nach oben

Neurotherapeutics

Erschienen in:

23.06.2023 | Current Perspectives

Lennox-Gastaut Syndrome: Current Treatments, Novel Therapeutics, and Future Directions

verfasst von: Julie A. Nelson, Kelly G. Knupp

Erschienen in: Neurotherapeutics | Ausgabe 5/2023

Einloggen, um Zugang zu erhalten

Abstract

Lennox-Gastaut syndrome is a severe drug-resistant developmental and epileptic encephalopathy with slow spike and wave on EEG (DEE-SSW) composing about 1–2% of epilepsy patients. Seizures in DEE-SSW are caused by a variety of etiologies, and there is a large unmet treatment need as seizures are usually treatment-resistant and individuals are often unable to function independently. The updated definition by the International League Against Epilepsy has established formal diagnostic criteria allowing for more uniform diagnosis. This article provides a review of typical medication management and treatment strategies, including new and developing surgical approaches. Future directions in treatment include expanding genetic testing with the potential for gene therapy and continuously improving surgical options with the goal to prevent progression to DEE-SSW.

Lennox Gastaut Syndrome. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=2382

Gastaut H, Roger J, Soulayrol R, Tassinari CA, Régis H, Dravet C, Bernard R, Pinsard N, Saint-Jean M. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as “petit mal variant”) or Lennox syndrome. Epilepsia. 1966;7(2):139–79. https://doi.org/10.1111/j.1528-1167.1966.tb06263.x. PMID: 4959714.CrossRefPubMed

Specchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, Guerreiro M, Gwer S, Zuberi SM, Wilmshurst JM, Yozawitz E, Pressler R, Hirsch E, Wiebe S, Cross HJ, Perucca E, Moshé SL, Tinuper P, Auvin S. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1398–442. https://doi.org/10.1111/epi.17241. Epub 2022 May 3 PMID: 35503717.CrossRefPubMed

Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1989 Jul-Aug;30(4):389–99. https://doi.org/10.1111/j.1528-1157.1989.tb05316.x. PMID: 2502382.

French J, Smith M, Faught E, Brown L. Practice advisory: the use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 1999;52(8):1540–5. https://doi.org/10.1212/wnl.52.8.1540. PMID: 10331676.CrossRefPubMed

French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004 Apr 27;62(8):1261–73. https://doi.org/10.1212/01.wnl.0000123695.22623.32. PMID: 15111660.

Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70(21):1950–8. https://doi.org/10.1212/01.wnl.0000303813.95800.0d. Epub 2008 Apr 9 PMID: 18401024.CrossRefPubMed

Ohtsuka Y, Yoshinaga H, Shirasaka Y, Takayama R, Takano H, Iyoda K. Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan. Epilepsy Res. 2014;108(9):1627–36. https://doi.org/10.1016/j.eplepsyres.2014.08.019. Epub 2014 Sep 2 PMID: 25219353.CrossRefPubMed

Kanner AM, Ashman E, Gloss D, Harden C, Bourgeois B, Bautista JF, Abou-Khalil B, Burakgazi-Dalkilic E, Llanas Park E, Stern J, Hirtz D, Nespeca M, Gidal B, Faught E, French J. Practice guideline update summary: efficacy and tolerability of the new antiepileptic drugs II: treatment-resistant epilepsy: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018 Jul 10;91(2):82–90. doi: https://doi.org/10.1212/WNL.0000000000005756. Epub 2018 Jun 13. Erratum in: Neurology. 2018 Dec 11;91(24):1117. PMID: 29898974.

10.

Conry JA, Ng YT, Paolicchi JM, Kernitsky L, Mitchell WG, Ritter FJ, Collins SD, Tracy K, Kormany WN, Abdulnabi R, Riley B, Stolle J. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia. 2009;50(5):1158–66. https://doi.org/10.1111/j.1528-1167.2008.01935.x. Epub 2008 Dec 15 PMID: 19170737.CrossRefPubMed

11.

Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011 Oct 11;77(15):1473–81. https://doi.org/10.1212/WNL.0b013e318232de76. Epub 2011 Sep 28. PMID: 21956725.

12.

Montouris G, Aboumatar S, Burdette D, Kothare S, Kuzniecky R, Rosenfeld W, Chung S. Expert opinion: Proposed diagnostic and treatment algorithms for Lennox-Gastaut syndrome in adult patients. Epilepsy Behav. 2020 Sep;110:107146. https://doi.org/10.1016/j.yebeh.2020.107146. Epub 2020 Jun 18. PMID: 32563898.

13.

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;29(8):505. https://doi.org/10.3389/fneur.2017.00505. PMID:29085326;PMCID:PMC5649136.CrossRef

14.

Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE, Zuberi SM; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018 May 17;378(20):1888–1897. https://doi.org/10.1056/NEJMoa1714631. PMID: 29768152.

15.

Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Mar 17;391(10125):1085–1096. https://doi.org/10.1016/S0140-6736(18)30136-3. Epub 2018 Jan 26. PMID: 29395273.

16.

Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, Devinsky O, Cross JH, Guerrini R, Talwar D, Miller I, Farfel G, Galer BS, Gammaitoni A, Mistry A, Morrison G, Lock M, Agarwal A, Lai WW, Ceulemans B; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019 Dec 21;394(10216):2243–2254. https://doi.org/10.1016/S0140-6736(19)32500-0. Epub 2019 Dec 17. PMID: 31862249.

17.

Nabbout R, Mistry A, Zuberi S, Villeneuve N, Gil-Nagel A, Sanchez-Carpintero R, Stephani U, Laux L, Wirrell E, Knupp K, Chiron C, Farfel G, Galer BS, Morrison G, Lock M, Agarwal A, Auvin S; FAiRE, DS Study Group. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020 Mar 1;77(3):300–308. https://doi.org/10.1001/jamaneurol.2019.4113. PMID: 31790543; PMCID: PMC6902175.

18.

Knupp KG, Scheffer IE, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Shore S, Agarwal A, Lock M, Farfel GM, Galer BS, Gammaitoni AR, Davis R, Gil-Nagel A. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 2022;79(6):554–64. https://doi.org/10.1001/jamaneurol.2022.0829. PMID:35499850;PMCID:PMC9062770.CrossRefPubMedPubMedCentral

19.

Auvin S, Dozieres B, Ilea A, Delanoë C. Use of perampanel in children and adolescents with Lennox-Gastaut syndrome. Epilepsy Behav. 2017;74:59–63. https://doi.org/10.1016/j.yebeh.2017.05.036. Epub 2017 Jul 14 PMID: 28715780.CrossRefPubMed

20.

Study of perampanel as adjunctive treatment for inadequately controlled seizures associated with Lennox-Gastaut syndrome. https://clinicaltrials.gov/ct2/show/results/NCT02834793?term=perampanel&cond=Lennox+Gastaut+Syndrome&draw=2&rank=1

21.

Falcicchio G, Lattanzi S, Negri F, de Tommaso M, La Neve A, Specchio N. Treatment with cenobamate in adult patients with Lennox-Gastaut syndrome: a case series. J Clin Med. 2022;12(1):129. https://doi.org/10.3390/jcm12010129. PMID:36614931;PMCID:PMC9821211.CrossRefPubMedPubMedCentral

22.

Nishi T, Kondo S, Miyamoto M, Watanabe S, Hasegawa S, Kondo S, Yano J, Watanabe E, Ishi T, Yoshikawa M, Ando HK, Farnaby W, Fujimoto S, Sunahara E, Ohori M, During MJ, Kuroita T, Koike T. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice. Sci Rep. 2020;10(1):17081. https://doi.org/10.1038/s41598-020-74036-6. PMID:33051477;PMCID:PMC7553946.CrossRefPubMedPubMedCentral

23.

