Chi D. Luu

First-in-Human Trial of a Novel Suprachoroidal Retinal Prosthesis

Retinal visual prostheses (“bionic eyes”) have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration. Trial Registration Clinicaltrials.gov NCT01603576

Retinal ganglion cell death is induced by microglia derived pro‐inflammatory cytokines in the hypoxic neonatal retina

Hypoxic injury, including that resulting in the retinopathy of prematurity, may induce retinal ganglion cell (RGC) death in the neonatal retina. We hypothesized that this may be mediated by excess production of tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) by microglia. One‐day‐old Wistar rats were subjected to hypoxia for 2 h and the expression of TNF‐α and IL‐1β and their receptors was determined in the retina. The mRNA and protein expression of TNF‐α, IL‐1β, TNF‐receptor 1 (TNF‐R1), and IL‐1 receptor 1 (IL‐1R1) and the tissue concentration of TNF‐α and IL‐1β were up‐regulated significantly after the hypoxic exposure. TNF‐α and IL‐1β immunoreactivity was localized in microglial cells, whereas that of TNF‐R1 and IL‐1R1 was restricted to RGCs, as confirmed by double immunofluorescence labelling. Along with this, increased expression of monocyte chemoattractant protein‐1 and its receptor CCR2 was detected in the microglia. Primary cultured microglia subjected to hypoxia showed enhanced release of TNF‐α and IL‐1β. Primary cultured retinal ganglion cells (RGCs) treated with conditioned medium derived from hypoxic microglia showed enhanced apoptosis, which was significantly reduced when the cells were treated with microglia conditioned medium neutralized with TNF‐α/IL‐1β antibody. Our results suggest that activated microglial cells in hypoxic neonatal retina produce increased amounts of TNF‐α and IL‐1β that could induce RGC death. Copyright

Evaluation of stimulus parameters and electrode geometry for an effective suprachoroidal retinal prosthesis

Several approaches have been proposed for placement of retinal prostheses: epiretinal, subretinal and suprachoroidal. We aimed to systematically evaluate the effectiveness of varying a range of stimulus parameters and electrode geometry for a suprachoroidal electrode array, using cortical evoked responses to monopolar electrical stimulation in cats. Our results indicate that charge thresholds were not dependent on electrode size, pulse widths or position of the return electrode tested, but were dependent on the number of sites stimulated in parallel. Further, we found that the combination of monopolar stimulation with large diameter electrodes, wide pulse widths and parallel stimulation minimized the voltage requirements for stimulation. These results provide useful insights for the design specifications of a low voltage suprachoroidal stimulator.

Intrasession Test-Retest Variability of Microperimetry in Age-Related Macular Degeneration

PURPOSE To determine the intrasession test-retest variability of microperimetry in participants with age-related macular degeneration (AMD). METHODS This study consisted of two separate groups of subjects who had not performed microperimetry previously. In group 1, 30 AMD and 14 control participants performed three microperimetry examinations of a selected eye within one session (test 1 and 2, first pair; test 2 and 3, second pair). Follow-up examination at 6 months was available in 20 AMD participants in group 1, who performed two microperimetry examinations. In group 2, 71 AMD participants performed a short practice examination, then two microperimetry examinations of the right eye (test 1 and 2, first pair) and two of the left eye (test 3 and 4, second pair). RESULTS There was a significant improvement in average point-wise sensitivity (PWS) between the first pair of examination in both groups (P < 0.001), but not in the subsequent pair (P ≥ 0.774). This improvement was not observed at the follow-up visit in the subset of AMD participants in group 1 (P = 0.433). The PWS coefficient of repeatability (CoR) for the second pair of examinations was ± 4.12 dB and ± 4.37 dB for AMD participants for group 1 and 2 respectively. CONCLUSIONS A significant increase in sensitivity between the first and second test, but not in the subsequent tests, was found for participants who had not performed microperimetry previously. Intrasession test-retest variability can therefore be minimized by discarding the first examination to avoid the influence of a learning effect.

Animal models of retinal disease.

