Investigating and managing neonatal seizures in the UK: an explanatory sequential mixed methods approach

Lucy Gossling, James J P Alix, Theocharis Stavroulakis, Anthony R Hart, Lucy Gossling, James J P Alix, Theocharis Stavroulakis, Anthony R Hart

Abstract

Background: Neonatal seizures are difficult to diagnose and, when they are, tradition dictates first line treatment is phenobarbital. There is little data on how consultants diagnose neonatal seizures, choose when to treat or how they choose aetiological investigations or drug treatments. The purpose of this study was to assess the variation across the UK in the management of neonatal seizures and explore paediatricians' views on their diagnosis and treatment.

Methods: An explanatory sequential mixed methods approach was used (QUAN→QUAL) with equal waiting between stages. We collected quantitative data from neonatology staff and paediatric neurologists using a questionnaire sent to neonatal units and via emails from the British Paediatric Neurology Association. We asked for copies of neonatal unit guidelines on the management of seizures. The data from questionnaires was used to identify16 consultants using semi-structured interviews. Thematic analysis was used to interpret qualitative data, which was triangulated with quantitative questionnaire data.

Results: One hundred questionnaires were returned: 47.7% thought levetiracetam was as, or equally, effective as phenobarbital; 9.2% thought it was less effective. 79.6% of clinicians had seen no side effects in neonates with levetiracetam. 97.8% of unit guidelines recommended phenobarbital first line, with wide variation in subsequent drug choice, aetiological investigations, and advice on when to start treatment. Thematic analysis revealed three themes: 'Managing uncertainty with neonatal seizures', 'Moving practice forward' and 'Multidisciplinary team working'. Consultants noted collecting evidence on anti-convulsant drugs in neonates is problematic, and recommended a number of solutions, including collaboration to reach consensus guidelines, to reduce diagnostic and management uncertainty.

Conclusions: There is wide variation in the management of neonatal seizures and clinicians face many uncertainties. Our data has helped reveal some of the reasons for current practice and decision making. Suggestions to improve certainty include: educational initiatives to improve the ability of neonatal staff to describe suspicious events, greater use of video, closer working between neonatologists and neurologists, further research, and a national discussion to reach a consensus on a standardised approach to managing neonatal epileptic seizures.

Keywords: Anticonvulsants; Differential diagnosis; Hypoxia-ischemia, Brain; Infant / newborn; Neurophysiology; Seizures.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Investigations recommended on received guidelines to determine the aetiology of neonatal seizures: Red – 1st line; blue – 2nd line or only to be requested under certain circumstances; orange – 3rd line. Guideline from centre G did not attempt to recommend investigations. Abbreviations: FBC – full blood count; U&E – urea and electrolytes; LFT – liver function tests; CK – creatine kinase, TFT – thyroid function test; AA – amino acids; VLCFA – very long chain fatty acids; CRP – C-reactive protein; OA – organic acids; AASA – alpha amino adipic semialdehyde; MRI – magnetic resonance imaging; aEEG – amplitude integrated electroencephalography; EEG – electroencephalography
Fig. 2
Fig. 2
Information from received guidelines on when to treat neonatal seizures, and recommended treatments and doses. Red – 1st line; blue - 2nd line; orange – 3rd line; pink – 4th line; green – 5th line; turquoise – 6th line; grey – 7th line; black – 8th line; purple – 9th line; yellow – to be tried at the discretion of the consultant at any time. Abbreviations: D – diazepam; L – lorazepam; mg – milligram; mcg – microgram; kg – kilogram; h – hour; d- day, BD – twice a day; TDS – three times a day
Fig. 3
Fig. 3
Summary of results of thematic analysis from qualitative interview study

