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Research Round Up April 2020

In this issue of Research Round Up we have included three interesting and recent research studies which seek to improve outcomes for children with TSC. TSA whole-heartedly supports this research and we are encouraged by some of the outcomes of these studies. We do however caution that all three of the studies reported on are very small scale studies. Further, larger scale research studies need to be conducted to validate these outcomes.

Developmental outcomes in six children with early diagnosis of tuberous sclerosis complex (TSC)

Seizures in tuberous sclerosis complex (TSC) commonly develop in the first year of life and they are often preceded by changes being evident on electroencephalogram (EEG).  The onset of such seizures is particularly significant as it is thought that they influence developmental development. Although early diagnosis of TSC offers a tremendous opportunity to monitor affected patients before the onset of seizures, studies of TSC in infants before seizure onset are still scarce.

About this study

This study followed six infants in Italy diagnosed with TSC at or within six months of birth who underwent serial video-EEG recordings every four to eight weeks during the first two years of life.  Vigabatrin was prescribed as needed. During the study, psychomotor development, cognitive functioning and behavioral problems were assessed and genetic testing was completed.

What did the study find?

The study found that EEG changes appeared at a mean age of four months.  Four of the six infants developed seizures. Of the four children who developed seizures, two had good seizure control and had normal development, and two had psychomotor delays.  The two children who did not develop seizures had normal development pathways according to the assessments made.

All six of the TSC children in the study had multiple cortical tubers and subependymal nodules (SENs).  Five of the six children had a variant in the TSC2 gene. The study suggests that a mutation in a specific region of the TSC2 gene is associated with an increased risk for more severe epilepsy and developmental delay.  However, this is a study of just six children and more research is needed to confirm this finding.  It does however build on earlier studies that suggest that better seizure control can lead to better neurodevelopment in children with TSC.

For more information on infantile seizures, visit https://tsa.org.au/information/epilepsy/

Savini, M. N., Mingarelli, A., Peron, A., La Briola, F., Cervi, F., Alfano, R. M., Canevini, M. P., & Vignoli, A. (2020). Electro-clinical and neurodevelopmental outcome in six children with early diagnosis of tuberous sclerosis complex and role of the genetic background. Italian journal of pediatrics, 46(1), 36.

Full paper available at: https://doi.org/10.1186/s13052-020-0801-0

Early use of sirolimus gel to diminish and prevent angiofibroma recurrence in TSC children

Angiofibromas (AF) are found in a majority of individuals with TSC over 5 years of age. These small bumps are usually scattered on the face, especially on the nose and cheeks, and sometimes on the forehead, eyelids, and chin.  Topical sirolimus reduces the volume and redness of AF, but the early use of sirolimus is still an area of evolving research.

About this study

This was a small trial of nine children in Japan aged from three and a half to eleven years of age with TSC and AF, who were followed for up to 36 months.  The aim of the trial was to determine if treatment initiation during the early stages of AF development can improve skin condition to near-normal levels.

During the study, the children used sirolimus gel (0.2%) over a six-month period.

Results of the study

There was an improvement in the size and redness of the angiofibromas in all nine patients after six months of treatment.

Three out of five children with fibrous plaques also showed improvements, with a reduction in size occurring after 6-18 months of treatment.  Two children also had hypopigmented macules (white spots) and whilst there were improvements, the goal of nearly normal skin could not be achieved.

The treatment was very well tolerated with no child reporting severe skin reactions. However, one child reported drug acne related to the treatment.

The authors of the paper suggest that early initiation of sirolimus treatment can lead to near-normal skin in the long term, possibly for the life span, in patients with TSC exhibiting AF.

TSA cautions however that whilst the results are promising, this is a small scale study and more research is needed to validate these claims.

For more on treating angiofibromas, see https://tsa.org.au/information/skin/

Okanishi, T., Fujimoto, A., Enoki, H., & Ogai, M. (2020). Early Sirolimus Gel Treatment May Diminish Angiofibromas and Prevent Angiofibroma Recurrence in Children With Tuberous Sclerosis Complex. Frontiers in Medicine, 7, 1.

Full paper available at:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987392/#!po=70.8333

Using mTOR inhibitors to treat renal angiomyolipomas (AMLs) in children with TSC

Kidney health is a serious concern for many people living with TSC. Renal cysts and angiomyolipomas (AMLs) often develop.  These can obliterate healthy renal tissue and cause bleeding as they grow, leading to chronic kidney disease or devastating bleeding complications.

Approximately 50% of children with TSC have a renal AML and the incidence increases with age. This study researches the use of mTOR inhibitor treatments for children with renal AMLs.

The need for this study

The mTOR inhibitors everolimus and sirolimus are now relatively well established in the treatment of renal AMLs in adults with TSC.  Despite this, to date the published research on mTOR inhibitor use in paediatric TSC-AML remains very limited. This study’s objectives were to investigate the behaviour of renal AMLs in children with TSC who were placed on mTOR inhibitor therapy, as well as to describe medication tolerability.

About this study

There were initially nineteen children in this study, eighteen were prescribed everolimus only and one was prescribed everolimus, then sirolimus after a three-year hiatus off the medication.  Seven patients (36%) reported a side effect, though in four of these patients there was only a mild effect, which either resolved or was tolerated. Three patients (16%) stopped the medication due to intolerable side effects. These included recurrent mouth ulcers, gastrointestinal upset, and recurrent upper respiratory tract infection.

Study results

The final study results included just fifteen patients, twelve of whom (80%) had AML at the start of the mTOR inhibitor treatment. The good news is that in all twelve of those patients, the AML remained either unchanged in size (33%) or decreased in size (67%). And, no patient experienced an increase in the size of their AML.

None of the three patients without an AML developed an AML during the treatment.

In this small study, the efficacy and tolerability profile of mTOR inhibitors in treating children with renal AMLs appears similar to the published research on adult patients.  The authors say that everolimus use may be most favourable in children older than age 11 years with the highest risk AMLs and/or with AML ≥2 cm, as this is where the treatment appears to confer the greatest absolute size reduction.

However, the authors also state that more research is needed into potentially detrimental effects of the treatment such as puberty suppression.  And, whilst the results are encouraging, it must be remembered that this was a very small scale study.

For more on the use of mTOR inhibitors to treat renal AMLs see https://tsa.org.au/mtor-inhibitors-in-tsc/

Wu, C. Q., Wolf, D. S., & Smith, E. A. (2020). Fate of Pediatric Renal Angiomyolipoma During mTOR Inhibitor Treatment in Tuberous Sclerosis Complex. Urology. DOI: 10.1016/j.urology.2019.12.041

Full paper available at:  https://www.goldjournal.net/article/S0090-4295(20)30175-8/fulltext