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Variability in Preferred Management of Electrographic Seizures in Neonatal Hypoxic Ischemic Encephalopathy
Accepted Manuscript Title: Variability in Preferred Management of Electrographic Seizures in Neonatal Hypoxic Ischemic Encephalopathy Author: Melanie A. McNally, Adam L. Hartman PII: DOI: Reference:
S0887-8994(17)30455-1 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.006 PNU 9176
To appear in:
Pediatric Neurology
Received date: Revised date: Accepted date:
3-5-2017 5-6-2017 13-6-2017
Please cite this article as: Melanie A. McNally, Adam L. Hartman, Variability in Preferred Management of Electrographic Seizures in Neonatal Hypoxic Ischemic Encephalopathy, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Variability in preferred management of electrographic seizures in neonatal hypoxic ischemic encephalopathy Melanie A. McNally* MD, Adam L. Hartman*† MD *Division of Pediatric Neurology, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland Division of Clinical Research, National Institute of Neurological Disorders and Stroke Corresponding author: Adam L. Hartman, MD Division of Clinical Research National Institute of Neurological Disorders and Stroke 6001 N. Executive Blvd Rockville, MD 20852 Funding Source: No funding was secured for this study. Financial disclosures: The authors have no financial relationships relevant to this article to disclose. Conflict of Interest: The authors have no conflicts of interest to disclose. This article was prepared while Adam L. Hartman, MD was employed at Johns Hopkins University. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Short Title: Survey of seizure management in HIE Word Count: 2,281
Abstract: Objective: Seizures occur commonly in neonates and growing evidence suggests they may cause added harm in neonates with hypoxic ischemic encephalopathy (HIE). However, specific recommendations about when and how to treat seizures in this context are lacking. The objective of this study was to determine the scope of practice
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2 nationally regarding management of non-status epilepticus electrographic-only seizures (ESzs) in neonates with HIE. Study Design: A case-based survey was distributed to members of the Child Neurology Society. Providers were asked about their preferred management strategy for sequential clinical scenarios. Results: 177 child neurologists responded to the survey. 77% of providers would treat 20 seconds or less of electrographic seizure activity. In a neonate with mild HIE and an ESz, there was no agreement among providers regarding whether to start maintenance therapy in addition to a one-time anti-seizure drug (ASD) load. In a neonate with moderate HIE on phenobarbital (PB) for early electro-clinical seizures, the majority of providers would escalate treatment for ongoing ESzs and would do so by increasing PB dosing. In a neonate with severe HIE complicated by status epilepticus on PB who subsequently develops recurrent ESzs, providers varied significantly in their management preferences. For all three cases, 75-85% of providers would not change their management preferences based on the presence or absence of a clinical correlate with the electrographic seizure. Conclusions: We found marked variability among providers regarding preferred management of non-status epilepticus ESzs after HIE. Our results identified specific aspects of ESz management in neonatal HIE where there is limited consensus. These discrepancies may serve as opportunities for future investigation.
Keywords: Neonatal seizures, phenobarbital, levetiracetam, phenytoin, survey
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3 Abbreviations: neonatal intensive care unit (NICU), neonatal seizures (NSs), hypoxic ischemic encephalopathy (HIE), therapeutic hypothermia (TH), anti-seizure drug (ASD), electrographic-only seizures (ESzs), continuous video electroencephalogram (cEEG), phenobarbital (PB), head ultrasound (HUS), phenytoin (PHT), levetiracetam (LEV)
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4 Introduction Seizures occur regularly in neonates with an incidence 1-5 per 1,000 life births in population-based studies and are associated with significant mortality and short and long-term morbidity, including developmental delay and postnatal epilepsy.1-5 40-60% percent of all neonatal seizures (NSs) occur after hypoxic ischemic encephalopathy (HIE), a common neonatal brain injury also associated with significant mortality and poor neurologic outcomes.6-9 The role of NSs in brain injury pathogenesis and their impact on long-term neurodevelopmental outcomes is an area of ongoing research.10 There is growing preclinical and clinical evidence suggesting that NSs after HIE may cause added harm to the neonatal brain independent of the original injury.3,11 In these neonates with HIE receiving therapeutic hypothermia (TH), recent clinical evidence shows that (1) electrographic seizure burden during TH and rewarming correlates with degree of brain injury on MRI regardless of initial clinical severity, (2) treating electrographic seizures with or without clinical correlates decreases seizure burden, and (3) decreased electrographic seizure burden correlates with improved long-term outcomes.3,12,13 These data suggest that optimizing treatment of electrographic seizures in neonates with HIE may improve outcomes. Management of NSs is challenging due to the known side effects and poor efficacy of available anti-seizure drugs (ASDs) in this patient population.10,14,15 Current treatment strategies remain largely based on expert opinion, rather than evidencebased guidelines.16,17 While there is general consensus in the field that treating status epilepticus in these patients is warranted, in developing a neonatal seizure
