TSC Research Round Up is a new enewsletter from TSA in which we present summary reports of some of the latest TSC-related research from Australia and around the world that we believe may be of relevance and importance to our TSC community. Citations to the full research articles/papers are included for those who would like to know more.
mTOR inhibitor treatment in TSC children under 2 years of age
The aim of this study was to assess the efficacy and safety of treatment of an mTOR inhibitor in children under 2 years of age. Seventeen children who received early treatment with an mTOR inhibitor were included.
The children had a range of TSC-related symptoms including cardiac rhabdomyomas; SEGAs, refractory epilepsy and one case of disabling congenital lymphoedema.
All the children in the study were prescribed everolimus, which was tolerated well with only mild side effects including an increase in cholesterol and mild transient stomatitis (mouth ulcers).
14 of the 17 children – over 80% – experienced an improvement in symptoms such as a decrease in cardiac rhabdomyoma or SEGA size and regression of lymphoedema. Of the 3 children who did not improve, 2 had no improvement in seizures, and another had no change in their SEGA size.
Why is this study important?
There is only very limited information on the safety and efficacy of mTOR treatments in children in the first 2 years of life. TSC-related early onset epilepsy and infantile spasms in the first year of life are important risk factors for mental impairment and autism spectrum disorder, and it is thought that early initiation of treatment with mTOR inhibitors may reduce the risk of neuropsychiatric deficits.
What does this study tell us?
Treatment with mTOR inhibitors in children aged under the age of 2 appears to be safe and effective. However, this is a small study, and the authors say that due to the size (only 17 children), they cannot draw solid conclusions about the potential benefits of early intervention with everolimus in regards to neurodevelopmental outcomes. This study does however provide a template for more studies to evaluate the benefits of early intervention with everolimus in young children with TSC.
For more information on mTOR inhibitors see https://tsa.org.au/mtor-inhibitors-in-tsc/
Saffari et al, Orphanet J Rare Dis. 2019 May 3;14(1):96. doi: 10.1186/s13023-019-1077-6.
Using the TAND checklist
While most paediatricians and child neurologists have become good at identifying and treating the physical manifestations of TSC, it remains difficult to identify and treat the neuropsychiatric issues commonly associated with TSC.
Why the TAND checklist was developed
In 2012, the Neuropsychiatry Panel of the International TSC Consensus Conference, coined the term ‘TAND’ (tuberous sclerosis complex-associated neuropsychiatric disorders) as an umbrella term for the wide range of behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial symptoms seen in TSC. The TAND checklist was developed to be used as a simple guide for a conversation between clinical teams and families to identify areas that need more comprehensive follow up.
But the issue remains – how best to use it?
A typical TAND checklist conversation takes between 10-15 minutes (it may be shorter if no concerns are identified) and allows for areas of prioritisation to be identified. In busy clinical settings families may be asked to fill in the checklist while waiting. Whilst this may seem to be a pragmatic use of the checklist, it is important to note that it has not been evaluated as a self-report tool. The primary purpose of the TAND checklist is to get doctors and families to talk to each other, identify issues and prioritise what to do next.
For more information on the TAND checklist, visit https://tsa.org.au/information/tand/
Everolimus and uncontrolled epilepsy associated with TSC: current perspectives
Up to 90% of patients with TSC have epilepsy and in over half of those, seizure control cannot be achieved by regular antiepileptic drugs. This is commonly known as uncontrolled, refractory, intractable, or drug-resistant epilepsy.
Everolimus and sirolimus are both mTOR-inhibiting drugs that have been shown to be effective in the treatment of TSC-related renal angiomyolipoma and subependymal giant cell astrocytoma (SEGA) in clinical trials. Trials such as EXIST-3 have changed treatment pathways in TSC-related epilepsy. The EXIST-3 trial involved 366 patients treated with everolimus and showed a 50% seizure reduction response rate, compared to a 15% response rate in those treated with a placebo.
This article asks questions around the use of evorolimus in uncontrolled epilepsy associated with TSC.
Does everolimus suppress seizures or prevent epilepsy and what does this mean for the optimal treatment timing?
This is an area of evolving research and currently there is no conclusive evidence. There is the suggestion that there may be a treatment window after birth that may influence brain development, and that treatment with everolimus may inhibit the development of epilepsy. But there is more work to be done in early intervention trials to ensure that this treatment is safe and effective in the very young, and there are questions around how long the treatment should continue, as the long-term side effects on growth and immunity in young children are largely unknown.
Can everolimus prevent intellectual disability and autism in TSC?
The age of onset of seizures and the response to treatment are the most important predictors of cognitive development in children with TSC. Treatment with vigabatrin soon after seizure onset in infants results in lower risks of autism and intellectual disability. Treatment with vigabatrin before the onset of seizures may be beneficial, and the EPISTOP and PREVENT trials are looking to answer these questions. Epilepsy is in an important driver of intellectual disability and autism in children with TSC, but at this point is it uncertain whether treatment with an mTOR inhibitor before the onset of seizures could prevent the development of epilepsy. More research is needed.
Summary
While mTOR inhibitors can be of great benefit to those with TSC in reducing tumour growth and in treating uncontrolled epilepsy, in the EXIST-3 trial at least half of TSC patients with uncontrolled epilepsy did not experience seizure frequency reduction. Further studies are needed into everolimus to determine the optimal timing, dose and effects of combination with other drugs.
For more information on mTOR inhibitors see https://tsa.org.au/mtor-inhibitors-in-tsc/
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.
FURTHER INFORMATION
Citations (and links where possible) to the full research articles/papers are included for those who would like to know more. TSA’s nurse service is also available and offers a free, confidential information and support service which provides TSC information and links to practical support. You can contact Kim, the TSA nurse, by phoning 1300 733 435, emailing [email protected] or visiting https://tsa.org.au/tsa-nurse/