Pattern Electroretinogram Research Articles

Objective functional monitoring of retinoprotective treatment in diabetic retinopathy

This study assesses the effect of the drug Retinalamin on the functional state of the retina in patients with DR using the Diopsys NOVA Vision Testing System that utilizes electrophysiological (EP) technology. The study included patients with type 1 and 2 diabetes mellitus (DM) with DR of any stage without macular edema. Patients underwent standard ophthalmological examination and objective functional examination of the retina using the Diopsys NOVA Vision Testing System. The control group consisted of patients with type 1 and 2 DM with DR who did not receive Retinalamin. Significant changes in pattern electroretinography and flash electroretinography parameters were recorded in patients who received a course of Retinalamin. Two clinical examples are presented, which can be designated as the first experience of objective functional monitoring of treatment of patients with DR with Retinalamin. Retinoprotective therapy is necessary already at the early stages of DR. Electroretinography is an objective tool for functional analysis of the earliest changes in retinal cells in DR. It is necessary to use the identified "therapeutic" window for the appointment of retinoprotective agents.

Update on the range of visual electrophysiology tests and heir application with clinical examples

The International Society for clinical electrophysiology of vision (ISCEV) publishes open‐access standards and guidelines for routine electrophysiological tests of the visual system in order to optimize diagnostic value, to promote consistency and to allow meaningful inter‐laboratory comparisons. The ISCEV also publishes extended protocols with the aim of promoting convergence of methods that are not yet standardized, for tests that are widely used but often performed as an addition to the minimum ISCEV standard procedures (see www.ISCEV.org for all publications).This talk will outline the main ISCEV standard methods including the full‐field electroretinogram (ERG), pattern ERG (PERG) and multifocal ERG (mfERG). Several extended full‐field ERG protocols will also be highlighted, including the dark‐adapted (DA) red flash ERG, photopic On–Off ERG and S‐cone ERG. The use of these methods in the clinic will be illustrated in cases of inherited and acquired retinal disorders, to show how the extended protocols complement standard techniques, to aid diagnosis and patient management and to probe and detail retinal function phenotypes.The Standard full‐field ERG is recorded under dark‐adapted (DA) and light‐adapted (LA) conditions and provides a measure of generalized rod and cone system function at the level of the outer and inner retina, with minimal contribution from the macula. The mfERG assesses cone system function across the posterior pole and the PERG assesses macular and macular retinal ganglion cell function.The DA red flash ERG is an extended protocol that provides a measure of generalized dark‐adapted retinal function, with the advantage of having both a cone system x‐wave and a rod system b‐wave within the same waveform. This enables the relative involvement of rod and cone systems to be assessed simultaneously and can help determine the origins of severely attenuated standard DA strong flash ERGs. The DA red flash ERG is also useful for assessing cone system function in photophobic patients, and in patients with variable ability to comply with longer ERG protocols. The photopic On–Off ERG is a response to an extended light stimulus (duration 150 or 200 ms) and is used to assess generalized cone system function of both the On and Off retinal pathways, useful when there is a locus of dysfunction that is post‐phototransduction or post‐receptoral, when On and Off retinal systems may be similarly, selectively or specifically affected e.g., in different forms of congenital stationary night blindness (CSNB) or in forms of toxic retinopathy. The S‐cone ERG (short‐wavelength or “blue” flash ERG) is used to probe the function of the S‐cone retinal pathway, and can aid diagnosis and characterization in a variety of retinal dystrophies and disorders e.g., distinguishing between achromatopsia and S‐cone monochromacy.

Association between alcohol use and retinal dysfunctions in patients with alcohol use disorder: A window on GABA, glutamate, and dopamine modulations

BackgroundAlcohol is the most widely consumed addictive substance around the world and have deleterious effect on the central nervous system. Alcohol consumption affect the balance of certain neurotransmitters like GABA, glutamate and dopamine. The retina provides an easy means of investigating dysfunctions of synaptic transmission in the brain. The purpose of this study is to assess the impact of alcohol consumption on retinal function using pattern electroretinogram (PERG) and flash electroretinogram (fERG). MethodsWe recorded PERG and fERG under scotopic and photopic condition in 20 patients with alcohol use disorder and 20 controls. Implicit time and amplitude of numerous parameters were evaluated: a- and b-waves for fERG, OP3 and OP4 for dark-adapted 3.0 oscillatory potentials fERG, P50 and N95 for PERG. ResultsPatients with alcohol use disorder showed a significant increase in N95 implicit time without a significant change in the amplitudes of oscillatory potentials. ConclusionThe results of our study reflect the impact of alcohol use on ganglion cell function and could highlight alterations in glutamatergic neurotransmission inside the retina. We believe that ERG could be used as an early marker of alcohol consumption.

