Inner and outer retinal mechanisms engaged by epiretinal stimulation in normal and rd mice.

Retinal prosthetic devices are being developed to bypass degenerated retinal photoreceptors by directly activating retinal neurons with electrical stimulation. However, the retinal circuitry that is activated by epiretinal stimulation is not well characterized. Whole-cell patch clamp recordings were obtained from ganglion cells in normal and rd mice using flat-mount and retinal slice preparations. A stimulating electrode was positioned along the ganglion cell side of the preparation at different distances from the stimulated tissue. Pulses of cathodic current evoked action potentials in ganglion cells and less frequently evoked sustained inward currents that appeared synaptic in origin. Sustained currents reversed around E(Cl) and were inhibited by blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-proprionate (AMPA)-type glutamate receptors with 2,3-dihydroxy-6-nitro-sulfamoyl-benzo(f)-quinoxaline-2,3-dione (NBQX), γ aminobutyric acid a/c (GABA(a/c)) receptors with picrotoxinin, or glycine receptors with strychnine. This suggests that epiretinal stimulation activates glutamate release from bipolar cell terminals, which in turn evokes release of GABA and glycine from amacrine cells. Synaptic current thresholds were lower in ON ganglion cells than OFF cells, but the modest difference did not attain statistical significance. Synaptic currents were rarely observed in rd mice lacking photoreceptors compared to normal retina. In addition, confocal calcium imaging experiments in normal mice retina slices revealed that epiretinal stimulation evoked calcium increases in the outer plexiform layer. These results imply a contribution from photoreceptor inputs to the synaptic currents observed in ganglion cells. The paucity of synaptic responses in rd mice retina slices suggests that it is better to target retinal ganglion cells directly rather than to attempt to engage the inner retinal circuitry.

Retinal Vascular Signs as Screening and Prognostic Factors for Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Current Evidence.

BACKGROUND: The substantial burden of kidney disease fosters interest in new ways of screening for early disease diagnosis, especially by non-invasive imaging. Increasing evidence for an association between retinal microvascular signs and kidney disease prompted us to investigate the relevant current literature on such an association systematically by performing a meta-analysis of our findings. METHODS: We scrutinized the current literature by searching PubMed and Embase databases from for clinical studies of the association between retinal microvascular signs and prevalent or incident kidney disease. After excluding cases that did not meet our criteria, we extracted relevant data from 42 published studies (9 prospective, 32 cross-sectional, and 1 retrospective). RESULTS: Our investigation yielded significant associations between retinal vascular changes (including retinopathy and retinal vascular diameter) and kidney dysfunction (including chronic kidney disease (CKD), end-stage renal disease (ESRD), albuminuria, and estimated glomerular filtration rate (eGFR) decline). According to our meta-analysis, retinopathy was associated with ESRD (hazard ratio (HR) 2.12 (95% confidence interval CI; 1.39-3.22)) and with CKD prevalence in the general population (odds ratio (OR) 1.31 (95% CI; 1.14-1.50)), and specifically in type 2 diabetic patients (OR 1.68 (95% CI; 1.68-2.16)). CRAE was associated with prevalent CKD (OR 1.41 (95% CI; 1.09-1.82)). CONCLUSIONS: Our findings suggest that the retinal microvasculature can provide essential data about concurrent kidney disease status and predict future risk for kidney disease development and progression.

Intraocular pressure and aqueous humor flow during a euglycemic-hyperinsulinemic clamp in patients with type 1 diabetes and microvascular complications.

