Influence of seizures on early development in tuberous sclerosis complex

Abstract

Objective: Epilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC.

Methods: Analysis of 130 patients ages 0-36months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency.

Results: Data were analyzed at 6, 12, 18, and 24months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome.

Conclusions: Results of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24months of age.

Keywords: Autism spectrum disorder; Cognitive development; Epilepsy; Infantile spasms; Seizures; Tuberous Sclerosis Complex.

Figure 1. Relationship between seizure history and overall developmental outcome

Mullen Scales of Early Learning Early Learning Composite (mean +/− S.D.) is plotted from 6 months to 24 months for all patients (dash/dotted line), those with (solid line) or without (dashed line) prior history of seizures.

Figure 2. Repeated Developmental Assessment in TSC infants and toddlers over time

Mean +/− S.D. for patients with (red) or without (green) history of seizures prior to assessment point. (A) Mullen Scales of Early Learning Early Learning Composite, (B) Vineland Adaptive Behavior Scales Adaptive Behavior Composite, and (C) Preschool Language Scale Total Language Score.

Figure 3. Logistic model predicting likelihood of developmental delay as a function of age of seizure onset

Each plot shows the probability of developmental delay at each time point of determining risk (6 months, blue; 12 months, red; 18 months, green; and 24 months, black), as a function of age at time of seizure onset.