magnetic attachment technique was piloted in a feline animal model (chronic, nonrecovery implantation). We also detail a new method to reliably control the magnet coupling force using heat. It was found that the force exerted upon the tissue that separates the two components could be minimized as the measured force is proportionately smaller at the working distance. We thus detail, for the first time, a surgical method using customized magnets to position and affix an epiretinal prosthesis on the retina. The position of the epiretinal prosthesis is reliable, and its location on the retina is accurately controlled by the placement of a secondary magnet in the suprachoroidal location. The electrode position above the retina is less than 50 microns at the center of the device, although there were pressure points seen at the two edges due to curvature misalignment. The degree of retinal compression found in this study was unacceptably high; nevertheless, the normal structure of the retina remained intact under the electrodes.

Wound-related complications and clinical outcomes following open globe injury repair.

BACKGROUND: Careful surgical management of traumatic wounds is important in open globe injury repair. This study examines the clinical outcomes following repair of open globe injuries with particular focus on wound-related issues. DESIGN: Retrospective, cohort study of consecutive open globe injuries presenting to a tertiary referral eye hospital from 1 January 2009 to 31 December 2011. PARTICIPANTS: A total of 267 eyes of 263 patients, mainly male (82.5%) with a mean age of 44.8 (range: 4-97) years. Average follow up was 6.9 months. METHODS: All cases classified according to Ocular Trauma Classification Group. MAIN OUTCOME MEASURES: Visual outcomes, risk factors for and rates of postoperative complications and endophthalmitis. RESULTS: There were 83 globe ruptures, 182 penetrating and 2 perforating eye injuries, of which 43 cases had intraocular foreign body. Factors contributing to final visual acuity (VA) <6/60 were poor presenting VA (odds ratio [OR] = 16.0, 95% confidence interval [CI]: 4.81-53.1), globe rupture (OR = 4.64, [1.99-10.8]), retinal detachment (OR = 3.40, [1.19-9.74]) and age ≥50 (OR = 2.45, [1.05-5.74]). Wound leak occurred in 44 eyes (16%). Of these, 18 (41%) proceeded to re-suturing. Factors contributing to wound leak were stellate-shaped wound (OR = 3.28, [1.39-7.73]) and delayed presentation (OR = 2.80, [1.02-7.71]). Ten eyes (3.7%) developed endophthalmitis. Factors associated with endophthalmitis were delayed presentation (OR = 8.91, [1.71-46.6]), microbial keratitis (OR = 12.5, [1.85-85.0]) and lens capsule breach (OR = 12.4, [1.85-83.1]). CONCLUSIONS: Wound leak is an important postoperative complication of open globe injury repair. Delayed presentation is an important risk factor for postoperative wound leak and endophthalmitis. Prompt and meticulous wound management of open globe injury may reduce these complications.

Safety and efficacy of explanting or replacing suprachoroidal electrode arrays in a feline model.

BACKGROUND: A key requirement for retinal prostheses is the ability for safe removal or replacement. We examined whether suprachoroidal electrode arrays can be removed or replaced after implantation. METHODS: Suprachoroidal electrode arrays were unilaterally implanted into 13 adult felines. After 1 month, arrays were surgically explanted (n = 6), replaced (n = 5) or undisturbed (n = 2). The retina was assessed periodically using fundus photography and optical coherence tomography. Three months after the initial implantation, the function of replaced or undisturbed arrays was assessed by measuring the responses of the visual cortex to retinal electrical stimulation. The histopathology of tissues surrounding the implant was examined. RESULTS: Array explantation or replacement was successful in all cases. Fundus photography showed localized disruption to the tapetum lucidum near the implant's tip in seven subjects following implantation. Although optical coherence tomography showed localized retinal changes, there were no widespread statistically significant differences in the thickness of the retinal layers or choroid. The distance between the electrodes and retina increased after device replacement but returned to control values within eight weeks (P < 0.03). Staphylomas developed near the scleral wound in five animals after device explantation. Device replacement did not alter the cortical evoked potential threshold. Histopathology showed localized outer nuclear layer thinning, tapetal disruption and pseudo-rosette formation, but the overall retinal morphology was preserved. CONCLUSIONS: It is feasible to remove or replace conformable medical grade silicone electrode arrays implanted suprachoroidally. The scleral wound requires careful closure to minimize the risk of staphylomas.