BACKGROUND: Microvascular complications, including retinopathy and nephropathy are seen with type 1 diabetes. It is unknown whether functional changes in aqueous humor flow or intraocular pressure (IOP) develop in parallel with these complications. This study was designed to test the hypothesis that clinical markers of microvascular complications coexist with the alteration in aqueous humor flow and IOP. METHODS: Ten patients with type 1 diabetes and ten healthy age- and weight-matched controls were studied. Aqueous flow was measured by fluorophotometry during a hyperinsulinemic-euglycemic clamp (insulin 2 mU/kg/min). Intraocular pressure was measured by tonometry at -10, 90 and 240 minutes from the start of the clamp, and outflow facility was measured by tonography at 240 minutes. RESULTS: During conditions of identical glucose and insulin concentrations, mean aqueous flow was lower by 0.58 microl/min in the diabetes group compared to controls (2.58 +/- 0.65 versus 3.16 +/- 0.66 microl/min, respectively, mean +/- SD, p = 0.07) but statistical significance was not reached. Before the clamp, IOP was higher in the diabetes group (22.6 +/- 3.0 mm Hg) than in the control group (19.3 +/- 1.8 mm Hg, p = 0.01) but at 90 minutes into the clamp, and for the remainder of the study, IOP was reduced in the diabetes group to the level of the control group. Ocular pulse amplitude and outflow facility were not different between groups. Systolic blood pressure was significantly higher in the diabetes group, but diastolic and mean arterial pressures were not different. CONCLUSIONS: We conclude that compared to healthy participants, patients with type 1 diabetes having microalbuminuria and retinopathy have higher IOPs that are normalized by hyperinsulinemia. During the clamp, a reduction in aqueous flow was not statistically significant.

Outcome of retinopathy of prematurity patients following adoption of revised indications for treatment.

BACKGROUND: The Early Treatment for Retinopathy of Prematurity study (ETROP), published in 2003, established new guidelines for treatment of retinopathy of prematurity (ROP) and demonstrated improved outcomes compared to previous guidelines. We examined outcomes before and after implementing the ETROP recommendations. METHODS: A retrospective chart review was performed using records of infants who had laser ablations for ROP performed from January, 2000 through December, 2005. Data collected included date of birth; birth weight; estimated gestational age (EGA); grading of ROP; date of laser ablation; and outcome of laser surgery. Univariate association with threshold or prethreshold treatment (Pre-ETROP and Post-ETROP, respectively) were assessed using t-tests or Wilcoxon tests. Additional comparison between groups was performed using Fisher's exact tests. RESULTS: 581 patients were examined before and 464 after December 2003. Of these, 29/581 (5% - Pre-ETROP Group) and 53/464 (11% - Post-ETROP Group) patients advanced to criteria requiring laser treatment respectively (P = 0.0001). The average estimated gestational age (EGA) at birth was 26.3 and 25.2 weeks, with an average birth weight of 888 and 707 grams for Pre and Post-ETROP Groups, respectively. Stage 5 retinal detachment (RD) developed in 10.3% of eyes in the Pre-ETROP Group and 1.9% of eyes in the Post-ETROP Group (P = 0.02). CONCLUSION: After the ETROP guidelines were implemented, there was a decrease from 10.3% to 1.9% of eyes developing Stage 5 retinal detachment, despite this group having a lower average EGA and lower average birth weight. These results underscore the importance of adoption of the Revised Indications.

The long-term natural history of geographic atrophy from age-related macular degeneration: enlargement of atrophy and implications for interventional clinical trials.

PURPOSE: To report the enlargement rate of geographic atrophy (GA) over time, its relationship to size of atrophy at baseline and to prior enlargement rate, and the implications for designing future treatment trials for GA. DESIGN: Prospective natural history study of GA resulting from age-related macular degeneration. PARTICIPANTS: Two hundred twelve eyes of 131 patients were included in the analysis. METHODS: Annual follow-up included stereo color fundus photographs. The areas of GA were identified and measured, and the rate of enlargement of the atrophy was assessed. Sample sizes for clinical trials using systemic treatment and uniocular treatment were determined. MAIN OUTCOME MEASURE: Rate of enlargement of the atrophy. RESULTS: The median overall enlargement rate was 2.1 mm2/year (mean, 2.6 mm2/year). Eyes with larger areas of atrophy at baseline tended to have larger enlargement rates, but knowledge of prior rates of enlargement was the most significant factor in predicting subsequent enlargement rates. There was high concordance between the enlargement rates in the 2 eyes of patients with bilateral GA (correlation coefficient, 0.76). To detect a 25% reduction in enlargement rate for a systemic treatment (alpha, 0.05; power, 0.80; losses to follow-up, 15%), 153 patients each in a control and treatment group would be required for a trial with a 2-year follow-up period for each patient. For a uniocular treatment, 38 patients with bilateral GA would be required, with the untreated eye serving as a control for the treated eye. CONCLUSIONS: Treatment trials for GA with an outcome variable of change in enlargement rate are feasible.

