Multisite Study of Evoked Potentials in Rett Syndrome

Abstract

Objective: The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett syndrome (RTT). As a number of disease-modifying therapeutics are currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments.

Method: Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study. Baseline and year 1 data, when available, were analyzed and the repeatability of the results was tested. Two syndrome-specific measures from the Natural History Study were used for evaluating the clinical relevance of the VEP and AEP parameters.

Results: At the baseline study, group level comparisons revealed reduced VEP and AEP amplitude in RTT compared to control participants. Further analyses within the RTT group indicated that this reduction was associated with RTT-related symptoms, with greater severity associated with lower VEP and AEP amplitude. In participants with RTT, VEP and AEP amplitude was also negatively associated with age. Year 1 follow-up data analyses yielded similar findings and evidence of repeatability of EPs at the individual level.

Interpretation: The present findings indicate the promise of evoked potentials (EPs) as an objective measure of disease severity in individuals with RTT. Our multisite approach demonstrates potential research and clinical applications to provide unbiased assessment of disease staging, prognosis, and response to therapy. ANN NEUROL 2021;89:790-802.

Conflict of interest statement

Potential Conflicts of Interest: All authors have nothing to report

© 2021 American Neurological Association.

Figures

Figure 1.

Demographic and clinical information for all participants enrolled in the study, reasons for exclusion, and final samples for the Baseline and Year 1 VEP and AEP analyses. For age, CSS, and MBA, data are presented median (interquartile range). CSS = Clinical Severity Score. MBA = Motor Behavioral Assessment.

Figure 2.

(a) Raw VEP and AEP waveforms from the traveling human phantom at each of the five sites. Data from the human phantom was used to determine adjustment factors to better align the latency and amplitude of the VEP/AEP components across sites. The derived adjustment factors were applied to the data for all participants and controls prior to final analysis. (b) VEP and AEP waveforms from the traveling human phantom with the adjustment applied.

Figure 3.

(a) Grand average VEP waveforms for RTT and TD subejcts at electrode Oz. The N1, P1, and N2 components are labeled for the TD waveform. (b) Bar graphs showing the median values and inter-quartile range for the latency of the VEP components for RTT and TD subjects. (c) Bar graphs showing the median values and inter-quartile range for VEP amplitude. The amplitude of the VEP components were significantly lower in the RTT group (***p < .001). (d,e) Regression plots for the association for age and VEP amplitude for RTT (d) and TD (e) partcipants. VEP amplitude declined with age in RTT. No association with age was observed for TD subejcts.

Figure 4.

(a,b) Grand average AEP waveforms for RTT and TD subjects. Due to a strong latency dependence with age, waveforms are plotted separately for younger (a; > 10 years) and older (b; > 10 years; ) participants to more accurately display group averages. The P1, N1, and P2 components are labeled for the TD waveform. (c) Bar graph showing the median values and inter-quartile range for the latency of the AEP components for all ages. (d) Bar graph showing the median values and inter-quartile range for the amplitude of the AEP components for all ages. Participants with RTT demonstrated lower P1–N1 and N1–P2 amplitudes compared to TD subjects (*p < .05). (e,f) Regression plots for age and AEP amplitude for the RTT (e) and TD (f) groups. AEP P1–N1 amplitude declined with age in participants with RTT. The association between age and P1–N1 amplitude was not significant in the TD group.

Figure 5.

The association between clinical scores (CSS and MBA) and VEP and AEP amplitude for Baseline and Year 1 analyses. Raw associations are shown in the left panel. Partial plots after controlling for the effect of age are shown in the right panel. For the Baseline data, VEP N1–P1 amplitude was negatively associated with both clinical measures (a) and this association remained signfiicant after controlling for the effect of age (b). AEP P1–N1 amplitude was negatively associated with clincial severity as measured by CSS, but not MBA (c, d). In the Year 1 data, VEP N1–P1 amplitude was not associated with either clincial measure after accounting for the effect of age (e, f). AEP P1–N1 amplitude was associated with both measures (g), but only the association with CSS remained significant after accounting for age (h). Dotted lines represent 95% confidence intervals.

Figure 6.

(a) Bland-Altman plots showing the agreement between clinical severity scores at Baseline and Year 1 for subjects in the analysis of the VEP. Horizontal lines are drawn at the mean difference from Baseline to Year 1 (solid black), the mean difference ±1 SD (solid gray), and the mean difference ±1.96 SD (dashed black). Subjects with more than ±1 SD change in clinical score are highlighted in green (improvement in symptoms) and red (worsening of symptoms). (b) Baseline (black) and Year 1 (blue) waveforms from four individuals with RTT highlighting the repeatability of VEPs acquired one year apart. (c) Bland-Altman plots demonstrating the varying degrees of agreement between Baseline and Year 1 for components of the VEP. (d) Bland-Altman plots showing the agreement in clinical scores for subjects included in the analysis of the AEP. (e) Example waveforms from individual subjects highlighting the repeatability of AEPs. (f) Bland-Altman plots for components of the AEP. For the VEP and AEP, change in the EPs was not systematically related to changes in clinical severity scores.