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Pharmacotherapy for Seizures in Tuberous Sclerosis Complex

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Abstract

Epilepsy is one of the main symptoms affecting the lives of individuals with tuberous sclerosis complex (TSC), causing a high rate of morbidity. Individuals with TSC can present with various types of seizures, epilepsies, and epilepsy syndromes that can coexist or appear in relation to age. Focal epilepsy is the most frequent epilepsy type with two developmental and epileptic encephalopathies: infantile spasms syndrome and Lennox–Gastaut syndrome. Active screening and early management of epilepsy is recommended in individuals with TSC to limit its consequences and its impact on quality of life, cognitive outcome and the economic burden of the disease. The progress in the knowledge of the mechanisms underlying epilepsy in TSC has paved the way for new concepts in the management of epilepsy related to TSC. In addition, we are moving from traditional “reactive” and therapeutic choices with current antiseizure medications used after the onset of seizures, to a proactive approach, aimed at predicting and preventing epileptogenesis and the onset of epilepsy with vigabatrin, and to personalized treatments with mechanistic therapies, namely mechanistic/mammalian target of rapamycin inhibitors. Indeed, epilepsy linked to TSC is one of the only epilepsies for which a predictive and preventive approach can delay seizure onset and improve seizure response. However, the efficacy of such interventions on long-term cognitive and psychiatric outcomes is still under investigation.

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References

  1. Osborne JP, Fryer A, Wabb D. Epidemiology of tuberous sclerosis. Ann NY Acad Sci. 1991;615:125–7.

    Article  CAS  PubMed  Google Scholar 

  2. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345–56.

    Article  CAS  PubMed  Google Scholar 

  3. Palavra F, Robalo C, Reis F. Recent advances and challenges of mTOR inhibitors use in the treatment of patients with tuberous sclerosis complex. Oxid Med Cell Longev. 2017;2017:9820181.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Nabbout R, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, et al. Epilepsy in tuberous sclerosis complex: findings from the TOSCA Study. Epilepsia Open. 2019;4:73–84.

    Article  PubMed  Google Scholar 

  5. Davis PE, Filip-Dhima R, Sideridis G, Peters JM, Au KS, Northrup H, et al. Presentation and diagnosis of tuberous sclerosis complex in infants. Pediatrics. 2017;140:e20164040.

    Article  PubMed  Google Scholar 

  6. Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;51:1236–41.

    Article  PubMed  Google Scholar 

  7. Ohtsuka Y, Ohmori I, Oka E. Long-term follow-up of childhood epilepsy associated with tuberous sclerosis. Epilepsia. 1998;39:1158–63.

    Article  CAS  PubMed  Google Scholar 

  8. Bombardieri R, Pinci M, Moavero R, Cerminara C, Curatolo P. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol. 2010;14:146–9.

    Article  PubMed  Google Scholar 

  9. Liu S, Yu T, Guan Y, Zhang K, Ding P, Chen L, et al. Resective epilepsy surgery in tuberous sclerosis complex: a nationwide multicentre retrospective study from China. Brain. 2020;143:570–81.

    Article  PubMed  Google Scholar 

  10. Grayson LE, Peters JM, McPherson T, Krueger DA, Sahin M, Wu JY, et al. Pilot study of neurodevelopmental impact of early epilepsy surgery in tuberous sclerosis complex. Pediatr Neurol. 2020;109:39–46.

    Article  PubMed  PubMed Central  Google Scholar 

  11. De Ridder J, Lavanga M, Verhelle B, Vervisch J, Lemmens K, Kotulska K, et al. Prediction of neurodevelopment in infants with tuberous sclerosis complex using early EEG characteristics. Front Neurol. 2020;11:582891.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Curatolo P, Nabbout R, Lagae L, Aronica E, Ferreira JC, Feucht M, et al. Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur J Paediatr Neurol. 2018;22:738–48.

    Article  PubMed  Google Scholar 

  13. Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Jansen F, et al. Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP Trial. Ann Neurol. 2021;89:304–14.

  14. Jozwiak S, Słowińska M, Borkowska J, Sadowski K, Łojszczyk B, Domańska-Pakieła D, et al. Preventive antiepileptic treatment in tuberous sclerosis complex: a long-term, prospective trial. Pediatr Neurol. 2019;101:18–25.

    Article  PubMed  Google Scholar 

  15. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512–21.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372:657–68.

    Article  CAS  PubMed  Google Scholar 

  17. Davies DM, Johnson SR, Tattersfield AE, Kingswood JC, Cox JA, McCartney DL, et al. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med. 2008;358:200–3.

    Article  CAS  PubMed  Google Scholar 

  18. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358:140–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74:679–87.

    Article  CAS  PubMed  Google Scholar 

  20. Overwater IE, Rietman AB, Bindels-De Heus K, Looman CWN, Rizopoulos D, Sibindi TM, et al. Sirolimus for epilepsy in children with tuberous sclerosis complex. Neurology. 2016;87:1011–8.

    Article  CAS  PubMed  Google Scholar 

  21. French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, 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;388:2153–63.

