The Efficacy and Safety of Rapamycin in Children with Tuberous Sclerosis: A Cross-sectional Study Efficacy of Rapamycin in treatment of Tuberous Sclerosis
Iranian Journal of Child Neurology,
Vol. 17 No. 2 (2023),
16 March 2023
,
Page 19-29
https://doi.org/10.22037/ijcn.v17i2.36243
Abstract
Objectives
Mutations in TSC1 or TSC2 genes have been proposed as the main causative factors responsible for developingTuberous Sclerosis Complex (TSC). Given the effect of these two genes on the mTOR pathway,rapamycin hasemerged as a novel therapeutic agent.The present study evaluated the effectiveness and safety of rapamycin on the multiple manifestations of TSC.
Materials & Methods
Twenty-three eligible children were enrolled in the present crosssectional study. They were prescribed rapamycin1mg tablet twice daily for the first two weeks of treatment and then once daily for at least one year.Periodicevaluations through follow-up visits were performed Besides, growth and developmental statuses wereevaluated. All data, including the number and size of brain tuberomas, size of renal angiomyolipomas, and skinlesions, were gathered and recorded, and then analyzed.
Results
During the study period, the mean number of epileptic episodes significantly reduced (p<0.0001), and nine cases were seizure-free at the final visit. The mean number of brain tuberomas decreased from 19.3±11.0 at the initial visit to 11.1±5.6 and 8.2±3.2 in the subsequent visits (p<0.001). The mean size of brain tuberomas similarly decreased from 17.9±18.5 cm at enrollment to 13.7±5.1 cm and 6.9±5.1 cm in the second and third visits, respectively (p=0.029). The mean size of renal angiomyolipomas significantly decreased (p<0.001). A significant trend toward a decrease in the number of skin lesions was observed (p<0.0001). No relationship was observed between the effects of rapamycin and the patient’s age or sex (p>0.05). Changes in patients’ growth and developmental features were not statistically significant through subsequent visits (p=0.507).
Conclusion
This study revealed the effectiveness and safety of rapamycin on TSC among our patients
- Rapamycin, Tuberous Sclerosis, Efficacy, Safety
How to Cite
References
Budde K, Gaedeke J. Tuberous sclerosis complex-associated angiomyolipomas: focus onmTOR inhibition. Am JKidney Dis 2012; 59: 276–283
Bissler, J. J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2.Nephrology Dialysis Transplantation 2019; 34(6): 1000-1008.
Bissler, J. J. and J. C. Kingswood. Optimal treatment of tuberous sclerosis complex associated renal angiomyolipomata: a systematic review. Therapeutic Advances in Urology 2016;8(4): 279-290.
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372: 657–668
European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75:1305-1315.
van Slegtenhorst M, deHoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805-808.
Sadowski K, Kotulska K, Schwartz RA, Jóźwiak S. Systemic effects of treatment with mTOR inhibitors in tuberous sclerosis complex: a comprehensive review. Journal of the European Academy of Dermatology and Venereology 2016 Apr;30(4):586-94.
Samueli S, Abraham K, Dressler A, Gröppel G, Mühlebner-Fahrngruber A, Scholl T, Kasprian G, Laccone F, Feucht M. Efficacy and safety of Everolimus in children with TSC-associated epilepsy–Pilot data from an open single-center prospective study. Orphanet journal of rare diseases 2016 Dec;11(1):1-8.
Palavra F, Robalo C, Reis F. Recent advances and challenges of mTOR inhibitors use in the treatment of patients with tuberous sclerosis complex. Oxidative medicine and cellular longevity 2017 Oct;2017.
Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrology Dialysis Transplantation 2019 Jun 1;34(6):1000-8.
Zou L, Liu Y, Pang L, Ju J, Shi Z, Zhang J, Chen X, Su X, Hu L, Shi X, Yang X. Efficacy and safety of rapamycin in treatment of children with epilepsy complicated with tuberous sclerosis. Zhonghua er ke za zhi= Chinese Journal of Pediatrics2014 Nov 1;52(11):812-6.)
