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Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current
Iris E Overwater1, André B Rietman2, Agnies M van Eeghen3
1Department of Pediatric Neurology and ENCORE Expertise Center, Erasmus MC, Rotterdam, the Netherlands.
Abstract:
Up to 90% of patients with tuberous sclerosis complex (TSC) have epilepsy, and in over half of patients seizure control cannot be achieved by regular antiepileptic drugs. The underlying problem is mTOR hyperactivation due to loss of function of the TSC proteins. Treatment with everolimus, an mTOR inhibitor, has been shown to be of great benefit to TSC patients, both in reducing tumor growth and as a treatment for intractable epilepsy. Up to 40% of TSC patients with intractable epilepsy show a clinically relevant seizure response to everolimus. It has not yet fully lived up to its promise as a disease-modifying drug, however, as half of TSC patients with intractable epilepsy do not show a clinically relevant seizure frequency reduction. There is no evidence yet of a positive effect on the cognitive and neuropsychiatric deficits in TSC patients. In preclinical studies, mTOR inhibition can rescue abnormal neuronal migration and synapse formation that is caused by mTOR hyperactivation. These studies show a critical time window that suggests that mTOR inhibition may be most beneficial in young children. The trials done so far have not studied treatment in children under 2 years of age, although case series suggest that the safety profile is similar to that in older children. Further studies into the optimal time window, dosing schedules and possibly combination with other drugs may further improve the benefit of everolimus for TSC patients.
Insights
Everolimus, an mTOR inhibitor, helps some tuberous sclerosis complex (TSC) patients with epilepsy. Further research is needed to optimize its use, especially in young children, for better seizure control and potential disease modification.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder causing benign tumors in vital organs.
- Epilepsy affects up to 90% of TSC patients, often resistant to standard antiepileptic drugs.
- Hyperactivation of the mTOR pathway is the underlying cause of TSC-related neurological issues.
Purpose of the Study:
- To evaluate the efficacy of everolimus, an mTOR inhibitor, in treating intractable epilepsy in TSC patients.
- To explore the potential disease-modifying effects of mTOR inhibition on neurological deficits in TSC.
- To investigate the optimal timing and conditions for mTOR inhibition therapy in TSC.
Main Methods:
- Review of clinical trial data and preclinical studies on everolimus in TSC.
- Analysis of seizure response rates in TSC patients treated with everolimus.
- Examination of mTOR inhibition's impact on neuronal development in preclinical models.
Main Results:
- Everolimus provides clinically relevant seizure response in up to 40% of TSC patients with intractable epilepsy.
- Current evidence does not support a positive effect of everolimus on cognitive or neuropsychiatric deficits in TSC.
- Preclinical studies suggest a critical time window for mTOR inhibition, potentially benefiting young children.
Conclusions:
- Everolimus shows promise for seizure control in a subset of TSC patients but is not a universal solution.
- Early mTOR inhibition may be crucial for mitigating TSC-related neurological abnormalities.
- Further research is essential to determine optimal dosing, timing, and combination therapies for everolimus in TSC.
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