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.

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.

Risk factors, microbial profiles and prognosis of microbial keratitis-associated endophthalmitis in high-risk eyes.

BACKGROUND: Microbial keratitis (MK) is a sight-threatening emergency. Delayed diagnosis and treatment may exacerbate the condition and infection may spread to the posterior segment with resultant endophthalmitis. We describe the presentation, management, visual outcomes and microbial profiles of MK-associated endophthalmitis presenting to a tertiary referral centre. METHODS: Prospective collection of data on all patients presenting with presumed MK-associated endophthalmitis from 1997 to 2007, to the Royal Victorian Eye and Ear Hospital. Outcome measures included: visual acuity, microbial profiles, and management strategy. RESULTS: Thirty-seven cases of MK-associated endophthalmitis were identified over the study period, with a mean age of 73 years and 19 were male. Presenting acuities ranged from Snellen 2/60 to no perception of light (NPL). Thrity-four (91.9%) patients had a prior history of ocular disease. Identifiable non-ocular risk factors were present in 31 (83.8%), including steroid use, dementia, nursing home care or relative systemic immunosuppression. A culture positivity rate of 83.8% was recorded. The most common organisms identified included: Streptococcal species in 12 (32.4%), Pseudomonas aeruginosa in 11 (29.7%), and Staphylococcus aureus in eight (21.6%). Final acuities ranged from 6/36 to NPL. Sixteen (43.2%) eyes were eviscerated/enucleated as primary treatment. Overall, 23 (62.2%) patients required evisceration/enucleation, of which nine (39.1%) were due to Pseudomonas aeruginosa and seven (30.4%) to Streptococcal species (Streptococcal pneumonia). CONCLUSIONS: MK-associated endophthalmitis is a serious ocular condition occurring more frequently in elderly populations, and those with long standing severe pre-existing ocular disease. Visual outcomes are poor, often requiring evisceration/enucleation.

The extended clinical phenotype of dome-shaped macula.

PURPOSE: To describe the phenotype, associations, and complications of dome-shaped macula (DSM) through the combination of spectral-domain optical coherence tomography (OCT) imaging and B-scan ultrasonography, when available. This retroprospective cohort study aims to gain further pathophysiological understanding in eyes with DSM. METHODS: Fifty-eight eyes of 36 patients were identified as having OCT features of DSM. Retinal and choroidal thicknesses were determined from enhanced depth imaging (EDI)-OCT image sets, with scleral thickness subsequently calculated by subtraction from the B-scan ultrasound-derived measurements of posterior coat thickness. RESULTS: DSM was associated with myopia in 81 % of eyes. The underlying clinical diagnosis was variable: central serous chorioretinopathy (CSCR)-like entity, choroidal neovascularization, and inherited retinal disorders. The subfoveal choroidal thickness of the nine highly myopic eyes with a CSCR-like phenotype was thicker than the 25 eyes without CSCR (p = 0.169). The mean subfoveal scleral thickness of the highly myopic eyes was 585 ± 196 µm, which was significantly different from those with a refractive error less than 6 diopters (1133 ± 290 µm) (P < 0.0001). CONCLUSIONS: This study highlights the novel observation of a thickened choroid when CSCR is present. In addition, we expand the associations of DSM to eyes with hypermetropia and acquired disease, and to those with inherited retinal dystrophies.

Enhanced depth imaging of the choroid in patients with neovascular age-related macular degeneration treated with anti-VEGF therapy versus untreated patients.

PURPOSE: To compare the subfoveal choroidal thickness (SFCT) between patients with neovascular age-related macular degeneration (nAMD) who had multiple intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents and those with treatment-naïve nAMD. METHODS: This retrospective case-control study included 15 patients in group 1 (nAMD in one eye which had received at least three anti-VEGF injections and early AMD in the fellow eye) and 15 patients in group 2 (newly diagnosed nAMD in one eye which had not received any treatment and early AMD in the fellow eye). They underwent enhanced depth imaging optical coherence tomography (OCT), and two OCT readers manually measured the SFCT. Inter-ocular difference in SFCT (nAMD eye minus fellow eye) was calculated for each patient. RESULTS: The nAMD eyes in group 1 had received a median (range) of four (3-8) intravitreal injections of anti-VEGF agents, and the OCT scans were performed at a median (range) of 9 (4-17) months after the first injection. The median inter-ocular difference in SFCT in groups 1 and 2 were not significantly different (13.5 and 3.0 µm in groups 1 and 2 respectively, p=0.60). There was also no statistically significant difference in SFCT between nAMD and fellow eyes (p=0.16), although there was a trend for greater median SFCT in the nAMD eyes. CONCLUSION: The data from this small cohort suggests that no gross reduction in SFCT appears in nAMD patients after a time interval of at least 4 months between initiating repeated treatment with anti-VEGF therapy and OCT imaging. However, a study with a much larger sample size or longitudinal design is required to detect possible small fluctuations in SFCT in nAMD eyes receiving anti-VEGF therapy.