    Article  CAS  PubMed  Google Scholar 

  22. Jeong A, Wong M. Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57:1443–9.

    Article  CAS  PubMed  Google Scholar 

  23. Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert opinion on the management of Lennox–Gastaut syndrome: treatment algorithms and practical considerations. Front Neurol. 2017;8:505.

  24. O’Callaghan FJK, Edwards SW, Alber FD, Cortina Borja M, Hancock E, Johnson AL, et al. Vigabatrin with hormonal treatment versus hormonal treatment alone (ICISS) for infantile spasms: 18-month outcomes of an open-label, randomised controlled trial. Lancet Child Adolesc Health. 2018;2:715–25.

    Article  PubMed  Google Scholar 

  25. O’Callaghan FJK, Edwards SW, Alber FD, Hancock E, Johnson AL, Kennedy CR, et al. Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. Lancet Neurol. 2017;16:33.

    Article  PubMed  CAS  Google Scholar 

  26. Horn CS, Ater SB, Hurst DL. Carbamazepine-exacerbated epilepsy in children and adolescents. Pediatr Neurol. 1986;2:340–5.

    Article  CAS  PubMed  Google Scholar 

  27. Muzykewicz DA, Costello DJ, Halpern EF, Thiele EA. Infantile spasms in tuberous sclerosis complex: prognostic utility of EEG. Epilepsia. 2009;50:290–6.

    Article  PubMed  Google Scholar 

  28. Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol. 1991;6(Suppl. 2):S52–9.

    Google Scholar 

  29. Chiron C, Dumas C, Jambaqué I, Mumford J, Dulac O. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res. 1997;26:389–95.

    Article  CAS  PubMed  Google Scholar 

  30. Elterman RD, Shields WD, Mansfield KA, Nakagawa J. Randomized trial of vigabatrin in patients with infantile spasms. Neurology. 2001;57:1416–21.

    Article  CAS  PubMed  Google Scholar 

  31. Wilmshurst JM, Gaillard WD, Vinayan KP, Tsuchida TN, Plouin P, Van Bogaert P, et al. Summary of recommendations for the management of infantile seizures: Task Force report for the ILAE Commission of Pediatrics. Epilepsia. 2015;56:1185–97.

    Article  PubMed  Google Scholar 

  32. Karvelas G, Lortie A, Scantlebury MH, Duy PT, Cossette P, Carmant L. A retrospective study on aetiology based outcome of infantile spasms. Seizure. 2009;18:197–201.

    Article  PubMed  Google Scholar 

  33. Camposano SE, Major P, Halpern E, Thiele EA. Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile. Epilepsia. 2008;49:1186–91.

    Article  CAS  PubMed  Google Scholar 

  34. Ando N, Fujimoto S, Ishikawa T, Kobayashi S, Hattori A, Ito T, et al. Effectiveness of vigabatrin in West syndrome associated with tuberous sclerosis. No To Hattatsu. 2010;42:444–8.

    PubMed  Google Scholar 

  35. Overwater IE, Bindels-De Heus K, Rietman AB, Ten Hoopen LW, Vergouwe Y, Moll HA, et al. Epilepsy in children with tuberous sclerosis complex: chance of remission and response to antiepileptic drugs. Epilepsia. 2015;56:1239–45.

    Article  CAS  PubMed  Google Scholar 

  36. Riikonen R, Rener-Primec Z, Carmant L, Dorofeeva M, Hollody K, Szabo I, et al. Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study. Dev Med Child Neurol. 2015;57:60–7.

    Article  PubMed  Google Scholar 

  37. Elterman RD, Shields WD, Bittman RM, Torri SA, Sagar SM, Collins SD. Vigabatrin for the treatment of infantile spasms: final report of a randomized trial. J Child Neurol. 2010;25:1340–7.

    Article  PubMed  Google Scholar 

  38. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial. Lancet Neurol. 2005;4:712–7.

  39. Darke K, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Lux AL, et al. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial. Arch Dis Child. 2010;95:382–6.

    Article  PubMed  Google Scholar 

  40. O’Callaghan FJK, Lux AL, Darke K, Edwards SW, Hancock E, Johnson AL, et al. The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study. Epilepsia. 2011;52:1359–64.

    Article  PubMed  Google Scholar 

  41. Djuric M, Kravljanac R, Tadic B, Mrlješ-Popovic N, Appleton RE. Long-term outcome in children with infantile spasms treated with vigabatrin: a cohort of 180 patients. Epilepsia. 2014;56:1918–25.

    Article  CAS  Google Scholar 

  42. Riikonen R. Long-term outcome of west syndrome: a study of adults with a history of infantile spasms. Epilepsia. 1996;37:367–72.

    Article  CAS  PubMed  Google Scholar 

  43. Jambaqué I, Chiron C, Dumas C, Mumford J, Dulac O. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res. 2000;38:151–60.

    Article  PubMed  Google Scholar 

  44. Józwiak S, Domańska-Pakieła D, Kotulska K, Kaczorowska M. Treatment before seizures: new indications for antiepileptic therapy in children with tuberous sclerosis complex. Epilepsia. 2007;48:1632.

