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Epileptogenese und Konsequenzen für die Therapie

Epileptogenesis and consequences for treatment

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Zusammenfassung

Epilepsien sind häufige und stark beeinträchtigende Hirnerkrankungen mit einer erheblichen Belastung für Betroffene und Angehörige weltweit. Die Epileptogenese wird gemeinhin als der plastische Prozess verstanden, der nach einer Schädigung (also bei erworbenen Epilepsien) mit einer Latenz zu epileptischen Anfällen führt. Er ist in einzelnen Fällen bereits bis auf die molekulare Ebene hin verstanden. Die Entdeckung genetischer Defekte hat parallel entscheidend dazu beigetragen, epileptische Krankheitsmechanismen zu entschlüsseln. Beide Forschungsrichtungen haben erste personalisierte Therapieansätze ermöglicht. Zudem können mit Epilepsie assoziierte genetische Varianten wahrscheinlich nicht nur selbst direkt Anfälle verursachen, sondern – wie bei den erworbenen Epilepsien – auch einen epileptogenen Prozess auslösen und mit der altersabhängigen Hirnentwicklung interagieren, sodass sich schließlich genetische Epilepsiesyndrome mit der typischen Altersabhängigkeit manifestieren. Diese Zusammenhänge und daraus erwachsende personalisierte Therapiemöglichkeiten werden in diesem Artikel dargestellt.

Abstract

Epilepsy is a frequent and disabling neurological disease with a significant burden for patients and their relatives worldwide. Epileptogenesis is understood as the plastic process that after an insult (in acquired epilepsies) finally leads to seizures with a latent period. In some cases, epileptogenesis has been clarified down to the molecular level. In parallel, the discovery of genetic defects has decisively contributed to unravel epileptic disease mechanisms. Both research directions have enabled first personalized treatment options. In addition, genetic variants associated with epilepsy can not only directly cause seizures but likely also induce an epileptogenic process (similar as in acquired epilepsies) and interact with developmental processes of the brain, finally leading to the typical age-dependent manifestation of genetic epilepsy syndromes. This article describes these correlations and the consequences for personalized treatment possibilities.

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Literatur

  1. Abou-Khalil B, Ge Q, Desai R et al (2001) Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation. Baillieres Clin Neurol 57:2265–2272

    CAS  Google Scholar 

  2. Ahrens-Nicklas RC, Umanah GK, Sondheimer N et al (2017) Precision therapy for a new disorder of AMPA receptor recycling due to mutations in ATAD1. Neurol Genet 3:e130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Becker AJ, Pitsch J, Sochivko D et al (2008) Transcriptional upregulation of Cav3.2 mediates epileptogenesis in the pilocarpine model of epilepsy. J Neurosci 28:13341–13353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bernard C, Anderson A, Becker A et al (2004) Acquired dendritic channelopathy in temporal lobe epilepsy. Science 305:532–535

    Article  CAS  PubMed  Google Scholar 

  5. Boerma RS, Braun KP, Van Den Broek MP et al (2016) Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics 13:192–197

    Article  CAS  PubMed  Google Scholar 

  6. Consortium on Complex Epilepsies of the International League Against Epilepsy (2014) Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol 13:893

    Article  CAS  Google Scholar 

  7. Consortium on Complex Epilepsies of the International League Against Epilepsy (2018) Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 9:5269

    Article  CAS  Google Scholar 

  8. Doeser A, Dickhof G, Reitze M et al (2015) Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug. Brain 138:371–387

    Article  PubMed  Google Scholar 

  9. Englander J, Bushnik T, Duong TT et al (2003) Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil 84:365–373

    Article  PubMed  Google Scholar 

  10. French JA, Lawson JA, Yapici Z et al (2016) 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 388:2153–2163

    Article  CAS  PubMed  Google Scholar 

  11. Gertler T, Bearden D, Bhattacharjee A et al (2018) KCNT1-Related Epilepsy. In: GeneReviews. University of Washington, Seattle

    Google Scholar 

  12. Goldberg EM, Coulter DA (2013) Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat Rev Neurosci 14:337–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guerrini R, Dravet C, Genton P et al (1998) Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 39:508–512

    Article  CAS  PubMed  Google Scholar 

  14. Gumus H, Bayram AK, Kardas F et al (2015) The effects of Ketogenic diet on seizures, cognitive functions, and other neurological disorders in classical phenotype of glucose transporter 1 deficiency syndrome. Neuropediatrics 46:313–320

    Article  CAS  PubMed  Google Scholar 

  15. Guo D, Zeng L, Brody DL et al (2013) Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PLoS ONE 8:e64078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hedrich UB, Liautard C, Kirschenbaum D et al (2014) Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human NaV1.1 mutation. J Neurosci 34:14874–14889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hedrich UB, Maljevic S (2016) Pathophysiologische Mechanismen genetischer Epilepsien. Z Epileptol 29:77–83

