Multisite Study of Evoked Potentials in Rett Syndrome

Saby, Joni N.; Benke, Timothy A.; Peters, Sarika U.; Standridge, Shannon; Matsuzaki, Junko; Cutri‐French, Clare; Swanson, Lindsay C.; Lieberman, David N.; Key, Alexandra P.; Percy, Alan K.; Neul, Jeffrey L.; Nelson, Charles A.; Roberts, Timothy P. L.; Marsh, Eric D.

doi:10.1002/ana.26029

Cited by 20 publications

(53 citation statements)

References 29 publications

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“…TD participants were pre-screened and excluded using the same criteria as Saby et al . 15 Briefly, potential TD participants were excluded if they had a history of developmental delay or known neurologic, neuropsychiatric or genetic condition. Typical development was confirmed using the Child/Adult Behavior Checklist and either the Ages and Stages Questionnaire (for >5 years of age) or Wide Range Achievement Test-4 (for ≤5 years of age).…”

Section: Methodsmentioning

confidence: 99%

“…Adjustments were based on data from a travelling, adult human phantom who completed the EP tasks at all study locations (for further details of equipment and correction, see Saby et al . 15 ).…”

Section: Methodsmentioning

confidence: 99%

“…EPs were analysed in BESA (BESA 6.0 GMbH, Grafelfing, Germany) using methods described previously. 15 Briefly, files collected at 1000 Hz were downsampled to 512 Hz. Bad channels and periods of excessive artefact were manually marked and excluded.…”

Section: Methodsmentioning

confidence: 99%

“…Components were identified using the automatic peak finder in BESA using predetermined criteria (see Saby et al . 15 ).…”

Section: Methodsmentioning

confidence: 99%

“… 11 , 13–18 Indeed, our recent analysis of evoked potentials (EPs) in individuals with Rett syndrome revealed an association between response amplitude and severity of Rett symptoms, underscoring the potential for these measures to serve as unbiased measures of severity in Rett syndrome. 15 In contrast, no studies to date have examined EPs in individuals with CDD. One prior study considered aspects of the resting EEG in individuals with CDD, but statistical analyses were limited due to a small sample size ( n = 4).…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological biomarkers of brain function in CDKL5 deficiency disorder

Saby

Mulcahey

Zavez

et al. 2022

Brain Communications

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CDKL5 deficiency disorder is a debilitating developmental and epileptic encephalopathy for which no targeted treatment exists. A number of promising therapeutics are under development for CDKL5 deficiency disorder but a lack of validated biomarkers of brain function and clinical severity may limit the ability to objectively assess the efficacy of new treatments as they become available. To address this need, the current study quantified electrophysiological measures in individuals with CDKL5 deficiency disorder and the association between these parameters and clinical severity. Visual and auditory evoked potentials, as well as resting EEG, were acquired across five clinical sites from 26 individuals with CDKL5 deficiency disorder. Evoked potential and quantitative EEG features were calculated and compared to typically developing individuals in an age- and sex-matched cohort. Baseline and Year 1 data, when available, were analyzed and the repeatability of the results was tested. Two clinician-completed severity scales were used for evaluating the clinical relevance of the electrophysiological parameters. Group-level comparisons revealed reduced visual evoked potential amplitude in CDKL5 deficiency disorder individuals versus typically-developing individuals. There were no group differences in the latency of the visual evoked potentials or in the latency or amplitude of the auditory evoked potentials. Within the CDKL5 deficiency disorder group, auditory evoked potential amplitude correlated with disease severity at Baseline as well as Year 1. Multiple quantitative EEG features differed between CDKL5 deficiency disorder and typically-developing participants, including amplitude standard deviation, 1/f slope, and global delta, theta, alpha, and beta power. Multiple quantitative EEG features correlated with clinical severity, including amplitude skewness, theta/delta ratio, and alpha/delta ratio. Theta/delta ratio was the overall strongest predictor of severity and also among the most repeatable qEEG measures from Baseline to Year 1. Together, the present findings point to the utility of evoked potentials and quantitative EEG parameters as objective measures of brain function and disease severity in future clinical trials for CDKL5 deficiency disorder. The results also underscore the utility of the current methods, which could be similarly applied to the identification and validation of electrophysiological biomarkers of brain function for other developmental encephalopathies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Components were identified using the automatic peak finder in BESA using predetermined criteria (see Saby et al . 15 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Electrophysiological biomarkers of brain function in CDKL5 deficiency disorder