    Article  PubMed  Google Scholar 

  45. Westall CA, Wright T, Cortese F, Kumarappah A, Snead OC, Buncic JR. Vigabatrin retinal toxicity in children with infantile spasms: an observational cohort study. Neurology. 2014;83:2262–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Camfield P, Camfield C, Lortie A, Darwish H. Infantile spasms in remission may reemerge as intractable epileptic spasms. Epilepsia. 2003;44:1592–5.

    Article  PubMed  Google Scholar 

  47. Nabbout R, Melki I, Gerbaka B, Dulac O, Akatcherian C. Infantile spasms in Down syndrome: good response to a short course of vigabatrin. Epilepsia. 2001;42:1580–3.

    Article  CAS  PubMed  Google Scholar 

  48. Capovilla G, Beccaria F, Montagnini A, Cusmai R, Franzoni E, Moscano F, et al. Short-term nonhormonal and nonsteroid treatment in West syndrome. Epilepsia. 2003;44:1085–8.

    Article  CAS  PubMed  Google Scholar 

  49. Kröll-Seger J, Kaminska A, Moutard ML, De Saint-Martin A, Guët A, Dulac O, et al. Severe relapse of epilepsy after vigabatrin withdrawal: for how long should we treat symptomatic infantile spasms? Epilepsia. 2007;48:612–3.

  50. Hussain SA, Schmid E, Peters JM, Goyal M, Bebin EM, Northrup H, et al. High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex. Epilepsy Res. 2018;148:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jammoul F, Wang Q, Nabbout R, Coriat C, Duboc A, Simonutti M, et al. Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity. Ann Neurol. 2009;65:98–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Police A, Shankar VK, Murthy SN. Role of taurine transporter in the retinal uptake of vigabatrin. AAPS PharmSciTech. 2020;21:1–9.

    Article  CAS  Google Scholar 

  53. Rasmussen AD, Truchot N, Pickersgill N, Thale ZI, Rosolen SG, Botteron C. The effects of taurine on vigabatrin, high light intensity and mydriasis induced retinal toxicity in the pigmented rat. Exp Toxicol Pathol. 2014;67:13–20.

    Article  PubMed  CAS  Google Scholar 

  54. Tao Y, Yang J, Ma Z, Yan Z, Liu C, Ma J, et al. The vigabatrin induced retinal toxicity is associated with photopic exposure and taurine deficiency: an in vivo study. Cell Physiol Biochem. 2016;40:831–46.

    Article  CAS  PubMed  Google Scholar 

  55. Spelbrink EM, Mabud TS, Reimer R, Porter BE. Plasma taurine levels are not affected by vigabatrin in pediatric patients. Epilepsia. 2016;57:e168–72.

    Article  CAS  PubMed  Google Scholar 

  56. Walters DC, Jansen EEW, Salomons GS, Arning E, Ashcraft P, Bottiglieri T, et al. Preferential accumulation of the active S-(+) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity. Epilepsy Res. 2021;170:106536.

    Article  CAS  PubMed  Google Scholar 

  57. Walters D, Vogel KR, Brown M, Shi X, Roullet JB, Gibson KM. Transcriptome analysis in mice treated with vigabatrin identifies dysregulation of genes associated with retinal signaling circuitry. Epilepsy Res. 2020;166:106395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wild JM, Martinez C, Reinshagen G, Harding GFA. Characteristics of a unique visual field defect attributed to vigabatrin. Epilepsia. 1999;40:1784–94.

    Article  CAS  PubMed  Google Scholar 

  59. Maguire MJ, Hemming K, Wild JM, Hutton JL, Marson AG. Prevalence of visual field loss following exposure to vigabatrin therapy: a systematic review. Epilepsia. 2010;51:2423–31.

    Article  PubMed  Google Scholar 

  60. Wohlrab G, Boltshauser E, Schmitt B, Schriever S, Landau K. Visual field constriction is not limited to children treated with vigabatrin. Neuropediatrics. 1999;30:130–2.

    Article  CAS  PubMed  Google Scholar 

  61. Gaily E, Jonsson H, Lappi M. Visual fields at school-age in children treated with vigabatrin in infancy. Epilepsia. 2009;50:206–16.

    Article  CAS  PubMed  Google Scholar 

  62. Portengen BL, Koenraads Y, Imhof SM, Porro GL. Lessons learned from 23 years of experience in testing visual fields of neurologically impaired children. Neuroophthalmology. 2020;44:1–10.

    Article  Google Scholar 

  63. Koenraads Y, Braun KPJ, Van Der Linden DCP, Imhof SM, Porro GL. Perimetry in young and neurologically impaired children: the Behavioral Visual Field (BEFIE) screening test revisited. JAMA Ophthalmol. 2015;133:319–25.

    Article  PubMed  Google Scholar 

  64. Wright T, Kumarappah A, Stavropoulos A, Reginald A, Buncic JR, Westall CA. Vigabatrin toxicity in infancy is associated with retinal defect in adolescence: a prospective observational study. Retina. 2017;37:858–66.

    Article  CAS  PubMed  Google Scholar 

  65. Origlieri C, Geddie B, Karwoski B, Berl MM, Elling N, McClintock W, et al. Optical coherence tomography to monitor vigabatrin toxicity in children. J Am Assoc Pediatr Ophthalmol Strabismus. 2016;20:136–40.

