Page 19 - Molecular features of low-grade developmental brain tumours

GENERAL INTRODUCTION & OUTLINE OF THE THESIS
Antiepileptic drugs (AEDs) are available for seizure treatment, with vigabatrin the AED of choice for infantile spasms and/or focal seizures in TSC 151-153. Treatment with vigabatrin prior to seizure development improves long-term epilepsy and neurodevelopment outcomes. Other AEDs such as, ACTH (natural or synthetic), prednisolone or GABAergic AEDs other than vigabatrin such as topiramate, carbamazepine and oxcarbazepine can be used as second line therapy 154-157.
Surgery can be an appropriate treatment option in TSC-associated epilepsy that is
inadequately controlled after trials of two AEDs, provided that the lesions are well-defined 151.
Cortical tubers are thought to represent the neuropathological substrate for epilepsy in TSC
patients and are targeted for surgical resection. Epilepsy surgery where the epileptogenic
focus is easily recognizable can improve the quality of life and IQ, especially in postoperative
patients who remained seizure-free. Although epilepsy surgery often results in freedom
from seizures, increasing evidence supports the importance of the perituberal cortex in TSC 158-165.
Currently, surgical resection is the treatment of choice for symptomatic SEGA (i.e. tumour growth, hydrocephalus, hemorrhage or cystization, and clinical deterioration) 124,125,166-174. Complete and safe removal of the tumour is curative in almost all cases, whereas subtotal removal increases the risk of recurrence 124,175. Tumour size correlates negatively with the probability of total resection 124,174. Therefore, it seems reasonable to resect the tumour as early as possible when no other risk factors are at play. When the probability of total resection seems low or when other potential complications with surgery are foreseen treatment with mTOR inhibitors is preferred. Moreover, treatment with mTOR inhibitors can reduce tumour size to improve the success rate of surgical resection or can even prevent the need for surgery altogether 176,177.
The first report of mTOR inhibitors as a TSC treatment occurred in 2006, where patients with SEGA treated with sirolimus demonstrated on average a 55% reduction in tumour volume, which is supported by other independent studies 61,178-180. However, to date the only mTOR inhibitor that is Food and Drug Administration (FDA) approved is everolimus. The EXIST-1 study showed that everolimus can reduce volume size of SEGA with at least a 50% reduction in 35% of the patients 181. The follow up open-label studies from EXIST-1 showed that this amount increased further to 58% of patients with a tumour reduction of more than 50%, indicating that even after 2.5 years patients can still benefit from treatment with everolimus 182,183. In accordance, a 5 year study showed that the majority of patients could maintain the tumour reduction that was achieved in the first 6 months 184. In a small cohort of congenital SEGA a good response was also seen 185,186. In addition to treatment of SEGA, mTOR inhibitors may have additional benefit for treatment of other TSC related manifestations, including seizure control, cognitive development, and volume reduction of other TSC tumours 187.
Although mTOR inhibitors have been shown to be effective in patients with TSC, the response to mTOR inhibitors can be variable and cessation of treatment may result in tumour regrowth 61,182,188-191. Furthermore, treatment with mTOR inhibitors can produce
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