Tuberous Sclerosis Complex
Epilepsy Management in Tuberous Sclerosis Complex: Evolving Treatment Approaches
Our knowledge of tuberous sclerosis complex (TSC) has expanded greatly with the discovery of the critical role of dysregulated mammalian target of rapamycin (mTOR) signaling. In parallel with these advancements, there is a renewed focus on the importance of aggressive seizure control in TSC-associated epilepsy.
How is the treatment of epilepsy in TSC evolving, and what are some novel approaches?
Professor of Pediatrics and Neurology
“There are many new and emerging treatments for epilepsy, and there is a growing recognition that epilepsy treatment in patients with TSC needs to be aggressive.”
Individuals with TSC have a 90% incidence rate of epilepsy, and many will become refractory. If we knew that a patient had a 90% chance of developing colon cancer, for instance, we would be very vigilant and act before it got out of control. The same principles must be applied to epilepsy treatment in TSC. We therefore use serial electroencephalogram (EEG) screening for epilepsy in infants. EEG abnormalities precede the onset of seizures by weeks or even months, and we can begin treatment before the patient is actually having seizures. Vigabatrin is a particularly effective medication for epilepsy in TSC, especially for infantile spasms. Ocular toxicity with visual field loss is a possibility with vigabatrin, and researchers are interested in better understanding the mechanism of action and potentially reducing the rates of this side effect.
There are many new and emerging treatments for epilepsy, and there is a growing recognition that epilepsy treatment in patients with TSC needs to be aggressive. Many patients with TSC have focal onset seizures, and there are some newer medications that seem to be particularly beneficial for that. Cenobamate is highly effective, has been US Food and Drug Administration (FDA) approved for adults with partial-onset seizures in the United States for approximately 2 years, and is currently being studied in children. Our experience is that cenobamate is very effective in TSC. The mTOR inhibitor everolimus is FDA approved for TSC-associated seizures. The ketogenic diet may also have beneficial effects in TSC. Finally, epidiolex, or cannabidiol, is FDA approved to treat TSC-associated seizures and may have some other benefits as well. For example, there is evidence that cannabidiol can improve quality of life even if the seizures do not improve, and the same is true for everolimus.
Epilepsy surgery still has an important role in patients with TSC who fail other treatments for epilepsy. There are a number of advances, including stereo-electroencephalography and magnetoencephalography, that have really enabled clinicians to identify areas of the brain where seizures are coming from that can then be resected.
Director, Pediatric Epilepsy Program
“Even though there are no 'silver bullets' that have been identified for treating refractory epilepsy, newer medications are helping these patients.”
As Dr Franz alluded to, approximately two-thirds of patients with TSC will develop refractory epilepsy. In refractory epilepsy and in TSC-associated epilepsy, these rates have not changed much, despite all of the new drugs that have been introduced over the last 20 years. There is a huge amount of excitement, therefore, because there is a substantial unmet need for effective, safe, and well-tolerated therapies. There was great excitement about the FDA approval of everolimus, even though the efficacy was modest, which I think reflects our realization that the treatment gap is significant for these rare disorders, and everolimus was an important addition.
Cannabidiol is another welcome addition. I was very involved in the early clinical development program. Patients with TSC who were treated with cannabidiol were among our most highly refractory patients; their seizure burden continued despite multiple interventions, including epilepsy surgery, diet therapy, and trials of numerous antiseizure medications. Following cannabidiol treatment, 50% of these individuals had a greater than 50% reduction in seizures. This was incredibly significant in such a refractory population, and these results led to the randomized controlled trial of cannabidiol in TSC, ultimately leading to FDA approval.
In the epilepsy professional and patient communities, there is a lot of excitement about therapies that are currently being developed because, for many of them, the safety profiles are looking better than those of some of our older medications. Even though there are no "silver bullets" that have been identified for treating refractory epilepsy, newer medications are helping these patients.
Professor In-Residence, Departments of Neurosurgery and Psychiatry and Biobehavioral Sciences
“Preventive treatment is a key aim, especially as patients with epilepsy and TSC may be at a higher risk of developing severe cognitive and behavioral impairment.”
Our current knowledge of epilepsy treatment in TSC has expanded immensely over the last decade. As noted by my colleagues, there are new approaches, such as EEG monitoring and preemptive vigabatrin therapy in infants with TSC. There are also newer treatments, such as the mTOR inhibitor everolimus and cannabidiol, both of which have been approved by the FDA for the treatment of epilepsy in TSC.
Preventive treatment is a key aim, especially as patients with epilepsy and TSC may be at a higher risk of developing severe cognitive and behavioral impairment. Additionally, improving seizure control really does make a difference. We are trying to overcome therapeutic nihilism, or the belief that persistent seizures are to be expected and that there is nothing to do about them. For any patient with persistent seizures after trying 2 drugs, the reason for failure needs to be determined, and the patients should probably be evaluated by a specialist. Even in the United States, the treatment gap for patients with epilepsy is great.
The future management of this disease could involve a great number of possibilities. Imagine if we could sequence tubers that are associated with seizures in TSC and find differences that account for the development of epilepsy in one scenario, but not in another. Surgically, we could take that particular tuber that was causing the seizures, sequence it, and then compare those findings with sequences from tubers that are not causing seizures. This type of research might one day identify new actionable pathways for precision therapies to address the seizures in individual patients.
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