Comparison of evoked potentials across four related developmental encephalopathies

Abstract

Background: Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies.

Methods: Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study.

Results: As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome.

Conclusions: There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.

Trial registration: ClinicalTrials.gov NCT02738281.

Fig. 1

Visual Evoked Potentials. A Grand average VEP waveforms for TD, RTT, CDD, MDS, and FOXG1 groups at electrode Oz. B Box plots showing the distribution of the latency and amplitude of the VEP components for TD, RTT, CDD, MDS, and FOXG1 participants. The amplitude of multiple components was reduced in RTT, CDD, and MDS groups compared to the TD group. Statistical analyses were performed with Kruskal–Wallis tests and post-hoc tests analyses with Bonferroni-adjusted p values for significance (*p < 0.005). C Scatterplots showing the association between VEP N1-P1 amplitude and clinical severity (CSS and MBA) for RTT, CDD, MDS, and FOXG1 participants. N1-P1 amplitude was significantly associated with both severity measures in participants with RTT and FOXG1. No aspects of the VEP were significantly associated with severity for the other groups. Statistical analyses were performed using linear regression (*p < 0.05)

Fig. 2

Auditory Evoked Potentials. A Box plots showing the distribution of the latency and amplitude of the AEP components for TD, RTT, CDD, MDS, and FOXG1 participants. The peak latencies of AEP components were prolonged in participants with MDS and FOXG1 compared to participants with RTT and CDD. Statistical analyses were performed with Kruskal–Wallis tests and post-hoc analyses with Bonferroni-adjusted p values for significance (*p < 0.005). B Scatterplots illustrating the association between AEP P1-N1 amplitude and the severity measures (CSS and MBA) for RTT, CDD, MDS, and FOXG1 participants. P1-N1 amplitude was significantly associated with severity in RTT and CDD. C Scatterplots showing the association between the latency of select AEP components and the clinical severity measures in participants with RTT, CDD, MDS, and FOXG1. The latency of one or more of the AEP components was significantly associated with severity in CDD, MDS, and FOXG1. Statistical analyses for B-C were performed using linear regression (*p < 0.05). The grand average AEP waveforms are not included due to age-related shifts in peak latency, particularly for the TD group, which obscure comparisons of peak amplitudes

Fig. 3

Associations between AEP and VEP Latency and Age for All Groups. A Scatterplot of AEP N1 latency and age in TD, RTT, CDD, MDS, and FOXG1 participants. N1 latency declined significantly with age in TD participants. Age was not significantly associated with AEP latency for participants with RTT, CDD, MDS, or FOXG1. B Scatterplot of VEP P1 latency and age for all groups. VEP latency did not change with age in any of the groups, consistent with the established literature on the stability of VEP P1 latency from early childhood. Statistical analyses for were performed using linear regression (*p < 0.05)