Q&A: Preventive treatment in TSC leads to ‘major reduction’ of epilepsy outcomes

Findings published last month in Annals of Neurology demonstrated that preventive use of vigabatrin, an antiepileptic drug, positively altered the natural history of seizures in infants with tuberous sclerosis complex.

“[Tuberous sclerosis complex] TSC is a major cause of severe and drug-resistant epilepsy, with focal seizures and infantile spasms occurring in about 80% of TSC infants. Neurodevelopmental comorbidities, including intellectual disability and autism, are also common in TSC,” the researchers wrote. “Current guidelines recommend antiepileptic treatment after two unprovoked clinical seizures or after one seizure in patients at high risk (> 60%) [for] recurrent seizures. Although immediate antiepileptic treatment after seizure onset in children with TSC decreases the risk of neurodevelopmental complications, still 50% [to] 60% of children develop intellectual disability.”

Katarzyna Kotulska, MD, PhD, of the department of neurology and epileptology at the Children’s Memorial Health Institute in Poland, and colleagues found that preventive treatment reduced the risk for and severity of epilepsy among infants with TSC. They conducted the study as part of the EPISTOP project, a long-term prospective study examining clinical and molecular biomarkers for epileptogenesis in a genetic model of epilepsy/TSC. Healio Neurology spoke with Kotulska to learn more about the study results.

Q: What prompted this research?

A: My colleagues and I in EPISTOP are experts in the care of infants and children with TSC, having collectively seen and treated many thousands of patients over the past 20 years. We realized that epilepsy in TSC is very common (seen in 80% to 90% of patients) and usually begins in the first year of life. It is associated with a high risk of neuropsychiatric comorbidities, including intellectual disability and autism spectrum disorder. Infants with TSC — up to 50% of patients — also frequently develop infantile spasms. These clinical observations led us to consider whether preventive treatment for seizures in TSC might be both possible and result in clinical benefit.

Because of the development of tumors in the heart, TSC is commonly diagnosed prenatally or soon after birth, well before seizures, enabling a preventive treatment approach. It is known that in TSC, clinical seizures are preceded by the development of epileptiform abnormalities on EEG. Further, the first seizures are usually short and subtle and can be easily overlooked by caregivers. Since a delay in treatment significantly increases the risk for drug-resistant epilepsy and worse neurocognitive outcome, EEG monitoring was recommended in 2011 for all infants with TSC in order to facilitate seizure identification as early as possible.

Q: Is the concept of preventive antiepileptic treatment for TSC new ?

A: The idea of preventive treatment for epilepsy is not entirely new, but it has not been feasible in other syndromic epilepsy disorders for a variety of reasons. Our use of EEG as a biomarker of epileptogenesis was based on previous studies. To our knowledge, this is the first time that a preventive treatment for epilepsy has been shown in a randomized trial in any clinical setting.

Q: What did the study findings demonstrate?

A: We previously conducted a small pilot non-randomized study that suggested that antiepileptic treatment after the onset of epileptiform abnormalities, but before the onset of seizures, reduced the risk for drug-resistant seizures and improved neurocognitive outcomes in infants with TSC. Therefore, we decided to perform a randomized, multicenter, blinded trial to assess the efficacy and safety of preventive vs. conventional treatment with vigabatrin in infants with TSC.

Early treatment with vigabatrin at the time of an abnormal EEG, compared with no treatment at that time, led to a major reduction in clinical seizures, drug-resistant epilepsy and a severe form of epilepsy known as infantile spasms, without adverse events related to preventive treatment.

Q: Was there anything unusual or surprising about the results?

A: In the entire EPISTOP cohort, we did not observe severe or moderate forms of neurodevelopmental delay. In the conventional treatment arm, vigabatrin was introduced after the onset of first seizures, either noticed on EEG or clinically evident, and even in this group the epilepsy outcome was better than in any previously reported TSC cohort. It shows the importance of EEG monitoring. However, it also highlights the significance of the results in our preventive group, which was compared with patients monitored via EEG.

Q: What are the clinical implications for these findings?

A: As showed by a report recently published in Pediatric Neurology, the majority of experts in TSC already perform EEG monitoring in infants with TSC and many consider preventive strategy. However, until now, the preventive use of vigabatrin in infants with TSC was based on the results of small, open-label studies. The publication of results from the EPISTOP project could significantly contribute to a change of clinical practice for TSC. For many infants with TSC and their families, it would be a chance for a better quality of life.

Q: What are the next steps for this research?

A: We hope that our results will lead to widespread adoption of this preventive approach for the care of infants with TSC. We have several parallel analyses in this set of infants, including genetic biomarkers of disease; some have been published and others are in progress. We hope that these results may yield even better biomarkers of seizure development than EEG. This preventive approach may be useful for other childhood epilepsies such as Sturge-Weber syndrome.

We are also planning a follow-up clinical trial to compare the disease-modifying effect of vigabatrin versus an mTOR inhibitor in newborns and infants with TSC.