Nasolacrimal duct screening to minimize post-cataract surgery endophthalmitis.

BACKGROUND: To examine unrecognized nasolacrimal duct obstruction as a risk factor for developing endophthalmitis post-cataract surgery in order to assess the value of preoperative lacrimal system screening. DESIGN: Prospective case-control study. PARTICIPANTS: A random sample of patients undergoing phacoemulsification cataract surgery (control group) and a consecutive series of patients admitted to our hospital with post-cataract surgery endophthalmitis. METHODS: We compared the rate of nasolacrimal duct obstruction in the control group versus the endophthalmitis series. Both groups underwent nasolacrimal duct syringing with normal saline on the ipsilateral side to the surgery. A standard macro-dacryocystogram was performed to confirm for obstruction detected on syringing. MAIN OUTCOME MEASURES: Nasolacrimal duct obstruction rate. RESULTS: Forty-four eyes from 39 patients were included in this study: 34 eyes from 29 patients formed the control group and 10 eyes from 10 patients formed the endophthalmitis group. A higher rate of nasolacrimal duct obstruction was found among patients who developed endophthalmitis post-cataract in comparison with the control group, on both nasolacrimal duct syringing (50.0% vs. 11.8%; P = 0.018) and macro-dacryocystogram (20.0% vs. 2.9%, P = 0.125). Two out of the three patients with radiologically confirmed nasolacrimal duct obstruction reported a long history of epiphora. CONCLUSION: The higher rates of obstruction on nasolacrimal duct syringing and macro-dacryocystogram among patients who developed endophthalmitis suggest that nasolacrimal duct obstruction is a significant risk factor for postoperative endophthalmitis. We recommend routine screening for symptoms and examination of the lacrimal system prior to cataract surgery.

Development of a surgical procedure for implantation of a prototype suprachoroidal retinal prosthesis.

BACKGROUND: Current surgical techniques for retinal prosthetic implantation require long and complicated surgery, which can increase the risk of complications and adverse outcomes. METHOD: The suprachoroidal position is known to be an easier location to access surgically, and so this study aimed to develop a surgical procedure for implanting a prototype suprachoroidal retinal prosthesis. The array implantation procedure was developed in 14 enucleated eyes. A full-thickness scleral incision was made parallel to the intermuscular septum and superotemporal to the lateral rectus muscle. A pocket was created in the suprachoroidal space, and the moulded electrode array was inserted. The scleral incision was closed and scleral anchor point sutured. In 9 of the 14 eyes examined, the device insertion was obstructed by the posterior ciliary neurovascular bundle. Subsequently, the position of this neurovascular bundle in 10 eyes was characterized. Implantation and lead routing procedure was then developed in six human cadavers. The array was tunnelled forward from behind the pinna to the orbit. Next, a lateral canthotomy was made. Lead fixation was established by creating an orbitotomy drilled in the frontal process of the zygomatic bone. The lateral rectus muscle was detached, and implantation was carried out. Finally, pinna to lateral canthus measurements were taken on 61 patients in order to determine optimal lead length. RESULTS: These results identified potential anatomical obstructions and informed the anatomical fitting of the suprachoroidal retinal prosthesis. CONCLUSION: As a result of this work, a straightforward surgical approach for accurate anatomical suprachoroidal array and lead placement was developed for clinical application.

Chronic electrical stimulation with a peripheral suprachoroidal retinal implant: a preclinical safety study of neuroprotective stimulation.