    Article  Google Scholar 

  66. Hébert-Lalonde N, Carmant L, Major P, Roy MS, Lassonde M, Saint-Amour D. Electrophysiological evidences of visual field alterations in children exposed to vigabatrin early in life. Pediatr Neurol. 2016;59:47–53.

    Article  PubMed  Google Scholar 

  67. Milh M, Villeneuve N, Chapon F, Pineau S, Lamoureux S, Livet MO, et al. Transient brain magnetic resonance imaging hyperintensity in basal ganglia and brain stem of epileptic infants treated with vigabatrin. J Child Neurol. 2009;24:305–15.

    Article  PubMed  Google Scholar 

  68. Hussain SA, Tsao J, Li M, Schwarz MD, Zhou R, Wu JY, et al. Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent. Epilepsia. 2017;58:674–82.

    Article  CAS  PubMed  Google Scholar 

  69. Wheless JW, Carmant L, Bebin M, Conry JA, Chiron C, Elterman RD, et al. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia. 2009;50:195–205.

    Article  CAS  PubMed  Google Scholar 

  70. Fong CY, Osborne JP, Edwards SW, Hemingway C, Hancock E, Johnson AL, et al. An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms. Dev Med Child Neurol. 2013;55:862–7.

    Article  PubMed  Google Scholar 

  71. Schonstedt V, Stecher X, Venegas V, Silva C. Vigabatrin-induced MRI changes associated with extrapyramidal symptoms in a child with infantile spasms. Neuroradiol J. 2015;28:515–8.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Vega YH, Kaliakatsos M, U-King-Im JM, Lascelles K, Lim M. Reversible vigabatrin-induced life-threatening encephalopathy. JAMA Neurol. 2014;71:108–9.

  73. Walzer M, Bekersky I, Wanaski S, Collins S, Jortner B, Patterson R, et al. Oral toxicity of vigabatrin in immature rats: characterization of intramyelinic edema. Neurotoxicology. 2011;32:963–74.

    Article  CAS  PubMed  Google Scholar 

  74. Rasmussen AD, Richmond E, Wegener KM, Downes N, Mullins P. Vigabatrin-induced CNS changes in juvenile rats: induction, progression and recovery of myelin-related changes. Neurotoxicology. 2015;46:137–44.

    Article  CAS  PubMed  Google Scholar 

  75. Preece NE, Houseman J, King MD, Weller RO, Williams SR. Development of vigabatrin-induced lesions in the rat brain studied by magnetic resonance imaging, histology, and immunocytochemistry. Synapse. 2004;53:36–43.

    Article  CAS  PubMed  Google Scholar 

  76. Pearl PL, Poduri A, Prabhu SP, Harini C, Goldstein R, Atkinson RM, et al. White matter spongiosis with vigabatrin therapy for infantile spasms. Epilepsia. 2018;59:e40–4.

    Article  CAS  PubMed  Google Scholar 

  77. Horton M, Rafay M, Del Bigio MR. Pathological evidence of vacuolar myelinopathy in a child following vigabatrin administration. J Child Neurol. 2009;24:1543–6.

    Article  PubMed  Google Scholar 

  78. Cohen JA, Fisher RS, Brigell MG, Peyster RG, Gordon S. The potential for vigabatrin-induced intramyelinic edema in humans. Epilepsia. 2000;41:148–57.

  79. Appleton RE, Peters ACB, Mumford JP, Shaw DE. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia. 1999;40:1627–33.

    Article  CAS  PubMed  Google Scholar 

  80. 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;45:1416–28.

    Article  PubMed  Google Scholar 

  81. Stafstrom CE. The use of felbamate to treat infantile spasms. J Child Neurol. 1996;11:170.

    Article  CAS  PubMed  Google Scholar 

  82. Hosain SA, Merchant S, Solomon GE, Chutorian A. Topiramate for the treatment of infantile spasms. J Child Neurol. 2006;21:17–9.

    Article  PubMed  Google Scholar 

  83. Lotze TE, Wilfong AA. Zonisamide treatment for symptomatic infantile spasms. Neurology. 2004;62:296–8.

    Article  CAS  PubMed  Google Scholar 

  84. Dozières-Puyravel B, Nasser H, Bellavoine V, Ilea A, Delanoe C, Auvin S. Felbamate for infantile spasms syndrome resistant to first-line treatments. Dev Med Child Neurol. 2020;62:581–6.

    Article  PubMed  Google Scholar 

  85. Park S, Lee EJ, Eom S, Kang H-C, Lee JS, Kim HD. Ketogenic diet for the management of epilepsy associated with tuberous sclerosis complex in children. J Epilepsy Res. 2017;7:45–9.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Okanishi T, Fujimoto A, Okanari K, Baba S, Ichikawa N, Nishimura M, et al. Corpus callosotomy for drug-resistant spasms associated with tuberous sclerosis complex. Epilepsy Behav. 2019;98:228–32.

    Article  PubMed  Google Scholar 

  87. Cusmai R, Moavero R, Bombardieri R, Vigevano F, Curatolo P. Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav. 2011;22:735–9.

