Abstract
BackgroundEpilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC). In 67 % disease onset is during childhood. In ≥ 50 % seizures are refractory to currently available treatment options.The mTOR-Inhibitor Everolimus (Votubia®) was approved for the treatment of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in Europe in 2011. It’s anticonvulsive/antiepileptic properties are promising, but evidence is still limited. Study aim was to evaluate the efficacy and safety of Everolimus in children and adolescents with TSC-associated epilepsies.MethodsInclusion-criteria of this investigator-initiated, single-center, open, prospective study were: 1) the ascertained diagnosis of TSC; 2) age ≤ 18 years; 3) treatment indication for Votubia® according to the European Commission guidelines; 4) drug-resistant TSC-associated epilepsy, 5) prospective continuous follow-up for at least 6 months after treatment initiation and 6) informed consent to participate.Votubia® was orally administered once/day, starting with 4.5 mg/m2 and titrated to achieve blood trough concentrations between 5 and 15 ng/ml. Primary endpoint was the reduction in seizure frequency of ≥ 50 % compared to baseline.ResultsFifteen patients (nine male) with a median age of six (range; 1–18) years fulfilled the inclusion criteria. 26 % (4/15) had TSC1, 66 % (10/15) had TSC2 mutations. In one patient no mutation was found. Time of observation after treatment initiation was median 22 (range; 6–50) months.At last observation, 80 % (12/15) of the patients were responders, 58 % of them (7/12) were seizure free. The overall reduction in seizure frequency was 60 % in focal seizures, 80 % in generalized tonic clonic seizures and 87 % in drop attacks.The effect of Everolimus was seen already at low doses, early after treatment initiation.Loss of efficacy over time was not observed.Transient side effects were seen in 93 % (14/15) of the patients. In no case the drug had to be withdrawn.ConclusionEverolimus seems to be an effective treatment option not only for SEGA and AML, but also for TSC-related epilepsies. Although there are potential serious side effects, treatment was tolerated well by the majority of patients, provided that patients are under close surveillance of epileptologists who are familiar with immunosuppressive agents.
Highlights
Epilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC)
Taking into consideration that epileptic seizures in patients with TSC are usually difficult to treat and that the children included into this study had been already refractory to various Anti - epileptic Drug (AED) as well as other treatment options including epilepsy surgery, vagus nerve stimulation (VNS) and the ketogenic diet (KD), the response to Everolimus in this study was good to excellent
The effect on seizure frequency was a secondary endpoint, and significant limitations made the interpretation of the results difficult: In the EXIST-1 study no change in seizure frequency compared with baseline was observed [17], whereas Krueger et al reported an increase in seizure free patients from 38.5 % (10/26) at baseline to 65.2 % (15/23) after 24 months’ treatment
Summary
Epilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC). The mTOR-Inhibitor Everolimus (Votubia®) was approved for the treatment of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in Europe in 2011. Tuberous sclerosis complex (TSC) is a genetic autosomal dominant multi-system disorder, affecting 1–2 million people worldwide. Hamartin and tuberin are widely expressed in all tissues, functioning as a tumor suppressor complex involved in the control of cell growth and division. Pathogenic mutations in either of the two genes (TSC1 or TSC2) cause dysfunction of the intracellular hamartin/tuberin-complex, leading to over-activation of the mTOR signaling pathway resulting in uncontrolled protein synthesis and cell growth [4, 5]
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