Purpose: Extraocular electrical stimulation is known to provide neuroprotection for retinal cells in retinal and optic nerve diseases. Currently, the treatment approach requires patients to set up extraocular electrodes and stimulate potentially weekly due to the lack of an implantable stimulation device. Hence, a minimally-invasive implant was developed to provide chronic electrical stimulation to the retina, potentially improving patient compliance for long-term use. The aim of the present study was to determine the surgical and stimulation safety of this novel device designed for neuroprotective stimulation. Methods: Eight normally sighted adult feline subjects were monocularly implanted in the suprachoroidal space in the peripheral retina for 9-39 weeks. Charge balanced, biphasic, current pulses (100 µA, 500 µs pulse width and 50 pulses/s) were delivered continuously to platinum electrodes for 3-34 weeks. Electrode impedances were measured hourly. Retinal structure and function were assessed at 1-, 2-, 4-, 6- and 8-month using electroretinography, optical coherence tomography and fundus photography. Retina and fibrotic thickness were measured from histological sections. Randomized, blinded histopathological assessments of stimulated and non-stimulated retina were performed. Results: All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. The device position was stable after a post-surgery settling period. Median electrode impedance remained within a consistent range (5-10 kΩ) over time. There was no change in retinal thickness or function relative to baseline and fellow eyes. Fibrotic capsule thickness was equivalent between stimulated and non-stimulated tissue and helps to hold the device in place. There was no scarring, insertion trauma, necrosis, retinal damage or fibroblastic response in any retinal samples from implanted eyes, whilst 19% had a minimal histiocytic response, 19% had minimal to mild acute inflammation and 28% had minimal to mild chronic inflammation. Conclusion: Chronic suprathreshold electrical stimulation of the retina using a minimally invasive device evoked a mild tissue response and no adverse clinical findings. Peripheral suprachoroidal electrical stimulation with an implanted device could potentially be an alternative approach to transcorneal electrical stimulation for delivering neuroprotective stimulation.

Endophthalmitis: Microbiology and Organism Identification Using Current and Emerging Techniques.

Endophthalmitis is an ophthalmological emergency requiring timely and appropriate diagnosis and treatment. Microbiological methods of microscopy (Gram's staining) and culture are the current gold standard for organism identification. However, a significant proportion of endophthalmitis remains culture-negative-perhaps the inflammation is non-infectious in origin, results from a novel organism are unidentifiable or because the causative organism is non-culturable often due to pre-treatment with antibiotics. This review outlines the microbiological profile of endophthalmitis, current clinically used methods for organism identification, and the newer molecular techniques of polymerase chain reaction (PCR) and next-generation sequencing (NGS) technology as diagnostic tools for endophthalmitis. They offer the potential to improve organism identification rates and clinical outcomes in infectious diseases, representing an exciting future direction for organism identification in endophthalmitis. Based on the largest ophthalmic hospital in Australia, we highlight the key practical challenges faced by Australian diagnostic laboratories for their use in a clinical setting.

Estimating Phosphene Locations Using Eye Movements of Suprachoroidal Retinal Prosthesis Users.

Purpose: Accurate mapping of phosphene locations from visual prostheses is vital to encode spatial information. This process may involve the subject pointing to evoked phosphene locations with their finger. Here, we demonstrate phosphene mapping for a retinal implant using eye movements and compare it with retinotopic electrode positions and previous results using conventional finger-based mapping. Methods: Three suprachoroidal retinal implant recipients (NCT03406416) indicated the spatial position of phosphenes. Electrodes were stimulated individually, and the subjects moved their finger (finger based) or their eyes (gaze based) to the perceived phosphene location. The distortion of the measured phosphene locations from the expected locations (retinotopic electrode locations) was characterized with Procrustes analysis. Results: The finger-based phosphene locations were compressed spatially relative to the expected locations all three subjects, but preserved the general retinotopic arrangement (scale factors ranged from 0.37 to 0.83). In two subjects, the gaze-based phosphene locations were similar to the expected locations (scale factors of 0.72 and 0.99). For the third subject, there was no apparent relationship between gaze-based phosphene locations and electrode locations (scale factor of 0.07). Conclusions: Gaze-based phosphene mapping was achievable in two of three tested retinal prosthesis subjects and their derived phosphene maps correlated well with the retinotopic electrode layout. A third subject could not produce a coherent gaze-based phosphene map, but this may have revealed that their phosphenes were indistinct spatially. Translational Relevance: Gaze-based phosphene mapping is a viable alternative to conventional finger-based mapping, but may not be suitable for all subjects.