Increasing the number and intensity of shock tube generated blast waves leads to earlier retinal ganglion cell dysfunction and regional cell death

The purpose of this study was to examine the effect of a blast exposure generated from a shock tube on retinal ganglion cell (RGC) function and structure. Mice were exposed to one of three blast conditions using a shock tube; a single blast wave of 20 PSI, a single blast wave of 30 PSI, or three blast waves of 30 PSI given on three consecutive days with a one-day inter-blast interval. The structure and function of the retina were analyzed using the pattern electroretinogram (PERG), the optomotor reflex (OMR), and optical coherence tomography (OCT). The in vivo parameters were examined at baseline, and then again 1-week, 4-weeks, and 16-weeks following blast exposure. The number of surviving RGCs was quantified at the end of the study. Analysis of mice receiving a 20 PSI injury showed decreased PERG and OMR responses 16-weeks post blast, without evidence of changed retinal thickness or RGC death. Mice subjected to a 30 PSI injury showed decreased PERG responses 4 weeks and 16 weeks after injury, without changes in the retinal thickness or RGC density. Mice subjected to 30 PSI X 3 blast exposures had PERG deficits 1-week and 4-weeks post exposure. There was also significant change in retinal thickness 1-week and 16-weeks post blast exposure. Mice receiving 30 PSI X 3 blast injuries had regional loss of RGCs in the central retina, but not in the mid-peripheral or peripheral retina. Overall, this study has shown that increasing the number of blast exposures and the intensity leads to earlier functional loss of RGCs. We have also shown regional RGC loss only when using the highest blast intensity and number of blast injuries.

Model‐EyeD: Harnessing the potential of the eye as a biomarker for Alzheimer’s disease and related dementias

AbstractBackgroundDisease‐modifying treatments for Alzheimer’s disease and related dementias (ADRD) will be most effective early in the disease process. Clinical use of these therapies will require practical, widely accessible biomarkers. Plasma‐based protein biomarkers hold promise for identifying core AD pathology, but this complex disease likely requires other markers to identify people at highest risk of progression to dementia. Studies support eye exams as a synergistic strategy since retinal imaging would be cost effective, but significant hurdles remain. The timing and subtypes of retinal biomarkers have not yet been determined and the identification of ADRD‐specific biomarkers independent of common ocular diseases is challenging. Here, we introduce a new program, Model‐EyeD, to evaluate the eye as an accessible biomarker in the mouse model and human subjects.MethodFor familial AD and mixed dementia, we have backcrossed the APPSAA knock‐in allele (humanized Abeta with Swedish, Artic, Austrian, mutations) from C57BL/6J (B6) to genetically diverse NZO/HILtJ (prone to obesity and diabetes), and WSB/EiJ (susceptible to cerebrovascular deficits) strains. To study late‐onset AD (LOAD), we are using strains created by the IU/JAX/PITT MODEL‐AD Center, including the common 677C>T variant in methylene tetrahydrofolate reductase gene (Mthfr677C>T ), a cardiovascular and cerebrovascular risk factor. A battery of ocular assays (pattern electroretinograms, fluorescence angiography, optical coherence tomography) are performed on four to 24 months old male and female mice. Results are being compared to MRI, PET/CT, cognition and blood biomarkers.ResultUnlike previous transgenic amyloid models, B6.APPSAA and WSB.APPSAA mice show no retinal amyloid deposition or retinal vascular deficits at 12 months. NZO (in the absence of amyloid deposition) show retinopathy lesions (cotton wool spots, vascular leakage), suggesting NZO.APPSAA are ideal to study interactions between metabolic syndrome retinopathy and mixed dementia. Young B6.Mthfr677C>T mice show cerebral and retinal vascular deficits. Aging studies are ongoing. Results will be confirmed in human subjects with clinical and biomarker‐confirmed AD and mixed AD/small vessel vascular disease.ConclusionOur extensive collection of genetically diverse mouse models, coupled with our alignment to data from human subjects, show promise in developing eye‐based protocols to identify early stages of different clinical phenotypes of ADRD in humans.