Ocular manifestations of Donnai-Barrow syndrome.

Donnai-Barrow syndrome is a rare autosomal recessive disorder first described in 1993. This report presents ocular manifestations of this rare autosomal recessive disorder through 2 additional cases. Ocular features include hypertelorism, down-slanting palpebral fissures, iris coloboma, high myopia, and retinal detachment. The extreme congenital myopia in these patients is a significant risk factor for retinal detachment, and prophylactic barrier photocoagulation may be considered to prevent retinal detachment and its associated functional disability.

Inner retinal mechanisms engaged by retinal electrical stimulation.

PURPOSE: Retinal prosthetic devices are being developed to bypass degenerated retinal photoreceptors by directly activating retinal neurons with electrical stimulation. However, little is known about retinal activity during such stimulation. METHODS: Whole cell patch-clamp recordings were obtained from ganglion and bipolar cells in the salamander retinal slice preparation. A stimulating electrode was positioned at the vitreal surface of the slice. RESULTS: Brief pulses of cathodic current evoked transient inward currents in ganglion cells arising from action potentials. Longer pulses (>5 milliseconds) also evoked sustained inward currents in ganglion cells that appeared synaptic in origin because, unlike transient currents, sustained currents were blocked by inhibiting synaptic transmission with Cd2+. These synaptic currents reversed around ECl and were blocked by picrotoxin, strychnine, or both, suggesting they were mediated by GABAa/c and glycine receptors. Synaptic currents were also blocked by the NMDA antagonist MK801 and the KA/AMPA antagonist NBQX, suggesting that epiretinal stimulation evoked glutamate release from bipolar cells, which in turn stimulated the release of GABA and glycine from amacrine cells. Sustained currents were also evoked by epiretinal stimulation in bipolar cells. These currents reversed near ECl and were blocked by picrotoxin, suggesting they arose from GABAa/c receptors. CONCLUSIONS: Pulse duration is an important parameter for effective activation of the inner retina by epiretinal stimulation. Brief pulses evoke action potentials only in ganglion cells. However, longer pulses also evoke sustained synaptic currents by stimulating glutamate release from bipolar cell terminals, which, in turn, evokes the release of GABA and glycine from amacrine cells.

The safety of intraocular ketorolac in rabbits.

PURPOSE: To assess the safety of a possible substitute treatment for intraocular steroid injections, intraocular injections of ketorolac tromethamine, one of the nonsteroidal anti-inflammatory drugs, were performed in rabbits. METHODS: Either 0.5% or 0.25% preservative-free ketorolac tromethamine ophthalmic solution (0.1 mL) was injected into the vitreous of the right eye of 15 rabbits. Physiologic saline solution (BSS; Alcon, Ft. Worth, TX) was injected into the left eye of each rabbit as a control. A standard electroretinogram and intraocular pressure measurements were obtained before injection, and repeated 1 day and 1, 2, 3, and 4 weeks after injection. After 4 weeks, the rabbits were euthanatized and the retinas examined by light and electron microscopy. Differences in the electroretinograms, intraocular pressure, and histopathology between the two eyes were recorded. Further, the elimination half-life of the drug in the vitreous was assessed. RESULTS: There were no statistically significant differences in electroretinograms, or intraocular pressure measurements obtained between the ketorolac-injected eyes and the control eyes. The half life of the drug was measured to be 2.3 hours. No histopathologic changes were observed in study eyes compared with control eyes. CONCLUSIONS: Preservative-free ketorolac tromethamine is nontoxic to the retinas of rabbits when injected intravitreally and could be considered as an alternative to intraocular steroid injections.

