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Neonatal seizures, Stroke, Seizures, Antiseizure Medication
Background and aim. Neonatal stroke is the second cause of acute symptomatic neonatal seizures after hypoxic-ischemic encephalopathy. The aim of this systematic review is to determine which drug among those available represents the best therapeutic choice for treatment of secondary seizures due to neonatal stroke.
Methods. We performed a systematic review searching on PubMed the keywords “Neonatal”, “Stroke”, “Seizures” and “Treatment”. Search was limited only to English language with no time limit. Last literature search was done on May 30, 2022.
Results. We selected 5 articles involving a total of 52 full-term neonates. In 96.1% the first line treatment was phenobarbital and in 3.9% was used phenobarbital associated with midazolam from the seizure onset but in all of these cases it was necessary to introduce further medications for controlling the seizures. As second line treatment was used lidocaine (response rate of 53.3%), midazolam (response rate of 15.38%) bumetanide (response rate of 100%), and fosphenytoin (no response). As third line treatment was used lidocaine (response rate of 87.5%), Midazolam (response rate of 60%), levetiracetam and clonazepam (response rate of 100%).
Conclusions. Our review shows that the use of ASMs that act throughout a gabaergic mechanism are inadequate in controlling seizures secondary to neonatal stroke in full-term newborns. Very effective seems to be lidocaine and levetiracetam with an apparent safer profile in short and long term. Bumetanide shows promising results, but they need to be confirmed by phase 3 studies.
2. Bernson-Leung ME, Rivkin MJ. Stroke in neonates and children. Pediatr Rev. 2016; 37:463-477.
3. Dunbar M, Kirton A. Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury. Lancet Child Adolesc Health. 2018 Sep;2(9):666-67
4. Morin L, Enderlin J, Leger PL. Different response to antiepileptic drugs according to the type of epileptic events in a neonatal ischemia-reperfusion model. Neurobiol Dis. 2017 Mar;99:145-153
5. Nardou R, Ferrari DC, Ben-Ari Y. Mechanisms and effects of seizures in the immature brain. Semin Fetal Neonatal Med. 2013 Aug;18(4):175-84.
6. Fox CK, Glass HC, Sidney S, Smith SE, Fullerton HJ. Neonatal seizures triple the risk of a remote seizure after perinatal ischemic stroke. Neurology. 2016 Jun 7;86(23):2179-86.
7. Pisani F, Fusco C, Nagarajan L, Spagnoli C. Acute symptomatic neonatal seizures, brain injury, and long-term outcome: The role of neuroprotective strategies. Expert Rev Neurother. 2021 Feb;21(2):189-203.
8. Pisani F, Cerminara C, Fusco C, Sisti L. Neonatal status epilepticus vs recurrent neonatal seizures: clinical findings and outcome. Neurology. 2007 Dec 4;69(23):2177-85).
9. Felling RJ, Dloce A, Hartman AL. Pediatric Stroke and Seizures. In: Seizures in cerebrovascular disorders. A clinical guide. Koubeissi MZ, Alshekhlee A, Mehndiratta P (Eds), Springer New York, NY. 2015 pp.103-119
10. He Y, Ying J, Tang J, Zhou R, Qu H, Qu Y, Mu D. Neonatal Arterial Ischaemic Stroke: Advances in Pathologic neural death, Diagnosis, Treatment, and Prognosis. Curr Neuropharmacol. 2022 Feb 22.
11. Auvin S, Charriaut-Marlangue C. Role of seizure in neonatal stroke. Oncotarget. 2017 Jul 25;8(30):48531-48532
12. Janet SS, Bergin AM, Stopp C et al. A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures. Ann Neurol. 2021; 89: 327–340.
13. Weeke LC, Toet MC, van Rooij LGM et al. Lidocaine response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and preterm infants. Epilepsia, 57:233–242, 2016
14. Shoemaker MT, Rotenberg JS. Levetiracetam for the Treatment of Neonatal Seizures. J Child Neurol. 2007;22: 95-98.
15. Jennekens W, Dankers F, Janssen F et al. Effects of midazolam and lidocaine on spectral properties of the EEG in full-term neonates with stroke. Eur J Paediatr Neurol. 2012;16: 642-652.
16. Govaert P, Dudink J, Visser G, Breukhoven P, Vanhatalo S, Lequin M. Top of the basilar artery embolic stroke and neonatal myoclonus. Dev Med Child Neurol. 2009 Apr;51(4):324-7.
17. Glass HC, Kan J, Bonifacio SL, Ferriero DM. Neonatal seizures: treatment practices among term and preterm infants. Pediatr Neurol. 2012;46:111–115.
