The message that needs to reach physicians, patients, families, and caregivers is that if you or your loved one has drug-resistant epilepsy, we want to understand why. The bar has been set too low for too long. As a consequence, stakeholders have accepted persistent seizures as an inevitable outcome in patients with TSC, and, in 2022, that is not acceptable for anybody with epilepsy. It is important for a patient with TSC who is experiencing persistent seizures after 2 or more drugs to be evaluated at a specialized epilepsy center where surgery can be considered as a potential treatment option. This does not necessarily mean that the surgery is going to happen. It just means that it should be considered.

In the United States, this may mean a referral to a level-4 center or a specialized epilepsy center with experience in treating patients with TSC; the TSC Alliance maintains a registry of certified centers of excellence on its website. One aspect that we consider from a surgical perspective is whether the patient has stereotypic epilepsy. If the seizures mostly begin and occur the exact same way each and every time, if the prodrome and aura are always the same, and if the seizures themselves begin and/or transition and end in very much the same way, it usually indicates that there is a single focus that is causing the seizures. In this case, the job of the epileptologist and the surgical center is to identify whether there is a single focus that can be removed safely. If there are multiple tubers, figuring out which tuber might be the responsible party is not very straightforward, but that is why a patient should go to a specialty center that has experience in evaluating patients with TSC. 

In the earliest cases of surgical treatment for epilepsy in TSC, often the patients had only 1 major tuber, in which case that tuber could be removed. It is important to emphasize to the family that these tubers are so malformed that they generally do not contain functional brain tissue and can be removed without greater deficits than the patient already has. Hence, the risk of resection is usually reasonably low compared with the chance of achieving seizure control. As the literature has shown, postsurgical seizure freedom occurs in approximately two-thirds of patients with TSC, but those rates decrease over longer follow-up periods. I think that the reduction in seizure freedom over time opens up opportunities for us to better understand the disease, its natural history, and its progression in the context of epilepsy. If a patient had surgery and their seizures were controlled initially but then recur, we need to know what happened. For example, did the seizures return because we did not remove enough of a single tuber, or has another tuber begun to produce seizures? If seizures come from another tuber, what process made that tuber produce seizures, and can that process be stopped before epilepsy begins?  

Initial successes with resective surgery, which were detailed early on in the 1990s, have progressed to the point where surgical centers are now conducting more investigations to ascertain whether multiple implicated tubers can be identified and safely removed to achieve seizure control. There are currently several centers that are performing multiple tuber resections for TSC. 

In the future, I hope that we can convert TSC into a chronic disease that is more manageable over the long-term, similar to what is being done in oncology. This might involve not only surgical resection when possible but also other treatment modalities. The discovery of the significance of the mammalian target of rapamycin (mTOR) pathway (or of “mTORopathies,” if you will) and drugs that inhibit the mTOR pathway offers hope that we can take a disease that can have a profound neurological impact on development and cognition and turn it into a more manageable entity that can be managed chronically, with interventions on multiple levels.