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5 management protocol for our hospital as part of a quality improvement initiative, we noted that preferred treatment regimens (including selection of medicines, dosing, and timing of administration) for non-status NSs remain controversial. Similarly, significant variability has also been demonstrated in clinical practice among other academic medical centers in terms of duration of treatment after neonatal seizures.18 Historically, an important discussion among neonatal providers was whether electro-clinical and electrographic-only seizures (ESzs) should be treated similarly. There was much debate regarding the effect of ESzs on the developing brain.19 When pediatric neurologists and neonatologists were surveyed in 2006, only one-third felt that ESzs could harm the brain and would treat ESzs.20 However, when providers were surveyed in 2010, three-quarters stated they would always or usually recommend treating ESzs in the neonatal population.17 This observed shift in provider attitude towards ESzs in the neonate was in line with guidelines from the American Clinical Neurophysiology Society published in 2011 stating that electroencephalography is the gold standard to identify NSs.25 However, specific recommendations about what ESz duration or frequency warrants treatment and in what clinical context remain unclear. The objective of this study was to determine the scope of practice nationally regarding management of non-status ESzs in neonates with HIE. We hypothesized that significant variability exists in determining which ASD to use, time to initiate treatment, and when to start maintenance therapy. Results of this study may guide future investigations into the optimal treatment of NSs. Methods
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6 A case-based survey (http://ictr.johnshopkins.edu/clinical/clinicalresources/clinical-research-informatics-core/qualtrics-survey/) was distributed through the Child Neurology Society email listserv and a reminder e-mail to optimize survey participation was sent four weeks later. The Johns Hopkins Institutional Review Board approved the survey. Prior to participating in the survey, providers were informed that by completing the survey they were giving consent to use their anonymous responses for research purposes. Descriptive statistics were used to report the percentage of respondents for each selection and open responses (e.g., number of years in practice). Three clinical cases and management options for sequential scenarios were presented. The full survey can be found in the supplementary materials. The first case described a male infant with mild HIE who underwent TH. His initial head ultrasound (HUS) and continuous video electroencephalography (cEEG) recording were normal. The infant developed a 20 second electrographic-only seizure at eight hours of life. The second case described a male infant with moderate HIE who underwent TH. His initial HUS revealed white matter echogenicities and decreased resistive indices and his cEEG showed a mildly suppressed background with increased discontinuity for gestational age. At six hours of life he developed electro-clinical seizures requiring two phenobarbital (PB) loads to stop and he was subsequently started on maintenance PB. At eighteen hours of life he was having a few 30-60 second ESzs per hour despite a PB level of 28 mg/L. The third case described a female infant with severe HIE who underwent TH. Her initial vEEG revealed electrographic status epilepticus (no clinical correlate) requiring termination with PB and phenytoin (PHT). She was started on PB maintenance therapy, but her vEEG continued to show 20-30 second ESzs four to five
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7 times per day during cooling and rewarming despite a serum PB level of 42 mg/L. Chisquared analyses were used to compare proportions of respondents for each choice.
Results Demographics Survey responses were received from 177 attending child neurologists, of 1100 total listserv recipients, with a median of ten years in practice (1st quartile four years, 3rd quartile 25 years). Our response rate is similar to previously published surveys in this field.21,22 65 providers also had fellowship training in epilepsy or neurophysiology, eight in neonatal neurology, and three in neonatology. Most of the responding providers work in an academic hospital and spend 1-25% of their clinical time taking care of neonates (Table 1).