18. Castro Conde JR, Borges AAH, Martínez ED, Campo CG, Soler RP. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. 2005;64:876–879.
19. Painter MJ, Scher MS, Stein AD et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341:485–489.
20. Boylan GB, Rennie JM, Chorley G et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. 2004;62:486–488
21. Shany E, Benzaqen O, Watemberg N. Comparison of continuous drip of midazolam or lidocaine in the treatment of intractable neonatal seizures. J Child Neurol. 2007;22:255–259.
22. Sheth RD, Buckley DJ, Gutierrez AR, Gingold M, Bodensteiner JB, Penney S. Midazolam in the treatment of refractory neonatal seizures. Clin Neuropharmacol. 1996;19:165–170.
23. Van den Broek MP, van Straaten HLM, Huitema ADR et al. Anticonvulsant effectiveness and hemodynamic safety of midazolam in full-term infants treated with hypothermia. Neonatology. 2015;107:150–156.
24. Lundqvist M, Ågren J, Hellström-Westas L, Flink R, Wickström R. Efficacy and safety of lidocaine for treatment of neonatal seizures. Acta Paediatr. 2013;102:863–867.
25. Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR. Levetiracetam for treatment of neonatal seizures. J Child Neurol 2011;26:465–470.
26. Falsaperla R, Vitaliti G, Mauceri L et al. Levetiracetam in Neonatal Seizures as First-line Treatment: A Prospective Study. Pediatr Neurosci. 2017 Jan-Mar;12(1):24-28. doi: 10.4103/jpn.JPN_172_16
27. Van Leuven K, Groenendaal F, Toet MC et al. Midazolam and amplitude-integrated EEG in asphyxiated full-term neonates. Acta Paediatr. 2004;93:1221–1227.
28. Hellstrom-Westas L, Svenningsen NW, Westgren U, Rosén I, Lagerström PO. Lidocaine for treatment of severe seizures in newborn infants. II. Blood concentrations of lidocaine and metabolites during intravenous infusion. Acta Paediatr. 1992;81:35–39.
29. Malingre MM, Van Rooij LGM, Rademaker CMA et al. Development of an optimal lidocaine infusion strategy for neonatal seizures. Eur J Pediatr. 2006;165:598–604.
30. Rey E, Radvanyi-Bouvet MF, Bodiou C. Intravenous lidocaine in the treatment of convulsions in the neonatal period: monitoring plasma levels. Ther Drug Monit. 1990 Jul;12(4):316-20.
31. Vento M, de Vries LS, Alberola A. Approach to seizures in the neonatal period: a European perspective. Acta Paediatr. 2010;99:497-501.
32. van den Broek MP, Rademaker CMA, van Straaten HLM et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed. 2013;98:F341–F345.
33. van den Broek MP, Huitema ADR, van Hasselt JGC et al. Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. Clin Pharmacokinet. 2011;50:461–469.
34. Bhardwaj SK, Forcelli PA, Palchik G, Gale K, Srivastava LK, Kondratyev A. Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat. Neuropharmacology. 2012;62:2336–44.
35. Forcelli PA, Janssen MJ, Vicini S, Gale K. Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol. 2012;72:363–72.
36. Mallard C, Zinaida S Vexler. Modeling ischemia in the immature brain how translational are animal models? Stroke. 2015;46:3006 –11
37. Katsarou AM, Galanopoulou AS, Moshé SL. Epileptogenesis in neonatal brain. Semin Fetal Neonatal Med. 2018;23:159 –67.
38. Kubova H, Bendova Z, Moravcova S, Pacesova D, Rocha L, Mares P. Neonatal Clonazepam Administration Induced Long-Lasting Changes in GABA A and GABA B Receptors. Int J Mol Sci 2020 Apr 3; 21(9):3184
39. Falsaperla R, Mauceri L, Pavone P, Short-Term Neurodevelopmental Outcome in Term Neonates Treated with Phenobarbital versus Levetiracetam: A Single-Center Experience. Behavioural Neurology volume 2019.
40. Kim J-S, Kondratyev A, Tomita Y, Gale K. Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia. 2007;48: 19 –26.
41. Gowda VK, Romana A, Shivanna NH, Benakappa N, Benakappa A. Levetiracetam versus phenobarbitone in neonatal seizures – a randomized controlled trial. Indian Pediatr. 2019;56(8):643–646.
42. Sharpe C, Reiner GE, Davis SL et al. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. PEDIATRICS Volume 145, number 6, June 2020:e20193182
43. Kaila K, Löscher W. Bumetanide for neonatal seizures: No light in the pharmacokinetic/dynamic tunnel. Epilepsia. 2022 May 6.
44. Pressler RM, Boylan GB, Marlow N, et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol.2015;14:469–77.