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Ethosuximid bei strukturellen und läsionellen Epilepsien

Ethosuximide in structural-metabolic epilepsy syndromes

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Zusammenfassung

Ethosuximid ist als Antiepileptikum zur Behandlung von kindlichen Absencen und einigen weiteren idiopathischen Epilepsien etabliert. Sein Hauptwirkungsmechanismus ist die Hemmung von Kalzium(Ca-)Kanälen des T-Typs. Neuere Untersuchungen zeigen weitere Wirkungsmechanismen, wie die Beeinflussung von rezeptorgesteuerten Kaliumkanälen („G protein activated inwardly rectifying K+ channel“, GIRK). Tierexperimentell lassen sich antikonvulsive Effekte an oszillatorischen thalamischen Neuronen, aber auch an neokortikalen Strukturen belegen. Diese Wirkungsmechanismen sind bei zur Therapie struktureller, fokaler Epilepsien angewendeten Antiepileptika nicht vorhanden. (Zonisamid hat eine schwache Wirkung auf T-Typ-Ca-Kanäle.) Daher bringt Ethosuximid (und das ähnliche Mesuximid) neue Angriffspunkte in eine Kombinationstherapie therapierefraktärer Epilepsien ein. Anhand von 3 Kasuistiken (2 jugendliche Patienten mit hypothalamischen Hamartomen, ein 3 Jahre alter Junge mit Miller-Dieker-Syndrom) wird gezeigt, dass die Kombination eines Succinimids mit einem Natrium(Na)-Kanal-Hemmer (Lamotrigin, Rufinamid) zur lange anhaltenden, deutlichen Besserung (> 90 % Anfallsreduktion) einer therapierefraktären strukturellen Epilepsie führen kann. Die klinische Wirkung war von dem Sistieren epilepsietypischer Potenziale im EEG begleitet. Diese Beispiele zeigen, dass Ethosuximid nicht nur bei idiopathischen Epilepsien, sondern auch bei schwer therapierbaren strukturellen Epilepsien einen Versuch wert ist. Der Stellenwert der Substanz bei dieser Indikation kann anhand der vorhandenen Datenlage nicht abgeschätzt werden.

Abstract

Ethosuximide is a well-established drug for the treatment of childhood absence epilepsies. In some reports it was also successfully used in other, mostly idiopathic epilepsy syndromes. Its main mechanism of action is blockade of T-type calcium channels but it also exhibits inhibitory effects on G protein-activated inwardly rectifying K+ (GIRK) channels. Animal experiments have shown that anticonvulsant effects are generated in thalamic oscillatory neurons and in some neocortical structures. Moreover, the substance shows antiepileptogenic effects in mouse models of genetic epilepsies. Due to the nearly unique effects (zonisamide shows a weak inhibition of T-type channels too) this drug is an interesting compound in antiepileptic combination therapies. This article presents three cases of severe, pharmacoresistant structural epilepsy where the list of unsuccessfully tried medications showed a gap with regard to T-type calcium channels. Two were adolescents with hypothalamic hamartoma where a long lasting seizure reduction of > 90 % could be achieved by combining lamotrigine and ethosuximide. A third case was a 3-year-old boy with Miller-Dieker syndrome. In this case a massive remission of seizures could be achieved for at least 2 years. In all three cases the effect was accompanied by the disappearance of electroencephalogram (EEG) spike discharges. These case studies show that ethosuximide is a potentially effective agent also in epilepsies with structural etiologies. Its specific mechanisms of action can contribute to polytherapy in highly phramacoresistant epilepsies besides its established indications. Further studies are needed to estimate the chance of a successful treatment under such conditions.

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Literatur

  1. Albus K, Wanhab A, Heinemann U (2012) Primary afterdischarge in organotypic hippocampal slice cultures: effects of standard antiepileptic drugs. Epilepsia 53:1928–1936

    Article  CAS  PubMed  Google Scholar 

  2. Bialer M, White HS (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82

    Article  CAS  PubMed  Google Scholar 

  3. Bonnanini P, Gubernale M, Martinez F et al (2012) Non-convulsive status epilepticus of frontal origin in mucopolysaccharidosis type II successfully treated with ethosuximide. Dev Med Child Neurol 54:961–964

    Article  Google Scholar 

  4. Brodie MJ, Covanis A, Gil-Nagel A et al (2011) Antiepileptic drug therapy: does mechanism of action matter? Epilepsy Behav 21:331–341

    Article  PubMed  Google Scholar 

  5. Brodie MJ, Mumford JP (1999) Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. 012 Study Group. Epilepsy Res 34:199–205

    Article  CAS  PubMed  Google Scholar 

  6. Brodie MJ, Yuen AW (1997) Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group. Epilepsy Res 26:423–432

    Article  CAS  PubMed  Google Scholar 

  7. Browne TR, Dreifuss FE, Dyken PR et al (1975) Ethosuximide in the treatment of absence (petit mal) seizures. Neurology 25:515–524