Electrical stimulation in isolated rabbit retina.

Experiments were conducted to assess the effect of stimulating electrode parameters (size, position, and waveform shape) on electrically elicited ganglion cell action potentials from isolated rabbit retina. Thirty-eight isolated rabbit retinas were stimulated with bipolar stimulating electrodes (either 125 or 25 microm in diameter) positioned on either the ganglion or the photoreceptor side. Recording electrodes were placed between the optic disc and the stimulating electrodes. Cathodic-first, biphasic, current waveforms of varying pulse durations (0.1, 0.5, 1 ms) were used. For the four conditions tested (125-electrode and 25-microm electrode, ganglion cell, and photoreceptor positions) threshold currents ranged from 6.7 to 23.6 microA, depending on location and pulse duration. With 1-ms pulse duration, no statistically significant difference was seen between threshold currents when either size electrode was used to stimulate either the ganglion cell side or the photoreceptor side. For all groups, the threshold currents using the 1-ms pulse were lower than those using 0.1 ms, but the 0.1-ms pulses used less charge. These experiments provide a number of valuable insights into the relative effects of several stimulation parameters critical to the development of an implanted electronic retinal prosthesis.

Electrical stimulation in normal and retinal degeneration (rd1) isolated mouse retina.

Stimulus threshold and response latencies were measured for electrically elicited retinal ganglion cell responses in retina isolated from the eyes of normal and retinal degenerate (rd1) mice. Stimulation of the ganglion cell-side in normal retina yielded a significantly lower mean threshold and shorter latency when compared with stimulation of the photoreceptor side in normal retina. The latency of the ganglion cell-side stimulation in normal retina also proved to be significantly shorter than the latency for stimulation of the ganglion cell side in rd1 retina. Thus both the electrode positioning as well as the health of the retinal tissue play a role in the stimulating current required to elicit a retinal response.

Vitreopapillary traction: cost-effective diagnosis by optical coherence tomography.

CASE REPORTS: A prospective, noncomparative, observational case series. Three patients, aged 76 to 81, all referred to subspecialty services for evaluation of optic disc elevation, and all were found to have optic disc (vitreopapillary) traction as verified by optical coherence tomography. COMMENTS: Vitreopapillary traction is a recently recognized syndrome characterized by incomplete posterior vitreous detachment. The use of optical coherence tomography is helpful in the diagnosis of this syndrome, preventing many costly, unwarranted evaluations.

Identification of visually significant operculum without macular hole by optical coherence tomography.

CASE REPORT: We report a case that illustrates the effectiveness of optical coherence tomography (OCT) in identifying visually significant vitreoretinal interface opacities in the absence of a macular hole. A patient presented with a scotoma in the right eye. Fundoscopic examination revealed a small lesion in close proximity to the foveal avascular zone. OCT of the right eye revealed a small operculum in the vitreous anterior to the fovea without evidence of a macular hole. COMMENTS: To our knowledge, ours is the first reported case of the use of OCT to identify the presence of a visually significant operculum without an associated macular hole.

Panuveitis in association with pseudotumor cerebri.

We report a case of an 11-year-old girl with bilateral panuveitis in association with pseudotumor cerebri. The patient underwent complete ophthalmologic, neurologic, and laboratory evaluations and was treated with therapy for pseudotumor cerebri. The patient met the diagnostic criteria for pseudotumor cerebri and also had panuveitis. Symptoms and findings of pseudotumor cerebri and panuveitis improved significantly after combination therapy of oral acetazolamide and weight reduction. The index case illustrates that pseudotumor cerebri can be associated with panuveitis. Therapy for pseudotumor cerebri might also help with the resolution of uveitis.

Analyzing OCT images of age-related macular degeneration patients to identify spatial health correlations.