Use of spectral-domain optical coherence tomography to differentiate acquired retinoschisis from retinal detachment in difficult cases.

PURPOSE: This study presents a series of 10 patients who posed a diagnostic challenge regarding the diagnosis of acquired retinoschisis (RS) or retinal detachment (RD), where spectral-domain optical coherence tomography (OCT) with the Spectralis HRA and OCT device (Heidelberg Engineering, Heidelberg, Germany) was able to help make a correct diagnosis. METHODS: Ten patients (five with acquired RS and five with RD) were referred to a vitreoretinal clinic at Moorfields Eye Hospital for definitive diagnosis and further management. All patients underwent scans with the Spectralis HRA and OCT device. RESULTS: The Spectralis HRA and OCT was able to make a clear diagnosis of RS or RD in all patients. Of the five patients with RS confirmed on OCT, two were referred with RD, and of the five patients with RD, four were referred with RS. New OCT features of RS include the double schisis cavity phenomenon, intraretinal pillars through the schisis cavity, and irregularity of the inner surface of the attached outer leaf. CONCLUSION: Spectral-domain OCT is a useful tool in distinguishing RS from RD, eliminating previous diagnostic uncertainty. The Spectralis HRA and OCT device has the added advantages of being able to reliably image anterior retinal pathology and produce high-definition images.

Interobserver Agreement of Electrode to Retina Distance Measurements in a Second-Generation (44-Channel) Suprachoroidal Retinal Prosthesis.

Purpose: The electrode to retina (ER) distance is an important contributory factor to the safety and efficacy of a suprachoroidal retinal prosthesis. Measuring ER distance may be performed by different observers during multisite studies. The aim of this study was to assess the interobserver agreement in measuring ER distance. Methods: Three independent, trained observers measured ER distance from the center of each suprachoroidal electrode to the inner retinal pigment epithelium in spectral-domain optical coherence tomography (SD-OCT) B-scans. A total of 121 ER distance measurements from 77 B-scans collected over 5 months from one subject implanted with a second-generation 44-channel suprachoroidal retinal prosthesis (NCT03406416) were made by each observer. Results: ER distance ranged from 208 to 509 µm. Pearson's correlation coefficient (ρ) showed agreement of 0.99 (95% confidence interval [CI] = 0.98-0.99) in measuring ER for each pairwise comparison. The mean difference in ER distance between observers ranged from 2.4 to 6.4 µm with pairwise limits of agreement (95% CI) of ±20 µm (5.5% of mean). Intraclass correlation coefficient (ICC) showed agreement of 0.98 (95% CI = 0.97-0.99) between observers. Conclusions: There is high agreement in measuring ER distances for suprachoroidal retinal prostheses using our systematic approach between multiple, trained observers, supporting the use of a single observer for each image. Translational Relevance: High interobserver agreement outcomes indicate that multiple, trained observers can be used to take ER measurements across different images in suprachoroidal retinal prosthesis studies. This improves multisite study efficiency and gives confidence in interpreting results relating to the safety and efficacy of suprachoroidal retinal prostheses.

Vitreomacular disorders: a review of the classification, pathogenesis and treatment paradigms including new surgical techniques.

This review explores how optical coherence tomography has guided our assessment of vitreomacular disorders. Vitreomacular disorders (VMD), such as macular holes and epiretinal membranes are common and potentially sight threatening. The introduction and widespread use of optical coherence tomography (OCT) imaging technology has transformed our ability to visualise the vitreoretinal interface. This review discusses the pathogenesis and updated classification scheme for VMD in the OCT era. Imaging biomarkers and the treatment algorithm, including the role of novel therapeutics, for managing patients with VMD are presented.

Choroidal imaging in inherited retinal disease using the technique of enhanced depth imaging optical coherence tomography.

