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Sirolimus treatment for tuberous sclerosis complex prior to epilepsy: Evidence from a registry-based real-world study
Yan-Wen Shen1, Yang-Yang Wang1, Meng-Na Zhang1
1Department of Pediatrics, Chinese PLA General Hospital, Beijing 100583, China.
Insights
Early sirolimus treatment for tuberous sclerosis complex (TSC) significantly delays seizure onset and reduces infantile spasms. This intervention modifies the disease course, offering a potential anti-epileptogenic effect.
Area of Science:
- Neurology
- Pediatrics
- Pharmacology
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder associated with neurological complications, including epilepsy.
- Epilepsy in TSC often presents early and can be difficult to manage.
- Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor used to manage various TSC-related symptoms.
Purpose of the Study:
- To investigate the efficacy of early sirolimus treatment in preventing or mitigating new-onset seizures in infants with TSC before epilepsy develops.
- To compare seizure characteristics and outcomes between patients receiving early sirolimus and those receiving late or no preventive treatment.
Main Methods:
- A real-world, matched case-control study nested within a registry cohort.
- Inclusion criteria: Infants with TSC (<12 months) without seizures, receiving sirolimus for other symptoms (early sirolimus group).
- Matching criteria: Age, genotype, and other symptoms; controls received no preventive drugs before seizure onset or 2 years of age (late sirolimus group).
Main Results:
- Early sirolimus treatment significantly reduced seizure onset, particularly in infants <6 months old.
- Mean seizure onset age was delayed (11.34 months in early vs. 6.94 months in late group, P<0.001).
- Infantile spasms were significantly reduced (11.90% vs. 43.45%, P<0.001), and drug-resistant epilepsy was less common with early treatment (23.81% vs. 47.62%, P=0.004).
Conclusions:
- Early sirolimus administration in TSC patients effectively modifies disease progression by preventing infantile spasms and delaying seizure onset.
- Sirolimus demonstrates an anti-epileptogenic effect in TSC, suggesting a potential time- and dose-dependent mechanism.
- This study supports early intervention with sirolimus to manage epilepsy risk in TSC.
Objective:
To evaluate whether sirolimus treatment could relieve the later burden of new-onset seizures in patients with tuberous sclerosis complex (TSC) prior to epilepsy.
Methods:
A real-world matched case-control study was nested in another registry cohort study. Infants with TSC (<12 months old) without seizures whose parents agreed on sirolimus treatment for other symptoms were eligible for inclusion to the early sirolimus (ES) group. These patients were enrolled from 2015 to 2018. Controls in the late sirolimus (LS) group were matched from the registry cohort database for 2015-2018. Age and genotype were used as the initial stratifying criteria and other symptoms as the greedy matching criteria at a matching ratio of 1:4. None of the preventive drugs were introduced before seizure onset or before 2 years of age in the LS group. Both groups were followed up until June 2020. The primary objective was a comparison of the characteristics of the first seizure between the two groups. The secondary objective was the assessment of the final seizure status at the endpoint.
Results:
There were 42 and 168 patients with TSC in the ES and LS groups, respectively. Early sirolimus treatment significantly reduced the seizure onset, especially in the patients aged <6 months. The mean onset-age was significantly delayed by sirolimus treatment (11.34±7.93 months vs. 6.94±6.03 months, P<0.001). The subtype of seizures that benefited the most was spastic (onset) seizures (all were infantile spasms) [5/42 (11.90%) vs. 73/168 (43.45%), P<0.001]; these seizures were either eliminated or alleviated. The sirolimus treatment addition prior to seizures was more effective than its addition after seizures in reducing drug-resistant epilepsy [10/42 (23.81%) vs. 70/147 (47.62%), P=0.004].
Conclusion:
Early sirolimus treatment for TSC effectively modified the disease by preventing infantile spasms, delaying seizure onset, and relieving its severity. The anti-epileptogenic effect of sirolimus may be time- and dose-dependent.
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