Hahn CD, Jiang Y, Villanueva V, Zolnowska M, Arkilo D, Hsiao S, Asgharnejad M, Dlugos D. A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox-Gastaut syndrome (ELEKTRA). Epilepsia. 2022 Oct;63(10):2671–2683. https://doi.org/10.1111/epi.17367. Epub 2022 Aug 4. PMID: 35841234; PMCID: PMC9804149.

24.

Liu Y, Yohrling GJ, Wang Y, Hutchinson TL, Brenneman DE, Flores CM, Zhao B. Carisbamate, a novel neuromodulator, inhibits voltage-gated sodium channels and action potential firing of rat hippocampal neurons. Epilepsy Res. 2009;83(1):66–72. https://doi.org/10.1016/j.eplepsyres.2008.09.006. Epub 2008 Nov 14 PMID: 19013768.CrossRefPubMed

25.

Lee CY, Lee ML, Shih CC, Liou HH. Carisbamate (RWJ-333369) inhibits glutamate transmission in the granule cell of the dentate gyrus. Neuropharmacology. 2011;61(8):1239–47. https://doi.org/10.1016/j.neuropharm.2011.07.022. Epub 2011 Jul 30 PMID: 21824485.CrossRefPubMed

26.

Faught E, Holmes GL, Rosenfeld WE, Novak G, Neto W, Greenspan A, Schmitt J, Yuen E, Reines S, Haas M. Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures. Neurology. 2008;71(20):1586–93. https://doi.org/10.1212/01.wnl.0000334751.89859.7f. PMID: 19001248.CrossRefPubMed

27.

Halford JJ, Ben-Menachem E, Kwan P, Ness S, Schmitt J, Eerdekens M, Novak G. A randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of adjunctive carisbamate treatment in patients with partial-onset seizures. Epilepsia. 2011;52(4):816–25. https://doi.org/10.1111/j.1528-1167.2010.02960.x. Epub 2011 Feb 14 PMID: 21320109.CrossRefPubMed

28.

Sperling MR, Greenspan A, Cramer JA, Kwan P, Kälviäinen R, Halford JJ, Schmitt J, Yuen E, Cook T, Haas M, Novak G. Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized, placebo-controlled trials. Epilepsia. 2010;51(3):333–43. https://doi.org/10.1111/j.1528-1167.2009.02318.x. Epub 2009 Oct 27 PMID: 19863578.CrossRefPubMed

29.

Carisbamate in adult & pediatric subjects with Lennox-Gastaut syndrome. https://clinicaltrials.gov/ct2/show/NCT04062981?term=lennox+gastaut&cond=carisbamate&draw=2&rank=1.

30.

Venzi M, David F, Bellet J, Cavaccini A, Bombardi C, Crunelli V, Di Giovanni G. Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures. Neuropharmacology. 2016 Sep;108:292–304. https://doi.org/10.1016/j.neuropharm.2016.04.016. Epub 2016 Apr 13. PMID: 27085605; PMCID: PMC4920646.

31.

Tolete P, Knupp K, Karlovich M, DeCarlo E, Bluvstein J, Conway E, Friedman D, Dugan P, Devinsky O. Lorcaserin therapy for severe epilepsy of childhood onset: a case series. Neurology. 2018 Oct 30;91(18):837–839. doi: https://doi.org/10.1212/WNL.0000000000006432. Epub 2018 Sep 26. PMID: 30258026; PMCID: PMC6207415.

32.

Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010 May;51(5):899–908. https://doi.org/10.1111/j.1528-1167.2010.02536.x. Epub 2010 Mar 17. PMID: 20331461.

33.

Ilyas A, Pizarro D, Romeo AK, Riley KO, Pati S. The centromedian nucleus: anatomy, physiology, and clinical implications. J Clin Neurosci. 2019;63:1–7. https://doi.org/10.1016/j.jocn.2019.01.050. Epub 2019 Feb 28 PMID: 30827880.CrossRefPubMed

34.