Role of Electrophysiologal Studies for Detection of Simulation and Aggravation in Ophthalmology

Abstract Objective To present the importance of the electrophysiological studies for detection of malingering and aggravation in ophthalmology. Materials and methods Six eyes of three patients underwent a complete clinical examination, fundus-autofluorescence (FAF), fluorescein angiography (FA), optical coherence tomography (OCT), visual field testing, electrophysiological (EF) studies – full-field, multifocal and pattern electroretinography (ffERG, mfERG and PERG) and visual evoked potentials (VEPs), for detection of simulation or aggravation. Results After the electrophysiological studies’ results, which are objective and non-manipulable, we purposefully reviewed and repeated some of the tests already done, which allowed a comprehensive interpretation of the results. It turned out that discrete changes in targeted search can be detected in several of the studies performed, which greatly facilitates the correct diagnosis. Conclusion EF studies are objective methods for studying the visual analyzer’s function, that can not be manipulated, which makes them indispensable for detecting simulation and aggravation in ophthalmology. A detailed extensive study of the degree of simulation and aggravation among the ophthalmological patients is needed, which will enrich our knowledge and make us more precise in our expertise.

The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes.

The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in Nlrp1-/-, Casp1-/-, and GsdmD-/- knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

Application of Electrophysiology in Non-Macular Inherited Retinal Dystrophies.

Inherited retinal dystrophies encompass a diverse group of disorders affecting the structure and function of the retina, leading to progressive visual impairment and, in severe cases, blindness. Electrophysiology testing has emerged as a valuable tool in assessing and diagnosing those conditions, offering insights into the function of different parts of the visual pathway from retina to visual cortex and aiding in disease classification. This review provides an overview of the application of electrophysiology testing in the non-macular inherited retinal dystrophies focusing on both common and rare variants, including retinitis pigmentosa, progressive cone and cone-rod dystrophy, bradyopsia, Bietti crystalline dystrophy, late-onset retinal degeneration, and fundus albipunctatus. The different applications and limitations of electrophysiology techniques, including multifocal electroretinogram (mfERG), full-field ERG (ffERG), electrooculogram (EOG), pattern electroretinogram (PERG), and visual evoked potential (VEP), in the diagnosis and management of these distinctive phenotypes are discussed. The potential for electrophysiology testing to allow for further understanding of these diseases and the possibility of using these tests for early detection, prognosis prediction, and therapeutic monitoring in the future is reviewed.

The diagnostic accuracy of photopic negative responses evoked by broadband and chromatic stimuli in a clinically heterogeneous population

PurposeTo compare the diagnostic accuracy of the photopic negative response (PhNR) elicited by red-blue (RB) and white-white (WW) stimuli, for detection of retinal ganglion cell (RGC) dysfunction in a heterogeneous clinical cohort.MethodsAdults referred for electrophysiological investigations were recruited consecutively for this single-centre, prospective, paired diagnostic accuracy study. PhNRs were recorded to red flashes (1.5 cd·s·m−2) on a blue background (10 cd·m−2) and to white flashes on a white background (the latter being the ISCEV standard LA 3 stimulus). PhNR results were compared with a reference test battery assessing RGC/optic nerve structure and function including optical coherence tomography (OCT) retinal nerve fibre layer thickness and mean RGC volume measurements, fundus photography, pattern electroretinography and visual evoked potentials. Primary outcome measures were differences in sensitivity and specificity of the two PhNR methods.ResultsTwo hundred and forty-three participants were initially enrolled, with 200 (median age 54; range 18–95; female 65%) meeting inclusion criteria. Sensitivity was 53% (95% confidence intervals [CI] 39% to 68%) and 62% (95% CI 48% to 76%), for WW and RB PhNRs, respectively. Specificity was 80% (95% CI 74% to 86%) and 78% (95% CI 72% to 85%), respectively. There was a statistically significant difference between sensitivities (p = 0.046) but not specificities (p = 0.08) of the two methods. Receiver operator characteristic (ROC) area under the curve (AUC) values were 0.73 for WW and 0.74 for RB PhNRs.ConclusionPhNRs to red flashes on a blue background may be more sensitive than white-on-white stimuli, but there is no significant difference between specificities. This study highlights the value and potential convenience of using white-on-white stimuli, already used widely for routine ERG assessment.