Survey Results To better understand each provider’s threshold to treat, we asked how long an ESz would have to last to initiate treatment in case #1 (mild HIE). The majority of providers (77%) reported that they would treat 20 seconds or less of ESz activity, whereas the remainder would wait 60 seconds or more before treating (Table 2). The most frequent response was ten seconds, consistent with the arbitrary cutoff that has long been utilized to define an electrographic seizure.23 Responses suggested a low threshold for most providers to treat an ESz. For the infant in case #1, there was general consensus among treating providers to use PB first line (82%; seventeen percent chose levetiracetam (LEV) and one provider chose PHT). These responses did
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8 not differ between providers with fellowship training in epilepsy or neurophysiology (n=65) versus those without (n=112) (Χ2=5.28, p=0.38). Interestingly, however, there was very little agreement among these providers regarding whether or not to start maintenance therapy in addition to the one-time ASD load. There was an almost equal split in terms of management preference among the treating providers (Table 2). These responses also did not differ between providers with fellowship training in epilepsy or neurophysiology (n=65) versus those without (n=112) (Χ2=0.2, p=0.90). In case #2, we presented an infant with moderate HIE on PB maintenance therapy for early electro-clinical seizures (serum level 28 mg/L). With this case, we wanted to assess if providers would escalate therapy for ongoing intermittent ESzs in this clinical context and, if so, how they would do it. We found good consensus among providers that escalating therapy in this scenario was warranted, with only three percent of providers choosing to observe. The majority of treating providers (77%) chose to give a 10 mg/kg load of PB and increase the maintenance dosing to 4 mg/kg/day (Table 2). Notably, similar to the results in the first case, eighteen percent of treating providers would instead utilize LEV in this situation (load or load with maintenance therapy as a second agent). These responses did not differ between providers with fellowship training in epilepsy or neurophysiology (n=62 cases) versus providers without this training (n=107) (X2=6.4, p=0.16). Finally, in case #3, we asked providers how they would manage ongoing intermittent ESzs in an infant with severe HIE on PB maintenance therapy with a higher serum level than case #2 (42 mg/L). Like the prior cases, there was general agreement to escalate treatment, with only fourteen percent of providers choosing to observe.
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9 However, unlike case #2, there was significant variability in how providers chose to escalate therapy in this clinical scenario. Most treating providers (48%) chose to add PHT as a second agent, but approximately quarter of them would increase PB to a serum level of 40-50 mg/L and another quarter would add LEV as a second agent (Table 2). These responses did not differ between providers with fellowship training in epilepsy or neurophysiology (n=62) versus providers without this training (n=99) (Χ2=0.68, p=0.87). Given that detecting neonatal seizures clinically is unreliable and recent guidelines state that the use of cEEG in these patients is considered the gold standard, we inquired whether management decisions would change in the presence of an electro-clinical seizure versus an ESz.24,25 Consistent with these previous studies and guidelines, the majority our responding providers (76% (n=132) for case #1, 84% for case #2 (n=143), 75% (n=122) for case #3) would not change management based on the presence or absence of a clinical correlate (e.g., apnea, limb stiffening, lip smacking).
Discussion In our national survey, we found significant variability among child neurologists regarding some management issues in non-status ESzs in neonates with HIE. Our three cases each involved a neonate with HIE receiving TH, but each neonate differed in his or her injury severity, seizure burden, and ASD regimen in order to identify specific areas where ESz management was or was not disputed. While half of providers agreed that 10 seconds of an ESz should prompt treatment, the other half varied
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10 significantly regarding the duration of an ESz that whould prompt treatment. Additionally, there was marked disagreement in how aggressive providers would be in treating both a first ESz in an neonate with mild HIE or ongoing ESzs in a neonate with severe HIE. In these two cases, there was no consensus regarding when to start maintenance therapy for non-status ESzs, when to add a second ASD, or which agent should be the adjuvant therapy. In our case involving a neonate with moderate HIE, we found more agreement in how to escalate treatment for ongoing ESzs, however there remained a significant portion of providers who chose a different ASD. While we did find many areas of dispute, we also found some important trends in preferred practice. Three-quarters of providers would treat a first ESz in an infant with mild HIE. Of these providers, the majority would use PB first, consistent with expert opinion and surveys of national and international practice.5,18,26 Interestingly, 17% of providers who chose to