Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Tuberous sclerosis complex (TSC) is a genetic disorder associated with intractable epilepsy.
• Mammalian target of rapamycin complex 1 (mTORC1) pathway dysregulation is implicated in TSC pathogenesis and epileptogenesis.
• Current treatments for TSC-related epilepsy are often inadequate.

Purpose of the Study:

• To evaluate the efficacy of mTORC1 inhibitors, specifically sirolimus, in reducing seizure frequency in pediatric patients with TSC.
• To assess the safety and tolerability of sirolimus as an add-on therapy for intractable epilepsy in TSC.

Main Methods:

• A randomized, open-label, add-on trial involving 23 children with TSC and intractable epilepsy.
• Participants were assigned to immediate sirolimus treatment or a 6-month delayed treatment group.
• Sirolimus dosage was adjusted to achieve trough levels of 5-10 ng/mL, with seizure frequency change as the primary endpoint.

Main Results:

• Intention-to-treat analysis revealed a 41% decrease in seizure frequency, though not statistically significant (p=0.11).
• Per-protocol analysis in 14 children reaching target trough levels showed a 61% seizure frequency reduction (p=0.06).
• Adverse events were common, leading to premature discontinuation in five children; cognitive development remained unchanged.

Conclusions:

• While sirolimus demonstrated a trend towards reducing seizure frequency in children with TSC, the study did not meet statistical significance.
• Further investigation through larger trials or meta-analyses is warranted to confirm the therapeutic benefit of mTORC1 inhibition for TSC-related epilepsy.
• The study highlights the potential of targeting specific molecular pathways in genetic epilepsy disorders.