Hypsarrhythmia assessment exhibits poor interrater reliability: A threat to clinical trial validity

Summary Objective Hypsarrhythmia is the classic interictal electroencephalographic pattern associated with infantile spasms, and characterized by high voltage, disorganization, and multifocal independent epileptiform discharges. Given this seemingly simple definition, one might expect excellent interrater reliability (IRR) in the identification of this pattern. Alternatively, it may be argued that assessments of voltage and disorganization are fairly subjective, and thus quite challenging in borderline cases. We sought to test the IRR of hypsarrhythmia assessment in a systematic fashion. Methods Six blinded pediatric electroencephalographers from four centers reviewed 22 electroencephalography (EEG) samples from patients with infantile spasms. Each sample was 5 min in duration and included only wakefulness. Raters determined if each EEG was abnormal and if hypsarrhythmia was present/absent, and characterized relevant features: voltage, organization, epileptiform discharges, slowing, interictal attenuations, symmetry, and synchrony. In addition, raters indicated their level of confidence for each assessment. Multirater kappa statistics (κ) were calculated for the assessment of hypsarrhythmia and each feature. Results Although IRR was favorable in determining whether a study was normal or abnormal (κ = 0.89), reliability was unfavorable for assessment of hypsarrhythmia (κ = 0.40), modified hypsarrhythmia (κ = 0.47), high voltage (κ = 0.37), disorganization (κ = 0.22), multifocal epileptiform discharges (κ = 0.68), interictal voltage attenuations (κ = 0.21), slowing (κ = 0.20), asymmetry (κ = 0.26), and asynchrony (κ = 0.08). Despite generally unsatisfactory interrater agreement, raters consistently reported high confidence in assessments. Significance This study contradicts the view that hypsarrhythmia assessment is straightforward. Even small variability in the identification of hypsarrhythmia has potentially deleterious consequences for clinical care, as its presence or absence impacts decisions to pursue high-risk and high-cost therapies. These inconsistencies may similarly confound studies in which abolition of hypsarrhythmia is an outcome measure. There is a great need for practical, reliable, and unbiased measures of hypsarrhythmia.