References

    1. Annegers JF, Hauser WA, Lee JR, Rocca WA. Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935-1984. Epilepsia. 1995;36(4):327–333. doi: 10.1111/j.1528-1157.1995.tb01005.x.
    1. Dzhala VI, Staley KJ. Excitatory actions of endogenously released GABA contribute to initiation of ictal epileptiform activity in the developing hippocampus. J Neurosci. 2003;23(5):1840–1846. doi: 10.1523/JNEUROSCI.23-05-01840.2003.
    1. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11(11):1205–1213. doi: 10.1038/nm1301.
    1. Glass HC. Neonatal seizures: advances in mechanisms and management. Clin Perinatol. 2014;41(1):177–190. doi: 10.1016/j.clp.2013.10.004.
    1. Hart AR, Pilling EL, Alix JJP. Neonatal seizures: part two - the neonatal epilepsy syndromes, aetiologies and treatments. Arch Dis Child Educ Pract Ed. 2015;100(5):226–232. doi: 10.1136/archdischild-2014-306388.
    1. Huttenlocher PR, de Courten C, Garey LJ, van der Loos H. Synaptogenesis in human visual cortex - evidence for synapse elimination during normal development. Neurosci Lett. 1982;33(3):247–252. doi: 10.1016/0304-3940(82)90379-2.
    1. Jensen FE. Neonatal seizures: an update on mechaninsms and management. Clin Perinatol. 2009;36(4):881–900. doi: 10.1016/j.clp.2009.08.001.
    1. Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment. 2. London: Springer; 2007. Neonatal epileptic seizures and neonatal epileptic syndromes; pp. 237–258.
    1. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed. 2008;93(3):F187–F191. doi: 10.1136/adc.2005.086314.
    1. Bye A, Flanagan D. Electroencephalograms, clinical observations and the monitoring of neonatal seizures. J Paediatr Child Health. 1995;31(6):503–507. doi: 10.1111/j.1440-1754.1995.tb00872.x.
    1. Boylan G, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed. 2002;86(3):F165–F170. doi: 10.1136/fn.86.3.F165.
    1. Clancy RR, Legido A, Lewis D. Occult neonatal seizures. Epilepsia. 1988;29(3):256–261. doi: 10.1111/j.1528-1157.1988.tb03715.x.
    1. Hellstrom-Westas L, Rosen I, Swenningsen NW. Silent seiuzres in sick infants in early life. Diagnosis by continuous cerebral function monitoring. Acta Paediatr Scand. 1985;74(5):741–748. doi: 10.1111/j.1651-2227.1985.tb10024.x.
    1. Wusthoff CJ, Dlugos DJ, Gutierrez-Colina A, Wang A, Cook N, Donnelly M, et al. Electrographic seizures during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy. J Child Neurol. 2011;26(6):724–728. doi: 10.1177/0883073810390036.
    1. Boylan GB, Stevenson NJ, Vanhatalo S. Monitoring neonatal seizures. Semin Fetal Neonatal Med. 2013;18(4):202–208. doi: 10.1016/j.siny.2013.04.004.
    1. Malone A, Ryan CA, Fitzgerald A, Burgoyne L, Connolly S, Boylan GB. Interobserver agreement in neonatal seizure identification. Epilepsia. 2009;50(9):2097–2101. doi: 10.1111/j.1528-1167.2009.02132.x.
    1. Hart AR, Ponnusamy A, Pilling E, Alix JJP. Neonatal cerebral function monitoring - understanding the amplitude integrated EEG. Paediatr Child Health. 2017;27(4):187–195. doi: 10.1016/j.paed.2016.11.006.
    1. Hellstrom-Westas L, Rosen I, de Vries LS, Griesen G. Amplitude-integrated EEG classification and interpretation in preterm and term infants. Neoreviews. 2006;7(2):e76–e87. doi: 10.1542/neo.7-2-e76.
    1. Mastrangelo M, Fiocchi I, Fontana P, Gorgone G, Lista G, Belcastro V. Acute neonatal encephalopathy and seizures recurrence: a combined aEEG/EEG study. Seizure. 2013;22(9):703–707. doi: 10.1016/j.seizure.2013.05.006.
    1. Hellstrom-Westas L. Amplitude-integrated electroencephalography for seizure detection in newborn infants. Semin Fetal Neonatal Med. 2018;23(3):175–182. doi: 10.1016/j.siny.2018.02.003.
    1. Rakshasbhuvankar A, Rao S, Palumbo L, Ghosh S, Nagarajan L. Amplitude integrated electroencephalography compared with conventional video EEG for neonatal seizure detection: a diagnostic accuracy study. J Child Neurol. 2017;32(9):815–822. doi: 10.1177/0883073817707411.
    1. McNally MA, Hartman AL. Variability in preferred Management of Electrographic Seizures in neonatal hypoxic ischemic encephalopathy. Pediatr Neurol. 2017;77:37–41. doi: 10.1016/j.pediatrneurol.2017.06.006.
    1. World Health Organisation . Guidelines on neonatal seizures. Geneva: World Health Organisation; 2011.