An approach to automatically group age-related macular degeneration (AMD) patients having similar retinal health profiles by clustering Optical Coherence Tomography (OCT) images is described. Spatial health patterns within and across profiles are discovered by identifying segments of images that have similar levels of health in a given retina region. Segmentations of various sizes are considered and the segmentation where the segment similarity most closely matches the discovered health profiles is used to identify health patterns. Our experiments with OCT images of 10 AMD patients show that - i) health profiles generated by clustering closely correspond to those identified by a physician expert, ii) a rich set of spatial patterns can be discovered within and across profiles using regular image segmentation, and iii) new images can be successfully classified into existing profiles so that physicians can provide effective profile-based treatments.

Retinal prosthesis for the blind.

Most of current concepts for a visual prosthesis are based on neuronal electrical stimulation at different locations along the visual pathways within the central nervous system. The different designs of visual prostheses are named according to their locations (i.e., cortical, optic nerve, subretinal, and epiretinal). Visual loss caused by outer retinal degeneration in diseases such as retinitis pigmentosa or age-related macular degeneration can be reversed by electrical stimulation of the retina or the optic nerve (retinal or optic nerve prostheses, respectively). On the other hand, visual loss caused by inner or whole thickness retinal diseases, eye loss, optic nerve diseases (tumors, ischemia, inflammatory processes etc.), or diseases of the central nervous system (not including diseases of the primary and secondary visual cortices) can be reversed by a cortical visual prosthesis. The intent of this article is to provide an overview of current and future concepts of retinal and optic nerve prostheses. This article will begin with general considerations that are related to all or most of visual prostheses and then concentrate on the retinal and optic nerve designs. The authors believe that the field has grown beyond the scope of a single article so cortical prostheses will be described only because of their direct effect on the concept and technical development of the other prostheses, and this will be done in a more general and historic perspective.

Retinal vein cannulation with prolonged infusion of tissue plasminogen activator (t-PA) for the treatment of experimental retinal vein occlusion in dogs.

PURPOSE: To evaluate the feasibility, safety, and efficacy of local thrombolytic agents directly injected into occluded retinal veins in an experimental animal model. DESIGN: Experimental animal study. METHODS: This experimental study was performed in two phases. In phase 1, 15 enucleated porcine eyes and 8 in vivo canine eyes were used for the development of the instrumentation and surgical technique required for retinal vein cannulation with prolonged intravascular infusion. In phase 2 of this study, experimental branch retinal vein occlusion was photo-chemically created using an intravenous injection of rose bengal followed by diode laser photocoagulation in eight eyes of eight dogs. Four eyes were treated by retinal vein cannulation and an injection of tissue plasminogen activator (t-PA) using a specifically designed microcatheter, while the remaining four eyes were untreated (control group). The total amount of t-PA injected intravenously ranged from 400 to 1000 mug, infused over a period ranging from 25 to 45 minutes with a mean pressure of 40 psi, resulting in a mean injection flow rate of 0.05 ml/min. The dogs underwent clinical examination, fluorescein angiography, and histologic examination. Main outcome measures were: Achievement of prolonged intravascular infusion of t-PA, changes in fundus appearance, fluorescein angiography, and histology. RESULTS: A microcatheter instrument and a surgical technique for retinal vein cannulation with prolonged intravascular infusion were developed. Cannulation and t-PA infusion for a period of at least 30 minutes was achieved in all four treated eyes with experimental branch retinal vein occlusion. No complications were recorded in all treated eyes. One week and 1 month postoperatively, treated eyes exhibited marked decreases in retinal hemorrhages, retinal vein dilation, and tortuosity, whereas nontreated eyes exhibited persistence of these findings. Fluorescein angiography demonstrated improved circulatory flow in treated relative to nontreated eyes. Histologic analysis confirmed the presence of thrombi in nontreated eyes only. CONCLUSIONS: Retinal vein cannulation with prolonged intravascular injection of t-PA is feasible and safe, and this may offer a new treatment option for retinal vein occlusion.

Heat effects on the retina.

