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Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option?
Gert Wiegand1, Theodor W May, Philipp Ostertag
1Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH, Campus Kiel), Arnold-Heller-Str. 3, Haus 9, 24105 Kiel, Germany.
Background:
Tuberous Sclerosis Complex (TSC) is an often severe neurodevelopmental disorder caused by overactivation of the mTOR pathway due to mutations in either the TSC1 or TSC2 genes. Seizures are the primary cause of neurologic morbidity and often refractory. The mTOR inhibitor everolimus was recently approved for the treatment of giant cell astrocytomas and renal angiomyolipomas in TSC. Whether everolimus has any direct effect on epilepsy in TSC is not known.
Methods:
Within the framework of a compassionate use trial, we evaluated the safety and efficacy of everolimus in seven patients with TSC and intractable epilepsy. We evaluated seizure frequency, seizure-free days and adverse effects including standard laboratory parameters. Seizure frequency was analysed in each patient using a non-parametric test for trend and using a Generalized Estimating Equations Model in the total patient group. The observation period was continued for nine months.
Results:
One patient discontinued the medication at the beginning of the observation period due to side effects (flushing). In the remaining 6 patients, we observed a reduction of seizures in 4/6 patients with a reduction of 25-100%. In addition, the percentage of seizure-free days increased in 3/4 of these patients. In 2/6 patients, no alteration of seizure frequency was noted. We observed an increase of mild infections and an increase of triglycerides and various liver function tests. We did not encounter life-threatening infections or other side effects of everolimus.
Interpretation:
In some patients with TSC, everolimus may have an anticonvulsant effect with a reduction in seizure frequency and increase of seizure-free days. Everolimus was well tolerated, with adverse effects similar to those reported in previous studies.
Insights
Everolimus may reduce seizures in some patients with Tuberous Sclerosis Complex (TSC), a neurodevelopmental disorder. This mTOR inhibitor showed a potential anticonvulsant effect and was generally well-tolerated in a compassionate use trial.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Tuberous Sclerosis Complex (TSC) is a severe neurodevelopmental disorder linked to mTOR pathway overactivation.
- Mutations in TSC1 or TSC2 genes cause TSC, leading to neurological issues, primarily refractory seizures.
- Everolimus, an mTOR inhibitor, is approved for TSC-related tumors but its effect on epilepsy is unknown.
Purpose of the Study:
- To evaluate the safety and efficacy of everolimus in patients with TSC and intractable epilepsy.
- To assess the impact of everolimus on seizure frequency and seizure-free days.
- To identify adverse effects associated with everolimus treatment in this patient population.
Main Methods:
- A compassionate use trial involving seven patients with TSC and intractable epilepsy.
- Evaluation of seizure frequency, seizure-free days, and laboratory parameters over a nine-month observation period.
- Statistical analysis using non-parametric tests for trend and Generalized Estimating Equations Model.
Main Results:
- One patient discontinued due to side effects (flushing).
- Four out of six remaining patients experienced a 25-100% reduction in seizure frequency.
- Increased seizure-free days in 3/4 of responders; mild infections and elevated triglycerides/liver function tests were observed.
Conclusions:
- Everolimus may possess an anticonvulsant effect in some TSC patients, reducing seizure frequency and increasing seizure-free days.
- The drug was generally well-tolerated, with adverse effects consistent with previous studies.
- Further investigation into everolimus for TSC-related epilepsy is warranted.
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