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Open Access 01-12-2020 | Epilepsy | Study protocol

Corticosteroids versus clobazam in epileptic encephalopathy with ESES: a European multicentre randomised controlled clinical trial (RESCUE ESES*)

Authors: Bart van den Munckhof, Alexis Arzimanoglou, Emilio Perucca, Heleen C. van Teeseling, Frans S. S. Leijten, Kees P. J. Braun, Floor E. Jansen, on behalf of the RESCUE ESES study group

Published in: Trials | Issue 1/2020

Abstract

Background

Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is an epilepsy syndrome occurring almost exclusively in children, usually at an age between 4 and 12 years. It is characterised by abundant sleep-induced epileptic activity in the electroencephalogram (EEG) and by acquired cognitive and behavioural deficits. The goal of treatment is to prevent further decline or even improve cognitive functioning. Based on mostly small and retrospective studies, corticosteroids and clobazam are regarded by many clinicians as the most effective pharmacological treatments. This European multicentre randomised controlled trial is designed to compare the effects of corticosteroids and clobazam on cognitive functioning after 6 months. Secondary outcomes include cognitive functioning after 18 months, EEG abnormalities in sleep, safety and tolerability, and seizure frequency. We also aimed at investigating whether treatment response in epileptic encephalopathy with ESES can be predicted by measurement of inflammatory mediators and autoantibodies in serum.

Methods

The pragmatic study will be performed in centres with expertise in the treatment of rare paediatric epilepsy syndromes across Europe. A total of 130 patients, 2 to 12 years of age, with epileptic encephalopathy with ESES will be enrolled and randomised in a 1:1 ratio to receive either corticosteroids (monthly intravenous methylprednisolone pulses or daily oral prednisolone) or oral clobazam for 6 months according to an open-label parallel-group design. Follow-up visits with clinical assessment, EEGs, and neuropsychological testing are scheduled for up to 18 months. Blood samples for cytokine and autoantibody testing are obtained before treatment and 8 months after treatment initiation.

Discussion

The treatment of epileptic encephalopathy with ESES aims at improving cognitive outcome. This randomised controlled study will compare the most frequently used treatments, i.e. corticosteroids and clobazam. If the study proves superiority of one treatment over the other or identifies biomarkers of treatment response, results will guide clinicians in the early treatment of this severe epilepsy syndrome.

Trial registration

ISRCTN, ISRCTN42686094. Registered on 24 May 2013.

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Patry G, Lyagoubi S, Tassinari CA. Subclinical “electrical status epilepticus” induced by sleep in children. Arch Neurol. 1971;24(3):242–52. https://doi.org/10.1001/archneur.1971.00480330070006.CrossRefPubMed

Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology. 1957;7(8):1241, 8 pages following 1241. https://doi.org/10.1212/WNL.7.8.523.CrossRef

Fernández IS, Chapman KE, Peters JM, et al. The tower of Babel: survey on concepts and terminology in electrical status epilepticus in sleep and continuous spikes and waves during sleep in North America. Epilepsia. 2013;54(4):741–50. https://doi.org/10.1111/epi.12039.CrossRefPubMed

Nickels K, Wirrell E. Electrical status epilepticus in sleep. Semin Pediatr Neurol. 2008;15(2):50–60. https://doi.org/10.1016/j.spen.2008.03.002.CrossRefPubMed

Sánchez Fernández I, Loddenkemper T, Peters JM, Kothare SV. Electrical status epilepticus in sleep: clinical presentation and pathophysiology. Pediatr Neurol. 2012;47(6):390–410. https://doi.org/10.1016/j.pediatrneurol.2012.06.016.CrossRefPubMed

Hughes JR. A review of the relationships between Landau–Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike–waves during sleep. Epilepsy Behav. 2011;20(2):247–53. https://doi.org/10.1016/j.yebeh.2010.10.015.CrossRefPubMed

Ballaban-Gil K, Tuchman R. Epilepsy and epileptiform EEG: association with autism and language disorders. Ment Retard Dev Disabil Res Rev. 2000;6(4):300–8. https://doi.org/10.1002/1098-2779(2000)6:4<300::AID-MRDD9>3.0.CO;2-R.CrossRefPubMed

Tassinari CA, Rubboli G. Encephalopathy related to Status Epilepticus during slow Sleep: current concepts and future directions. Epileptic Disord. 2019. https://doi.org/10.1684/epd.2019.1062.

Bölsterli BK, Schmitt B, Bast T, et al. Impaired slow wave sleep downscaling in encephalopathy with status epilepticus during sleep (ESES). Clin Neurophysiol. 2011;122(9):1779–87. https://doi.org/10.1016/j.clinph.2011.01.053.CrossRefPubMed

10.

Kersbergen KJ, De Vries LS, Leijten FSS, et al. Neonatal thalamic hemorrhage is strongly associated with electrical status epilepticus in slow wave sleep. Epilepsia. 2013;54(4):733–40. https://doi.org/10.1111/epi.12131.CrossRefPubMed

11.

van den Munckhof B, Zwart AF, Weeke LC, et al. Perinatal thalamic injury: MRI predictors of electrical status epilepticus in sleep and long-term neurodevelopment. NeuroImage Clin. 2020. https://doi.org/10.1016/j.nicl.2020.102227.

12.

