Anti-NOGO Antibody Neuroprotection in a Rat Model of NAION.

Purpose: To evaluate the efficacy and mechanisms of anti-NOGO receptor monoclonal antibody 11C7mAb in a rat model of nonarteritic anterior ischemic optic neuropathy (rNAION). Methods: The rNAION was induced in one eye of 20 Long-Evans rats, which were studied in 10 groups of two rats, each group containing a sham rat receiving intravitreal injections of vehicle and a treatment rat receiving intravitreal injections of 11C7mAb. Fellow eyes served as naïve controls. The rats were tested using flash electroretinograms (ERGs), flash visual evoked potentials (VEPs), and optical coherence tomography (OCT). Thirty days after induction, they were euthanized, and the eyes were prepared for immunohistochemistry (two groups), hematoxylin and eosin staining (two groups) or transmission electron microscopy (TEM; six groups). Results: Ninety-five percent of the VEP amplitude was preserved in eyes treated with 11C7mAb, versus 69% in the control eyes. Immunohistochemistry revealed a large reduction in microglia and extrinsic macrophages with axon sparing. In addition to axon preservation, TEM also showed reduced extracellular debris and only slight myelin damage compared with the vehicle-treated animals. There were no significant differences in retinal ganglion cell counts, nor was there a difference in optic nerve swelling as measured by OCT. ERGs were used to exclude eyes with retinal vascular occlusions, an occasional complication of the induction technique. Conclusions: The 11C7mAb preserves optic nerve integrity and reduces inflammation in rNAION. Translational Relevance: This study evaluates the efficacy of an anti-NOGO receptor antibody in a rat model of NAION, a disorder that currently has no universally-acknowledged treatment.

Enhancing Risk Assessment in Patients with Diabetic Retinopathy by Combining Measures of Retinal Function and Structure.

Purpose: To determine whether combining measures of retinal structure and function predicts need for intervention for diabetic retinopathy (DR) better than either modality alone. Methods: The study sample consisted of 279 diabetic patients who participated in an earlier cross-sectional study. Patients were excluded if they were previously treated for macular edema or proliferative DR or if they had other retinopathies. Medical records were reviewed for ocular interventions including vitrectomy, intravitreal injection, and laser treatment. Need for intervention was analyzed using Kaplan-Meier analyses and Cox proportional hazards. Baseline electroretinograms and fundus photographs were obtained. Two definitions of structural positive findings were as follows: 1. Early Treatment of Diabetic Retinopathy Study diabetic retinopathy severity scale (ETDRS-DR) severity ≥ level 53 (ETDRS-DR+) and 2. ETDRS-DR+ or clinically significant macular edema (VTDR+). A positive function finding corresponded to a RETeval DR Score >23.5 (RETeval+). Results: For patients with VTDR+ the incidence of intervention was 19%, 31%, and 53% after 1, 2, and 3 years of follow-up. In these patients, intervention incidence increased to 34%, 54%, and 74% the subsequent 1, 2, and 3 years if function was above criterion (RETeval+), whereas RETeval- results reduced the risk to 3%, 4%, and 29%, respectively, reducing risk to similar levels seen for patients with VTDR- results at baseline. Conclusions: Prediction of subsequent intervention was best when combining structural and functional information. Translational Relevance: This study demonstrates that clinical management of diabetic retinopathy is improved by adding electroretinography to fundus photographic information in assessing the risk of the need for intervention.

ISCEV Standard for full-field clinical electroretinography (2015 update).

This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV), presents an updated and revised ISCEV Standard for full-field clinical electroretinography (ffERG or simply ERG). The parameters for Standard flash stimuli have been revised to accommodate a variety of light sources including gas discharge lamps and light emitting diodes. This ISCEV Standard for clinical ERGs specifies six responses based on the adaptation state of the eye and the flash strength: (1) Dark-adapted 0.01 ERG (rod ERG); (2) Dark-adapted 3 ERG (combined rod-cone standard flash ERG); (3) Dark-adapted 3 oscillatory potentials; (4) Dark-adapted 10 ERG (strong flash ERG); (5) Light-adapted 3 ERG (standard flash "cone" ERG); and (6) Light-adapted 30 Hz flicker ERG. ISCEV encourages the use of additional ERG protocols for testing beyond this minimum standard for clinical ERGs.

Twelve-month natural history of dark adaptation in patients with AMD.

PURPOSE: A sensitive endpoint is required for clinical trials evaluating preventative therapies for early age-related macular degeneration (AMD). Dark adaptation (DA) is a sensitive marker of AMD and has been proposed as a potential endpoint. This study evaluated whether significant changes in DA speed could be detected in participants with early to intermediate AMD at 12 months following baseline DA measurement. METHODS: Dark adaptation, visual acuity (VA), and fundus photography were obtained at baseline and at 6 and 12 months in 26 subjects with AMD and in 6 subjects with normal retinal health. Disease severity was assessed by the Nine-Step Age-Related Eye Disease Study AMD severity scale. RESULTS: At 12 months, significant progression of DA impairment occurred in 5 of 26 (19%) participants with AMD. None of the participants with AMD exhibited a significant worsening of fundus grade or decrease of acuity related to disease progression. The normal group exhibited stable DA and VA during the observation period. CONCLUSIONS: Significant worsening of DA was observed in 19% of subjects with AMD in 12 months of observation, despite stable VA and fundus appearance. This study suggests that DA may be a suitable functional endpoint for early clinical studies evaluating novel treatments for early to intermediate AMD.

ISCEV standard for clinical pattern electroretinography (PERG): 2012 update.

The pattern electroretinogram (PERG) is a retinal response evoked by a contrast-reversing pattern, usually a black and white checkerboard, which provides information about macular and retinal ganglion cell function. This document from the International Society for Clinical Electrophysiology of Vision (www.iscev.org) is a scheduled revision of the ISCEV PERG Standard, which updates and replaces the 2007 update and all earlier versions. The standard defines a single minimum stimulus and recording protocol for clinical PERG testing to assist practitioners in obtaining good quality responses and to facilitate inter-laboratory comparison. The present revision tightens stimulus specifications, expands on steady-state PERG recording, addresses visual stimulus display distinctions (CRT vs. LCD), and provides a more explicit definition of response components.

ISCEV standard for clinical electro-oculography (2010 update).

The clinical electro-oculogram (EOG) is an electrophysiological test of function of the outer retina and retinal pigment epithelium (RPE) in which changes in electrical potential across the RPE are recorded during successive periods of dark and light adaptation. This document presents the 2010 EOG Standard from the International Society for Clinical Electrophysiology of Vision (ISCEV: www.iscev.org ). This revision has been reorganized and updated, but without changes to the testing protocol from the previous version published in 2006. It describes methods for recording the EOG in clinical applications and gives detailed guidance on technical requirements, practical issues, and reporting of results. It is intended to promote consistent quality of testing and reporting within and between clinical centers.

Is reduced ornithine-δ-aminotransferase activity the cause of vigabatrin-associated visual field defects?

BACKGROUND: A gabaergic antiepileptic drug, vigabatrin (VGB), is known to induce bilateral concentric visual field defects (VFD) in 30-40% of treated patients. Although the clinical and electrophysiological features of VFDs are well documented, the mechanism of retinal toxicity is still unclear. PURPOSE: To determine if low basal ornithine-δ-aminotranspherase (OAT) activity is implicated in the etiology of VGB retinotoxicity, resulting in a phenotype of a mild form of gyrate atrophy. METHODS: Assays of OAT activity in lymphocytes and GABA-transaminase activity in platelets were performed, and plasma levels of GABA, ornithine, lysine, glutamic acid and glutamine were measured, and visual fields were examined. A total of 47 subjects, aged 14-78 years, were examined. Twenty-one epileptic patients were off VGB more than 1 year; 11 patients with VGB-induced VFD and 10 with normal visual fields. Ten epileptic patients were on current VGB therapy more than 1 year; four patients with VGB-induced VFD and six with normal visual fields. The results were compared with those of 10 epilepsy patients taking tiagabine and six patients who suffered from gyrate atrophy (GA) or were obligate carriers of the disease. RESULTS: In patients who had stopped VGB and who had VFDs, OAT activity was significantly reduced as compared with those who had normal visual fields (77.4pmol P5C/min/mgPro vs. 181.9pmol P5C/min/mgPro, p=0.002). In patients with ongoing VGB therapy, no difference was found between the patients with and without VFDs (149.4pmol P5C/min/mgPro vs. 159.1pmol P5C/min/mgPro). CONCLUSIONS: : The results suggest that VGB retinotoxicity might be associated with elevated retinal ornithine mediated by low basal OAT activity.