Saby

Mulcahey

Zavez

et al. 2022

Brain Communications

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Electroencephalographic Correlates of Clinical Severity in the Natural history study of RTT and Related Disorders

Saby,

Mulcahey,

Benke

et al. 2024

Annals of Neurology

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ObjectiveThis study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders and to assess the potential for these features to act as objective measures of cortical function for Rett syndrome (RTT).MethodsEEG amplitude and power features were derived from the resting EEG of 60 females with RTT (median age = 10.7 years) and 26 neurotypical females (median age = 10.6 years). Analyses focus on group differences and within the RTT group, associations between the EEG parameters and clinical severity. For a subset of participants (n = 20), follow‐up data were available for assessing the reproducibility of the results and the stability in the parameters over 1 year.ResultsCompared to neurotypical participants, participants with RTT had greater amplitude variability and greater low‐frequency activity as reflected by greater delta power, more negative 1/f slope, and lower theta/delta, alpha/delta, beta/delta, alpha/theta, and beta/theta ratios. Greater delta power, more negative 1/f slope, and lower power ratios were associated with greater severity. Analyses of year 1 data replicated the associations between 1/f slope and power ratios and clinical severity and demonstrated good within‐subject consistency in these measures.InterpretationOverall, group comparisons reflected a greater predominance of lower versus higher frequency activity in participants with RTT, which is consistent with prior clinical interpretations of resting EEG in this population. The observed associations between the EEG power measures and clinical assessments and the repeatability of these measures underscore the potential for EEG to provide an objective measure of cortical function and clinical severity for RTT. ANN NEUROL 2024

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Rett syndrome: The Natural History Study journey

Percy,

Benke,

Marsh

et al. 2024

Annals of the Child Neurology Society

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Understanding clinical features and disease progression of Rett syndrome (RTT) and establishing clinical trial readiness was enhanced by the RTT Natural History Study (NHS). The NHS benefited from two key developments: one, the Orphan Drug Act passed by Congress in 1983 defining criteria for rare disorders in the United States and creating opportunities for pharmaceutical companies to develop products for individuals with rare disorders, and two, the Rare Diseases Act of 2002, which established the National Institutes of Health Office of Rare Diseases and provided research funding. Funding for the RTT and related disorders NHS was obtained in 2003, creating a broad network of experienced clinical investigators across the United States and producing critical results not only for RTT but also for related disorders: CDKL5 deficiency disorder, FOXG1 disorder, and MECP2 duplication syndrome. Longitudinal information from over 1800 participants (more than 1600 diagnosed with RTT) led to multiple reports describing their clinical features and natural progression and identified putative biomarkers and clinical outcome measures. Establishing clinical trial readiness assisted in evaluating the first FDA‐approved medication for RTT in 2023 and continues to provide opportunities to develop potentially life‐altering therapies. The experiences of the RTT NHS journey provide informative guidance for studying other rare neurological disorders. These lessons include positive features of developing productive collaborations focused on improving lives of people and families with RTT and related disorders, as well as lessons learned through retrospective analysis for improving overall conduct of natural history studies in rare disorders.

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Multisite Study of Evoked Potentials in Rett Syndrome

Cited by 20 publications

References 29 publications

Electrophysiological biomarkers of brain function in CDKL5 deficiency disorder

Electrophysiological biomarkers of brain function in CDKL5 deficiency disorder

Electroencephalographic Correlates of Clinical Severity in the Natural history study of RTT and Related Disorders

Rett syndrome: The Natural History Study journey

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