Tafluprost promotes axon regeneration after optic nerve crush via Zn2+-mTOR pathway

PurposeTo investigate whether Tafluprost could promote optic nerve regeneration in mice after optic nerve crush (ONC) and determine the underlying molecular mechanism. MethodsTafluprost was injected into the vitreous body immediately after ONC. The level of Zn2+ in the inner plexiform layer (IPL) of the retina was stained using autometallography (AMG). The number of survival retinal ganglion cells (RGCs) was determined via dual staining with RGC markers Tuj1 and RBPMS. Individual axons that regenerated to 0.25, 0.5, 0.75 and 1 mm were manually counted in the whole-mount optic nerve labeled by cholera toxin B fragment (CTB). Immunofluorescence and Western blot were performed to detect protein expression levels. Pattern electroretinogram was used to evaluate RGCs function. ResultsTafluprost promoted RGC survival in a dose-dependent manner with an optimal concentration of 1 μM. Tafluprost significantly decreased ZnT-3 expression and Zn2+ accumulation in the IPL of retina. Tafluprost stimulated intense axonal regeneration and maintained RGCs function compared to control. Mechanistically, Tafluprost and Zn2+ elimination treatment (TPEN or ZnT-3 deletion) can activate the mTOR pathway with an improved percentage of pS6+ RGCs in the retina. However, rapamycin, a specific inhibitor of the mTOR1, inhibited the activation of the mTOR pathway and abolished the regenerative effect mediated by Tafluprost. Tafluprost also inhibited the upregulation of p62, LC3 and Beclin-1, attenuated the overactivation of microglia/macrophages and downregulated the expression of TNFα and IL-1β. ConclusionsOur results suggest that Tafluprost promoted axon regeneration via regulation of the Zn2+-mTOR pathway, and provide novel research directions for glaucomatous optic nerve injury mechanisms.

RBP3-Retinopathy—Inherited High Myopia and Retinal Dystrophy: Genetic Characterization, Natural History, and Deep Phenotyping

To examine the genetic and clinical features and the natural history of RBP3-associated retinopathy. Multi-center international, retrospective, case series of adults and children, with moleculraly confirmed RBP3-asociated retinopathy. The genetic, clinical, and retinal imaging findings, including optical coherence tomography (OCT) and fundus autofluorescence (FAF), were investigated both cross-sectionally and longitudinally. The results of international standard full-field electroretinography (ERG) and pattern electroretinography (PERG) were reviewed. We ascertained 12 patients (5 female and 7 male) from 10 families (4 patients previously reported). Ten novel disease-causing RBP3 variants were identified. Ten patients were homozygous. The mean age (±SD, range) of the group was 21.4 years (±19.1, 2.9-60.5 years) at baseline evaluation. All 12 patients were highly myopic, with a mean spherical equivalent of -16.0D (range, -7.0D to -33.0D). Visual acuity was not significantly different between eyes, and no significant anisometropia was observed. Mean best-corrected visual acuity (BCVA) was 0.48 logMAR (SD, ±0.29; range, 0.2-1.35 logMAR); at baseline. Eleven patients had longitudinal BCVA assessment, with a mean BCVA of 0.46 logMAR after a mean follow-up of 12.6 years. All patients were symptomatic with reduced VA and myopia by the age of 7 years old. All patients had myopic fundi and features in keeping with high myopia on OCT, including choroidal thinning. The 4 youngest patients had no fundus pigmentary changes, with the rest of the patients presenting with a variable degree of mid-peripheral pigmentation and macular changes. FAF showed variable phenotypes, ranging from areas of increased signal to advanced atrophy in older patients. OCT showed cystoid macular edema at presentation in 3 patients, which persisted during follow-up in 2 patients and resolved to atrophy in the third patient. The ERGs were abnormal in 9 of 9 cases, revealing variable relative involvement of rod and cone photoreceptors with additional milder dysfunction post-phototransduction in some. All but 1 patient had PERG evidence of macular dysfunction, which was severe in most cases. This study details the clinical and functional phenotype of RBP3-retinopathy in the largest cohort reported to date. RBP3-retinopathy is a disease characterized by early onset, slow progression over decades, and high myopia. The phenotypic spectrum and natural history as described herein has prognostic and counseling implications. RBP3-related disease should be considered in children with high myopia and retinal dystrophy.

Restoration of vision by combined experimental antithymocyte therapy, and orbital radiation with high-dose steroids for severe, acute, steroid-refractory, congestive thyroid orbitopathy

PurposeWe report diagnostic and therapeutic dilemmas in the difficult case of compressive optic neuropathy with severe visual acuity and visual field loss with subsequent visual recovery in both eyes, in a patient with Graves’ orbitopathy (GO) by a combination of experimental antithymocyte therapy, orbital radiotherapy with high-dose steroids.MethodsA 72-year-old man presented with severe vision loss in both eyes. The visual symptoms had appeared over a year before the GO diagnosis. He was initially misdiagnosed with neuroborreliosis and optic neuritis based on brain and orbital magnetic resonance imaging. There was no exophthalmos. The ophthalmological examination included visual acuity, visual field, tonometry in primary and upgaze eye position, optical coherence tomography (OCT), pattern electroretinogram (PERG), pattern, and flash visual evoked potentials (PVEP and FVEP). The patient received experimental therapy with ATG, followed by high-dose of intravenous steroids and orbital radiotherapy.ResultsDelayed VEP peaks became shorter after treatment. After systemic and local therapy lowering of intraocular pressure was achieved. Abnormal PERG has been found three months before ganglion cells atrophy was detected in OCT. Visual acuity and visual field improvement occurred in both eyes after therapy, despite partial left optic nerve atrophy. The patient regained full decimal visual acuity (1.0 right from as poor as 0.3 to 1.0 in the right eye and from hand movements to 0.9 in the left. Severe visual field loss with advanced absolute scotomata has improved to slight relative scotomata. The duration of follow-up time after the treatment was 4 months.ConclusionsIntensive treatment of steroid-resistant Graves’ orbitopathy (GO) may prevent total optic nerve atrophy. Despite severely advanced optic neuropathy, this report emphasizes the necessity of therapy even with nearly complete visual function loss hence there is always a possibility to regain full visual acuity and visual field. Patients with tense orbital septum may not present with significant exophthalmos, thus delaying the correct diagnosis of orbitopathy. A supporting sign of GO was the difference in intraocular pressure in the primary and upgaze eye positions. Electrophysiological examinations are helpful in the diagnosis and monitoring of GO therapy. To our knowledge, this is the first report of this kind presenting visual function restoration and structural recovery in a patient with advanced optic neuropathy in GO.

Efficacy of citicoline as a supplement in glaucoma patients: A systematic review.

Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in glaucoma, leading to blindness. Elevated intraocular pressure (IOP) is the only modifiable risk factor, however, many patients progress despite excellent IOP control. Thus, alternative treatment strategies to prevent glaucoma progression are an unmet need. Citicoline has demonstrated neuroprotective properties in central neurodegenerative diseases. However, conclusive evidence of the effect of citicoline on glaucoma progression is missing. This systematic review investigates first-time the therapeutic potential of citicoline in glaucoma patients. The present study was conducted according to the PRISMA 2020 statement. PubMed, Web of Science, Google Scholar, and Embase were accessed in July 2023 to identify all clinical studies investigating the efficacy of citicoline on IOP, the mean deviation of the 24-2 visual field testing (MD 24-2), retinal nerve fibre layer (RNFL), and the pattern electroretinogram (PERG) P50-N95 amplitude in glaucoma patients. The risk of bias was assessed using the Review Manager 5.3 software (The Nordic Cochrane Collaboration, Copenhagen) and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool. Ten studies were eligible for this systematic review, including 424 patients. The mean length of the follow-up was 12.1 ± 11.6 months. The overall risk of bias was low to moderate. The mean age of the patients was 56.7 years. There were no significant differences in the IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude between patients receiving citicoline and the control group. There was no improvement from baseline to the last follow-up in IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude. There is a lack of sufficient evidence to support that citicoline slows the progression of glaucoma.