PURPOSE: The aim of this study is to image and describe the in vivo choroidal changes in various retinal dystrophies using the technique of enhanced depth imaging (EDI) optical coherence tomography (OCT) and to correlate these findings with the clinical appearance. Associations between choroidal change and genotype, visual acuity and results of retinal electrophysiology are also explored. DESIGN: Retrospective observational case series. METHODS: Twenty patients attending the medical retina clinics at Moorfields Eye Hospital underwent EDI OCT choroidal scans as part of the scanning protocol when they underwent OCT imaging with the Spectralis HRA and OCT. The choroidal images were obtained by moving the Spectralis camera close enough to obtain an inverted image of the retina. The scans were read by two experienced OCT readers assessing the choroidal thickness as well as the choroidal contour for focal areas of choroidal thinning corresponding to the areas of RPE/outer retinal atrophy. The spectrum of patients included those with Stargardt macular dystrophy, macular dystrophies secondary to known mutations such as peripherin/RDS, uncharacterised macular dystrophies, Best disease, bifocal chorioretinal atrophy, Bietti crystalline retinal dystrophy and choroideraemia. RESULTS: The choroidal appearance was symmetrical in all patients who had both eyes scanned. Ten patients showed no choroidal thinning, five had focal mild to moderate choroidal thinning, three had focal severe choroidal thinning, and two patients had diffuse severe choroidal thinning. There was no association between choroidal thinning and visual acuity [Fisher's exact test, p = 0.350 (right eye), p = 1.000 (left eye)], or extent of retinal dysfunction on electrophysiology (Fisher's exact test, p = 1.000). CONCLUSION: Enhanced depth imaging using spectral domain OCT can be used to identify choroidal changes in inherited retinal disease. The pattern of choroidal change correlates well with the clinical appearance. It appears that the extent and pattern of choroidal thinning is dependent on the stage of the disease in some cases, and in others the causative gene defect.

In vivo feasibility of epiretinal stimulation using ultrananocrystalline diamond electrodes.

OBJECTIVE: Due to their increased proximity to retinal ganglion cells (RGCs), epiretinal visual prostheses present the opportunity for eliciting phosphenes with low thresholds through direct RGC activation. This study characterised the in vivo performance of a novel prototype monolithic epiretinal prosthesis, containing Nitrogen incorporated ultrananocrystalline (N-UNCD) diamond electrodes. APPROACH: A prototype implant containing up to twenty-five 120 × 120 µm N-UNCD electrodes was implanted into 16 anaesthetised cats and attached to the retina either using a single tack or via magnetic coupling with a suprachoroidally placed magnet. Multiunit responses to retinal stimulation using charge-balanced biphasic current pulses were recorded acutely in the visual cortex using a multichannel planar array. Several stimulus parameters were varied including; the stimulating electrode, stimulus polarity, phase duration, return configuration and the number of electrodes stimulated simultaneously. MAIN RESULTS: The rigid nature of the device and its form factor necessitated complex surgical procedures. Surgeries were considered successful in 10/16 animals and cortical responses to single electrode stimulation obtained in eight animals. Clinical imaging and histological outcomes showed severe retinal trauma caused by the device in situ in many instances. Cortical measures were found to significantly depend on the surgical outcomes of individual experiments, phase duration, return configuration and the number of electrodes stimulated simultaneously, but not stimulus polarity. Cortical thresholds were also found to increase over time within an experiment. SIGNIFICANCE: The study successfully demonstrated that an epiretinal prosthesis containing diamond electrodes could produce cortical activity with high precision, albeit only in a small number of cases. Both surgical approaches were highly challenging in terms of reliable and consistent attachment to and stabilisation against the retina, and often resulted in severe retinal trauma. There are key challenges (device form factor and attachment technique) to be resolved for such a device to progress towards clinical application, as current surgical techniques are unable to address these issues.

Syphilitic punctate inner retinitis in immunocompetent gay men.