    Article  PubMed  Google Scholar 

  88. Capal JK, Bernardino-Cuesta B, Horn PS, Murray D, Byars AW, Bing NM, et al. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav. 2017;70:245–52.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Krueger DA, Northrup H, Krueger DA, Roberds S, Smith K, Sampson J, et al. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:255–65.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Curatolo P, Jóźwiak S, Nabbout R. Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol. 2012;16:582–6.

    Article  PubMed  Google Scholar 

  91. Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, et al. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex. JAMA Neurol. 2020;02114:1–9.

    Google Scholar 

  92. Weinstock A, Bebin EM, Checketts D, Clark G, Szaflarski J, Seltzer L, et al. Long-term efficacy and safety of cannabidiol (CBD) in patients with tuberous sclerosis complex (TSC): 4-year results from the expanded access program (EAP) (EAP). In: Annual meeting abstracts. American Epilepsy Society. 2020. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/2422485. Accessed 19 Dec 2020.

  93. Sahebkar F, Thiele E, Bebin EM, Bhathal H, Jansen FE, Kotulska K, et al. Cannabidiol (CBD) treatment in patients with seizures associated with tuberous sclerosis complex (TSC): a randomised, double-blind, placebo-controlled phase 3 trial (GWPCARE6). Dev Med Child Neurol. 2020;62:4–14.

    Google Scholar 

  94. D’Onofrio G, Kuchenbuch M, Hachon-Le Camus C, Desnous B, Staath V, Napuri S, et al. Slow titration of cannabidiol add-on in drug-resistant epilepsies can improve safety with maintained efficacy in an open-label study. Front Neurol. 2020;11:829.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Morrison G, Crockett J, Blakey G, Sommerville K. A phase 1, open-label, pharmacokinetic trial to investigate possible drug–drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Clin Pharmacol Drug Dev. 2019;8:1009–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51.

    Article  CAS  PubMed  Google Scholar 

  98. Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89:165–70.

    Article  CAS  PubMed  Google Scholar 

  99. Ebrahimi-Fakhari D, Agricola KD, Tudor C, Krueger D, Franz DN. Cannabidiol elevates mechanistic target of rapamycin inhibitor levels in patients with tuberous sclerosis complex. Pediatr Neurol. 2020;105:59–61.

    Article  PubMed  Google Scholar 

  100. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58:1586–92.

    Article  CAS  PubMed  Google Scholar 

  101. Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E, et al. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Neurology. 1999;53:1724–31.

    Article  CAS  PubMed  Google Scholar 

  102. Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pledger G. A double-blind randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group. Neurology. 1999;52:1338–44.

    Article  CAS  PubMed  Google Scholar 

  103. Glauser TA, Nigro M, Sachdeo R, Pasteris LA, Weinstein S, Abou-Khalil B, et al. Adjunctive therapy with oxcarbazepine in children with partial seizures. Neurology. 2000;54:2237–44.

    Article  CAS  PubMed  Google Scholar 

  104. Appleton R, Fichtner K, LaMoreaux L, Alexander J, Maton S, Murray G, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study. Dev Med Child Neurol. 2001;43:269–73.

    Article  CAS  PubMed  Google Scholar 

  105. Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006;66:1654–60.

    Article  CAS  PubMed  Google Scholar 

  106. Guerrini R, Rosati A, Segieth J, Pellacani S, Bradshaw K, Giorgi L. A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy. Epilepsia. 2013;54:1473–80.

    Article  CAS  PubMed  Google Scholar 

  107. Rosenfeld W, Conry J, Lagae L, Rozentals G, Yang H, Fain R, et al. Efficacy and safety of perampanel in adolescent patients with drug-resistant partial seizures in three double-blind, placebo-controlled, phase III randomized clinical studies and a combined extension study. Eur J Paediatr Neurol. 2015;19:435–45.

    Article  PubMed  Google Scholar 

  108. Sperling MR, Abou-Khalil B, Harvey J, Rogin JB, Biraben A, Galimberti CA, et al. Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: results of a phase III, double-blind, randomized, placebo-controlled trial. Epilepsia. 2015;56:244–53.

  109. Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, Rosenow F, Doty P, Hebert D, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50:443–53.

    Article  PubMed  CAS  Google Scholar 

  110. Piña-Garza JE, Levisohn P, Gucuyener K, Mikati MA, Warnock CR, Conklin HS, et al. Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months. Neurology. 2008;70:2099–108.

    Article  PubMed  CAS  Google Scholar 

  111. Piña-Garza JE, Espinoza R, Nordli D, Bennett DA, Spirito S, Stites TE, et al. Oxcarbazepine adjunctive therapy in infants and young children with partial seizures. Neurology. 2005;65:1370–5.

    Article  PubMed  CAS  Google Scholar 

  112. Piñea-Garza JE, Nordli DR, Rating D, Yang H, Schiemann-Delgado J, Duncan B, et al. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia. 2009;50:1141–9.

    Article  CAS  Google Scholar 

  113. Geffrey AL, Belt OD, Paolini JL, Thiele EA. Lacosamide use in the treatment of refractory epilepsy in tuberous sclerosis complex. Epilepsy Res. 2015;112:72–5.

