Abstract
ObjectiveTo evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80–150 mg/kg/day).MethodsInfants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule).ResultsEighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months.InterpretationThis study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.
Highlights
Tuberous Sclerosis Complex (TSC) is a multisystem disorder caused by a mutation in the TSC1 or TSC2 gene, associated with intellectual disability or autism spectrum disorder (ASD) in 40–50% of affected individuals.[1,2] Failure of TSC1 or TSC2 gene products hamartin/tuberin to suppress mTORC1 may lead to alterations in brain development, as well as abnormal cell growth and differentiation interfering with synaptogenesis and balance of excitation/inhibition.[3]
From 1 November 2013 to 31 August 2016, male or female infants with a definite diagnosis of TSC,[22] aged < 4 months, with no seizures reported by caregivers and with no previous AED treatment, were enrolled in the Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy – Tuberous SclerOsis ComPlex (EPISTOP - NCT02098759, clinicaltrials.gov) study, a prospective study aimed at evaluating efficacy of Vigabatrin treatment initiated after the appearance of seizures or after first recorded interictal epileptiform discharges (IED) on EEG before the appearance of seizures
developmental delay (DD) was present in 15/43 (34.9%) children who received early treatment and in 11/33 (33.3%) children who received conventional treatment (ChiSquare = 0.10; P = 0.9). In this cohort of infants with TSC, prospectively evaluated during early development and closely followed by clinical and EEG examinations, children with a history of epilepsy were found to have a higher risk of ASD and lower DQ at 24 months of age when compared to children without epilepsy, consistent with other studies.[24,25]
Summary
Tuberous Sclerosis Complex (TSC) is a multisystem disorder caused by a mutation in the TSC1 or TSC2 gene, associated with intellectual disability or autism spectrum disorder (ASD) in 40–50% of affected individuals.[1,2] Failure of TSC1 or TSC2 gene products hamartin/tuberin to suppress mTORC1 may lead to alterations in brain development, as well as abnormal cell growth and differentiation interfering with synaptogenesis and balance of excitation/inhibition.[3]. TSC-associated ASD is a multifactorial condition, influenced by many risk factors including early seizure onset, infantile spasms, persistent and frequent seizures, longer treatment lag to antiepileptic drug treatment, and temporal interictal epileptiform discharges (IED) on the electroencephalogram (EEG).[9,10,11]
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