Early Intervention to Prevent First Seizures in Infants with Tuberous Sclerosis Complex

March 2022

Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disease that causes benign tumors in multiple organs, including the brain. People with TSC usually have epilepsy and many have intellectual disabilities. Conventional treatment is to start antiepileptic therapy after the first or second seizure. Most children with TSC who develop epilepsy will have epileptiform activity on electroencephalography (EEG) followed by asymptomatic electrographic seizures before the first clinical seizure. Researchers have hypothesized that starting antiepileptic therapies before the onset of asymptomatic seizures could delay the development of clinically evident seizures in patients with TSC.

To determine whether antiseizure therapy could be effective as a preventive treatment, the EPISTOP clinical trial was conducted to compare the time to first seizure in infants with TSC who were treated before or after the onset of seizures.

Participants with TSC aged ≤4 months who had no asymptomatic electrographic seizures or clinical seizures were enrolled in 1 of 2 parallel trials. All received monthly EEG monitoring. Infants in the preventive treatment group received daily vigabatrin after epileptiform activity was detected by EEG. Infants in the conventional treatment group received daily vigabatrin after an asymptomatic electrographic seizure or a clinical seizure occurred. Physicians were free to add other antiepileptic therapies if warranted.

At 6 trial sites, the study was a double-blind randomized clinical trial in which infants were randomized to receive preventive or conventional therapy. Because some ethics boards did not approve randomization, 4 sites conducted an open-label trial. Two of the open-label sites had conventional treatment only and the other 2 sites had preventive treatment only.

For all sites, the primary outcome was the time to the first clinical seizure and secondary outcomes were other epilepsy and neurodevelopmental assessments. There were 54 patients enrolled in the trial who developed epileptiform activity during surveillance and were eligible for treatment; 50 of these patients completed the study.

In both the randomized trial and the open-label trial, the median time from birth to the first clinical seizure was 4 times longer in patients receiving the preventive treatment compared with patients receiving the conventional treatment. The investigators pooled the data and found that the median time to clinical seizure was 614 days for the preventive group and 124 days for the conventional treatment group. Patients in the preventive group were also 3 times more likely to have had no seizures by age 2 years than those in the conventional treatment group.

Some secondary outcomes favored preventive treatment. Patients in the preventive treatment group had a 2-fold reduced risk of drug-resistant epilepsy by age 2 years. In addition, no patients in the preventive group experienced spasms, compared with 40% in the conventional group. Cognitive scores and the incidence of neurodevelopmental delay were not significantly different between treatment groups, and adverse events were comparable.

The investigators reached 2 main conclusions: “Our findings support the use of serial video-EEG monitoring beginning at the time of diagnosis of TSC in infants and the immediate initiation of antiepileptic treatment with vigabatrin at the onset of epileptiform activity.”


Kotulska K, Kwiatkowski DJ, Curatolo P, et al. Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP trial. Ann Neurol. 2021;89:304-314.

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