Longitudinal EEG, Seizure, and Developmental Patterns in Children With <i>CDKL5</i> Deficiency Disorder in the First 2 Years of Life.

Abstract (English)

BACKGROUND AND OBJECTIVES: Although there is near-universal early-onset epileptic encephalopathy in cyclin-dependent kinase-like 5 (<i>CDKL5</i>) deficiency disorder (CDD), it has been observed clinically that EEGs are initially only mildly abnormal and worsen in the first 2 years of life. This study aimed to identify specific EEG patterns, ictal and interictal, in individuals with CDD during the first 2 years of life and to explore their relationship with clinical and developmental outcomes. METHODS: This multicenter study included 48 infants and young children with CDD (75% female) aged 0-24 months, recruited to a clinic-based research study from 2 <i>CDKL5</i> Centers of Excellence, in whom 152 longitudinal clinical EEGs were rigorously analyzed. The retrospectively analyzed data consisted of EEG background, interictal, and ictal parameters, scoring according to the Burden of AmplitudeS and Epileptiform Discharges (BASED) scale, as well as clinical seizure-related features, demographic details, and scores of a CDD-specific developmental scale. RESULTS: Across the first 2 years of life, EEGs obtained at older ages showed greater background severity than those obtained earlier, including higher odds of discontinuity (<i>p</i> = 0.002) and generalized slowing (<i>p</i> ≤ 0.001) in mixed-effects models accounting for repeated measures. Paroxysmal fast activity was more common in parieto-occipital regions compared with frontal, central, and temporal areas. The 2 most observed seizure types were epileptic spasms (peaking between 7.5 and 11.5 months) and tonic seizures (peaking between 6.5 and 14 months). Sequential seizures, predominantly observed between 7 and 11 months, were most commonly 2 sequenced, consisting of tonic seizures followed by epileptic spasms. The cutoff age with the highest discriminatory value for high-severity BASED scores (indicating epileptic encephalopathy) was 9 months (Youden index 0.58, specificity of 95%, sensitivity of 62%). Lower developmental scale <i>Z</i>-scores (indicating worse severity) were significantly correlated with age (<i>p</i> = 0.03), with an EEG denoting hypsarrhythmia (<i>p</i> = 0.03), and with epileptic encephalopathy (<i>p</i> = 0.001), as well as with the presence of parieto-occipital epileptiform patterns (<i>p</i> = 0.04) and paroxysmal fast activity (<i>p</i> = 0.008). DISCUSSION: In CDD, EEG background severity, burden of interictal epileptiform activities, and parieto-occipital paroxysmal fast activity may be associated with developmental and clinical severity. Parieto-occipital paroxysmal fast activity and sequential seizures, while not specific to CDD, are highly suggestive of it.