Everolimus as a therapeutic option in refractory epilepsy in children with tuberous sclerosis: a systematic review

 

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Abstract

Background Tuberous sclerosis (TS) is a multisystem genetic disease in which epilepsy is a frequent manifestation and is often difficult to control. Everolimus is a drug with proven efficacy in the treatment of other conditions related to TS, and some evidence suggests that its use benefits the treatment of refractory epilepsy in these patients.

Objective To evaluate the efficacy of everolimus in controlling refractory epilepsy in children with TS.

Methods A literature review was conducted in the Pubmed, BVS, and Medline databases, using the descriptors Tuberous sclerosis, Children, Epilepsy, and Everolimus. Original clinical trials and prospective studies published in Portuguese or English in the last decade that evaluated the use of everolimus as an adjuvant therapy in the control of refractory epilepsy in pediatric patients with TS were included.

Results Our search screened 246 articles from electronic databases, 6 of which were chosen for review. Despite the methodological variations between the studies, most patients benefited from the use of everolimus to control refractory epilepsy, with response rates ranging from 28.6 to 100%. Adverse effects were present in all studies leading to dropouts of some patients; however, the majority were of low severity.

Conclusion The selected studies suggest a beneficial effect of everolimus in the treatment of refractory epilepsy in children with TS, despite the adverse effects observed. Further studies involving a larger sample in double-blind controlled clinical trials should be performed to provide more information and statistical credibility.

Resumo

Antecedentes A esclerose tuberosa (ET) é uma doença genética multissistêmica na qual a epilepsia é a manifestação neurológica mais frequente, sendo muitas vezes de difícil controle. O everolimo é uma droga com eficácia comprovada no tratamento de outras condições relacionadas à ET, e indícios sugerem benefícios de seu uso também no controle da epilepsia refratária nesses pacientes.

Objetivo Avaliar a eficácia do everolimo no controle da epilepsia refratária em crianças com ET.

Métodos Revisão de literatura nas bases de dados Pubmed, BVS e Medline, utilizando os descritores Tuberous sclerosis, Children, Epilepsy e Everolimus. Incluíram-se ensaios clínicos originais e estudos prospectivos publicados em português ou inglês na última década e que avaliassem o uso do everolimo como terapia adjuvante no controle da epilepsia refratária em pacientes pediátricos com ET.

Resultados Nossa busca rastreou 246 artigos nas bases de dados, dos quais 6 foram escolhidos para a revisão. Apesar das variações metodológicas entre os estudos, a maioria dos pacientes tiveram benefício no uso do everolimo para controle da epilepsia refratária, com taxas de resposta variando entre 28.6 e 100%. Os efeitos adversos estiveram presentes em todos os estudos, levando à desistência de alguns pacientes, contudo a maioria foi de baixa gravidade.

Conclusão Os estudos selecionados sugerem efeito benéfico do everolimo no tratamento da epilepsia refratária em crianças com ET, apesar dos efeitos adversos observados. Novos estudos envolvendo uma amostra maior em ensaios clínicos controlados duplo-cegos devem ser realizados para fornecer mais informações e credibilidade estatística.

Authors' Contributions

All the authors contributed equally to the development, elaboration, and writing of this work. All authors reviewed and approved the final version of the manuscript before submission.

