Understanding Early Relationship between Autism Spectrum Disorder, Cognitive Impairment and Epilepsy in Infants with Tuberous Sclerosis Complex: Preliminary Results from the Epistop Project

Background: Tuberous sclerosis complex (TSC) is a rare genetic multisystem disorder that confers a high risk of early neuropsychiatric conditions. Epilepsy is one of the major issues in TSC and is considered a potential risk factor for autism spectrum disorders (ASD) and developmental delay (DD), but the relationship between autistic traits, epilepsy, and cognitive functioning remains poorly understood. The EPISTOP project is a multi-center prospective European study focused on discovering correlation between epileptogenesis and neurodevelopmental disorders in TSC.

Objectives: The aim of EPISTOP was to compare neurodevelopmental outcome of the infants according to epilepsy variables and timing of antiepileptic treatment; we compared preventive group, in which antiepileptic treatment was started immediately after the first appearance of EEG abnormalities, versus conservative group, in which antiepileptic treatment was administered after the appearance of (sub)clinical seizures.

Methods: 97 TSC subjects were prospectively followed from 6 to 24 months of age with neuropsychological assessment (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule), in order to evaluate early interplay between developmental level and ASD risk. We correlated neuropsychological outcome at 24 months with epilepsy variables including history and type of seizures, age at seizure onset/first abnormal EEG, and finally according to type (conservative versus preventive) and response to treatment. Comparisons between groups were performed with two-sample t test, ANOVA models, and Spearman's correlations. An alpha level of 0.05 was used for all statistical analyses, which were performed using SPSS v.23.0 (IBM Corp., Armonk, NY, USA).

Results: Data for the final analysis were available for 82 patients. A cognitive developmental quotient higher than 80 at 6 months of age was able to predict a positive developmental trajectory towards normal developmental level and no ASD symptoms at 2 years of age (p =0.025). ASD rate was significantly higher in patients with a history of epilepsy (p=0.017; risk rate or RR: 6.0), particularly if the onset of seizures was in the first 12 months of age (p=0.025, RR: 2.7). An onset of seizures in the first year of life was also associated with a high risk for DD/cognitive impairment (p=0.001, RR: 4.6). According to type of treatment, in the preventive group 65% of children had normal development at age 24 months, compared to 47% in the conservative group. ASD rate (with or without associated DD) was similar in the two groups (conservative 33%, preventive 30%), but DD without ASD was significantly lower in preventive group compared to conservative group (4% versus 21%; RR 0.6).

Conclusions: ASD presence in TSC was inextricably linked with cognitive level and severe, early onset epilepsy, but these correlations are not sufficient to explain the complex underlying mechanisms of ASD in TSC model. A rigorous, prospective follow-up with EEG and formal developmental assessment is mandatory to identify those infants and children at risk for developmental delay and/or ASD, in order to ensure early referral for parent-mediated implementation and training of cognitive skills and to potentially minimize the impact of these risk factors on ASD outcome.