Updated clinical recommendations for the management of TSC-associated epilepsy
This paper reviewed the latest research on epilepsy associated with TSC (Tuberous Sclerosis Complex) and provided updated guidelines for its management.
About this review
Children living with TSC often experience various seizure types, particularly focal seizures, and infantile spasms in their first year of life. Many show early drug resistance, posing a significant challenge for clinicians managing TSC-associated epilepsy. In 2018, European experts published clinical recommendations for TSC-associated epilepsy management. Over the past few years, progress has been made in understanding the underlying biological processes leading to the development of epilepsy, influencing changes in how treatment is approached and managed.
How the review was conducted
In November 2022, a group of experts gathered in Rome to review recent findings and discuss various aspects related to TSC and epilepsy. Each expert focused on a specific topic, genetic biomarkers and the potential advantages of treatments. The group also explored emerging treatment options like cannabidiol (CBD) and criteria for pre-surgical evaluation. This paper presents the key discussions and provides updated clinical recommendations for managing TSC-associated epilepsy, considering new insights and changes since the 2018 clinical recommendations.
Insights from the review
Understanding the mTOR pathway in TSC-associated epilepsy and neurodevelopmental disorders: The mTOR pathway controls essential functions like energy use, protein production, and cell growth, influencing the development of the human brain. Dysregulation of this pathway is common in conditions characterised by abnormal brain structure, including epilepsy and other developmental disorders.
In TSC, epilepsy is often associated with cortical tubers, which pose challenges for early detection using brain imaging techniques. However, advancements in imaging technology are enhancing our ability to identify these tubers.
Recent insights from a range of genetic models, both in the lab and in humans, as well as from studying brain tissue, reveal that the process relating to epilepsy in TSC is ongoing and complex, leading to early and difficult-to-treat seizures, along with other neurodevelopmental disorders and issues with the mTOR pathway. Researchers are exploring additional pathways that could be connected to the mTOR pathway as potential targets for treating seizures in TSC, including pathways involved in inflammation. Combining these targeted approaches may enhance the effectiveness of mTOR inhibitor treatments for seizures in individuals with TSC, however more research is needed.
The connection between epilepsy and autism is complex, with TSC being a significant genetic cause of Autism Spectrum Disorder (ASD). Certain factors in TSC, such as infantile spasms, contribute to ASD risk. Disruptions in specific brain processes also play a role in both epilepsy and autism. While epilepsy is often noticed early in life, signs of ASD may not become apparent until later. Recent evidence suggests that autism risk can be detected in the first year of life, emphasizing the need to consider both epilepsy and ASD as interconnected aspects of TSC.
Predicting and managing drug-resistant epilepsy: Managing epilepsy in TSC is challenging, with a high risk of drug-resistant epilepsy (DRE). Predicting DRE is complex; TSC2 gene mutations, tuber characteristics, and treatment-resistant spasms have been identified as predictors of DRE. Early identification of disease-causing genetic changes, coupled with EEG and MRI markers, allows for pre-symptomatic interventions and pre-symptomatic treatment with vigabatrin which may delay seizures and reduce DRE risk. This approach, now an established practice in several European countries, appears to have good safety and a positive effect on seizure outcomes. ASD symptoms may appear regardless of the chosen treatment approach, but early intervention and consistent monitoring are essential for better neurodevelopmental outcomes, particularly in ASD.
Pre-symptomatic treatment: Pre-symptomatic treatment with vigabatrin for infants living with TSC has proven effective in reducing infantile spasms. This was validated by the EPISTOP trial.
Research into the effect of early treatment on developmental outcomes continues.
Ongoing research into mTOR inhibitors like sirolimus and everolimus shows promise in managing TSC-associated epilepsy. Everolimus, especially in younger age groups, demonstrates effectiveness as an additional treatment, as seen in the EXIST-3 trial. However, uncertainties persist regarding the optimal timing for mTOR inhibition, its foetal effects, and potential mTOR inhibitor combinations. The focus is on providing effective treatment while minimising side effects, particularly for symptoms like subependymal giant cell astrocytoma (SEGA) or angiomyolipoma (AML) alongside DRE. Ongoing research seeks to establish greater clarity on the efficacy and safety of combination therapies.
