Practical Neurology spoke with Darcy Krueger, MD, PhD, who provides an overview of tuberous sclerosis complex (TSC) and the current landscape of ongoing clinical trials exploring new therapeutic strategies that leverage mammalian target of rapamycin (mTOR) inhibitors. Dr. Krueger is a board-certified neurologist, Professor at the University of Cincinnati Department of Pediatrics, Clack Endowed Professor and Co-Director of the Tuberous Sclerosis Clinic, and Sponsor and Principal Investigator of the Tuberous Sclerosis Complex Sirolimus and TSC Epilepsy Prevention (TSC-STEPS) clinical trial (NCT05104983), which is evaluating the early use of sirolimus to prevent or delay seizure onset in infants with TSC.
What Is the Incidence of TSC?
Approximately 1 in 6000 births will be affected by TSC.1
How Is TSC Diagnosed?
Because it is a genetic disorder, TSC can affect any tissue or organ system in the body. Different parts of the body are more or less commonly affected, and some manifestations may appear earlier in life than others. Typically, TSC is diagnosed based on clinical features that are common to the disorder. There are characteristic skin manifestations; brain findings that can be detected by CT or MRI scans; as well as cardiac, kidney, and lung manifestations. Once TSC is suspected clinically, or when TSC is present in a parent or sibling, we can also confirm the diagnosis through genetic testing.
Today, >50% of people are diagnosed or at least suspected to have a diagnosis of TSC before they are born.2,3 This is because tumors often form in the heart as early as 20 weeks of gestation and become more detectable by 24 or 25 weeks gestation and beyond. Although these tumors are benign, they can grow to affect the heart’s development or the blood flow of the developing fetus, and can result in major clinical implications as soon as an infant with TSC is born, including heart failure and arrythmias. Prenatal diagnosis of TSC is possible because there are relatively few conditions that will cause these features to appear in a prenatal ultrasound.
In addition, it is now possible to detect TSC through genetic testing, which enables neurologists to confirm a TSC diagnosis or make a diagnosis when few clinical features are present. It is about equally as likely that a person will be diagnosed before birth as after birth, whether through genetic testing or the prenatal recognition of clinical features.
How Does the Current Diagnostic Pathway for TSC Compare With That of the Past?
Historically, postnatal diagnoses were more common. Diagnosis after birth was the main way or often the only way possible. The most common scenario is a child would present with new-onset seizures, would be evaluated with careful skin examination and brain imaging, and enough features of TSC would be identified to make the diagnosis. Over time, prenatal ultrasounds became more standard, more clinical features were identified, and genetic testing became more common and accessible, leading to other pathways for a TSC diagnosis to be made.
Is TSC Ever Diagnosed in Adults?
Cases of TSC are usually detected in childhood due to the recognizable features associated with the disorder, or because of its high likelihood to present with seizures early in life. However, because TSC is a highly variable disorder, there is a range from exhibiting all of the typical manifestations of TSC to having few signs of the condition. When a person with TSC does not receive a diagnosis in childhood, this usually results from 1 of 2 scenarios.
First, some manifestations of TSC may be difficult to treat and require early medical attention, whereas others may be mild and go unrecognized by the individual and their medical providers. Occasionally, diagnosis of TSC in a child may prompt a medical provider to evaluate the child’s parents, leading to a new diagnosis of TSC for a parent. There are also specific adult manifestations of TSC, such as abnormal lung findings, which may arise in people who have gone most of their lives without suspecting that they have the disorder.
In the second scenario, a person may have generic or nonspecific manifestations of TSC, such as epilepsy. These individuals may be diagnosed with another epileptic disorder and receive treatment without identifying TSC as the root cause of their epilepsy.
How Has TSC Historically Been Treated?
There is no cure for TSC; treatment consists of managing manifestations of TSC, which are treated according to their severity and type. For example, vigabatrin is a mainstay of treatment for the infantile spasms that occur in infancy in most individuals with TSC. There are 20 to 30 different antiseizure medications available to treat generalized and focal seizures, which also occur in TSC. However, some individuals with TSC have seizures that cannot be controlled with any of these medications, or even with combinations of multiple medications. Epilepsy surgery is increasingly used as a treatment option for individuals whose epilepsy does not improve with the use of medications, and is associated with favorable outcomes, including seizure remission.4,5
There are other strategies used to treat the neurodevelopmental and cognitive difficulties commonly associated with TSC, as well as the disorder’s associated heart and lung manifestations. mTOR inhibitors comprise one class of medications that have been particularly important for treating different manifestations of TSC. Sirolimus and everolimus are the most commonly used mTOR inhibitors, and are approved by the Food and Drug Administration (FDA) for use in the treatment of TSC.
