Rationale:
Epilepsy develops in 70–90% of children with Tuberous Sclerosis Complex (TSC) and is often resistant to medication. Recently, everolimus, an mTOR inhibitor has been approved as an add-on therapy in drug-resistant epilepsy in TSC patients, but is not available in some countries, including Poland. Our study evaluated the antiepileptic effect of another mTOR inhibitor, rapamycin, in TSC children suffering from drug-resistant epilepsy.
Method:
The inclusion criteria for this single center, open-label, prospective study were: age between 6 months and 18 years, definite diagnosis of TSC, drug-resistant epilepsy according to ILAE definition, at least one seizure per week within last 8 weeks preceding rapamycin introduction.
All participants were intended to receive rapamycin treatment for 12 months. Children received a starting dose of rapamycin based on their body surface area, ranging from 0.5mg/m2 in infants and children aged < 3 years, 1mg/m2 in children aged from 3 to 10 years, and to 2mg/m2 in teenagers. Rapamycin dosage was titrated to blood trough levels between 5 and 10 ng/mL. In case of adverse events of grade 2 or higher, rapamycin was discontinued until the adverse event subsided or reached grade 1 and was restarted at the last dose without adverse events. In case of grade 3 or higher, the drug was discontinued permanently.
The primary endpoint of this study was the proportion of patients showing decrease in the number of seizures per week after 6 and 12 months of rapamycin treatment as well as the number of adverse events.
Results:
Thirty-five patients, 17 females and 18 males, aged from 11 to 171 months (median: 49 months) met the inclusion criteria for this study. Thirty-two patients (18 males and 16 females) received rapamycin for at least 12 months. Mean daily dose of rapamycin was 1.1mg/day ( 0.4 to 3mg/day) and 3 mg/day ( 0.4 -3 mg) in the first and second 6 months of treatment.
At baseline, mean frequency of seizures was 8 per day (Tab. 1). After the first 6 months 18 subjects (56.25%) reported at least 50% reduction in the number of seizures per week compared to baseline. No change was seen in 12 cases (37.5%) and 2 patients reported the increase in the number of seizures (6.25%). At 12 months, all previous improvement were sustained and another 3 patients reported response (total clinical improvement in 65.6%). No patient reported worsening in seizure frequency (Fig 1).
The impact of rapamycin blood level and its efficacy over time showed a curvilinear relationship, with an optimum at the level of 4.5 ng/ml/day. Concomitant treatment with vigabatrin was a good prognostic factor for the better epilepsy outcome.
Rapamycin was well tolerated in thus study. The most common adverse events included respiratory tract infections and stomatitis. None of the patients required drug withdrawal or the reduction of rapamycin dose due to adverse events.
Conclusion:
Long-term use of rapamycin, especially in combination with vigabatrin, might be a beneficial therapeutic option in the treatment of drug-resistant epilepsy in children with TSC.
Funding:
:The work was partially supported by the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016.
FIGURES
Figure 1