Tyvaert L, Chassagnon S, Sadikot A, LeVan P, Dubeau F, Gotman J. Thalamic nuclei activity in idiopathic generalized epilepsy: an EEG-fMRI study. Neurology. 2009;73(23):2018–22. https://doi.org/10.1212/WNL.0b013e3181c55d02. PMID: 19996076.CrossRefPubMed

35.

Velasco AL, Velasco F, Jiménez F, Velasco M, Castro G, Carrillo-Ruiz JD, Fanghänel G, Boleaga B. Neuromodulation of the centromedian thalamic nuclei in the treatment of generalized seizures and the improvement of the quality of life in patients with Lennox-Gastaut syndrome. Epilepsia. 2006;47(7):1203–12. https://doi.org/10.1111/j.1528-1167.2006.00593.x. PMID: 16886984.CrossRefPubMed

36.

Dalic LJ, Warren AEL, Bulluss KJ, Thevathasan W, Roten A, Churilov L, Archer JS. DBS of thalamic centromedian nucleus for Lennox-Gastaut syndrome (ESTEL trial). Ann Neurol. 2022 Feb;91(2):253–267. https://doi.org/10.1002/ana.26280. Epub 2021 Dec 28. Erratum in: Ann Neurol. 2022 Apr 12; PMID: 34877694.

37.

Kwon CS, Schupper AJ, Fields MC, Marcuse LV, La Vega-Talbott M, Panov F, Ghatan S. Centromedian thalamic responsive neurostimulation for Lennox-Gastaut epilepsy and autism. Ann Clin Transl Neurol. 2020 Oct;7(10):2035–2040. https://doi.org/10.1002/acn3.51173. Epub 2020 Aug 29. PMID: 32860345; PMCID: PMC7545608.

38.

RNS System LGS feasibility study. ClinicalTrials.gov Identifier: NCT05339126. https://clinicaltrials.gov/ct2/show/NCT05339126

39.

Zhang L, Wang Y. Gene therapy in epilepsy. Biomed Pharmacother. 2021 Nov;143:112075. https://doi.org/10.1016/j.biopha.2021.112075. Epub 2021 Sep 3. PMID: 34488082.

Titel: Lennox-Gastaut Syndrome: Current Treatments, Novel Therapeutics, and Future Directions
verfasst von: Julie A. Nelson
Kelly G. Knupp
Publikationsdatum: 23.06.2023
Verlag: Springer International Publishing
Erschienen in: Neurotherapeutics / Ausgabe 5/2023
Print ISSN: 1933-7213
Elektronische ISSN: 1878-7479
DOI: https://doi.org/10.1007/s13311-023-01397-x

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Was nützt die Kraniektomie bei schwerer tiefer Hirnblutung?

17.05.2024 Hirnblutung Nachrichten

Eine Studie zum Nutzen der druckentlastenden Kraniektomie nach schwerer tiefer supratentorieller Hirnblutung deutet einen Nutzen der Operation an. Für überlebende Patienten ist das dennoch nur eine bedingt gute Nachricht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2023

Fecal Microbiota Transplantation from Aged Mice Render Recipient Mice Resistant to MPTP-Induced Nigrostriatal Degeneration Via a Neurogenesis-Dependent but Inflammation-Independent Manner

A Novel Drosophila-based Drug Repurposing Platform Identified Fingolimod As a Potential Therapeutic for TDP-43 Proteinopathy

Dimethyl Fumarate or Teriflunomide for Relapsing–Remitting Multiple Sclerosis: A Meta-analysis of Post-marketing Studies

Olaparib Attenuates Demyelination and Neuroinflammation in an Organotypic Slice Culture Model of Metachromatic Leukodystrophy

The Neuropsychiatric Safety Profile of Lasmiditan: A Comparative Disproportionality Analysis with Triptans