Download PDF
Nervenheilkunde 2014; 33(05): 356-361
DOI: 10.1055/s-0038-1633401
Epilepsie
Schattauer GmbH

Rationale Epilepsiebehandlung bei tuberöser Sklerose

Rational epilepsy therapy in tuberous sclerosis complex
T. Bast
1   Epilepsiezentrum Kork, Kehl-Kork
,
A. Wiemer-Kruel
1   Epilepsiezentrum Kork, Kehl-Kork
› Author Affiliations
Further Information

Publication History

eingegangen am: 01 November 2013

angenommen am: 10 November 2013

Publication Date:
02 February 2018 (online)

    Permissions and Reprints

Zusammenfassung

Die tuberöse Sklerose (tuberous sclerosis complex, TSC) ist eine Systemerkrankung aufgrund eines Defekts der Tumorsuppressorgene TSC1 (Hamartin) und TSC2 (Tuberin) und der damit verbundenen reduzierten Hemmung des mTOR-Stoffwechsel (mammilian target of rapamycin). Etwa 85% der Patienten leiden an einer Epilepsie, die meist im ersten Lebensjahr und nicht selten als WestSyndrom beginnt und häufig pharmakorefraktär verläuft. Mindestens 60% der Patienten entwickeln kognitive Defizite, Verhaltensstörungen und/oder einen Autismus. Ein früher Epilepsiebeginn korreliert mit diesen Entwicklungsstörungen. Vigabatrin ist bei Säuglingen die Therapie der ersten Wahl. Bei älteren Patienten gibt es keine sicheren Hinweise auf eine höhere Wirksamkeit gegenüber anderen Standardantiepileptika. Die Therapie erfolgt syndromspezifisch nach den Leitlinien. Nach Versagen von zwei Standardtherapien sollte eine prächirurgische Epilepsiediagnostik an einem erfahrenen Zentrum erfolgen, auch bei multiplen Läsionen oder (scheinbar) generalisierten Anfällen. Patienten mit TSC sprechen sehr gut auf ketogene Diäten an. Auch die Vagusnervstimulation zeigt bemerkenswerte Effekte. Erste Berichte legen einen antiepileptischen Effekt von mTOR-Inhibitoren bei TSC nahe.

Summary

Tuberous sclerosis complex (TSC) is a disorder resulting from defects of the tumorsuppressor genes TSC1 (hamartin) and TSC2 (tuberin) and consecutively reduced inhibition of the mTOR pathway. About 85% of the patients suffer from epilepsy. The onset is typically in the first year of life and many patients present with infantile spasms. Epilepsies are frequently pharmacorefractory. At least 60% of the patients present with cognitive deficits, behavioral problems and/or autism. An early epilepsy onset correlates with the degree of the developmental impairment. Vigabatrin is the first line drug in infants. However, there is no evidence of a higher efficacy compared to other standard antiepileptic drugs in older patients. Therefore, epilepsy should be treated according to general guidelines taking into account the electro-clinical syndrome. Presurgical evaluation at an experienced centre is indicated after failure of two standard therapies, even in cases with multiple lesions and (apparently) generalized seizures. Because of apparently good response, ketogenic diets play an important role in TSC-related epilepsy. In addition, remarkable responder rates were reported for vagus nerve stimulation. First studies in a few patients indicate antiepileptic effects of mTOR inhibitors in TSC.