Diseases of the retina are the leading causes of blindness in the industrialized world. The recognition that animals develop retinal diseases with similar traits to humans has led to not only a dramatic improvement in our understanding of the pathogenesis of retinal disease but also provided a means for testing possible treatment regimes and successful gene therapy trials. With the advent of genetic and molecular biological tools, the association between specific gene mutations and retinal signs has been made. Animals carrying natural mutations usually in one gene now provide well-established models for a host of inherited retinal diseases, including retinitis pigmentosa, Leber congenital amaurosis, inherited macular degeneration, and optic nerve diseases. In addition, the development of transgenic technologies has provided a means by which to study the effects of these and novel induced mutations on retinal structure and function. Despite these advances, there is a paucity of suitable animal models for complex diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, largely because these diseases are not caused by single gene defects, but involve complex genetics and/or exacerbation through environmental factors, epigenetic, or other modes of genetic influence. In this review, we outline in detail the available animal models for inherited retinal diseases and how this information has furthered our understanding of retinal diseases. We also examine how transgenic technologies have helped to develop our understanding of the role of isolated genes or pathways in complex diseases like AMD, diabetes, and glaucoma.

Cellular and Vascular Changes in the Retina of Neonatal Rats after an Acute Exposure to Hypoxia

PURPOSE This study was undertaken to examine the effects of an acute hypoxic exposure on the retinal cells and production of vascular factors such as vascular endothelial growth factor (VEGF) and nitric oxide (NO), which may affect vascular permeability in the developing retina. METHODS Retinas of 1-day-old rats were examined at 3 hours to 14 days after hypoxic exposure. The mRNA and protein expression of hypoxia-inducible factor-1alpha (HIF-1alpha), VEGF, endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) were determined by real-time RT-PCR, Western blot analysis, and immunohistochemistry. Electron microscopy was used to examine the structural alterations in retinal cells, and rhodamine isothiocyanate (RhIC) or horseradish peroxidase (HRP) was administered intraperitoneally or intravenously to determine vascular permeability. RESULTS The mRNA and protein expression of HIF-1alpha, VEGF, eNOS, nNOS, and iNOS, along with VEGF concentration and NO production, were increased in response to hypoxia. Swollen Müller cell processes, apoptotic and necrotic cells in the inner nuclear layer, and changes in ganglion cells such as swollen and disrupted mitochondria were observed in hypoxic animals. Increased leakage of RhIC and HRP from retinal and hyaloid vessels was seen after hypoxic exposure. CONCLUSIONS The authors suggest that increased VEGF and NO production in hypoxia resulted in increased vascular permeability, leading to changes in Müller cells and degeneration of neural cells. Melatonin administration reduced VEGF and NO production, diminished leakage of RhIC and HRP, and promoted cell proliferation, suggesting this as a potential therapeutic agent in reducing hypoxia-associated damage in the developing retina.

A Wide-Field Suprachoroidal Retinal Prosthesis Is Stable and Well Tolerated Following Chronic Implantation

PURPOSE The safety of chronic implantation of a retinal prosthesis in the suprachoroidal space has not been established. This study aimed to determine the safety of a wide-field suprachoroidal electrode array following chronic implantation using histopathologic techniques and electroretinography. METHODS A platinum electrode array in a wide silicone substrate was implanted unilaterally in the suprachoroidal space in adult cats (n = 7). The lead and connector were tunneled out of the orbit and positioned subcutaneously. Postsurgical recovery was assessed using fundus photography and electroretinography (ERG). Following 3 months of passive implantation, the animals were terminated and the eyes assessed for the pathologic response to implantation. RESULTS The implant was mechanically stable in the suprachoroidal space during the course of the study. The implanted eye showed a transient increase in ERG response amplitude at 2 weeks, which returned to normal by 3 months. Pigmentary changes were observed at the distal end of the implant, near the optic disc. Histopathologic assessment revealed a largely intact retina and a thin fibrous capsule around the suprachoroidal implant cavity. The foreign body response was minimal, with sporadic presence of macrophages and no active inflammation. All implanted eyes were negative for bacterial or fungal infections. A midgrade granuloma and thick fibrous buildup surrounded the extraocular cable. Scleral closure was maintained in six of seven eyes. There were no staphylomas or choroidal incarceration. CONCLUSIONS A wide-field retinal prosthesis was stable and well tolerated during long-term suprachoroidal implantation in a cat model. The surgical approach was reproducible and overall safe.