How Is mTOR Involved in TSC?
The TSC-causing genes, TSC1 and TSC2, form a complex that regulates the mTOR protein, which is central to different processes in the body related to growth, metabolism, recycling proteins, and survival. In the brain, mTOR serves an important role in directing how cells migrate to create connections and form synapses, critical for development and learning. In TSC, TSC1 and TSC2 are not properly controlling mTOR, which causes tumors and tubers to develop in the brain, resulting in the characteristic neurodevelopmental and cognitive manifestations associated with the disorder. Treatment with mTOR inhibitors restores mTOR regulation that is lost in TSC.
What Pivotal Clinical Trials Have Assessed the Use of mTOR Inhibitors for TSC?
In 2003, preliminary trials were initiated to assess the use of mTOR inhibitors in the treatment of TSC-associated lung disease, kidney tumors, and brain tumors, which are the 3 most life-threatening manifestations of the disorder, with high rates of mortality and morbidity.
The efficacy and safety of sirolimus were investigated as a treatment for lymphangioleiomyomatosis in the pivotal Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) clinical trial (NCT00414648), which started in 2006.6 Lymphangioleiomyomatosis is a cystic disease that predominantly affects adult women who have TSC. Sirolimus was approved by the FDA in 2015. More recently, the use of sirolimus as a topical formulation to treat facial angiofibromas in individuals with TSC was approved by the FDA in 2022.
Starting in 2009, Novartis Pharmaceuticals initiated the Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST) clinical trial program, including Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (EXIST-1, NCT00789828), investigating the safety and efficacy of everolimus as a treatment for subependymal giant cell astrocytoma associated with TSC;7 Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis (EXIST-2, NCT00790400), investigating the medication’s safety and efficacy for treating renal angiomyolipoma associated with TSC;8 and A Placebo-Controlled Study of Efficacy & Safety of 2 Trough Ranges of Everolimus as Adjunctive Therapy in Patients With Tuberous Sclerosis Complex & Refractory Partial-Onset Seizures (EXIST-3, NCT01713946), investigating its safety and efficacy as an adjunctive therapy for people with refractory focal seizures in TSC.9
What Makes the TSC-STEPS Clinical Trial Different From Previous Studies?
TSC-STEPS was initiated to address whether TSC symptoms or manifestations can be targeted and treated before they appear, progress, and cause additional medical complications and difficulties (Figure). In a 2020 prospective study, Kotulska et al10 found that treating infants with vigabatrin before they had clinical seizures resulted in fewer infantile spasms and fewer seizures overall, and, as participants aged, their epilepsy was easier to treat.
In the United States, a similar clinical trial—Preventing Epilepsy Using Vigabatrin in Infants With Tuberous Sclerosis Complex (PREVeNT, NCT02849457) —was completed in 2023, similarly finding that infantile spasms could be delayed or even prevented from occurring. However, the use of vigabatrin in infants was not found to prevent focal seizures, or the closely associated neurocognitive or neurodevelopmental difficulties accompanying seizures in these individuals.
TSC-STEPS was launched in 2021 and is still enrolling, investigating the use of sirolimus as a treatment for infants with TSC. It is a multicenter study at 13 sites: 12 in the United States and 1 in Sydney, Australia. What distinguishes TSC-STEPS from the vigabatrin studies is that we are initiating treatment as early as day 1 of life, before clinical symptoms have manifested, using the prenatal diagnosis methods previously discussed. Treatment this early is critical, considering that two thirds of people with TSC will have seizures before their first birthday. Participants in TSC-STEPS must be younger than 6 months, not have experienced any seizures, and have a diagnosis of TSC without other medical complications associated with TSC, pregnancy, or delivery that would separately cause added risks for developing epilepsy. Participants will receive treatment until they are aged ≥1 year, with the option to continue treatment for another year. The primary outcome measures are time to seizure onset and adverse events at 12 months, with secondary end points for neurodevelopmental outcomes, quality of life, and EEG and MRI biomarkers measured at 12 and 24 months.
What Is Next on the Horizon of TSC Treatment?
I have been researching TSC for close to 25 years, and the landscape of how we diagnose and treat the disorder has changed completely. mTOR inhibitors have been a large part of that change, but there is still more progress to be made. Moving forward, I would not be surprised if in 10 or 20 years we have next-generation mTOR inhibitors or combinations of mTOR inhibitors that are able to work effectively to provide a permanent response. We may even develop novel treatments that target mechanisms beyond the mTOR pathway. I am particularly optimistic about gene therapies for TSC. There are neurologic disorders that now have genetic treatments, which I never would have expected to be in clinical use when I started out 25 years ago.
