Importance of Seizure Control in Tuberous Sclerosis Complex
Epilepsy is the most common neurologic manifestation of TSC, affecting 80% to 90% of patients with the disease, with high rates of treatment resistance. The onset of epilepsy in the majority of those with TSC occurs before the age of 2 years, which is a critical time in neurodevelopment.
How does seizure control impact outcomes in patients with TSC?
David N. Franz, MD
Professor of Pediatrics and Neurology
“Providing the best-possible seizure control in TSC is critically important for a child's ultimate long-term development, including their intellectual and social development.”
Providing the best-possible seizure control in TSC is critically important for a child's ultimate long-term development, including their intellectual and social development. Infantile spasms are typically associated with the worst developmental outcomes in TSC. Moreover, the earlier that infantile spasms begin, the worse the developmental prognosis, particularly if the spasms begin before the age of 6 months.
Patients with TSC often begin having seizures before the second year of life. Infantile spasms are essentially a type of myoclonic seizure that develops in babies, and these seizures are linked to the worst outcomes. Focal onset seizures may occur in TSC and can be accompanied by altered mental status, automatisms, or simple movements. Focal onset seizures in patients with TSC are not good for development, but their impact is less significant than that of infantile spasm–associated seizures.
Sometimes, these 2 types of seizures occur together in the same individual; if that happens, it does not necessarily mean that the child will experience severe impairment. In these instances, we want to be as aggressive as possible with treatment (ie, initially with medications and then with other therapies) to gain seizure control. If not, these patients could lose this critical window of development. Early seizure control maximizes the likelihood of the patient having a normal IQ and positive functional outcomes, such as achieving independence and living productively in society. Therefore, the potential payoff for early seizure control in these patients is substantial.
Gary W. Mathern, MD
Professor In-Residence, Departments of Neurosurgery and Psychiatry and Biobehavioral Sciences
“Both treatment-refractory and early onset epilepsy are associated with intellectual disability in TSC, while seizure control and remission are associated with lower rates of cognitive impairment.”
Controlling seizures in individuals with TSC is critically important. If patients are still having seizures from TSC despite treatment, as clinicians, we need to understand why. Both treatment-refractory and early onset epilepsy are associated with intellectual disability in TSC, while seizure control and remission are associated with lower rates of cognitive impairment. The early onset of epilepsy (ie, in the first year of life) is also linked to a high risk of cognitive decline and neuropsychiatric problems, including autism.
Epilepsy and the other neurologic symptoms of TSC, cognitive impairment, autism, and behavioral disorders are interconnected. Many researchers have shown that early onset seizures, infantile spasms, and refractory epilepsy have a significantly negative impact in TSC, and this is true with other epilepsies as well. Having infantile spasms constitutes a medical emergency, and prompt diagnosis and treatment are critical, yet this can be challenging because spasms can be subtle or they can be mistaken for normal baby movements.
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 pathway—or of “mTORopathies,” if you will—and drugs that inhibit that pathway offers hope that we can take a disease that can have a profound neurologic impact on development and cognition and turn it into a more manageable entity that can be managed chronically, with interventions on multiple levels.
Elizabeth A. Thiele, MD, PhD
Director, Pediatric Epilepsy Program
“Approximately one-third of children with TSC who do develop infantile spasms have a normal cognitive outcome, which has always been very intriguing to me. Good outcomes were dependent on how quickly the infantile spasms were identified and treated, and on the features of the EEG at the time of diagnosis.”
It is critically important to control seizures in patients with TSC. Approximately one-third of children with TSC will have infantile spasms. Unfortunately, there are often delays from the onset of infantile spasms to the diagnosis, and this stems from a number of causes. We need to do all that we can to improve the recognition and awareness of infantile spasms by parents, primary care physicians, pediatricians, and any other practitioners or individuals who are positioned to assist with early detection. If a baby is diagnosed early on, either prenatally or in infancy, prior to the onset of seizures, in our practice we initiate monthly electroencephalograms (EEGs). We also show parents videotapes on YouTube of what infantile spasms look like to help them become more aware and detect them early.
Approximately one-third of children with TSC who do develop infantile spasms have a normal cognitive outcome, which has always been very intriguing to me. Good outcomes were dependent on how quickly the infantile spasms were identified and treated, and on the features of the EEG at the time of diagnosis. Earlier onset and greater severity during the first 2 years of life are observed in individuals with a slower gain in intellectual ability. Overall, these observations demonstrate a cascading longitudinal pathway from early epilepsy severity to long-term intellectual ability, underscoring the importance of early detection and the control of seizures, as well as regular neurocognitive assessments and support to improve the intellectual outcomes of patients with TSC.
Mizuguchi M, Ohsawa M, Kashii H, Sato A. Brain symptoms of tuberous sclerosis complex: pathogenesis and treatment. Int J Mol Sci. 2021;22(13):6677. doi:10.3390/ijms22136677
Northrup H, Aronow ME, Bebin EM, et al; International Tuberous Sclerosis Complex Consensus Group. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66. doi:10.1016/j.pediatrneurol.2021.07.011
Schubert-Bast S, Strzelczyk A. Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine. Ther Adv Neurol Disord. 2021;14:17562864211031100. doi:10.1177/17562864211031100
Strzelczyk A, Rosenow F, Zöllner JP, et al. Epidemiology, healthcare resource use, and mortality in patients with tuberous sclerosis complex: a population-based study on German health insurance data. Seizure. 2021;91:287-295. doi:10.1016/j.seizure.2021.06.027