    Article  CAS  PubMed  Google Scholar 

  114. Jennesson M, van Eeghen AM, Caruso PA, Paolini JL, Thiele EA. Clobazam therapy of refractory epilepsy in tuberous sclerosis complex. Epilepsy Res. 2013;104:269–74.

    Article  CAS  PubMed  Google Scholar 

  115. Collins JJ, Tudor C, Leonard JM, Chuck G, Franz DN. Levetiracetam as adjunctive antiepileptic therapy for patients with tuberous sclerosis complex: a retrospective open-label trial. J Child Neurol. 2006;21:53–7.

    Article  PubMed  Google Scholar 

  116. Franz DN, Tudor C, Leonard J, Egelhoff JC, Byars A, Valerius K, et al. Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia. 2001;42:935–40.

    Article  CAS  PubMed  Google Scholar 

  117. Nabbout RC, Chiron C, Mumford J, Dumas C, Dulac O. Vigabatrin in partial seizures in children. J Child Neurol. 1997;12:172–7.

    Article  CAS  PubMed  Google Scholar 

  118. Friedman D, Bogner M, Parker-Menzer K, Devinsky O. Vigabatrin for partial-onset seizure treatment in patients with tuberous sclerosis complex. Epilepsy Behav. 2013;27:118–20.

    Article  PubMed  Google Scholar 

  119. Greiner HM, Lynch ER, Fordyce S, Agricola K, Tudor C, Franz DN, et al. Vigabatrin for childhood partial-onset epilepsies. Pediatr Neurol. 2012;46:83–8.

    Article  PubMed  Google Scholar 

  120. van der Poest Clement EA, Sahin M, Peters JM. Vigabatrin for epileptic spasms and tonic seizures in tuberous sclerosis complex. J Child Neurol. 2018;33:519–24.

  121. Takeda Pharmaceutical Company Limited. A phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of TAK-935 (OV935) as an adjunctive therapy in pediatric participants with developmental and/or epileptic encephalopathies: NCT03650452. In: ClinicalTrials. US National Library of Medicine. 2018. https://www.clinicaltrials.gov/ct2/show/NCT03650452?cond=tuberous+sclerosis&draw=8&rank=69. Accessed 7 Apr 2021.

  122. Peking Unon Medical College Hospital. Aspirin as an add-on treatment of refractory epilepsy in tuberous sclerosis complex: NCT03356769. In: ClinicalTrials. US National Library of Medicine. 2017. https://www.clinicaltrials.gov/ct2/show/NCT03356769?cond=tuberous+sclerosis&draw=6&rank=41. Accessed 7 Apr 2021.

  123. Marinus Pharmaceuticals. Adjunctive ganaxolone treatment (Part A) in TSC followed by long-term treatment (Part B): NCT04285346. In: ClinicalTrials. US National Library of Medicine. 2020. https://www.clinicaltrials.gov/ct2/show/NCT04285346?cond=tuberous+sclerosis&draw=3&rank=16. Accessed 7 Apr 2021.

  124. Gaillard WD, Jette N, Arnold ST, Arzimanoglou A, Braun KPJ, Cukiert A, et al. Establishing criteria for pediatric epilepsy surgery center levels of care: report from the ILAE Pediatric Epilepsy Surgery Task Force. Epilepsia. 2020;61:2629–42.

    Article  PubMed  Google Scholar 

  125. Dulac O, N’Guyen T. The Lennox–Gastaut syndrome. Epilepsia. 1993;34:S7-17.

    Article  PubMed  Google Scholar 

  126. Vignoli A, La BF, Turner K, Scornavacca G, Chiesa V, Zambrelli E, et al. Epilepsy in TSC: certain etiology does not mean certain prognosis. Epilepsia. 2013;54:2134–42.

    Article  PubMed  Google Scholar 

  127. Kingswood JC, D’Augères GB, Belousova E, Ferreira JC, Carter T, Castellana R, et al. TuberOus SClerosis registry to increase disease Awareness (TOSCA): baseline data on 2093 patients. Orphanet J Rare Dis. 2017;12:2.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox–Gastaut syndrome). N Engl J Med. 1993;328:29–33.

    Article  Google Scholar 

  129. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G. A double-blind, randomized trial of topiramate in Lennox–Gastaut syndrome. Topiramate YL Study Group. Neurology. 1999;52:1882–7.

    Article  CAS  PubMed  Google Scholar 

  130. Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA. Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology. 2011;77:1473–81.

    Article  CAS  PubMed  Google Scholar 

  131. Motte J, Trevathan E, Arvidsson JFV, Barrera MN, Mullens EL, Manasco P. Lamotrigine for generalized seizures associated with the Lennox–Gastaut syndrome. N Engl J Med. 1997;337:1807–12.

  132. Nabbout R, Kuchenbuch M. Impact of predictive, preventive and precision medicine strategies in epilepsy. Nat Rev Neurol. 2020;16:674–88.

    Article  PubMed  Google Scholar 

  133. Westont AD, Hood L. Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. J Proteome Res. 2004;3:179–96.

  134. Hood L, Heath JR, Phelps ME, Lin B. Systems biology and new technologies enable predictive and preventative medicine. Science. 2004;306:640–3.