BACKGROUND AND OBJECTIVE: To study the heat and power dissipation effect of anintraocular electronic heater on the retina. The determination of thermal parameters that are nonharmful to the retina will aid in the development of an implantable intraocular electronic retinal prosthesis. MATERIALS AND METHODS: In dogs, five different retinal areas were touched with a custom intraocular heater probe (1.4 x 1.4 x 1.0 mm) for 1 second while the heater dissipated 0 (control), 10, 20, 50, or 100 mW. In a second protocol, the heater was mechanically held in the vitreous cavity while dissipating 500 mW for 2 hours while monitoring intraocular temperature. The animals were observed for 4 weeks with serial fundus photography and electroretinography. The procedure was then repeated in the fellow eye. The dogs were killed and both eyes were enucleated and submitted for histology. RESULTS: In experiments using protocol 1, heater settings of 50 mW or higher caused an immediate visible whitening of the retinal tissue. Histologically, this damage was evident only if the eyeswere immediately enucleated. Permanent damage was caused by heater settings of 100 mW or higher. Under protocol 2, no ophthalmologic, electroretinography, or histologic differences were noted between the groups. Temperature increases of 5 degrees C in the vitreous and 2 degrees C near the retina were noted. CONCLUSIONS: The liquid environment of the eye acts as a heat sink that is capable of dissipating a significant amount of power. An electronic chip positioned away from the retina can run at considerably higher powers than a chip positioned on the retinal surface.

Comparison of electrical stimulation thresholds in normal and retinal degenerated mouse retina.

PURPOSE: To compare the threshold for electrically elicited action potentials of retinal ganglion cells in normal mouse retina and photoreceptor degenerated (rd) mouse retina. METHODS: Microelectrode recordings were made from retinal ganglion cells of normal and rd mice. Mice with a genetically based retinal degeneration (rd mice) were grown to the age of 16 weeks, when light-evoked responses could no longer be recorded. A bare wire was placed in the vitreous to stimulate the retina with charge-balanced current pulses. The following pulse shapes were investigated: single, square biphasic pulse, single sine wave, and biphasic pulse trains. RESULTS: Normal mice had significantly lower stimulus thresholds than rd mice for all pulse shapes. In normal and rd mice, short pulses were more efficient with respect to total charge used, but required a higher current. In normal mice, sine wave stimulation was significantly more efficient than a biphasic pulse of the same duration. No difference was noted between sine wave and square wave stimulation in rd mice. Pulse trains offered little benefit over single pulses. CONCLUSION: The amount of electrical charge required to elicit an action potential is dependent on the condition of the retina and the shape of the stimulus pulse used to deliver the charge.

Listeria monocytogenes panophthalmitis: a novel strain follows a virulent course.

PURPOSE: To describe the findings and clinical course of a case of Listeria endophthalmitis as it progressed to panophthalmitis despite vitrectomy and intravitreal and systemic antibiotic therapy. METHODS: A case report of Listeria endophthalmitis progressing to panophthalmitis with a brief retrospective review of the literature pertaining to Listeria-related eye infections and endogenous endophthalmitis. RESULTS: A 70-year-old man presented with fulminant, hypertensive endophthalmitis and underwent pars plana vitrectomy, vitreous tap for Gram stain and culture, with intravitreal antibiotic injection and systemic intravenous antibiotic therapy, given the concern for an endogenous source. Despite this treatment, the patient progressed to no light perception vision with progressive orbital inflammatory signs. He then required enucleation with pathology, demonstrating an acute necrotizing panophthalmitis. DISCUSSION: This case demonstrates the importance of a high index of suspicion for endophthalmitis in the setting of progressive uveitis despite titration of topical corticosteroid therapy while describing the preferred management and antibiotic regimen for patients with Listeria-related infections. Previous reported cases of Listeria endophthalmitis characteristically present as a hypertensive endophthalmitis with pigment dispersion and a dark hypopyon. If endophthalmitis is suspected, an anterior chamber paracentesis with Gram stain and culture can aid in earlier diagnosis, thus allowing for prompt, targeted therapy and improved outcomes.