    1. Tashakkori A, Creswell JW. Exploring the nature of research questions in mixed methods research. J Mixed Methods Res. 2007;1(3):207–211. doi: 10.1177/1558689807302814.
    1. Ivankova NV, Creswell JW, Stick SL. Using mixed-methods sequential explanatory design: from theory to practice. Field Methods. 2006;18(1):3–20. doi: 10.1177/1525822X05282260.
    1. Wickstrom R, Hallberg B, Bartocci M. Differing attitudes toward phenobarbital use in the neonatal period among neonatologists and child neurologists in Sweden. Eur J Paediatr Neurol. 2013;17(1):55–63. doi: 10.1016/j.ejpn.2012.09.001.
    1. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77–101. doi: 10.1191/1478088706qp063oa.
    1. Guest G, Brunce A, Johnson L. How many interviews are enough? Field Methods. 2006;18(1):59–82. doi: 10.1177/1525822X05279903.
    1. Hagaman AK, Wutoch A. How many interviews are enough to identify Metathemes in multisited and cross-cultural research? Another perspective on Guest, Bunce, and Johnson’s (2006) landmark study. Field Methods. 2017;29(1):23–41. doi: 10.1177/1525822X16640447.
    1. Namey E, Guest G, McKenna K. Evaluating bang for the Buck: a cost-effectiveness comparison between individual interviews and focus groups based on thematic saturation levels. Am J Eval. 2016;37(3):425–440. doi: 10.1177/1098214016630406.
    1. Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics. 1989;84(3):422–428.
    1. Wusthoff CJ. Diagnosing neonatal seizures and status epilepticus. J Clin Neurophysiol. 2013;30(2):115–121. doi: 10.1097/WNP.0b013e3182872932.
    1. Shah DK, Boylan GB, Rennie JM. Monitoring of seizures in the newborn. Arch Dis Child Fetal Neonatal Ed. 2012;97(1):F65–F69. doi: 10.1136/adc.2009.169508.
    1. Kalra V, Shaw SS, Dixon S, Shah DK, Clarke P. Cerebral function monitoring on a general paediatric ward: feasibility and potential. Eur J Pediatr. 2016;175(8):1059–1064. doi: 10.1007/s00431-016-2737-3.
    1. Epilepsies: diagnosis and management. Clinical Guidline CG137 [Internet]. 2012. Cited 13/11/2018.
    1. Dereymaeker A, Ansari AH, Jansen K, Cherian PJ, Vervisch J, Govaert P, et al. Interrater agreement in visual scoring of neonatal seizures based on majority voting on a web-based system: the Neoguard EEG database. Clin Neurophysiol. 2017;128(9):1737–1745. doi: 10.1016/j.clinph.2017.06.250.
    1. Wusthoff CJ, Sullivan J, Glass HC, Shellhaas RA, Abend NS, Chang T, et al. Interrater agreement in the interpretation of neonatal electroencephalography in hypoxic-ischemic encephalopathy. Epilepsia. 2017;58(3):429–435. doi: 10.1111/epi.13661.
    1. Sankar R, Shin DH, Liu H, Mazarati A. Pereira de Vasconcelos a, Wasterlain CG. Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J Neurosci. 1998;18(20):8382–8393. doi: 10.1523/JNEUROSCI.18-20-08382.1998.
    1. Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res. 2001;50(4):445–454. doi: 10.1203/00006450-200110000-00005.
    1. Mitra S, Bale G, Mathieson S, Uria-Avellanal C, Meek J, Tachtsidis I, et al. Changes in Cerebral Oxidative Metabolism during Neonatal Seizures Following Hypoxic-Ischemic Brain Injury. Front Pediatr. 2016;4:83. doi: 10.3389/fped.2016.00083.
    1. Sokoloff MD, Plegue MA, Chervin RD, Barks JD, Shellhaas RA. Phenobarbital and neonatal seizures affect cerebral oxygen metabolism: a near-infrared spectroscopy study. Pediatr Res. 2015;78(1):91–96. doi: 10.1038/pr.2015.64.
    1. Miller SP, Weiss J, Barnwell A, Ferriero DM, Latal-Hajnal B, Ferrer-Rogers A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002;58(4):542–548. doi: 10.1212/WNL.58.4.542.
    1. van Rooij LG, Toet MC, van Huffelen AC, Groenendaal F, Laan W, Zecic W, et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomised, controlled trial. Pediatrics. 2010;125(2):e358–e366. doi: 10.1542/peds.2009-0136.
    1. Srinivasakumar P, Zempel J, Trivedi S, Wallendorf M, Rao R, Smith B, et al. Treating EEG seizures in hypoxic ischemic encephalopathy: a randomized controlled trial. Pediatrics. 2015;136(5):e1302–e1309. doi: 10.1542/peds.2014-3777.
    1. Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr. 2009;155(3):318–323. doi: 10.1016/j.jpeds.2009.03.040.
