The pattern of retinal ganglion cell dysfunction in Leber hereditary optic neuropathy

Abstract

Leber inherited optic neuropathy (LHON) is characterized by subacute bilateral loss of central vision due to dysfunction and loss of retinal ganglion cells (RGCs). Comprehensive visual electrophysiological investigations (including pattern reversal visual evoked potentials, pattern electroretinography and the photopic negative response) performed on 13 patients with acute and chronic LHON indicate early impairment of RGC cell body function and severe axonal dysfunction. Temporal, spatial and chromatic psychophysical tests performed on 7 patients with acute LHON and 4 patients with chronic LHON suggest severe involvement or loss of the midget, parasol and bistratified RGCs associated with all three principal visual pathways.

Keywords: Chromatic resolution; Critical flicker fusion; Leber hereditary optic neuropathy (LHON); Spatial contrast sensitivity; The pattern electroretinogram (PERG); The photopic negative responses (PhNR).

Fig. 1

Optical coherence tomography data. Macular ganglion cell – inner plexiform layer complex (GCL-IPL) and peripapillary retinal nerve fiber layer (RNFL) thicknesses of 22 eyes have been presented as percentages of the normal mean and plotted as a function of time from LHON onset in each eye. The data have been shown for temporal (T), nasal (N) and combined supero- and inferotemporal (TS and TI) sectors of peripapillary RNFL. Generalized additive model (GAM) fits to data are indicated by the color coded lines. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Photopic negative responses from the right (a) and left (b) eyes of a patient with LHON (A3). For comparison, representative normal recordings over a range of flash strengths (0.5–10.0 unit) have been provided (c). Pattern reversal VEPs, flash VEPs and pattern ERGs are shown for the right (d) and left (e) eyes of Patient A3 compared with representative normal recordings (f). The patient's recordings have been superimposed for all the parameters tested to demonstrate reproducibility.

Fig. 3

Pattern ERG data. Pattern ERG parameters were obtained to a standard (12° × 15°; a–c) and large (24 × 30°; d–f) checkerboard stimulus field for right and left eyes (RE; LE). Broken lines show the limits of normality defined as the minimum/maximum amplitude or peak time in a healthy cohort of subjects +/− the reference interval (maximum normal value-minimum normal value). Pattern ERG peak times and/or the N95:P50 ratio were abnormal in all the cases. Large field pattern ERG parameters were abnormal in most cases, including those in which PERG to the smaller field was excluded. The P50 amplitude of the pattern ERG was normal or near-normal in most cases, indicating good fixation despite of poor visual acuity.

Fig. 4

Photopic negative response (PhNR) data. Mean photopic negative responses (a) and the mean PhNR/b-wave ratio (b) were recorded in 7 individuals with LHON and compared with normal values at 5 flash strengths. The solid line and error bars show the mean normal values and 2 standard deviations from the mean. Broken lines show the limits of normality defined as the minimum amplitude in the normal cohort minus the 5% of the reference interval (maximum normal value-minimum normal value). Ratios from each individual are shown for right (RE; c) and left (LE; d) eyes. Sixty percent of responses were just outside the limits of normality (see text for details).

Fig. 5

L-cone critical flicker fusion. L-cone critical flicker frequencies (cff) were measured on a 481–nm background of 8.26 log₁₀ quanta s^− 1 deg^− 2 and plotted as a function of the mean log₁₀ radiance of a 650-nm flickering target for the affected (A) and unaffected (B) LHON carriers. The mean cff data for 15 normal observers are represented by the grey triangles in all panels. The yellow squares (A6 F) indicate follow-up data for Patient A6, which were obtained after spontaneous recovery of best corrected visual acuity from 1.6 logMAR to 0.1 logMAR in the right eye. (C) Mean L-cone cff data for all unaffected LHON carriers (yellow circles)were compared with the mean normal data (grey triangles). The best-fitting Ferry-Porter slopes are indicated by the blue lines. The error bars represent ± 1 SEM either between runs for the individual patients or between observers for the mean data. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Log₁₀ L-cone temporal contrast sensitivity. Log₁₀ L-cone TCSFs were measured using a sinusoidally-modulated 650-nm target with a time-averaged mean radiance of 10.28 log₁₀ quanta s^− 1 deg^− 2 superimposed on a 481-nm background of 8.29 log₁₀ quanta s^− 1 deg^− 2 plotted as a function temporal frequency (logarithmic axis) for three affected LHON carriers (A3, A7, A9) (pink, blue and green triangles, respectively) and for the mean of 9 unaffected LHON carriers (yellow triangles). The mean TCSFs for 12 normal observers have been shown as grey triangles. The error bars represent ± 1 SEM either between runs for the individual patients or between subjects for the mean data. The mean difference in log sensitivity between each affected or the mean of unaffected LHON carrier and normal subjects are shown in the lower part of each panel (circles). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 7

S-cone critical flicker frequencies (cff). This parameter was measured on a 9° 620-nm background of 11.41 log₁₀ quanta s⁻¹°deg^− 2 and plotted as a function of the time-averaged mean log₁₀ radiance of a 440-nm flickering target for each affected (A) and unaffected (B) LHON carrier (colored symbols). The mean cff data for 15 normal subjects are shown by the grey triangles in all panels. (C). Mean S-cone cff data for all unaffected LHON carriers (yellow circles) compared with the mean normal data (grey triangle). The best-fitting Ferry-Porter slopes are indicated by the blue lines (C). The error bars represent ± 1 SEM either between runs for the individual patients, or between subjects for the mean data. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

The Trivector Cambridge Color Test. (A) Box plots of the logarithmic vector lengths along the protan, deutan and tritan confusion lines expressed in 10^− 4 u′v′ units (defined by the CIE 1976 u′v′ color space) for the affected (1, n = 8) and unaffected (2, n = 9) LHON carriers, and for normal observers (3, n = 15), showing median, range, inter-quartile range and outliers for all groups. (B) Changes in the vector lengths along the protan, deutan and tritan confusion lines have been expressed as 10^− 4 u′v′ units for successive measurements of 6 affected LHON carriers and plotted as a function of time from disease onset.

Fig S1

Achromatic spatial contrast sensitivity functions. CSFs expressed as log₁₀ sensitivity as a function of spatial frequency (cycles per degree, cpd – logarithmic scale) are shown for two affected LHON carriers (A7, A9) (blue triangles), for the mean of the 9 unaffected LHON carriers (yellow triangles) and for normal controls (inverted grey triangles). The difference in sensitivity between LHON carriers and normal is also indicated in each panel by colored circles. The symbols and error bars represent the mean ± 1 SEM across normal observers, repeated runs of individual LHON patients or across 9 unaffected LHON carriers.