The Relationship Between Stage of Leber's Hereditary Optic Neuropathy and Pattern Electroretinogram Latency

Abstract

Purpose: The purpose of this study was to compare the baseline steady-state pattern electroretinogram (SS-PERG) of patients with G11778A Leber hereditary optic neuropathy (LHON) with different stages of visual acuity (VA) loss before allotopic gene therapy (GT).

Methods: Patients (n = 28) were enrolled into groups (GT I: chronic bilateral VA ≤35 Early Treatment Diabetic Retinopathy Study [ETDRS]; GT II: acute bilateral VA ≤35 ETDRS; GT III: acute unilateral, VA ≤35 ETDRS, and better eye VA ≥70 ETDRS) and tested with SS-PERG together with 210 age-matched normal controls (NCs). SS-PERG amplitude (nV) and latency (ms) of each eye were averaged for groups GT I, GT II, and NC. Symptomatic eyes (GT III-S) and asymptomatic eyes (GT III-A) of group GT III were included separately and accounted for by using generalized estimating equation (GEE) methods.

Results: Compared to NC, SS-PERG amplitudes were reduced similarly by approximately 50% (P < 0.001) among all GT groups (NC > GT I, GT II, GT III-S, and GT III-A). SS-PERG latencies were shorter by ≥3.5 ms in all LHON groups and differed by disease stage (G III-A < NC, P = 0.002; GT III-S < GT III-A, P = 0.01; GT II < GT III-S, P = 0.03; GT I < NC, P < 0.001, but not different from other GT groups, all P > 0.1).

Conclusions: Although SS-PERG amplitude reduction did not distinguish between disease stages, SS-PERG latency shortening occurred in asymptomatic eyes and symptomatic eyes and distinguished between disease stages.

Translational relevance: SS-PERG latency shortening is consistent with primary damage of smaller/slower axons and sparing of larger/faster axons and may provide an objective staging of LHON, which may be helpful to determine efficacy in LHON trials.

Conflict of interest statement

Disclosure: V. Porciatti, None; D.E. Alba, None; W.J. Feuer, None; J. Davis, None; J. Guy, None; B.L. Lam, None

Figures

Figure 1.

Outline of SS-PERG setup. (A) Pattern stimulus. (B) Surface electrode placement. (C) The SS-PERG and noise waveforms for each eye (continuous lines) in response to one stimulus cycle (two pattern reversals). The dashed sinusoidal waveforms superimposed to the SS-PERG waveforms represent the frequency-domain component that is measured. The vertical arrows represent the SS-PERG amplitude (zero-to-peak amplitude of the isolated sinusoidal component) and the horizontal arrow represents the SS-PERG latency (time-to-peak of the isolated sinusoidal component). (D) Examples of SS-PERG waveforms recorded in representative subjects of study groups (NC = normal controls; GT I = bilateral-chronic; GT II = bilateral-acute; GT III-A = unilateral asymptomatic; and GT III-S = unilateral symptomatic). Note in D that waveforms of all LHON groups, compared to controls, have reduced amplitude, and are shifted to the left (shortened latency).

Figure 2.

Changes in SS-PERG amplitude and latency with increasing stage of LHON symptoms. Distribution of amplitude (A) and latency (B) data in different study groups (NC = normal controls; GT I = chronic bilateral; GT II = acute bilateral; GT III-A = acute unilateral asymptomatic eyes; and GT III-S = acute unilateral symptomatic eyes). Note in A and B that interquartile ranges (boxes) of all LHON groups do not overlap with corresponding interquartile ranges of normal controls, and the medians tend to decrease with increasing stage except for the chronic bilateral LHON group.

Figure 3.

Correlation between SS-PERG amplitude and SS-PERG latency. The scattergram includes data of both normal controls (smaller black symbols) and the patients with LHON groups with different stages of the disease (larger symbols with different color). NCs, normal controls; GT I, chronic bilateral; GT II, acute bilateral; GT III-A, acute unilateral asymptomatic eyes; GT III-S, acute unilateral symptomatic eyes. Note that both amplitude and latency are reduced in patients with LHON (r = 0.40, P < 0.001), and the magnitude of reduction depends on the stage of condition.