Quality-controlled measurement methods for quantification of variations in transcript abundance in whole blood samples from healthy volunteers.

BACKGROUND: Transcript abundance (TA) measurement in whole blood frequently is conducted to identify potential biomarkers for disease risk and to predict or monitor drug response. Potential biomarkers discovered in this way must be validated by quantitative technology. In this study we assessed the use of standardized reverse transcription PCR (StaRT-PCR) to validate potential biomarkers discovered through whole blood TA profiling. METHODS: For each of 15 healthy volunteers, 6 blood samples were obtained, including 3 samples at each of 2 separate visits. Total variation in TA for each gene was partitioned into replicate, sample, visit, study participant, and residual components. RESULTS: Variation originating from technical processing was <5% of total combined variation and was primarily preanalytical. Interindividual biological sample variation was larger than technical variation. For 12 of 19 tests, the distribution of measured values was gaussian (Shapiro-Wilks test). CONCLUSION: For control or diseased population groups with variation rates as low as those observed in this control group, 17 individuals per group would be required to detect 1 SD change with 80% power with a 2-sided alpha = 0.05 statistical test for mean differences.

ISCEV standard for clinical pattern electroretinography--2007 update.

The pattern electroretinogram (PERG) is a retinal response evoked by viewing a temporally alternating pattern, usually a black and white checkerboard or grating. The PERG is important in clinical and research applications because it provides information both about retinal ganglion cell function and, because the stimulus is customarily viewed with central fixation, the function of the macula. The PERG can therefore facilitate interpretation of an abnormal pattern VEP by revealing the retinal responses to a similar stimulus to that used for the VEP. However, practitioners may have difficulty choosing between the different techniques for recording the PERG that have been described in the literature. The International Society for Clinical Electrophysiology of Vision published a standard for clinical PERG recording in 2000 to assist practitioners in obtaining good quality reliable responses and to facilitate inter-laboratory communication and comparison. This document is the scheduled revision of that standard.

Recommendations for a toxicological screening ERG procedure in laboratory animals.

Electroretinography, using laboratory animals, is a commonly used technique for determining the retinal toxicity of chemical agents. In this paper, guidelines for performing this test are provided. The physiologic basis for visual testing is presented with attention to inter-species differences. Technical aspects of animal recordings are reviewed, including animal preparation, stimulation, signal conditioning, recording and data analysis. Finally, suggested protocols for recording in diurnal and nocturnal species are presented.

Extraction and modeling of the Oscillatory Potential: signal conditioning to obtain minimally corrupted Oscillatory Potentials.

A method of extracting a temporally bounded component of a composite signal has been developed which minimizes data corruption in signal processing. The composite signal is windowed in the time domain, padding signals are attached, and finally, the conditioned signal is filtered to extract the component of interest. The method has been utilized to extract the Oscillatory Potential (OP) from the Electroretinogram (ERG). ERGs can contain impulse like transients, including flash artifacts and a-b wave transition, which may not be related to the Oscillatory Potential. Such transients will stimulate a filter, yielding its natural (filter) response and thus distort the actual OP signal. To avoid this effect, time-domain windowing and signal conditioning is used to extract the OP from the ERG. The extraction and modeling approach is applied to ERGs obtained from patients with recent monocular central retinal vein occlusion (CRVO). Model parameters clearly differentiate affected from fellow eyes and show subtle differences between eyes with benign and complicated outcomes.