A spatially specified systems pharmacology therapy for axonal recovery after injury.

There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that regulates multiple subcellular processes in the cell body and axons using the optic nerve crush model in rats. We intravitreally injected agonists HU-210 (cannabinoid receptor-1) and IL-6 (interleukin 6 receptor) to stimulate retinal ganglion cells for axonal growth. We applied, in gel foam at the site of nerve injury, Taxol to stabilize growing microtubules, and activated protein C to clear the debris field since computational models predicted that this drug combination regulating two subcellular processes at the growth cone produces synergistic growth. Physiologically, drug treatment restored or preserved pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. Morphology experiments show that the four-drug combination protects axons or promotes axonal regrowth to the optic chiasm and beyond. We conclude that spatially targeted drug treatment is therapeutically relevant and can restore limited functional recovery.

Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures

To assess longitudinal relationships among visual function and anatomical measures of gene therapy in G11778A Leber hereditary optic neuropathy (LHON). Phase 1 clinical trial. This was a single-institution study of patients with G11778A LHON. Patients with chronic bilateral visual loss >12 months (group 1, n=11), acute bilateral visual loss <12 months (group 2, n=9), or unilateral visual loss (group 3, n=8) were administered unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. Oucome measures were best-corrected visual acuity (BCVA), visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and ganglion cell+inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores. Mean follow-up was 33.6 months (range=18-36 months). Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of group 3, and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes, with some eyes having modest improvement that may be related to natural history or to gene therapy. Mean NEI-VFQ-25 scores declined in group 3 subjects (P=.023), CONCLUSION: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of effective neuroprotection given reduced GCIPL and SS-PERG. Randomization of patients to an untreated control group would help to assess treatment effect by accounting for variable natural history. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Phase I NT-501 Ciliary Neurotrophic Factor Implant Trial for Primary Open-Angle Glaucoma: Safety, Neuroprotection, and Neuroenhancement.

To assess the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma. Open-label, prospective, phase I clinical trial. A total of 11 participants were diagnosed with primary open-angle glaucoma (POAG). One eye of each patient was assigned as the study (implant) eye. The study eye was implanted with a high-dose CNTF-secreting NT-501 implant, whereas the other eye served as a control. All patients were followed up for 18 months. Analysis was limited to descriptive statistics. Primary outcome was safety through 18 months after implantation assessed by serial eye examinations, structural and functional testing, and adverse events (AEs) recording. Parameters measured included visual acuity (VA), Humphrey visual field (HVF), pattern electroretinogram, scanning laser polarimetry with variable corneal compensation (GDx VCC), and OCT. These parameters were also used for secondary analysis of efficacy outcome. All NT-501 implants were well tolerated with no serious AEs associated with the implant. The majority of AEs were related to the implant placement procedure and were resolved by 12 weeks after surgery. Foreign-body sensation was the most commonly reported AE and was self-limited to the postoperative period. The most common implant-related AE was pupil miosis; no patients underwent explant. Visual acuity and contrast sensitivity decreased more in fellow eyes than in study eyes (VA,-5.82 vs.-0.82 letters; and contrast sensitivity,-1.82 vs.-0.37 letters, for fellow vs. study eyes, respectively). The median HVF visual field index and mean deviation measurements worsened (decreased) in fellow eyes (-13.0%,-3.9 dB) and improved (increased) in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer thickness measured by OCT and by GDx VCC (OCT, 2.66 μm vs. 10.16 μm; and GDx VCC, 1.58μmvs. 8.36μm in fellow vs. study eyes, respectively). The NT-501 CNTF implant was safe and well tolerated in eyes with POAG. Eyes with the implant demonstrated both structural and functional improvements suggesting biological activity, supporting the premise for a randomized phase II clinical trial of single and dual NT-501 CNTF implants in patients with POAG, which is now underway. Proprietary or commercial disclosure may be found after the references.

