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      Impaired Ganglion Cell Function Objectively Assessed by the Photopic Negative Response in Affected and Asymptomatic Members From Brazilian Families With Leber's Hereditary Optic Neuropathy

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          Abstract

          Purpose: The photopic negative response (PhNR) is an electrophysiological method that provides retinal ganglion cell function assessment using full-field stimulation that does not require clear optics or refractive correction. The purpose of this study was to assess ganglion cell function by PhNR in affected and asymptomatic carriers from Brazilian families with LHON.

          Methods: Individuals either under suspicion or previously diagnosed with LHON and their family members were invited to participate in this cross-sectional study. Screening for the most frequent LHON mtDNA mutations was performed. Visual acuity, color discrimination, visual fields, pattern-reversal visual evoked potentials (PRVEP), full-field electroretinography and PhNR were tested. A control group of healthy subjects was included. Full-field ERG PhNR were recorded using red (640 nm) flashes at 1 cd.s/m 2, on blue (470 nm) rod saturating background. PhNR amplitude (μV) was measured using baseline-to-trough (BT). Optical coherence tomography scans of both the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were measured. PhNR amplitudes among affected, carriers and controls were compared by Kruskal-Wallis test followed by post-hoc Dunn test. The associations between PhNR amplitude and OCT parameters were analyzed by Spearman rank correlation.

          Results: Participants were 24 LHON affected patients (23 males, mean age=30.5 ± 11.4 yrs) from 19 families with the following genotype: m.11778G>A [ N = 15 (62%), 14 males]; m.14484T>C [ N = 5 (21%), all males] and m.3460G>A [ N = 4 (17%), all males] and 14 carriers [13 females, mean age: 43.2 ± 13.3 yrs; m.11778G>A ( N = 11); m.3460G>A ( N = 2) and m.14484T>C ( N = 1)]. Controls were eight females and seven males (mean age: 32.6 ± 11.5 yrs). PhNR amplitudes were significantly reduced ( p = 0.0001) in LHON affected (−5.96 ± 3.37 μV) compared to carriers (−16.53 ± 3.40 μV) and controls (−23.91 ± 4.83; p < 0.0001) and in carriers compared to controls ( p = 0.01). A significant negative correlation was found between PhNR amplitude and total macular ganglion cell thickness ( r = −0.62, p < 0.05). Severe abnormalities in color discrimination, visual fields and PRVEPs were found in affected and subclinical abnormalities in carriers.

          Conclusions: In this cohort of Brazilian families with LHON the photopic negative response was severely reduced in affected patients and mildly reduced in asymptomatic carriers suggesting possible subclinical abnormalities in the latter. These findings were similar among pathogenic mutations.

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          Most cited references69

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          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.
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            Visual acuities "hand motion" and "counting fingers" can be quantified with the freiburg visual acuity test.

            The visual acuity (VA) of patients with very low vision is classified using the semiquantitative scale "counting fingers" (CF), "hand motion" (HM), "light perception" (LP), and "no light perception." More quantitative measures would be desirable, especially for clinical studies. The results of clinical VA measurements, Early Treatment Diabetic Retinopathy Study (ETDRS) charts, and the Freiburg Visual Acuity Test (FrACT) were compared. The FrACT is a computerized visual acuity test that can present very large Landolt C optotypes when necessary. Examined were 100 eyes of 100 patients with various eye diseases (e.g., diabetic retinopathy, ARMD), covering a range of VAs from LP to decimal 0.32. The FrACT optotypes were presented on a 17-inch LCD monitor with random orientation. After extensive training, two ETDRS and FrACT measurements were obtained. The testing distance was 50 or 100 cm. ETDRS and FrACT coincided closely for VA > or = 0.02 (n = 80). ETDRS measures were successfully obtainable down to CF (at 30 cm; test-retest averaged over all patients, coefficient of variation [CV](ETDRS) = 9% +/- 8%), and FrACT provided reproducible measurements down to HM (test-retest CV(FrACT) =12% +/- 11%). For CF (n = 6), both ETDRS and FrACT resulted in a mean VA of 0.014 +/- 0.003 (range, 0.01-0.02). The VA results of FrACT for HM (n = 12) were 0.005 +/- 0.002 (range, 0.003-0.009); the individual values were highly reproducible. No results were obtainable for LP (n = 2). The three acuity procedures concur above a VA of 0.02. The results suggest that the category CF at 30 cm can be replaced by 0.014, using ETDRS or FrACT. Using FrACT, one can even reproducibly quantify VA in the HM-range, yielding a mean VA of 0.005.
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              ISCEV standard for clinical visual evoked potentials: (2016 update).

              Visual evoked potentials (VEPs) can provide important diagnostic information regarding the functional integrity of the visual system. This document updates the ISCEV standard for clinical VEP testing and supersedes the 2009 standard. The main changes in this revision are the acknowledgment that pattern stimuli can be produced using a variety of technologies with an emphasis on the need for manufacturers to ensure that there is no luminance change during pattern reversal or pattern onset/offset. The document is also edited to bring the VEP standard into closer harmony with other ISCEV standards. The ISCEV standard VEP is based on a subset of stimulus and recording conditions that provide core clinical information and can be performed by most clinical electrophysiology laboratories throughout the world. These are: (1) Pattern-reversal VEPs elicited by checkerboard stimuli with large 1 degree (°) and small 0.25° checks. (2) Pattern onset/offset VEPs elicited by checkerboard stimuli with large 1° and small 0.25° checks. (3) Flash VEPs elicited by a flash (brief luminance increment) which subtends a visual field of at least 20°. The ISCEV standard VEP protocols are defined for a single recording channel with a midline occipital active electrode. These protocols are intended for assessment of the eye and/or optic nerves anterior to the optic chiasm. Extended, multi-channel protocols are required to evaluate postchiasmal lesions.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                18 January 2021
                2020
                : 11
                : 628014
                Affiliations
                [1] 1Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, Brazil
                [2] 2Departamento de Neurologia e Neurocirurgia, Escola Paulista de Medicina, Universidade Federal de São Paulo , São Paulo, Brazil
                [3] 3Doheny Eye Institute, University of California Los Angeles , Los Angeles, CA, United States
                [4] 4Department of Ophthalmology, Doheny Eye Center, David Geffen School of Medicine at UCLA , Los Angeles, CA, United States
                [5] 5Ottawa Eye Institute, University of Ottawa , Ottawa, ON, Canada
                [6] 6Ottawa Hospital Research Institute , Ottawa, ON, Canada
                [7] 7Instituto da Visão-IPEPO , São Paulo, Brazil
                [8] 8Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna School of Medicine , Bologna, Italy
                Author notes

                Edited by: Heather E. Moss, Stanford University, United States

                Reviewed by: Gregory Van Stavern, Washington University in St. Louis, United States; Marcela Votruba, Cardiff University, United Kingdom

                *Correspondence: Adriana Berezovsky aberezovsky@ 123456unifesp.br

                This article was submitted to Neuro-Ophthalmology, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2020.628014
                7874135
                33584522
                93216189-12e2-4051-a96c-af5a9e1d4f35
                Copyright © 2021 Botelho, Salomão, Tengan, Karanjia, Moura, Rocha, Silva, Fernandes, Watanabe, Sacai, Belfort, Carelli, Sadun and Berezovsky.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 November 2020
                : 21 December 2020
                Page count
                Figures: 7, Tables: 4, Equations: 0, References: 69, Pages: 15, Words: 9509
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807
                Categories
                Neurology
                Original Research

                Neurology
                leber's hereditary optic neuropathy,photopic negative response,retinal ganglion cell,visual evoked cortical potentials,electroretinography

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