Schlüsselwörter

West-Syndrom - pharmakorefraktär - ketogene Diät - mTOR

Keywords

Infantile spasms - refractory epilepsy - ketogenic diet - mTOR inhibition
 

  • Literatur

  • 1 Bast T. Therapie von Epilepsien im Kindesund Jugendalter. Z Epileptol 2013; 26: 134-141.
    CrossrefGoogle Scholar
  • 2 Baumgartner C. et al. Erster epileptischer Anfall und Epilepsien im Erwachsenenalter. In: Diener HC, Weimar C. (Hrsg.) Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart: Thieme 2012: 28-47.
    Google Scholar
  • 3 Bombardieri R. et al. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol 2010; 14: 146-149.
    CrossrefPubMedGoogle Scholar
  • 4 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: 1186-11971.
    CrossrefPubMedGoogle Scholar
  • 5 Chiron C. et al. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol 1991; (Suppl. 02) S252-9.
    Google Scholar
  • 6 Chu-Shore CJ. et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51: 1236-1241.
    CrossrefPubMedGoogle Scholar
  • 7 Collins JJ. et al. Levetiracetam as adjunctive antiepileptic therapy for patients with tuberous sclerosis complex: a retrospective open-label trial. J Child Neurol 2006; 21: 53-57.
    CrossrefPubMedGoogle Scholar
  • 8 Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372: 657-668.
    CrossrefPubMedGoogle Scholar
  • 9 Cusmai R. et al. Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav 2011; 22: 735-739.
    CrossrefPubMedGoogle Scholar
  • 10 Curatolo P, Jówiak S, Nabbout R. Management of epilepsy associated with tuberous sclerosis complex (TSC): Clinical recommendations. Eur J Paed Neurol 2012; 16: 582-586.
    CrossrefPubMedGoogle Scholar
  • 11 Dulac O. et al. Infantile spasms: toward a selective diagnostic and therapeutic approach. Epilepsia. 2010 51. 2218-2219 author reply 2221..
    PubMedGoogle Scholar
  • 12 Elliott RE. et al. Refractory epilepsy in tuberous sclerosis: vagus nerve stimulation with or without subsequent resective surgery. Epilepsy Behav 2009; 16: 454-460.
    CrossrefPubMedGoogle Scholar
  • 13 Elterman RD, Shields WD, Mansfield KA, Nakagawa J. Randomized trial of vigabatrin in patients with infantile spasms. Neurology 2001; 57: 1416-1421.
    CrossrefPubMedGoogle Scholar
  • 14 Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. J Neurosurg 2011; 115: 1248-1255.
    CrossrefPubMedGoogle Scholar
  • 15 Evans LT, Morse R, Roberts DW. Epilepsy surgery in tuberous sclerosis: a review. Neurosurg Focus 2012; 32: E5.
    CrossrefPubMedGoogle Scholar
  • 16 Franz DN. et al. Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia 2001; 42: 935-940.
    CrossrefPubMedGoogle Scholar
  • 17 Franz DN. 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.
    CrossrefPubMedGoogle Scholar
  • 18 Friedman D. et al. Vigabatrin for partial-onset seizure treatment in patients with tuberous sclerosis complex. Epilepsy Behav 2013; 27: 118-120.
    CrossrefPubMedGoogle Scholar
  • 19 Gaily E, Jonsson H, Lappi M. Visual fields at school-age in children treated with vigabatrin in infancy. Epilepsia 2009; 50: 206-216.
    CrossrefPubMedGoogle Scholar
  • 20 Greiner HM. et al. Vigabatrin for childhood partial-onset epilepsies. Pediatr Neurol 2012; 46: 83-88.
    CrossrefPubMedGoogle Scholar
  • 21 Guerreiro MM. et al. Surgical treatment ofepilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurology 1998; 51: 1263-1269.
    CrossrefPubMedGoogle Scholar
  • 22 Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol 1999; 14: 71-74.
    CrossrefPubMedGoogle Scholar
  • 23 Henderson CB. et al. Efficacy of the ketogenic diet as a treatment option for epilepsy: Meta-analysis. J Child Neurol 2006; 21: 193-198.
    PubMedGoogle Scholar
  • 24 Jansen FE. et al. Epilepsy surgery in tuberous sclerosis: a systematic review. Epilepsia 2007; 48: 1477-1484.
    CrossrefPubMedGoogle Scholar
  • 25 Jansen FE. et al. Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations. Neurology 2008; 70: 908-915.
    CrossrefPubMedGoogle Scholar
  • 26 Jennesson M. et al. Clobazam therapy of refractory epilepsy in tuberous sclerosis complex. Epilepsy Res 2013; 104: 269-274.
    CrossrefPubMedGoogle Scholar
  • 27 Józwiak S. et al. 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 2012; 15: 424-431.
    Google Scholar
  • 28 Kagawa K. et al. Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-(11C)methyl-L-tryptophan positron emission tomography (PET). J Child Neurol 2005; 20: 429-438.
    CrossrefPubMedGoogle Scholar
  • 29 Karvelas G. et al. A retrospective study on aetiology based outcome of infantile spasms. Seizure 2009; 18: 197-201.
    CrossrefPubMedGoogle Scholar
  • 30 Kossoff EH, Thiele EA, Pfeifer HH, McGrogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005; 46: 1684-1686.