Epilepsy Surgery: In 2017, the panel suggested that surgery could be a helpful option for treating epilepsy in people living with TSC. Recent evidence supports this recommendation, showing that surgery can lead to freedom from seizures in about 50-60% of patients living with TSC, and another 15% of patients experience a reduction of more than 50% in their seizures, even if they have multiple tubers. A recent study of 364 patients who underwent surgery reported that 51% remained seizure-free at 10 years. However, other studies have shown that the number of seizure-free patients decreases over time with longer follow-up periods. While surgery can also lead to developmental progress, it may not substantially improve standard developmental outcomes. Further research is needed to understand why some surgeries fail and how to predict success.
In this current review, the authors suggest that surgery is underused in TSC. It has traditionally been considered only for definite cases of epilepsy arising from one location in the brain, but the majority of patients living with TSC have abnormalities in multiple brain areas. Patient satisfaction with surgery, even if complete seizure freedom is not achieved, is generally high. Laser ablation, a newer technique, shows promise but requires more research before becoming a widely recommended option.
Other treatment options: Recent studies have shown that both the ketogenic diet and vagus nerve stimulation (VNS) can help reduce seizures in people with epilepsy that doesn’t respond well to medication and who are not candidates for surgery. Limited data shows that VNS can lead to a reduction in seizures for many patients, but it is rare to experience complete seizure freedom. The ketogenic diet is more effective in infants and young children than adults.
In a study involving 224 patients with TSC-associated seizures, cannabidiol (CBD) was found to reduce seizure frequency compared to a placebo. Common side effects included diarrhoea, sleepiness, and elevated liver enzymes, which were more common at higher doses. CBD can also affect the levels of mTOR inhibitors in the body, so if taken together, the mTOR inhibitor dosage should be reduced and monitored regularly.
Ganaxolone, an antiseizure medication, was recently approved in the USA for treating seizures in certain conditions and is being studied for use in TSC-associated seizures.
Metformin, a drug commonly used for diabetes, has shown promise in reducing seizures in a small study, but more research is needed to confirm its effectiveness.
Overall, while these treatments show potential, more research is needed to fully understand their benefits and risks before they can be widely recommended.
Conclusions of the review
The authors highlight the ongoing challenges of managing TSC-associated epilepsy but also point to promising recent advances in therapy. They emphasise that a better understanding of how epilepsy develops and the early identification of risk factors are key to improving treatment outcomes. Based on their review of current research, the authors suggest that pre-symptomatic interventions, mTOR inhibition, cannabidiol, and epilepsy surgery could be effective approaches to manage TSC.
The authors advocate for early genetic testing and the use of EEG and MRI biomarkers to improve patient outcomes. They note that progress in identifying risk factors, assessing symptoms before they appear, and using targeted therapy has significantly improved the management of TSC-related epilepsy. They stress the importance of early intervention and monitoring a patient’s development. The authors also mention the ongoing efforts to develop a scoring method that can predict epilepsy risk and guide treatment decisions. Despite these advancements, they acknowledge that finding a personalised treatment approach for TSC-associated epilepsy remains a challenge.
Implications of the review
The authors suggest that managing epilepsy in people living with TSC requires a comprehensive and varied approach. They recommend doctors consider treating patients before epilepsy symptoms appear and consider epilepsy surgery and mTOR inhibition as treatment options. They also stress the importance of identifying high-risk patients early, understanding what factors increase risk, and using insights from brain science to develop specific treatments.
Specchio, N., Nabbout, R., Aronica, E., Auvin, S., Benvenuto, A., de Palma, L., Feucht, M., Jansen, F., Kotulska, K., Sarnat, H., Lagae, L., Jozwiak, S., & Curatolo, P. (2023). Updated clinical recommendations for the management of tuberous sclerosis complex associated epilepsy. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 47, 25–34.
Full paper available at: https://doi.org/10.1016/j.ejpn.2023.08.005
DISCLAIMER
This information is intended to provide some insights into recent TSC-related research. It is not intended to, and it should not, constitute medical or other advice. Readers are warned not to take any action without first seeking medical advice.