  135. Hood L, Auffray C. Participatory medicine: a driving force for revolutionizing healthcare. Genome Med. 2013;5:1–4.

  136. Martin-Sanchez F, Lopez-Campos G, Gray K. Biomedical informatics methods for personalized medicine and participatory health. In: Sarkar IN, editor. Methods in biomedical informatics. Cambridge: Academic Press; 2014. pp. 347–94.

    Chapter  Google Scholar 

  137. Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol. 2015;52:281–9.

  138. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991;253:905–9.

    Article  CAS  PubMed  Google Scholar 

  139. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII). Epilepsia. 2017;58:181–221.

    Article  PubMed  Google Scholar 

  140. MacKeigan JP, Krueger DA. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex. Neuro Oncol. 2015;17:1550–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14:733–45.

  142. Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, et al. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci. 2007;27:5546–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63:444–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kovarik JM, Hartmann S, Figueiredo J, Rordorf C, Golor G, Lison A, et al. Effect of food on everolimus absorption: quantification in healthy subjects and a confirmatory screening in patients with renal transplants. Pharmacotherapy. 2002;22:154–9.

    Article  CAS  PubMed  Google Scholar 

  145. Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Everolimus for treatment-refractory seizures in TSC: extension of a randomized controlled trial. Neurol Clin Pract. 2018;8:412–20.

    Article  PubMed  PubMed Central  Google Scholar 

  146. 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;17:631–8.

    Article  PubMed  Google Scholar 

  147. Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA. Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr. 2014;164:1195–200.

    Article  CAS  PubMed  Google Scholar 

  148. Samueli S, Abraham K, Dressler A, Gröppel G, Mühlebner-Fahrngruber A, Scholl T, et al. Efficacy and safety of everolimus in children with TSC-associated epilepsy: pilot data from an open single-center prospective study. Orphanet J Rare Dis. 2016;11:1–8.

    Article  Google Scholar 

  149. Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, 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;2:495–504.

    Article  PubMed  Google Scholar 

  150. Krueger DA, Capal JK, Curatolo P, Devinsky O, Ess K, Tzadok M, et al. Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): multicentre clinical experience. Eur J Paediatr Neurol. 2018;22:1066–73.

    Article  PubMed  Google Scholar 

  151. Saffari A, Brösse I, Wiemer-Kruel A, Wilken B, Kreuzaler P, Hahn A, et al. 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. 2019. https://doi.org/10.1186/s13023-019-1077-6.

    Article  PubMed  PubMed Central  Google Scholar 

  152. He W, Chen J, Wang Y-YY, Zhang M-NN, Qian-Lu, Wang Q-HH, et al. Sirolimus improves seizure control in pediatric patients with tuberous sclerosis: a prospective cohort study. Seizure. 2020;79:20–6.

    Article  PubMed  Google Scholar 

  153. 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;12:35.

  154. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev. 2014;28:126–33.

  155. Curatolo P, Bjørnvold M, Dill PE, Ferreira JC, Feucht M, Hertzberg C, et al. The role of mTOR Inhibitors in the treatment of patients with tuberous sclerosis complex: evidence-based and expert opinions. Drugs. 2016;76:551–65.

    Article  CAS  PubMed  Google Scholar 

  156. Zhang B, Mcdaniel SS, Rensing NR, Wong M. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLoS ONE. 2013;8:57445.

    Article  CAS  Google Scholar 

  157. McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia. 2011;52:e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Serra I, Scheldeman C, Bazelot M, Whalley BJ, Dallas ML, de Witte PAM, et al. Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex. Behav Brain Res. 2019;363:135–44.

    Article  CAS  PubMed  Google Scholar 

  159. Wu Y, Wang W, Richerson GB. Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release. J Neurophysiol. 2003;89:2021–34.

    Article  CAS  PubMed  Google Scholar 

  160. Koene LMC, Grondelle SE, Proietti Onori M, Wallaard I, Kooijman NHRM, Oort A, et al. Effects of antiepileptic drugs in a new TSC/mTOR-dependent epilepsy mouse model. Ann Clin Transl Neurol. 2019;6:1273–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Coppola G, Klepper J, Ammendola E, Fiorillo M, della Corte R, Capano G, et al. The effects of the ketogenic diet in refractory partial seizures with reference to tuberous sclerosis. Eur J Paediatr Neurol. 2006;10:148–51.

    Article  PubMed  Google Scholar 

  162. Youn SE, Park S, Kim SH, Lee JS, Kim HD, Kang HC. Long-term outcomes of ketogenic diet in patients with tuberous sclerosis complex-derived epilepsy. Epilepsy Res. 2020;164:106348.

  163. Kossoff EH, Thiele EA, Pfeifer HH, McGrogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia. 2005;46:1684–6.

    Article  PubMed  Google Scholar 

  164. Gavrilovici C, Rho JM. Metabolic epilepsies amenable to ketogenic therapies: Indications, contraindications, and underlying mechanisms. J Inherit Metab Dis. 2021;44:42–53.

