Abstract
Background
Tuberous sclerosis complex is a multiorgan disease resulting from a mutation of one
of two TSC genes. The two gene products form a functional complex that regulates the
mTOR signaling pathway (mTOR initially represented mammalian target of rapamycin,
but increasingly the term mechanistic target of rapamycin is used to reflect the ubiquitous
occurrence of mTOR). Epilepsy is the most common neurological symptom of tuberous
sclerosis complex, occurring in 80% to 90% of affected individuals over the course
of their lifetimes and causing significant morbidity and mortality. The mechanistic
target of rapamycin (mTOR) signaling pathway is intricately involved in multiple cellular
functions—including protein synthesis, cell growth and proliferation, and synaptic
plasticity—which may influence neuronal excitability and precipitate epileptogenesis.
Recent preclinical and clinical studies have increased interest in the potential role
of mTOR inhibitors for the treatment of tuberous sclerosis complex-related epilepsy.
Methods
Medline and PubMed database searches were used to identify relevant studies and other
information on tuberous sclerosis complex-related epilepsies, the mTOR pathway, and
current advances in treatment approaches.
Results
Although current management strategies that provide symptomatic relief are effective
at reducing the frequency of seizures in individuals with tuberous sclerosis complex,
there is further room for the exploration of therapies that directly address hyperactive
mTOR signaling—the underlying etiology of the disease. The role of the antiepileptic
effect of mTOR inhibition was first demonstrated in knockout TSC1 mouse models. Additionally, several case studies demonstrated a positive effect on
seizure frequency and severity in patients with pharmacoresistant epilepsy. In a phase
1/2 clinical trial with 28 patients, clinically relevant reduction in overall seizure
frequency was documented in individuals treated with the mTOR inhibitor everolimus.
In a phase 3 trial evaluating the role of everolimus in subependymal giant cell astrocytoma,
seizures were a secondary end point. Because the median seizure frequency was zero
in this study, the analysis was inconclusive.
Conclusion
Various preclinical models provide substantial evidence for the role of mTOR inhibition
in the treatment of epilepsy in individuals with tuberous sclerosis complex. Preliminary
clinical studies provide supportive evidence for a role of mTOR inhibition in the
management of tuberous sclerosis complex-associated epilepsy and pave the way for
new randomized placebo-controlled studies. This article reviews current treatment
recommendations for the management of tuberous sclerosis complex-associated epilepsy
as well as the rationale and evidence to support the use of mTOR inhibitors.
Keywords
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Article info
Publication history
Published online: November 19, 2014
Accepted:
October 29,
2014
Received:
July 10,
2014
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