    Article  CAS  PubMed  Google Scholar 

  8. Caraballo RH, Cejas N, Chamorro N et al (2014) Landau-Kleffner syndrome: a study of 29 patients. Seizure 23:98–104

    Article  PubMed  Google Scholar 

  9. Cereghino JJ, Brock JT, Van Meter JC et al (1975) The efficacy of carbamazepine combinations in epilepsy. Clin Pharmacol Ther 18:733–741

    CAS  PubMed  Google Scholar 

  10. Chen SD, Yeh KH, Huang YH, Shaw FZ (2011) Effect of intracranial administration of ethosuximide in rats with spontaneous or pentylenetetrazol-induced spike-wave discharges. Epilepsia 52:1311–1318

    Article  CAS  PubMed  Google Scholar 

  11. Chen A, Weston JK, Bratton AC Jr (1963) Anticonvulsant activity and ethosuximide. Epilepsia 4:66–67

    Article  CAS  PubMed  Google Scholar 

  12. Dezsi G, Ozturk E, Stanic D et al (2013) Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 54:635–643

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Farell K (1993) Secondary generalized epilepsy and Lennox-Gastaut syndrome. In: Wyllie E (Hrsg) The treatment of epilepsy. Lea & Febiger, Philadelphia, S 604–613

  14. Glauser TA, Cnaan A, Shinnar S et al (2010) Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362:790–799

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Glauser T, Cnaan A, Shinnar S et al (2013) Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 54:141–155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Greenhill D, Morgan NH, Massey PV et al (2012) Ethosuximide modifies network excitability in the rat entorhinal cortex via an increase in GABA release. Neuropharmacology 62:807–814

    Article  CAS  PubMed  Google Scholar 

  17. Kobayashi T, Hirai H, Iino M et al (2009) Inhibitory effects of the antiepileptic drug ethosuximide on G protein-activated inwardly rectifying K+ channels. Neuropharmacology 56:499–506

    Article  CAS  PubMed  Google Scholar 

  18. Li G, Yang K, Zheng C et al (2011) Functional rundown of gamma- aminobutyric acid A receptors in human hypothalamic hamartomas. Ann Neurol 69:644–672

    Article  Google Scholar 

  19. Polack PO, Charpier S (2009) Ethosuximide converts ictogenic neurons initiating absence seizures into normal neurons in a genetic model. Epilepsia 50:1817–1820

    Article  Google Scholar 

  20. Rowan AJ, Meijer JW, Beer-Pawlikowski N de et al (1983) Valproate – ethosuximide combination therapy for refractory absence seizures. Arch Neurol 40:797–802

    Article  CAS  PubMed  Google Scholar 

  21. Russo E, Citraro R, Scicchitano F et al (2010) Comparison of the antiepileptogenic effects of an early long-term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy. Epilepsia 51:1560–1569

    Article  CAS  PubMed  Google Scholar 

  22. Saké J-K, Herbert D, Isojarvi J et al (2010) A pooled analysis of lacosamide clinical trial data grouped by mechanisms of action of concomitant antiepileptic drugs. CNS Drugs 24:1055–1068

    Article  CAS  PubMed  Google Scholar 

  23. Sánchez-Fernández I, Chapman K, Peters JM et al (2013) Continuous spikes and waves during sleep: electroclinical presentation and suggestions for management. Epilepsy Res Treat 2013:583531

    PubMed Central  PubMed  Google Scholar 

  24. Serratosa JM, Delgado-Esqueta AV (1993) Juvenile myoclonic epilepsy. In: Wyllie E (Hrsg) The treatment of epilepsy. Lea & Febiger, Philadelphia, S 552–570

  25. Simeone KA, Sabesan S, Kim DY et al (2011) L-type calcium channel blockade reduces network activity in human epileptic hypothalamic hamartoma tissue. Epilepsia 52:531–540

    Article  PubMed Central  PubMed  Google Scholar 

  26. Steriade M, Deschenes M (1984) The thalamus as a neuronal oscillator. Brain Res Rev 8:1–63

    Article  Google Scholar 

  27. Vossen R (1958) On the anticonvulsant effect of succinimides. Dtsch Med Wochenschr 83:1227–1230

    Article  CAS  PubMed  Google Scholar 

  28. Zhang C, Kwan P, Zuo Z, Baum L (2010) In vitro concentration dependent transport of phenytoin and phenobarbital, but not ethosuximide, by human P-glycoprotein. Life Sci 86:899–905

    Article  CAS  PubMed  Google Scholar 

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Einhaltung der ethischen Richtlinien

Interessenkonflikt. U. Brandl erhält Honorare für Vorträge von verschiedenen Antiepileptikaherstellern (Desitin, Eisai, UCB, Viropharma). Keines dieser Honorare steht im Zusammenhang mit der in diesem Beitrag behandelten Substanz. Der Beitrag enthält keine Studien an Menschen oder Tieren.

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  1. Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Jena, Kochstr. 2, 07743, Jena, Deutschland

    U. Brandl

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Brandl, U. Ethosuximid bei strukturellen und läsionellen Epilepsien. Z. Epileptol. 27, 132–138 (2014). https://doi.org/10.1007/s10309-013-0353-z

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