    Article  PubMed  Google Scholar 

  165. Liu H, Huang J, Liu H, Li F, Peng Q, Liu C. Effects of ketogenic diet containing medium-chain fatty acids on serum inflammatory factor and mTOR signaling pathway in rats. Chem Biol Technol Agric. 2020;7:1–9.

    Article  CAS  Google Scholar 

  166. Giacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia. 2017;116:77–84.

    Article  CAS  PubMed  Google Scholar 

  167. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource. Silver Spring: Food and Drug Administration and Bethesda: National Institutes of Health; 2017.

  168. Wu JY, Goyal M, Peters JM, Krueger D, Sahin M, Northrup H, et al. Scalp EEG spikes predict impending epilepsy in TSC infants: a longitudinal observational study. Epilepsia. 2019;60:2428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wu JY, Peters JM, Goyal M, Krueger D, Sahin M, Northrup H, et al. Clinical electroencephalographic biomarker for impending epilepsy in asymptomatic tuberous sclerosis complex infants. Pediatr Neurol. 2016;54:29–34.

    Article  PubMed  Google Scholar 

  170. De Ridder J, Verhelle B, Vervisch J, Lemmens K, Kotulska K, Moavero R, et al. Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes. Epilepsia. 2021;62:1208–19.

    Article  PubMed  CAS  Google Scholar 

  171. Jozwiak S, Kotulska K, Wong M, Bebin M. Modifying genetic epilepsies: results from studies on tuberous sclerosis complex. Neuropharmacology. 2020;166:107908.

    Article  CAS  PubMed  Google Scholar 

  172. Bebin M. Preventing epilepsy using vigabatrin in infants with tuberous sclerosis complex: NCT02849457. In: Clinicaltrials. US National Library of Medicine. 2000. https://clinicaltrials.gov/ct2/show/NCT02849457?term=NCT02849457&draw=2&rank=1%0Ahttps://clinicaltrials.gov/ct2/show/NCT02849457. Accessed 27 Feb 2020.

  173. Moavero R, Kotulska K, Lagae L, Benvenuto A, Emberti Gialloreti L, Weschke B, et al. Is autism driven by epilepsy in infants with tuberous sclerosis complex? Ann Clin Transl Neurol. 2020;7:1371–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Słowińska M, Kotulska K, Szymańska S, Roberds SL, Fladrowski C, Jóźwiak S. Approach to preventive epilepsy treatment in tuberous sclerosis complex and current clinical practice in 23 countries. Pediatr Neurol. 2021;115:21–7.

    Article  PubMed  Google Scholar 

  175. Children’s Hospital Medical Center. Stopping TSC onset and progression 2: epilepsy prevention in TSC infants: NCT04595513. In: Clinicaltrials. US National Library of Medicine. 2020. https://clinicaltrials.gov/ct2/show/NCT04595513. Accessed 8 Apr 2021.

  176. Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia. 1997;38:1270–4.

    Article  CAS  PubMed  Google Scholar 

  177. Knupp KG, Coryell J, Nickels KC, Ryan N, Leister E, Loddenkemper T, et al. Response to treatment in a prospective national infantile spasms cohort. Ann Neurol. 2016;79:475–84.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Knupp KG, Leister E, Coryell J, Nickels KC, Ryan N, Juarez-Colunga E, et al. Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort. Epilepsia. 2016;57:1834–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Oxford Centre for Evidence-Based Medicine. Levels of evidence. In: Centre for Evidence-Based Medicine (CEBM), University of Oxford. 2009. https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009. Accessed 8 Apr 2021.

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Authors and Affiliations

  1. Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker Enfants Malades University Hospital, APHP, Université de Paris, 149 rue de Sèvres, 75015, Paris, France

    Rima Nabbout, Mathieu Kuchenbuch & Catherine Chiron

  2. UMR 1163, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine Institute, Université de Paris, Paris, France

    Rima Nabbout & Mathieu Kuchenbuch

  3. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1141, Neurospin, Gif sur Yvette, France

    Catherine Chiron

  4. Department of System Medicine, Child Neurology and Psychiatry Unit, Tor Vergata University Hospital, Rome, Italy

    Paolo Curatolo

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Rima Nabbout reports grants from EU, Horizons 2020, and FP7, unrestricted educational grants from Shire, Eisai, and UCB, and consultancy and lecturer personal fees from Zogenix, Novartis, GW Pharma, Advicenne, Lundebeck, Eisai, Nutricia, and Biocodex, outside the submitted work. Catherine Chiron reports consultancy and lecturer personal fees from Advicenne, Biocodex, Eisai, Orphelia, UCB, and Zogenix, outside the submitted work. Mathieu Kuchenbuch has no conflicts of interest that are directly relevant to the content of this article. Paolo Curatolo reports grants from EU FP7, unrestricted educational grants from Shire, Eisai, and Novartis, and consultancy and lecturer personal fees from Novartis, Eisai, and Humana outside the submitted work.

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Nabbout, R., Kuchenbuch, M., Chiron, C. et al. Pharmacotherapy for Seizures in Tuberous Sclerosis Complex. CNS Drugs 35, 965–983 (2021). https://doi.org/10.1007/s40263-021-00835-8

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