PURPOSE: To describe the features of an unusual syphilitic uveitis syndrome in a cluster of homosexual patients. DESIGN: Retrospective case series. PARTICIPANTS: Five consecutive patients diagnosed with syphilitic retinitis in our Melbourne uveitis clinic over a period of 8 months. METHODS: The case notes of patients diagnosed with syphilitic retinitis were reviewed and the clinical features are presented and discussed. MAIN OUTCOME MEASURES: Description of retinal findings and documentation of any associated sequelae. RESULTS: All patients were homosexual men. Two were human immunodeficiency virus positive. None of the patients had been previously diagnosed with syphilis, although 3 presented with systemic symptoms and signs of secondary syphilis. All patients had marked anterior uveitis and vitritis. All patients had acute retinal arteriolitis and inner retinitis, with distinctive, inner retinal and preretinal white dots. These retinal findings were remarkably similar in all patients, and resolved with little or no sequelae after standard systemic treatment for syphilis, combined with oral prednisolone. CONCLUSIONS: Syphilitic retinitis may be an increasingly common clinical problem, reflecting the growing incidence of syphilis among homosexual men in Australia. Our patients showed stereotypical ocular and systemic features, which are useful in differentiating this condition clinically from other types of acute posterior uveitis, such as necrotizing viral retinitis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Acute retinal necrosis: a case series with clinical features and treatment outcomes.

PURPOSE: To determine clinical features, viral aetiology and treatment outcomes of eyes with acute retinal necrosis (ARN). METHODS: Retrospective, interventional, non-comparative case series. RESULTS: Twenty-two patients (23 eyes) were identified between 1996 and 2007. Varicella zoster virus was the causative agent in 12 patients (nine confirmed by polymerase chain reaction), herpes simplex virus type 1 in six (five polymerase chain reaction-confirmed) and unknown in three patients. Five patients had documented herpes zoster infection in the month prior to the onset of ARN. Twelve patients (55%) had identifiable (clinical or subclinical) immune dysfunction. At 6 months, 3 out of 15 eyes (20%) maintained vision 6/12 or better and 7 (47%) were 6/60 or worse. Median final VA was 6/60. Nine eyes developed retinal detachment and two-thirds of these had received prior barrier laser. Poor prognostic factors for severe visual loss by univariate analysis were male gender (P = 0.019), and the development of retinal detachment (P = 0.05). Delay between onset of symptoms and diagnosis was associated with moderate visual loss (P = 0.018). Barrier laser did not reduce the risk of retinal detachment. CONCLUSIONS: Acute retinal necrosis still has poor visual prognosis. Early diagnosis and initiation of treatment may improve outcome.

Cataract surgery in high-risk age-related macular degeneration: a randomized controlled trial.

BACKGROUND: To investigate if cataract surgery causes progression, from high-risk early age-related macular degeneration (AMD) to choroidal neovascularization (CNV), in the postoperative period. METHODS: Randomized controlled trial. Patients, with visually significant cataract and fundus features of early AMD at high risk of progression to CNV, were randomized into two groups and were evaluated at baseline and 6 months. The study patients (n = 27) underwent immediate cataract surgery. The control group (n = 29) comprised patients who had cataract surgery deferred until after the 6-month visit. Assessment included visual acuity, quality of life (QoL) and fundus fluorescein angiography (FFA). RESULTS: Of 68 eligible eyes, 60 participated and 56 completed the study. Three referred eyes (3.2%) were ineligible on the basis of a pre-existing, unsuspected occult CNV that was detected by baseline FFA. All three cases had end-stage exudative AMD in the fellow eye. Of the study eyes in the immediate surgery arm (n = 27), one (3.7%) developed CNV compared with none (0/29) in the deferred arm (chi(2); P = 1.0) at 6 months. In the operated group, there was a 2.8-line improvement in logMAR visual acuity and 2.1-fold average gain in QoL at 6 months. CONCLUSIONS: No increased short-term risk of progression of AMD to CNV in high-risk fundi following uncomplicated phacoemulsification surgery was found. A low threshold for performing preoperative imaging in patients with AMD, especially in those with exudative AMD in the fellow eye, to exclude undetected CNV is recommended. Provided there is no CNV, there are distinct benefits of cataract surgery in people with early AMD.

Avastin as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy: a prospective case series.

PURPOSE: Bevacizumab (Avastin) is a monoclonal antibody which targets all isoforms of vascular endothelial growth factor A. Its potent anti-angiogenic effects have been shown to cause regression of neovascularization in proliferative diabetic retinopathy. The aim of this study is to investigate the role of Avastin as an adjunct to vitrectomy in the management of severe diabetic eye disease. METHODS: Sixteen patients (18 eyes) with severe proliferative diabetic retinopathy were recruited into the study. All eyes underwent a single intravitreal injection of bevacizumab 1.25 mg in 0.05 mL prior to vitrectomy surgery for the management of tractional retinal detachment or vitreous haemorrhage due to severe proliferative diabetic retinopathy. RESULTS: At 3 months, seven eyes had visual acuities which were better than baseline, four were unchanged and seven were worse. At 6 months, 14 eyes had visual acuities better than baseline, one was unchanged and three were worse. Seven of the 18 eyes (38.8%) had postoperative rebleeds, six of which required surgical washout. CONCLUSION: Avastin improved the ease of the surgery in these complex eyes and the early results are encouraging. We have found it to be particularly useful in diabetic eyes with traction detachments of short duration in which there is still active neovascularization.