Canpolat M, Per H, Gumus H, Yikilmaz A, Unal E, Patiroglu T, Cinar L, et al. Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86. Child's Nervous System 2014 Feb;30(2):227-40.
Northrup H, Krueger DA, Roberds S, Smith K, Sampson J, Korf B, Kwiatkowski DJ, Mowat D, Nellist M, Povey S, de Vries P. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatric neurology 2013 Oct 1;49(4):243-54.
Wang DD, Chen X, Xu H, Li ZP. Initial dosage recommendation for sirolimus in children with tuberous sclerosis complex. Frontiers in Pharmacology 2020 Jun 11;11:890.
Sheldrick RC, Schlichting LE, Berger B, Clyne
A, Ni P, Perrin EC, Vivier PM. Establishing new
norms for developmental milestones. Pediatrics.
Dec 1;144(6).
Franz DN, Belousova E, Sparagana S., et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013; 381: 125–132.
Napolioni V, Moavero R, Curatolo P. Recent advances in neurobiology of tuberous sclerosis complex. Brain Dev 2009;31: 104–113.
Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: from tuberous sclerosis to common acquired epilepsies. Epilepsia 2010;51:27–36.
Krueger DA, Wilfong AA, Holland‐Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Annals of neurology 2013 Nov;74(5):679-87.
Krueger D, Care M, Holland-Bouley K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801–1811.
Jozwiak S, Nabbout R, Curatolo P. Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol 2013; 17: 348– 352.
Rosado C, Garcıa-Cosmes P, Fraile P, Vazquez-Sanchez F. Tuberous sclerosis associated with polycystic kidney disease: effects of rapamycin after renal transplantation. Case Rep Transplant 2013 Jan 17;2013.
Kim HS, Kim ST, Kang SH, et al. The use of everolimus to target carcinogenic pathways in a patient with renal cell carcinoma and tuberous sclerosis complex: a case report. J Med Case Rep 2014; 8: 95.
Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991; 66: 792–796.
Wienecke R, Fackler I, Linsenmaier U, Mayer K, Licht T, Kretzler M. Antitumoral activity of rapamycin in renal angiomyolipoma associated with tuberous sclerosis complex. Am J Kidney Dis 2006; 48: e27–e29.
Bissler J, McCormack F. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. NEngl J Med 2008; 358: 140–151.
Krueger D, Northrup H. International Tuberous Sclerosis Complex Consensus GroupTuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49: 255–265.
Haemel AK, O’Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 2010; 146: 715–718.
Mutizwa MM, Berk DR, Anadkat MJ. Treatment of facial angiofibromas with topical application of oral rapamycin solution (1 mgmL(-1)) in two patients with tuberous sclerosis. Br J Dermatol 2011; 165: 922–923.
Salido R, Garnacho-Saucedo G, Cuevas-Asencio I et al. Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis - associated facial angiofibroma. J Eur Acad Dermatol Venereol 2012; 26: 1315–1318.
Moavero R, Coniglio A, Garaci F, Curatolo P. Is mTOR inhibition a systemic treatment of tuberous sclerosis? Ital.J.Pediatr 2013; 39:57.
Beghetti M, Gow RM, Haney I, Mawson J, Williams WG, Freedom RM. Pediatric primary benign cardiac tumors: A 15-year review. Am. Heart J 1997; 134: 1107–14.
Saffari A, Brösse I, Wiemer-Kruel A, Wilken B, Kreuzaler P, Hahn A, Bernhard MK, Van Tilburg CM, Hoffmann GF, Gorenflo M, Hethey S. Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age–a multicenter retrospective study. Orphanet journal of rare diseases 2019 Dec;14(1):1-3.
Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, et al. Adjunctive everolimus for children and adolescents with treatmentrefractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. The Lancet Child & adolescent health 2018;2(7):495-504.
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