Lemke JR, Lal D, Reinthaler EM, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45(9):1067–72. https://doi.org/10.1038/ng.2728.CrossRefPubMed

13.

Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet. 2013;45(9):1061–6. https://doi.org/10.1038/ng.2726.CrossRefPubMed

14.

de Vries EE, van den Munckhof B, Braun KPJ, van Royen-Kerkhof A, de Jager W, Jansen FE. Inflammatory mediators in human epilepsy: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2016;63:177–90. https://doi.org/10.1016/j.neubiorev.2016.02.007.CrossRefPubMed

15.

Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deul RK. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999;134(5):607–13. https://doi.org/10.1016/S0022-3476(99)70248-9.CrossRefPubMed

16.

Van Den Munckhof B, De Vries EE, Braun KPJ, et al. Serum inflammatory mediators correlate with disease activity in electrical status epilepticus in sleep (ESES) syndrome. Epilepsia. 2016;57(2):e45–50. https://doi.org/10.1111/epi.13274.CrossRefPubMed

17.

Giovanardi Rossi P, Parmeggiani A, Posar A, Scaduto MC, Chiodo S, Vatti G. Landau–Kleffner syndrome (LKS): long-term follow-up and links with electrical status epilepticus during sleep (ESES). Brain and Development. 1999;21(2):90–8. https://doi.org/10.1016/S0387-7604(98)00071-0.CrossRef

18.

Pera MC, Brazzo D, Altieri N, Balottin U, Veggiotti P. Long-term evolution of neuropsychological competences in encephalopathy with status epilepticus during sleep: a variable prognosis. Epilepsia. 2013;54(SUPPL.7):77–85. https://doi.org/10.1111/epi.12313.CrossRefPubMed

19.

van den Munckhof B, van Dee V, Sagi L, et al. Treatment of electrical status epilepticus in sleep: a pooled analysis of 575 cases. Epilepsia. 2015;56(11):1738–46. https://doi.org/10.1111/epi.13128.CrossRefPubMed

20.

van den Munckhof B, Alderweireld C, Davelaar S, et al. Treatment of electrical status epilepticus in sleep: clinical and EEG characteristics and response to 147 treatments in 47 patients. Eur J Paediatr Neurol. 2018;22(1):64–71. https://doi.org/10.1016/j.ejpn.2017.08.006.CrossRefPubMed

21.

Liukkonen E, Kantola-Sorsa E, Paetau R, Gaily E, Peltola M, Granström ML. Long-term outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome. Epilepsia. 2010. https://doi.org/10.1111/j.1528-1167.2010.02578.x.

22.

Sánchez Fernández I, Chapman K, Peters JM, et al. Treatment for continuous spikes and waves during sleep (CSWS): survey on treatment choices in North America. Epilepsia. 2014;55:1099–108. https://doi.org/10.1111/epi.12678.CrossRefPubMed

23.

Veggiotti P, Pera MC, Teutonico F, Brazzo D, Balottin U, Tassinari CA. Therapy of encephalopathy with status epilepticus during sleep (ESES/CSWS syndrome): an update. Epileptic Disord. 2012;14(1):1–11. https://doi.org/10.1684/epd.2012.0482.CrossRefPubMed

24.

van Coevorden-Hameete MH, Titulaer MJ, Schreurs MWJ, de Graaff E, Sillevis Smitt PAE, Hoogenraad CC. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016. https://doi.org/10.3389/fnmol.2016.00037.

25.

Nguyen TL, Collins GS, Lamy A, et al. Simple randomization did not protect against bias in smaller trials. J Clin Epidemiol. 2017. https://doi.org/10.1016/j.jclinepi.2017.02.010.

26.

Saquib N, Saquib J, Ioannidis JPA. Practices and impact of primary outcome adjustment in randomized controlled trials: meta-epidemiologic study. BMJ. 2013. https://doi.org/10.1136/bmj.f4313.

27.

Donders ART, van der Heijden GJMG, Stijnen T, Moons KGM, Van Der Heijden G. Review: a gentle introduction to imputation of missing values. J Clin Epidemiol. 2006;59(10):1087–91. https://doi.org/10.1016/j.jclinepi.2006.01.014.CrossRefPubMed

28.

Kramer U, Sagi L, Goldberg-Stern H, Zelnik N, Nissenkorn A, Ben-Zeev B. Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep (ESES). Epilepsia. 2009;50(6):1517–24. https://doi.org/10.1111/j.1528-1167.2008.01891.x.CrossRefPubMed

29.

Cohen J. Statistical power analysis for the behavioural science (2nd Edition). In: Statistical power anaylsis for the behavioural science (2nd Edition); 1988. p. 25–7.

Title: Corticosteroids versus clobazam in epileptic encephalopathy with ESES: a European multicentre randomised controlled clinical trial (RESCUE ESES*)
Authors: Bart van den Munckhof
Alexis Arzimanoglou
Emilio Perucca
Heleen C. van Teeseling
Frans S. S. Leijten
Kees P. J. Braun
Floor E. Jansen
on behalf of the RESCUE ESES study group
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Epilepsy
Clobazam
Encephalopathy
Published in: Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-020-04874-2

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Corticosteroids versus clobazam in epileptic encephalopathy with ESES: a European multicentre randomised controlled clinical trial (RESCUE ESES*)

Abstract

Background

Methods

Discussion

Trial registration

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Abstract

Background

Methods

Discussion

Trial registration

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