    CrossrefPubMedGoogle Scholar
  • 31 Kossoff EH, Freeman JM, Turner Z, Rubenstein JE. Ketogenic diets. Treatments for Epilepsy and Other Disorders. New York: Demos; 2011
    Google Scholar
  • 32 Krueger DA. et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363: 1801-1811.
    CrossrefPubMedGoogle Scholar
  • 33 Krueger DA. et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013 Jun 24. doi: 10.1002/ana.23960.
    PubMedGoogle Scholar
  • 34 Krueger DA. et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 2013; 80: 574-580.
    CrossrefPubMedGoogle Scholar
  • 35 Kurul SH. et al. Protective effects of topiramate against hyperoxic brain injury in the developing brain. Neuropediatrics 2009; 40: 22-27.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Larson AM, Pfeifer HH, Thiele EA. Low glycemic index treatment for epilepsy in tuberous sclerosis complex. Epilepsy Res 2012; 99: 180-182.
    CrossrefPubMedGoogle Scholar
  • 37 Liu SY. et al. Surgical treatment for epilepsy in 17 children with tuberous sclerosis-related West syndrome. Epilepsy Res 2012; 101: 36-45.
    CrossrefPubMedGoogle Scholar
  • 38 Loring DW, Williamson DJ, Meador KJ, Wiegand F, Hulihan J. Topiramate dose effects on cognition: a randomized double-blind study. Neurology 2011; 76: 131-137.
    CrossrefPubMedGoogle Scholar
  • 39 Madhavan D. et al. Surgical outcome in tuberous sclerosis complex: a multicenter survey. Epilepsia 2007; 48: 1625-1628.
    CrossrefPubMedGoogle Scholar
  • 40 Major P, Thiele EA. Vagus nerve stimulation for intractable epilepsy in tuberous sclerosis complex. Epilepsy Behav 2008; 13: 357-360.
    CrossrefPubMedGoogle Scholar
  • 41 Martinez C, Pyzik PL, Kossoff EH. Discontinuing the ketogenic diet in seizure-free children: recurrence and risk factors. Epilepsia 2007; 48: 187-190.
    PubMedGoogle Scholar
  • 42 McDaniel SS. et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 2011; 52: e7-11.
    CrossrefPubMedGoogle Scholar
  • 43 Nangia S. et al. Is the ketogenic diet effective in specific epilepsy syndromes?. Epil Res 2012; 100: 252-257.
    CrossrefPubMedGoogle Scholar
  • 44 O’Callaghan FJ. et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004; 89: 530-533.
    CrossrefPubMedGoogle Scholar
  • 45 Osborne JP. et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia 2010; 51: 2168-2174.
    CrossrefPubMedGoogle Scholar
  • 46 Parain D. et al. Vagal nerve stimulation in tuberous sclerosis complex patients. Pediatr Neurol 2001; 25: 213-216.
    CrossrefPubMedGoogle Scholar
  • 47 Rintahaka P. et al. Visual field defects in vigabatrin-treated children with epilepsy. Epilepsia 2000; 41 (Suppl): 196-197.
    Google Scholar
  • 48 Teutonico F. et al. Epilepsy surgery in tuberous sclerosis complex: early predictive elements and outcome. Childs Nerv Syst 2008; 24: 1437-1445.
    CrossrefPubMedGoogle Scholar
  • 49 van Eeghen AM. et al. Cognitive and adaptive development of patients with tuberous sclerosis complex: a retrospective, longitudinal investigation. Epilepsy Behav 2012; 23: 10-15.
    CrossrefPubMedGoogle Scholar
  • 50 Weiner HL. et al. Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics 2006; 117: 1494-1502.
    CrossrefPubMedGoogle Scholar
  • 51 Wiegand G. et al. Everolimus in tuberous sclerosis patients with intractable epilepsy: A treatment option?. Eur J Paediatr Neurol. 2013 Jul 8. doi: pii: S1090-3798(13)00102-5.10.1016/j.ejpn.2013.06.002.
    PubMedGoogle Scholar
  • 52 Wiemer-Kruel A, Wörle H, Strobl K, Bast T. Case Report: Everolimus for the treatment of subependymal giant cell astrocytoma probably causing seizure aggravation in a child with tuberous sclerosis complex. Neuropediatrics. 2013 DOI: 10.1055/5-0033-13604. E-pub ahead of print.
    PubMedGoogle Scholar
  • 53 Wild JM. et al. Vigabatrin and epilepsy: lessons learned. Epilepsia 2007; 48: 1318-1327.
    CrossrefPubMedGoogle Scholar
  • 54 Willmore LJ. et al. Vigabatrin: 2008 update. Epilepsia 2009; 50: 163-173.
    CrossrefPubMedGoogle Scholar
  • 55 Wohlrab G. et al. Vigabatrin therapy in infantile spasms: solving one problem and inducing another?. Epilepsia 2009; 50: 2006-2007.
    CrossrefPubMedGoogle Scholar
  • 56 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.
    PubMedGoogle Scholar
  • 57 Wu JY. et al. Noninvasive testing, early surgery, and seizure reedom in tuberous sclerosis complex. Neurology 2010; 74: 392-398.
    CrossrefPubMedGoogle Scholar
  • 58 Zamponi N. et al. Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis. Pediatr Neurol 2010; 43: 29-34.
    CrossrefPubMedGoogle Scholar
  • 59 Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 2008; 63: 444-453.
    CrossrefPubMedGoogle Scholar