I believe that the use of mTOR inhibitors in TSC-associated epilepsy is a game changer in the field. There are calls to change the term antiepilepsy drugs to antiseizure drugs for reasons that are fairly clear. The typical drugs that we use to control seizures work through mechanisms that are relevant to seizures but not necessarily mechanisms that underlie the patient’s epilepsy; thus, targeting the mTOR pathways in a disease such as TSC is very innovative. 

With regard to other manifestations of TSC that can be treated with mTOR inhibitors, in subependymal giant cell astrocytoma and renal angiomyolipoma, we have evidence that biallelic mutations may often be involved. In contrast, a prominent role of biallelic mutations in cortical tubers that are associated with epilepsy has not been observed. So, in many cases, patients with TSC-associated epilepsy have 1 functioning copy of the gene and protein. You might not expect an mTOR inhibitor to work as dramatically in that setting as it would when both copies are mutated, so the fact that mTOR inhibitors have had positive results and US Food and Drug Administration (FDA) approval for TSC-related seizures is impressive. 

In patients who have had surgical resections to successfully improve seizure control, the later recurrence of seizures sometimes occurs in association with a different site or another tuber rather than the area that was initially resected. Why did we not detect the new site initially? This suggests that there may be a progression, or a new growth, against which we could possibly intervene. We might be able to control seizures up front through a combination of medicine and/or surgery and then prevent other tubers from becoming epileptogenic by prophylactically using targeted therapy. This is where, I think, mTOR inhibitors and other targeted therapies could have an important role.

Data from the phase 3 EXIST-3 trial of everolimus led to the FDA approval of the adjunctive treatment of adult and pediatric patients with TSC-associated seizures. And, for those with TSC, having an FDA-approved medication specifically for the management of epilepsy in TSC was a substantial development. We already knew from other trials that mTOR inhibitors could be very effective in TSC-associated subependymal giant cell astrocytoma, TSC-associated renal angiomyolipoma, and other manifestations of TSC. And I think that, for patients with TSC, these treatments offer a unique opportunity to not only effectively improve seizure control but also have an impact on other manifestations and outcomes.

There is excitement about mTOR inhibitors in both the TSC and the epilepsy communities because these agents treat the underlying pathophysiology of TSC-associated epilepsy, in addition to treating the seizures. The great dream is that of precision medicine: we hope to provide more precise therapies for epilepsy based on a patient's genetic mutation or the other molecular aspects of the pathophysiology in specific patients, for their specific type of epilepsy. Thus, the EXIST-3 trial with everolimus was very important in the world of epilepsy. Even though this is not a “silver bullet,” the use of mTOR inhibitors is still a welcome change in the treatment paradigm, and we hope for additional advancements to come.

Since the 1990s, there has been an explosion of knowledge about the primary role of mTOR signaling in TSC. The mTOR proteins serve as a regulator of cell growth and development. If mTOR signaling is too active, abnormal cell growth develops. This abnormal cell growth in TSC leads to hamartomas, which are essentially malformed areas of tissue, in various organs, including the brain, kidney, bones, and intestines. These malformations result in TSC-associated symptoms.

mTOR inhibitors have a role in treating tumors that are associated with both TSC and epilepsy, which was not anticipated initially. Studies of these agents for TSC-associated tumors led to the observation that, in addition to experiencing antitumor effects, mTOR inhibitor–treated patients also reported fewer seizures. This led to dedicated studies of mTOR inhibitors for seizure control. The treatment was found to be effective. Everolimus, in particular, has been approved by the FDA to treat epilepsy in patients with TSC.

Interestingly, the longer the patient takes mTOR inhibitors, the better they work. They work differently from most seizure medicines, as Dr Mathern noted. Most antiseizure medications affect the flow of ions across channels that are associated with neurotransmitter receptors. mTOR inhibitors actually change the biology of the nerve cell and are disease modifying. Another interesting aspect of mTOR inhibitors is that their effects are long lasting. For example, if a patient has to stop taking an mTOR inhibitor for an infection or some other reason, the drugs typically do not lose effectiveness for weeks or sometimes even months. In contrast, the seizure-preventive effects of traditional antiseizure medications are lost soon after discontinuation.