Evaluating fine changes in visual function of diabetic eyes using spatial-sweep steady-state pattern electroretinography

The visual function of diabetic eyes was assessed to evaluate spatial-sweep steady-state pattern electroretinography (swpPERG) as a potential high-sensitivity analysis method. Data from 24 control eyes, 28 diabetic eyes without diabetic retinopathy (DR), and 30 diabetic eyes with DR (all with best-corrected visual acuity [BCVA] better than logMAR 0.05; median age, 51) in response to spatial-patterned and contrast-reversed stimuli of sizes 1 (thickest) to 6 were converted into the frequency domain using a Fourier transform and expressed as signal-to-noise ratios (SNRs). SNRs of diabetic eyes, both with and without DR, were lower than those of controls (P < 0.05), and those of DR eyes were lower than those of diabetic eyes without DR (P < 0.05). The SNRs were correlated with ganglion cell layer volume measured using optical coherence tomography (OCT) and foveal vascular length density at the superficial retinal layer measured using OCT angiography (P < 0.05 or < 0.01, according to stimulus size). Therefore, swpPERG SNRs could detect fine reductions in visual function in diabetic eyes and were particularly low in DR eyes. Moreover, SNRs were correlated with inner retinal morphological changes in diabetic eyes, both with and without DR. swpPERG may therefore be useful for detecting fine fluctuations in visual function in diabetic eyes.

The Pattern electroretinogram as an indirect measure of central dopamine

The Pattern electroretinogram as an indirect measure of central dopamine

Neural binocular summation and the effect of defocus on the pattern electroretinogram and visual evoked potentials for different pupil sizes.

To evaluate the influence of defocus and pupil size on subjective (visual acuity [VA]) and objective (electrophysiology) descriptors of human vision and their effect on binocular visual performance by means of neural binocular summation (BS). Fifteen healthy young subjects were recruited in this crossover study. Pattern electroretinogram (PERG) and visual evoked potentials (VEP) were measured under two levels of positive (+1.5 and +3.0 D) spherical and astigmatic defocus (axis 90°). Pupil size was controlled to reduce the inter-individual variability factor. Low- and high-contrast VA showed poorer visual performance in the monocular versus the binocular condition. Positive BS (for VA) was higher with greater pupil size and higher levels of defocus. In the visual electrophysiology tests (i.e., VEP and PERG), peak time and amplitude were affected by pupil size and defocus. The increase in peak time was larger and the reduction in amplitude was more significant with greater levels of defocus and smaller pupil sizes. For the VEP, positive BS was found in all conditions, being stronger with larger amounts of defocus and pupil size (for the P100 amplitude). Significant negative correlations were observed between the P100 amplitude and VA BSs. Smaller pupil size and levels of defocus produced greater changes in cortical activity as evidenced by both the PERG and VEP. Considering these changes and the obtained positive BS, the mechanism could be initiated as early as the retinal processing stage, then being modulated and enhanced along the visual pathway and within the visual cortex.

Impact of text contrast polarity on the retinal activity in myopes and emmetropes using modified pattern ERG

Environmental factors favoring myopia development are still being studied and there is accumulating evidence for a significant role of nearwork. Recently, reading standard black-on-white text was found to activate the retinal OFF pathway and induce choroidal thinning, which is associated with myopia onset. Contrarily, reading white-on-black text led to thicker choroids, being protective against myopia. Respective effects on retinal processing are yet unknown. Here, we exploratively assessed the impact of contrast polarity on the retinal activity and possible interactions with eccentricity and refractive error. We recorded pattern electroretinograms in myopic and emmetropic adults while presenting a dead leaves stimulus (DLS), overlaid by masks of different size in ring or circle shape, either filled with uniform gray or text of inverted or standard contrast. In myopes, retinal responses for DLS with standard and inverted contrast were larger when the perifovea was stimulated (6–12 deg), however, including the fovea resulted in smaller amplitudes for inverted contrast than in emmetropes. The retina of emmetropes was more sensitive to inverted contrast than to standard and gray within 12 deg, but most sensitive for gray in the perifovea. This demonstrates that the refractive error influences the sensitivity to text contrast polarity, with a special role of the peripheral retina, which is in line with previous studies about blur sensitivity. Defining whether the differences derive from retinal processing or anatomical features of a myopic eye requires further investigation. Our approach might be a first step to explain how nearwork promotes the eye’s elongation.