Safety Studies for a 44-Channel Suprachoroidal Retinal Prosthesis: A Chronic Passive Study.

Purpose: Following successful clinical outcomes of the prototype suprachoroidal retinal prosthesis, Bionic Vision Australia has developed an upgraded 44-channel suprachoroidal retinal prosthesis to provide a wider field of view and more phosphenes. The aim was to evaluate the preclinical passive safety characteristics of the upgraded electrode array. Methods: Ten normal-sighted felines were unilaterally implanted with an array containing platinum electrodes (44 stimulating and 2 returns) on a silicone carrier near the area centralis. Clinical assessments (color fundus photos, optical coherence tomography, full-field electroretinography, intraocular pressure) were performed under anesthesia prior to surgery, and longitudinally for up to 20 weeks. Histopathology grading of fibrosis and inflammation was performed in two animals at 13 to 15 weeks. Results: Eight animals showed safe electrode array insertion (good retinal health) and good conformability of the array to the retinal curvature. Eight animals demonstrated good mechanical stability of the array with only minor (<2 disc diameters) lateral movement. Four cases of surgical or stability complications occurred due to (1) bulged choroid during surgery, (2) hemorrhage from a systemic bleeding disorder, (3) infection, and (4) partial erosion of thin posterior sclera. There was no change in retinal structure or function (other than that seen at surgery) at endpoint. Histopathology showed a mild foreign body response. Electrodes were intact on electrode array removal. Conclusions: The 44-channel suprachoroidal electrode array has an acceptable passive safety profile to proceed to clinical trial. The safety profile is expected to improve in human studies, as the complications seen are specific to limitations (anatomic differences) with the feline model.

CHORIORETINAL BIOPSY FOR THE DIAGNOSIS OF ENDOGENOUS ENDOPHTHALMITIS DUE TO ESCHERICHIA COLI.

PURPOSE: To describe the novel use of a chorioretinal biopsy technique to confirm the microbiological diagnosis of endogenous Escherichia coli (E. coli) endophthalmitis, when other investigations have been proven nondiagnostic. METHODS: Case report of an 82-year-old white man with endogenous endophthalmitis without a clearly identifiable source of infection. RESULTS: After systemic cultures and multiple aqueous and vitreous samples were unable to identify a causative organism, chorioretinal biopsy of a subretinal abscess was used to confirm the microbiological diagnosis. This ensured appropriate ophthalmic and systemic treatment of infection. CONCLUSION: Endogenous E. coli endophthalmitis is a rare and aggressive condition usually seen in patients with insulin-dependent diabetes with concurrent urinary tract infection. This case demonstrates chorioretinal biopsy to be a viable and effective method of establishing a firm microbiological diagnosis in cases of culture-negative endophthalmitis.

Improved Placement of Multi-mapping Small RNAs.

High-throughput sequencing of small RNAs (sRNA-seq) is a popular method used to discover and annotate microRNAs (miRNAs), endogenous short interfering RNAs (siRNAs), and Piwi-associated RNAs (piRNAs). One of the key steps in sRNA-seq data analysis is alignment to a reference genome. sRNA-seq libraries often have a high proportion of reads that align to multiple genomic locations, which makes determining their true origins difficult. Commonly used sRNA-seq alignment methods result in either very low precision (choosing an alignment at random), or sensitivity (ignoring multi-mapping reads). Here, we describe and test an sRNA-seq alignment strategy that uses local genomic context to guide decisions on proper placements of multi-mapped sRNA-seq reads. Tests using simulated sRNA-seq data demonstrated that this local-weighting method outperforms other alignment strategies using three different plant genomes. Experimental analyses with real sRNA-seq data also indicate superior performance of local-weighting methods for both plant miRNAs and heterochromatic siRNAs. The local-weighting methods we have developed are implemented as part of the sRNA-seq analysis program ShortStack, which is freely available under a general public license. Improved genome alignments of sRNA-seq data should increase the quality of downstream analyses and genome annotation efforts.