Choroidal thickness profiles in retinitis pigmentosa.

Little quantitative information exists regarding the effect that retinitis pigmentosa (RP) has on the choroid. The aim of this study was to determine choroidal thickness profiles in patients with RP.

Correlation between retinal oscillatory potentials and retinal vascular caliber in type 2 diabetes.

PURPOSE To assess retinal function in individuals with type 2 diabetes with no retinopathy or nonproliferative diabetic retinopathy (NPDR) and determine the relationship between retinal function and retinal vascular caliber. METHODS A full-field electroretinogram (ERG) and retinal vascular caliber measurements were performed in subjects with nonproliferative diabetic retinopathy (NPDR, n = 10), diabetic subjects without retinopathy (no-DR, n = 18), and normal control subjects (n = 18). The response amplitudes and implicit times of scotopic and photopic ERG and the retinal arteriolar and venular calibers were compared among the study groups. The relationships between ERG parameters and retinal vascular calibers were determined. RESULTS There were statistically significant differences between diabetic (no-DR and NPDR groups) and control subjects in the amplitudes and implicit times of rod-derived ERG responses, but not in the cone-derived ERG responses. All the oscillatory potential (OP) components (OP1-OP4) were significantly reduced in amplitude and increased in implicit time in the no-DR and NPDR groups. No significant difference was found in any of the ERG parameters between the no-DR and NPDR groups. Of all the ERG parameters examined, only OP4 amplitude correlated significantly with the retinal arteriolar caliber (r = -0.556, P = 0.006). None of the OP components correlated significantly with retinal venular caliber. CONCLUSIONS Significant retinal dysfunction was demonstrated in all diabetic patients, even in those without clinically detectable retinopathy, with the rod system being predominantly affected. OP4 amplitude correlates with retinal arteriolar caliber in diabetic patients, suggesting a correlation between retinal neuronal dysfunction and microvasculature changes.

Visual function in Vogt-Koyanagi-Harada patients

BackgroundVogt-Koyanagi-Harada (VKH) disease presents with anterior segment inflammation, choroiditis and exudative retinal detachment. Following resolution of the inflammation, VKH patients have been noted to complain of visual disturbances despite good visual acuity. We therefore investigated the visual function deficits of convalescent VKH patients.MethodsA cross-sectional observational nonrandomized controlled study of convalescent VKH patients from the Uveitis Service of the Singapore National Eye Centre, and normal subjects was performed. The best-corrected visual acuities (BCVA) and multifocal electroretinograms (mfERGs) of VKH patients with and without peripapillary atrophy (PPA) were compared with those of the normal eyes. The mfERG results were subdivided into those obtained from the peripapillary area and those from the rest of the macular.ResultsEleven VKH eyes with large PPA to disc ratios (PPA/D ratio >2), 15 VKH eyes with PPA/D ratios<1 and 6 normal eyes were included in the study. Five eyes (54.5%) of VKH patients with PPA/D>2 had a BCVA of less than 20/40. All the other eyes had 20/20 vision. Nine of the 11 VKH eyes with PPA/D>2 also had large areas of chorioretinal atrophy.The mfERG responses of VKH eyes with PPA/D ratio >2 were markedly reduced in amplitude (p<0.001) and delayed in implicit time (p<0.001) throughout the entire macular area. VKH patients with PPA/D ratio<1 had significantly reduced mfERG amplitudes throughout the entire macular area, as well as delayed implicit times at the peripapillary region (p=0.026). Sub-division of VKH eyes with PPA/D<1 into eyes with no PPA and eyes with a small PPA, showed that both groups had a similar reduction in response amplitude over the entire macular region. However, the implicit time was significantly delayed in eyes with small PPA when compared to those without PPA (p<0.03).ConclusionsVKH patients with large PPA have clinically significant visual dysfunction. VKH patients without PPA also have subclinical retinal dysfunction. The mfERG may be a useful adjunct in the management of VKH by detecting early retinal damage.