Photopic negative response using a handheld mini-ganzfeld stimulator in healthy adults: normative values, intra- and inter-session variability.

PURPOSE: To determine normative values, intra- and inter-session variability for a range of parameters derived from the photopic negative response (PhNR) using a handheld mini-Ganzfeld stimulator in healthy normal adults. METHODS: Light-adapted flash full-field electroretinograms (ERGs) were recorded from healthy individuals with no visual complaints, visual acuity equal to or better than 0.0 logMAR (20/20 Snellen), and negative family history for visual diseases. ERGs were recorded from both eyes using a DTL® type fiber electrode after dilation of the pupils with instillation of 1 drop of tropicamide eye drops (1%). The full-field PhNR stimulus conditions were produced by a LED-based ColorBurst™ (Diagnosys LLC, Lowell, MA, USA) handheld stimulator. Red flashes of 1, 5 and 7 cd.s/m2 on a blue background of 10 cd/m2 were presented. A-wave, b-wave and PhNR amplitude (determined by both baseline to trough-BT and peak to trough-PT) and peak times were analyzed. Normal limits were determined as 5% percentile for amplitudes and 95% percentile for latencies. Intra- and inter-session variability were assessed with Wilcoxon signed-rank test, intraclass correlation coefficient (ICC) and the coefficient of variability (COV). RESULTS: Normative limits for PhNR amplitude (µV) using 1, 5 and 7 cd.s./m2 stimuli were, respectively: 20.81; 18.06 and 19.60 for BT and 69.11; 77.98; 76.51 for PT. Peak times (ms) normative limits for 1, 5 and 7 cd.s/m2 intensities were, respectively, 65.98; 78.20 and 77.96. Overall, intra-session variability assessed by coefficients of variation ranged from 1.35 to 10.28%. Inter-session variability disclosed significant intraclass correlation values for all PhNR parameters only for 1 cd.s/m2 stimuli. CONCLUSIONS: The normative values provided by this study are clinically helpful in the diagnosis of inner retinal disorders, especially those affecting retinal ganglion cells such as glaucoma and other optic neuropathies. Further studies, including a larger sample with variable age range would extend the validity of the current results.

Visual evoked potentials findings in non-affected subjects from a large Brazilian pedigree of 11778 Leber's hereditary optic neuropathy.

To investigate pattern-reversal visual evoked potentials (PRVEP) in asymptomatic maternally and non-maternally related members from a large Brazilian 11778/ND4 LHON pedigree. Transient PRVEP for check sizes 15' and 60' were recorded from asymptomatic mutation carriers and non-mutant descendants of affected/non-affected males, all with best-corrected visual acuity of 20/20. A control group of spouses (off-pedigree) was also included. Parameters of N75, P100 and N135 latencies (ms) and N75-P100 peak-to-peak amplitude (µV) as well as temporal dispersion (latency of N135-latency of N75) were determined. Longitudinal testing was obtained in a subseries of carriers in three annual consecutive visits. We tested 48 asymptomatic mutation carriers, 19 descendants of affected males, 9 descendants of non-affected males and 27 off-pedigrees, all of the latter being non-mutant. All non-mutant male descendants did not differ from off-pedigree controls. Statistically prolonged P100 latencies were found in mutation carriers (P = 0.0143) when compared with off-pedigrees for check sizes 15', as well as significantly larger temporal dispersions for both check size 15' (P = 0.0012) and check size 60' (P = 0.0271). Serial testing in 15 mutation carriers disclosed prolonged P100 latencies and larger temporal dispersion that did not change over time. Subclinical PRVEP abnormalities were detected in this large group of asymptomatic carriers of the 11778/ND4 LHON mutation from the same family, confirming and extending previous psychophysical and structural findings of a selective involvement of the parvocellular pathway. PRVEP is a useful test to characterize and monitor visual dysfunction in this devastating disease.

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.

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/m2, 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.

Medical management of hereditary optic neuropathies.

Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber's hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated.