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01-10-2020 | Tuberous Sclerosis | Annual issue paper

Medical treatment of tuberous sclerosis-related epilepsy

Authors: Shimrit Uliel-Sibony, Veronika Chernuha, Hadas Meirson, Aviva Fattal-Valevski

Published in: Child's Nervous System | Issue 10/2020

Abstract

Epilepsy is one of the most frequent CNS manifestations of tuberous sclerosis, and for most patients, it is the major debilitating factor. In up to 70% of the cases, the epilepsy is refractory and usually associated with significant behavioral as well as developmental consequences. Therefore, controlling seizures is one of the biggest medical and surgical challenges. Understanding the cellular mechanism involved in the disease empowered targeted research aimed toward early intervention in the epileptogenicity process. In this review, we present an update on the pharmacological treatments in tuberous sclerosis-related epilepsy.

Aw F, Goyer I, Raboisson MJ, Boutin C, Major P, Dahdah N (2017) Accelerated cardiac rhabdomyoma regression with everolimus in infants with tuberous sclerosis complex. Pediatr Cardiol 38:394–400. https://doi.org/10.1007/s00246-016-1528-yCrossRefPubMed

Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K (2013) Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381:817–824. https://doi.org/10.1016/S0140-6736(12)61767-XCrossRefPubMed

Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA (2010) The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 51:1236–1241. https://doi.org/10.1111/j.1528-1167.2009.02474.xCrossRefPubMed

Chung CWT, Lawson JA, Sarkozy V, Riney K, Wargon O, Shand AW, Cooper S, King H, Kennedy SE, Mowat D (2017) Early detection of tuberous sclerosis complex: an opportunity for improved neurodevelopmental outcome. Pediatr Neurol 76:20–26. https://doi.org/10.1016/j.pediatrneurol.2017.05.014CrossRefPubMed

Collins JJ, Tudor C, Leonard JM, Chuck G, Franz DN (2006) Levetiracetam as adjunctive antiepileptic therapy for patients with tuberous sclerosis complex: a retrospective open-label trial. J Child Neurol 21:53–57. https://doi.org/10.1177/08830738060210011201CrossRefPubMed

Curatolo P (2015) Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol 52:281–289. https://doi.org/10.1016/j.pediatrneurol.2014.10.028CrossRefPubMed

Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, de Vries PJ, Dlugos DJ, Fan J, Ridolfi A, Pelov D, Voi M, French JA (2018) 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 2:495–504. https://doi.org/10.1016/S2352-4642(18)30099-3CrossRefPubMed

Curatolo P, Nabbout R, Lagae L, Aronica E, Ferreira JC, Feucht M, Hertzberg C, Jansen AC, Jansen F, Kotulska K, Moavero R, O'Callaghan F, Papavasiliou A, Tzadok M, Jozwiak S (2018) Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur J Paediatr Neurol 22:738–748. https://doi.org/10.1016/j.ejpn.2018.05.006CrossRefPubMed

Cusmai R, Moavero R, Bombardieri R, Vigevano F, Curatolo P (2011) Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav 22:735–739. https://doi.org/10.1016/j.yebeh.2011.08.037CrossRefPubMed

10.

Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S, Cannabidiol in Dravet Syndrome Study G (2017) Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 376:2011–2020. https://doi.org/10.1056/NEJMoa1611618CrossRefPubMed

11.

Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, Roberts C (2019) Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia 60:294–302. https://doi.org/10.1111/epi.14628CrossRefPubMed

12.

Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, KE VL, Zuberi SM, Group GS (2018) Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med 378:1888–1897. https://doi.org/10.1056/NEJMoa1714631CrossRefPubMed

13.

Elterman RD, Shields WD, Bittman RM, Torri SA, Sagar SM, Collins SD (2010) Vigabatrin for the treatment of infantile spasms: final report of a randomized trial. J Child Neurol 25:1340–1347. https://doi.org/10.1177/0883073810365103CrossRefPubMed

14.

Fong CY, Osborne JP, Edwards SW, Hemingway C, Hancock E, Johnson AL, Kennedy CR, Kneen R, Likeman M, Lux AL, Mordekar SR, Murugan V, Newton RW, Pike M, Quinn M, Spinty S, Vassallo G, Verity CM, Whitney A, O'Callaghan FJ (2013) An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms. Dev Med Child Neurol 55:862–867. https://doi.org/10.1111/dmcn.12188CrossRefPubMed

15.

Franco V, Perucca E (2019) Pharmacological and therapeutic properties of cannabidiol for epilepsy. Drugs 79:1435–1454. https://doi.org/10.1007/s40265-019-01171-4CrossRefPubMed

16.

Franz DN, Krueger DA (2018) mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex. Am J Med Genet C Semin Med Genet 178:365–373. https://doi.org/10.1002/ajmg.c.31655CrossRefPubMed

17.

Franz DN, Tudor C, Leonard J, Egelhoff JC, Byars A, Valerius K, Sethuraman G (2001) Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia 42:935–940. https://doi.org/10.1046/j.1528-1157.2001.042007935.xCrossRefPubMed

18.

Geffrey AL, Belt OD, Paolini JL, Thiele EA (2015) Lacosamide use in the treatment of refractory epilepsy in tuberous sclerosis complex. Epilepsy Res 112:72–75. https://doi.org/10.1016/j.eplepsyres.2015.02.008CrossRefPubMed

19.

Goyer I, Dahdah N, Major P (2015) Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex. Pediatr Neurol 52:450–453. https://doi.org/10.1016/j.pediatrneurol.2015.01.004CrossRefPubMed

20.

Hancock E, Osborne JP (1999) Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol 14:71–74. https://doi.org/10.1177/088307389901400201CrossRefPubMed

21.

Hartman AL (2008) Does the effectiveness of the ketogenic diet in different epilepsies yield insights into its mechanisms? Epilepsia 49(Suppl 8):53–56. https://doi.org/10.1111/j.1528-1167.2008.01835.xCrossRefPubMedPubMedCentral

22.

Herlopian A, Hess EJ, Barnett J, Geffrey AL, Pollack SF, Skirvin L, Bruno P, Sourbron J, Thiele EA (2020) Cannabidiol in treatment of refractory epileptic spasms: an open-label study. Epilepsy Behav 106:106988. https://doi.org/10.1016/j.yebeh.2020.106988CrossRefPubMed

23.

Hernandez Vega Y, Kaliakatsos M, U-King-Im J-M, Lascelles K, Lim M (2014) Reversible vigabatrin-induced life-threatening encephalopathy. JAMA Neurol 71:108–109. https://doi.org/10.1001/jamaneurol.2013.1858CrossRefPubMed

24.

Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, Paolini JL, Thiele EA (2016) Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 57:1617–1624. https://doi.org/10.1111/epi.13499CrossRefPubMed

25.

Hoshal SG, Samuel BP, Schneider JR, Mammen L, Vettukattil JJ (2016) Regression of massive cardiac rhabdomyoma on everolimus therapy. Pediatr Int 58:397–399. https://doi.org/10.1111/ped.12816CrossRefPubMed

26.

Hussain SA, Dlugos DJ, Cilio MR, Parikh N, Oh A, Sankar R (2020) Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: a multicenter phase-2 study. Epilepsy Behav 102:106826. https://doi.org/10.1016/j.yebeh.2019.106826CrossRefPubMed

27.

Jennesson M, van Eeghen AM, Caruso PA, Paolini JL, Thiele EA (2013) Clobazam therapy of refractory epilepsy in tuberous sclerosis complex. Epilepsy Res 104:269–274. https://doi.org/10.1016/j.eplepsyres.2012.10.010CrossRefPubMed

28.

Jozwiak S, Kotulska K, Domanska-Pakiela D, Lojszczyk B, Syczewska M, Chmielewski D, Dunin-Wasowicz D, Kmiec T, Szymkiewicz-Dangel J, Kornacka M, Kawalec W, Kuczynski D, Borkowska J, Tomaszek K, Jurkiewicz E, Respondek-Liberska M (2011) Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 15:424–431. https://doi.org/10.1016/j.ejpn.2011.03.010CrossRefPubMed

29.

Jozwiak S, Slowinska M, Borkowska J, Sadowski K, Lojszczyk B, Domanska-Pakiela D, Chmielewski D, Kaczorowska-Frontczak M, Glowacka J, Sijko K, Kotulska K (2019) Preventive antiepileptic treatment in tuberous sclerosis complex: a long-term, prospective trial. Pediatr Neurol 101:18–25. https://doi.org/10.1016/j.pediatrneurol.2019.07.008CrossRefPubMed

30.

Kadish NE, Bast T, Reuner G, Wagner K, Mayer H, Schubert-Bast S, Wiegand G, Strobl K, Brandt A, Korinthenberg R, van Velthoven V, Schulze-Bonhage A, Zentner J, Ramantani G (2019) Epilepsy surgery in the first 3 years of life: predictors of seizure freedom and cognitive development. Neurosurgery 84:E368–E377. https://doi.org/10.1093/neuros/nyy376CrossRefPubMed

31.

Klinaki E, Argyri I, Amountza G, Ioannidou G, Maritsi D, Garoufi A, Vartzelis G (2019) Vigabatrin-induced encephalopathy in a 5.5-month-old girl with infantile spasms due to tuberous sclerosis. Case Rep Pediatr 2019:7249237. https://doi.org/10.1155/2019/7249237CrossRefPubMedPubMedCentral

32.

Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801–1811. https://doi.org/10.1056/NEJMoa1001671CrossRefPubMed

33.

Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus G (2013) Tuberous sclerosis complex surveillance and management: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol 49:255–265. https://doi.org/10.1016/j.pediatrneurol.2013.08.002CrossRefPubMedPubMedCentral

34.

Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN (2013) Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 74:679–687. https://doi.org/10.1002/ana.23960CrossRefPubMed

35.

Larson AM, Pfeifer HH, Thiele EA (2012) Low glycemic index treatment for epilepsy in tuberous sclerosis complex. Epilepsy Res 99:180–182. https://doi.org/10.1016/j.eplepsyres.2011.10.021CrossRefPubMed

36.

Liang S, Zhang J, Yang Z, Zhang S, Cui Z, Cui J, Zhang J, Liu N, Ding P (2017) Long-term outcomes of epilepsy surgery in tuberous sclerosis complex. J Neurol 264:1146–1154. https://doi.org/10.1007/s00415-017-8507-yCrossRefPubMed

37.

Liu S, Yu T, Guan Y, Zhang K, Ding P, Chen L, Shan Y, Guo Q, Liu Q, Yao Y, Yang M, Zhang S, Lin Y, Zhao R, Mao Z, Zhang J, Zhang C, Zhang R, Yang Z, Qian R, Li Y, Zhang G, Yuan L, Yang W, Tian H, Zhang H, Li W, Zhang X, Yin J, Guo Y, Zou L, Qin J, Fang F, Wang X, Ge M, Liang S (2020) Resective epilepsy surgery in tuberous sclerosis complex: a nationwide multicentre retrospective study from China. Brain 143:570–581. https://doi.org/10.1093/brain/awz411CrossRefPubMed

38.

MacKeigan JP, Krueger DA (2015) Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex. Neuro-Oncology 17:1550–1559. https://doi.org/10.1093/neuonc/nov152CrossRefPubMedPubMedCentral

39.

Maguire MJ, Hemming K, Wild JM, Hutton JL, Marson AG (2010) Prevalence of visual field loss following exposure to vigabatrin therapy: a systematic review. Epilepsia 51:2423–2431. https://doi.org/10.1111/j.1528-1167.2010.02772.xCrossRefPubMed

40.

Nabbout R, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, Dahlin M, DA L, d'Augeres GB, de Vries PJ, Ferreira JC, Feucht M, Fladrowski C, Hertzberg C, Jozwiak S, Lawson JA, Macaya A, Marques R, O'Callaghan F, Qin J, Sander V, Sauter M, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Jansen A, Kingswood JC, Consortium T, Investigators T (2019) Epilepsy in tuberous sclerosis complex: findings from the TOSCA study. Epilepsia Open 4:73–84. https://doi.org/10.1002/epi4.12286CrossRefPubMed

41.

Neal A, Ostrowsky-Coste K, Jung J, Lagarde S, Maillard L, Kahane P, Touraine R, Catenoix H, Montavont A, Isnard J, Arzimanoglou A, Bartolomei F, Guenot M, Rheims S (2020) Epileptogenicity in tuberous sclerosis complex: a stereoelectroencephalographic study. Epilepsia 61:81–95. https://doi.org/10.1111/epi.16410CrossRefPubMed

42.

Nomura S, Shimakawa S, Tanabe T, Fukui M, Kashiwagi M, Tamai H (2011) Efficacy of topiramate for relapsed epileptic spasms with tuberous sclerosis: report of three cases. No To Hattatsu 43:476–481PubMed

43.

Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus G (2013) Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol 49:243–254. https://doi.org/10.1016/j.pediatrneurol.2013.08.001CrossRefPubMedPubMedCentral

44.

Park S, Lee EJ, Eom S, Kang HC, Lee JS, Kim HD (2017) Ketogenic diet for the management of epilepsy associated with tuberous sclerosis complex in children. J Epilepsy Res 7:45–49. https://doi.org/10.14581/jer.17008CrossRefPubMedPubMedCentral

45.

Pearl PL, Poduri A, Prabhu SP, Harini C, Goldstein R, Atkinson RM, Armstrong D, Kinney H (2018) White matter spongiosis with vigabatrin therapy for infantile spasms. Epilepsia 59:e40–e44. https://doi.org/10.1111/epi.14032CrossRefPubMed

46.

Perek-Polnik M, Jozwiak S, Jurkiewicz E, Perek D, Kotulska K (2012) Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur J Paediatr Neurol 16:83–85. https://doi.org/10.1016/j.ejpn.2011.09.006CrossRefPubMed

47.

Pitkanen A, Lukasiuk K (2011) Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 10:173–186. https://doi.org/10.1016/S1474-4422(10)70310-0CrossRefPubMed

48.

Riikonen R, Rener-Primec Z, Carmant L, Dorofeeva M, Hollody K, Szabo I, Krajnc BS, Wohlrab G, Sorri I (2015) Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study. Dev Med Child Neurol 57:60–67. https://doi.org/10.1111/dmcn.12573CrossRefPubMed

49.

Saffari A, Brosse I, Wiemer-Kruel A, Wilken B, Kreuzaler P, Hahn A, Bernhard MK, van Tilburg CM, Hoffmann GF, Gorenflo M, Hethey S, Kaiser O, Kolker S, Wagner R, Witt O, Merkenschlager A, Mockel A, Roser T, Schlump JU, Serfling A, Spiegler J, Milde T, Ziegler A, Syrbe S (2019) Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age - a multicenter retrospective study. Orphanet J Rare Dis 14:96. https://doi.org/10.1186/s13023-019-1077-6CrossRefPubMedPubMedCentral

50.

Schubert-Bast S, Rosenow F, Klein KM, Reif PS, Kieslich M, Strzelczyk A (2019) The role of mTOR inhibitors in preventing epileptogenesis in patients with TSC: current evidence and future perspectives. Epilepsy Behav 91:94–98. https://doi.org/10.1016/j.yebeh.2018.05.039CrossRefPubMed

51.

Sourbron J, Klinkenberg S, van Kuijk SMJ, Lagae L, Lambrechts D, Braakman HMH, Majoie M (2020) Ketogenic diet for the treatment of pediatric epilepsy: review and meta-analysis. Childs Nerv Syst 36:1099–1109. https://doi.org/10.1007/s00381-020-04578-7CrossRefPubMed

52.

Stafstrom CE, Staedtke V, Comi AM (2017) Epilepsy mechanisms in neurocutaneous disorders: tuberous sclerosis complex, Neurofibromatosis type 1, and Sturge-Weber syndrome. Front Neurol 8:87. https://doi.org/10.3389/fneur.2017.00087CrossRefPubMedPubMedCentral

53.

Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K, Group GS (2018) Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 391:1085–1096. https://doi.org/10.1016/S0140-6736(18)30136-3CrossRefPubMed

54.

Vergeer M, de Ranitz-Greven WL, Neary MP, Ionescu-Ittu R, Emond B, Sheng Duh M, Jansen F, Zonnenberg BA (2019) Epilepsy, impaired functioning, and quality of life in patients with tuberous sclerosis complex. Epilepsia Open 4:581–592. https://doi.org/10.1002/epi4.12365CrossRefPubMedPubMedCentral

55.

Walker SD, Kalviainen R (2011) Non-vision adverse events with vigabatrin therapy. Acta Neurol Scand Suppl 124:72–82. https://doi.org/10.1111/j.1600-0404.2011.01602.xCrossRef

56.

Westall CA, Wright T, Cortese F, Kumarappah A, Snead OC 3rd, Buncic JR (2014) Vigabatrin retinal toxicity in children with infantile spasms: an observational cohort study. Neurology 83:2262–2268. https://doi.org/10.1212/WNL.0000000000001069CrossRefPubMedPubMedCentral

57.

Zeng LH, Xu L, Gutmann DH, Wong M (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63:444–453. https://doi.org/10.1002/ana.21331CrossRefPubMedPubMedCentral

Title: Medical treatment of tuberous sclerosis-related epilepsy
Authors: Shimrit Uliel-Sibony
Veronika Chernuha
Hadas Meirson
Aviva Fattal-Valevski
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keywords: Tuberous Sclerosis
Epilepsy
Zonisamide
Vigabatrin
Everolimus
Published in: Child's Nervous System / Issue 10/2020
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-020-04772-7

At a glance: The STEP trials

Springer Medicine

Medical treatment of tuberous sclerosis-related epilepsy

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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