    Article  Google Scholar 

  18. Kass HR, Winesett SP, Bessone SK et al (2016) Use of dietary therapies amongst patients with GLUT1 deficiency syndrome. Seizure 35:83–87

    Article  PubMed  Google Scholar 

  19. Koch H, Garcia AJ 3rd, Ramirez JM (2011) Network reconfiguration and neuronal plasticity in rhythm-generating networks. Integr Comp Biol 51:856–868

    Article  PubMed  PubMed Central  Google Scholar 

  20. Koch H, Huh SE, Elsen FP et al (2010) Prostaglandin E2-induced synaptic plasticity in neocortical networks of organotypic slice cultures. J Neurosci 30:11678–11687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lauxmann S, Verbeek NE, Liu Y et al (2018) Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies. Hum Mutat 39:1942–1956

    Article  CAS  PubMed  Google Scholar 

  22. Lerche H, Biervert C, Alekov AK et al (1999) A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol 46:305–312

    Article  CAS  PubMed  Google Scholar 

  23. Lerche H, Shah M, Beck H et al (2013) Ion channels in genetic and acquired forms of epilepsy. J Physiol 591:753–764

    Article  CAS  PubMed  Google Scholar 

  24. Liu Y, Schubert J, Sonnenberg L et al (2019) Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain 142:376–390

    Article  PubMed  Google Scholar 

  25. Maljevic S, Moller RS, Reid CA et al (2019) Spectrum of GABAA receptor variants in epilepsy. Curr Opin Neurol 32:183–190

    Article  CAS  PubMed  Google Scholar 

  26. Marguet SL, Le-Schulte VT, Merseburg A et al (2015) Treatment during a vulnerable developmental period rescues a genetic epilepsy. Nat Med 21:1436–1444

    Article  CAS  PubMed  Google Scholar 

  27. May P, Girard S, Harrer M et al (2018) Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study. Lancet Neurol 17:699–708

    Article  CAS  PubMed  Google Scholar 

  28. Mctague A, Howell KB, Cross JH et al (2016) The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 15:304–316

    Article  PubMed  Google Scholar 

  29. Millichap JJ, Park KL, Tsuchida T et al (2016) KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2:e96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mullen SA, Carney PW, Roten A et al (2018) Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Baillieres Clin Neurol 90:e67–e72

    CAS  Google Scholar 

  31. Nava C, Dalle C, Rastetter A et al (2014) De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet 46:640–645

    Article  CAS  PubMed  Google Scholar 

  32. Pierson TM, Yuan H, Marsh ED et al (2014) GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 1:190–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pisano T, Numis AL, Heavin SB et al (2015) Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 56:685–691

    Article  CAS  PubMed  Google Scholar 

  34. Pitkänen A, Löscher W, Vezzani A et al (2016) Advances in the development of biomarkers for epilepsy. Lancet Neurol 15:843–856

    Article  CAS  PubMed  Google Scholar 

  35. Surges R, Kukley M, Brewster A et al (2012) Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy. Biochem Biophys Res Commun 420:156–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Syrbe S, Hedrich UBS, Riesch E et al (2015) De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 47:393–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Turrigiano GG, Nelson SB (2004) Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci 5:97–107

    Article  CAS  PubMed  Google Scholar 

  38. Van Loo KM, Schaub C, Pitsch J et al (2015) Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1. Nat Commun 6:8688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vieira AS, De Matos AH, Do Canto AM et al (2016) RNA sequencing reveals region-specific molecular mechanisms associated with epileptogenesis in a model of classical hippocampal sclerosis. Sci Rep 6:22416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wolff M, Johannesen KM, Hedrich UBS et al (2017) Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 140:1316–1336

    Article  PubMed  Google Scholar 

  41. Yu FH, Mantegazza M, Westenbroek RE et al (2006) Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci 9:1142–1149

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Abteilung Neurologie mit Schwerpunkt Epileptologie, Hertie-Institut für klinische Hirnforschung, Universität Tübingen, Hoppe Seyler Straße 3, 72076, Tübingen, Deutschland

    Ulrike B. S. Hedrich, Henner Koch &  Holger Lerche

  2. Institut für Neuropathologie, Universitätsklinikum Bonn, Bonn, Deutschland

    Albert Becker

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  1. Ulrike B. S. Hedrich
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  2. Henner Koch
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  3. Albert Becker
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  4. Holger Lerche
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Correspondence to Holger Lerche.

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Interessenkonflikt

U.B.S. Hedrich, H. Koch, A. Becker und H. Lerche geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Förderung: Diese Übersichtsarbeit wurde unterstützt durch die DFG Forschungsgruppe FOR-2715.

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Hedrich, U.B.S., Koch, H., Becker, A. et al. Epileptogenese und Konsequenzen für die Therapie. Nervenarzt 90, 773–780 (2019). https://doi.org/10.1007/s00115-019-0749-8

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  • DOI: https://doi.org/10.1007/s00115-019-0749-8

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