Publication History

Received: 16 May 2022

Accepted: 25 July 2022

Article published online:
02 March 2023

© 2023. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

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• References

• 1 Portocarrero LKL, Quental KN, Samorano LP, Oliveira ZNP, Rivitti-Machado MCDM. Tuberous sclerosis complex: review based on new diagnostic criteria. An Bras Dermatol 2018; 93 (03) 323-331 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0365-05962018000300323&lng=en&tlng=en
  CrossrefPubMedGoogle Scholar
• 2 Curatolo P, Bombardieri R. Tuberous sclerosis. Handb Clin Neurol 2008; 87: 129-151
  CrossrefPubMedGoogle Scholar
• 3 Curatolo P, Moavero R. mTOR Inhibitors in Tuberous Sclerosis Complex. Curr Neuropharmacol 2012; 10 (04) 404-415
  CrossrefPubMedGoogle Scholar
• 4 Uysal SP, Şahin M. Tuberous sclerosis: a review of the past, present, and future. Turk J Med Sci 2020; 50 (SI-2): 1665-1676
  CrossrefPubMedGoogle Scholar
• 5 Overwater IE, Rietman AB, van Eeghen AM, de Wit MCY. Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives. Ther Clin Risk Manag 2019; 15: 951-955 https://www.dovepress.com/everolimus-for-the-treatment-of-refractory-seizures-associated-with-tu-peer-reviewed-fulltext-article-TCRM
  CrossrefPubMedGoogle Scholar
• 6 Curatolo P, Nabbout R, Lagae L. et al. Management of epilepsy associated with tuberous sclerosis complex: Updated clinical recommendations. Eur J Paediatr Neurol 2018; 22 (05) 738-748 http://www.ejpn-journal.com/article/S1090379817320573/fulltext
  CrossrefPubMedGoogle Scholar
• 7 Salussolia CL, Klonowska K, Kwiatkowski DJ, Sahin M. Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex. Annu Rev Genomics Hum Genet 2019; 20: 217-240 https://pubmed.ncbi.nlm.nih.gov/31018109/
  CrossrefPubMedGoogle Scholar
• 8 Kossoff EH, Thiele EA, Pfeifer HH, McGrogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005; 46 (10) 1684-1686 https://onlinelibrary.wiley.com/doi/full/10.1111/j.1528-1167.2005.00266.x
  CrossrefPubMedGoogle Scholar
• 9 Kwan P, Arzimanoglou A, Berg AT. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010; 51 (06) 1069-1077 https://pubmed.ncbi.nlm.nih.gov/19889013/
  CrossrefPubMedGoogle Scholar
• 10 Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51 (07) 1236-1241 https://pubmed.ncbi.nlm.nih.gov/20041940/
  CrossrefPubMedGoogle Scholar
• 11 Rosset C, Netto CBO, Ashton-Prolla P. TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review. Genet Mol Biol 2017; 40 (01) 69-79 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572017000100069&lng=en&tlng=en
  CrossrefPubMedGoogle Scholar
• 12 Wiegand G, May TW, Ostertag P, Boor R, Stephani U, Franz DN. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option?. Eur J Paediatr Neurol 2013; 17 (06) 631-638 https://pubmed.ncbi.nlm.nih.gov/23845174/
  CrossrefPubMedGoogle Scholar
• 13 Krueger DA, Wilfong AA, Mays M. et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology 2016; 87 (23) 2408-2415 https://pubmed.ncbi.nlm.nih.gov/27815402/
  CrossrefPubMedGoogle Scholar
• 14 Samueli S, Dressler A, Gröppel G, Scholl T, Feucht M. Everolimus in infants with tuberous sclerosis complex-related West syndrome: First results from a single-center prospective observational study. Epilepsia 2018; 59 (09) e142-e146 https://pubmed.ncbi.nlm.nih.gov/30098008/
  CrossrefPubMedGoogle Scholar
• 15 Svarrer EMM, Fischer CM, Frederiksen MG, Born AP, Hoei-Hansen CE. Everolimus as adjunctive treatment in tuberous sclerosis complex-associated epilepsy in children. Dan Med J 2019; 66 (12) A5582 https://ugeskriftet.dk/files/scientific_article_files/2019-11/a5582_1.pdf
  PubMedGoogle Scholar
• 16 Curatolo P, Franz DN, Lawson JA. et al. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Health 2018; 2 (07) 495-504 http://www.ncbi.nlm.nih.gov/pubmed/30169322
  CrossrefPubMedGoogle Scholar
• 17 Kotulska K, Chmielewski D, Borkowska J. et al. Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neurol 2013; 17 (05) 479-485 https://pubmed.ncbi.nlm.nih.gov/23567018/
  CrossrefPubMedGoogle Scholar
• 18 French JA, Lawson JA, Yapici Z. et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016; 388 (10056): 2153-2163 http://www.ncbi.nlm.nih.gov/pubmed/27613521
  CrossrefPubMedGoogle Scholar
• 19 Shepherd CW, Stephenson JBP. Seizures and intellectual disability associated with tuberous sclerosis complex in the west of Scotland. Dev Med Child Neurol 1992; 34 (09) 766-774 https://pubmed.ncbi.nlm.nih.gov/1526347/
  CrossrefPubMedGoogle Scholar
• 20 Webb DW, Fryer AE, Osborne JP. Morbidity associated with tuberous sclerosis: a population study. Dev Med Child Neurol 1996; 38 (02) 146-155 https://pubmed.ncbi.nlm.nih.gov/8603782/
  CrossrefPubMedGoogle Scholar
• 21 Thiele EA. Managing epilepsy in tuberous sclerosis complex. J Child Neurol 2004; 19 (09) 680-686 https://pubmed.ncbi.nlm.nih.gov/15563014/
  CrossrefPubMedGoogle Scholar
• 22 Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991; 66 (08) 792-796 https://pubmed.ncbi.nlm.nih.gov/1861550/
  CrossrefPubMedGoogle Scholar
• 23 Lux AL, Osborne JP. A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group. Epilepsia 2004; 45 (11) 1416-1428 https://pubmed.ncbi.nlm.nih.gov/15509243/
  CrossrefPubMedGoogle Scholar
• 24 Curatolo P, Seri S, Verdecchia M, Bombardieri R. Infantile spasms in tuberous sclerosis complex. Brain Dev 2001; 23 (07) 502-507 https://pubmed.ncbi.nlm.nih.gov/11701245/
  CrossrefPubMedGoogle Scholar
• 25 Capal JK, Bernardino-Cuesta B, Horn PS. et al; TACERN Study Group. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav 2017; 70 (Pt A): 245-252
  CrossrefPubMedGoogle Scholar
• 26 Hasskarl J. Everolimus. Recent Results Cancer Res 2018; 211: 101-123 https://pubmed.ncbi.nlm.nih.gov/30069763/
  CrossrefPubMedGoogle Scholar
• 27 Arena C, Troiano G, Zhurakivska K, Nocini R, Lo Muzio L. Stomatitis And Everolimus: A Review Of Current Literature On 8,201 Patients. OncoTargets Ther 2019; 12: 9669-9683 https://pubmed.ncbi.nlm.nih.gov/31814732/
  CrossrefPubMedGoogle Scholar
• 28 Davies M, Saxena A, Kingswood JC. Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide. Orphanet J Rare Dis 2017; 12 (01) 35
  CrossrefPubMedGoogle Scholar