    1. Kharoshankaya L, Stevenson NJ, Livingstone V, Murray DM, Murphy BP, Ahearne CE, et al. Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy. Dev Med Child Neurol. 2016;58(12):1242–1248. doi: 10.1111/dmcn.13215.
    1. Kwon JM, Guillet R, Shankaran S, Laptook AR, McDonald SA, Ehrenkranz RA, et al. Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial. J Child Neurol. 2011;26(3):322–328. doi: 10.1177/0883073810380915.
    1. Oh A, Thurman DJ, Kim H. Independent role of neonatal seizures in subsequent neurological outcomes: a population-based study. Dev Med Child Neurol. 2019;61(6):661–666. doi: 10.1111/dmcn.14174.
    1. Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci. 2003;993:103–114. doi: 10.1111/j.1749-6632.2003.tb07517.x.
    1. Stefovska VG, Uckermann O, Czuczwar M, Smitka M, Czuczwar P, Kis J, et al. Sedative and anticonvulsant drugs suppress postnatal neurogenesis. Ann Neurol. 2008;64(4):434–445. doi: 10.1002/ana.21463.
    1. Kim JS, Kondratyev A, Tomita Y, Gale K. Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia. 2007;48(Suppl5):19–26. doi: 10.1111/j.1528-1167.2007.01285.x.
    1. Glier C, Dzietko M, Bittigau P, Jarosz B, Korobowicz E, Ikonomidou C. Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol. 2004;187(2):403–409. doi: 10.1016/j.expneurol.2004.01.025.
    1. Schubert S, Brandl U, Brodhun M, Ulrich C, Spaltmann J, Fiedler N, et al. Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets. Brain Res. 2005;1058(102):129–136. doi: 10.1016/j.brainres.2005.07.061.
    1. Sfaello I, Baud O, Arzimanoglou A, Gressens P. Topiramate prevents excitotoxic damage in the newborn rodent brain. Neurobiol Dis. 2005;20(3):837–848. doi: 10.1016/j.nbd.2005.05.019.
    1. Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol. 2013;33(11):841–846. doi: 10.1038/jp.2013.116.
    1. Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures - effects on intelligence and on seizure recurrence. N Engl J Med. 1990;322(6):364–369. doi: 10.1056/NEJM199002083220604.
    1. Sulzbacher SI, Farwell JR, Temkin N, Lu AS, Hirtz DG. Late cognitive effects of early treatment with phenobarbital. Clin Pediatr (Phila) 1999;38(7):387–394. doi: 10.1177/000992289903800702.
    1. Hellstrom-Westas L, Boylan G, Agren J. Systematic review of neonatal seizure management strategies provides guidance on anti-epileptic treatment. Acta Paediatr. 2015;104(2):123–129. doi: 10.1111/apa.12812.
    1. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital compared to phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341(7):485–489. doi: 10.1056/NEJM199908123410704.
    1. McHugh DC, Lancaster S, Manganas LN. A systematic review of the efficacy of Levetiracetam in neonatal seizures. Neuropediatrics. 2017;49(1):12–17. doi: 10.1055/s-0037-1608653.
    1. Venkatesan C, Young S, Schapiro M, Thomas C. Levetiracetam for the treatment of seizures in neonatal hypoxic ischemic encephalopathy. J Child Neurol. 2017;32(2):210–214. doi: 10.1177/0883073816678102.
    1. Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR. Levetiracetam for treatment of neonatal seizures. J Child Neurol. 2011;26(4):465–470. doi: 10.1177/0883073810384263.
    1. Furwentsches A, Bussmann C, Ramantani G, Ebinger F, Philippi H, Poschl J, et al. Levetiracetam in the treatment of neonatal seizures: a pilot study. Seizure. 2010;19(3):185–189. doi: 10.1016/j.seizure.2010.01.003.
    1. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B. Use of intravenous levetiracetam for managment of acute seizures in neonates. Pediatr Neurol. 2011;44(4):265–269. doi: 10.1016/j.pediatrneurol.2010.11.005.
    1. Rakshasbhuvankar A, Rao S, Kohan R, Simmer K, Nagarajan L. Intravenous levetiracetam for treatment of neonatal seizures. J Clin Neurosci. 2013;20(8):1165–1167. doi: 10.1016/j.jocn.2012.08.014.
    1. Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol. 2011;15(1):1–7. doi: 10.1016/j.ejpn.2010.10.003.
    1. Van Meurs KP, Yan ES, Randall KS, Chock VY, Davis AS, Glennon CS, et al. Development of a NeuroNICU with a broader focus on all newborns at risk of brain injury: the first 2 years. Am J Perinatol. 2018;35(12):1197–1205. doi: 10.1055/s-0038-1646954.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe