Experience using mTOR inhibitors for subependymal giant cell astrocytoma in tuberous sclerosis complex at a single facility

Abstract

Background Subependymal giant cell astrocytoma (SEGA) is occasionally seen in tuberous sclerosis complex (TSC). Two main options are currently available for treating SEGA: surgical resection or pharmacotherapy using mammalian target of rapamycin inhibitors (mTORi). We hypothesized that opportunities for surgical resection of SEGA would have reduced with the advent of mTORi. Methods We retrospectively reviewed the charts of patients treated between August 1979 and July 2020, divided into a pre-mTORi era group (Pre-group) of patients treated before November 2012, and a post-mTORi era group (Post-group) comprising patients treated from November 2012, when mTORi became available in Japan for SEGA. We compared groups in terms of treatment with surgery or mTORi. We also reviewed SEGA size, rate of acute hydrocephalus, recurrence of SEGA, malignant transformation and adverse effects of mTORi. Results In total, 120 patients with TSC visited our facility, including 24 patients with SEGA. Surgical resection was significantly more frequent in the Pre-group (6 of 7 patients, 86 %) than in the Post-group (2 of 17 patients, 12 %; p = 0.001). Acute hydrocephalus was seen in 1 patient (4 %), and no patients showed malignant transformation of SEGA. The group treated using mTORi showed significantly smaller SEGA compared with the group treated under a wait-and-see policy (p = 0.012). Adverse effects of pharmacotherapy were identified in seven (64 %; 6 oral ulcers, 1 irregular menstruation) of the 11 patients receiving mTORi. Conclusions The Post-group underwent surgery significantly less often than the Pre-group. Since the treatment option to use mTORi in the treatment of SEGA in TSC became available, opportunities for surgical resection have decreased in our facility.

Complex Factors in Hydrocephalus Development in Tuberous Sclerosis Complex: A Case Report of Subependymal Giant Cell Astrocytoma

“…In our case, the intraoperative level of CSF protein was as high as 123 mg/dL, which is consistent with findings from studies on hydrocephalus associated with other benign tumors. Although the nature of the tumors differs between vestibular schwannoma and SEGA, the similarity in elevated CSF protein levels suggests that the underlying mechanism of hydrocephalus may involve impaired CSF circulation or increased osmotic pressure within the ventricles, rather than just physical obstruction [ 2 , 17 ]. This case report supports the hypothesis that factors other than tumor size contribute to hydrocephalus in patients with SEGA and TSC.…”

“…Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) occurs in 5-20% of TSC patients [ 1 ]. Approximately 4-14% of these cases present with hydrocephalus, and ventricular dilatations are seen in 85% [ 2 , 3 ]. Studies have indicated that the mechanism by which SEGA causes hydrocephalus involves enlargement of the SEGA leading to blockage of the foramen of Monro and the subsequent development of hydrocephalus [ 3 - 5 ].…”

Effect of mTOR Inhibitors in Epilepsy Treatment in Children with Tuberous Sclerosis Complex Under 2 Years of Age

“…mTOR inhibitors were recently approved in the EU, USA, and Japan [8]. Besides focal-onset seizures, everolimus is currently approved for treating SEGA and LAM and used as an off-label treatment for CR reduction [9][10][11][12][13]. Sirolimus is approved only as LAM therapy in patients with TSC, while its impact on seizure frequency is not yet determined.…”

The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation

“…New rapamycin analogs (Rapalogs) have been developed for TSC patients and other diseases with mTORC1 hyperactivation. Everolimus, the hydroxyethyl ester of rapamycin, was successful in shrinking SEGAs [11,12]. Long-term Everolimus treatment efficiently reduced SEGAs and prevented new SEGAs formation [13].…”