treat a first ESz (either with a one-time ASD load or with a ASD load and maintenance) would use LEV first line. Additionally, when managing recurrent ESzs, approximately 20% of our respondents would use LEV as a second agent in both the moderate or severe HIE scenarios. When providers were surveyed in 2010, only one percent answered they would use LEV first line and only nine percent would use LEV second line for neonatal seizures.17 However, more recent prospective cohort studies of neonates in the National Seizure Registry found that 28% of neonates with HIE received LEV for seizures at some point in their hospital course and 24% were prescribed LEV at the time of discharge, suggesting that our results reflect current clinical practice and a growing tendency to use LEV in this patient population (although in comparison, 94% of them received PB at some point and 63% were on PB at time of
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11 discharge).5,18 Finally, our results also indicated that providers would treat ESzs the same way as electro-clinical seizures in all the clinical scenarios, congruent with previously published survey data and practice guidelines.17,25 There are limitations to our survey. The responding pediatric neurologists worked primarily in academic medical centers and did not spend a significant amount of their clinical time managing neonates, a common academic model. It is possible that this may have biased our results, however many academic centers have NICUs where a sizeable number of infants are referred for HIE and seizures. Similarly, our results may represent attitudes toward clinical management in a survey scenario but may not represent what is actually clinical practice, given the number of trainees and rotating attending physicians commonly involved in academic environments. Moreover, providers may have made management decisions that were not listed as one of the answer choices in the multiple-choice format. Also, although our survey response rate was similar to that published in previous studies21,22, it still only represents sixteen percent of possible participants introducing possible bias to our results. Finally, this survey represents opinion of pediatric neurologists, who typically are not the clinicians initially managing these patients, although they are often involved in more advanced clinical states reflected in our cases. Neonatologists, who are most commonly prescribing initial management, may have had different responses. Prior surveys have shown that neonatologists and pediatric neurologists agree that PB should be used firstline, however neonatologists were found to use other drugs (e.g., LEV) and, in one study, advocate for shorter duration of ASD treatment in this patient population than pediatric neurologists.17,26,27 Despite these limitations, our results reveal a significant
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12 lack of consensus in how pediatric neurologists approach ESzs in this patient population. Neonatal seizures are common and providers are regularly faced with determining when and how to treat them. Our study found wide variation in some aspects of neonatal ESz management. With growing evidence suggesting that seizures may cause additional harm in neonates with HIE, it is important to generate evidence based guidelines for providers in these situations to optimize outcomes. 3,12,13 Our data have identified specific aspects of neonatal seizure management where there is limited consensus.
Acknowledgements: We would like to acknowledge Roger Larson for helping us access the Child Neurology Society Listserv. We are grateful to the many pediatric neurologists and neonatologists at Johns Hopkins Hospital who provided feedback on initial versions of the survey. This manuscript is dedicated to the memory of Sheila Pakula, a lifelong supporter of neonatal care at Johns Hopkins Hospital.
References 1. Holden KR, Mellits ED, Freeman JM. Neonatal seizures. I. Correlation of prenatal and perinatal events with outcomes. Pediatrics 1982;70(2):165-76. 2. Ronen G, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: A population-based study. J Pediatr 1999;134(1):71–75. 3. Glass H, Pham T, Danielsen B, Towner D, Glidden D, Wu Y. Antenatal and intrapartum risk factors for seizures in term newborns: A population-based study, California 1998-2002. J Pediatr 2009;154(1):24–28.e1. 4. Pisani F, Facini C, Pavlidis E, Spagnoli C, Boylan G. Epilepsy after neonatal seizures: Literature review. Eur J Paediatr Neurol 2014;19(1):6–14.
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13 5. Glass H, Shellhaas R, Wusthoff C, Chang T, Abend N, Chu C, et al. Contemporary profile of seizures in neonates: A prospective cohort study. J Pediatr 2016;174:98– 103.e1. 6. Levene MI, Traunce JQ. Cause of neonatal convulsions. Towards more precise diagnosis. Arch Dis Child 1986;61(1):78-9. 7. Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117(4):1270–1280. 8. Kurinczuk J, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic–ischaemic encephalopathy. Early Hum Dev 2010;86(6):329–38. 9. Vasudevan C, Levene M. Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med 2013 Aug;18(4):185-91. 10. Rooij L van, Broek M van den, Rademaker C, Vries L de. Clinical Management of Seizures in Newborns. Paediatr Drugs 2013 Feb;15(1):9-18. 11. Holmes GL. The long-term effects of neonatal seizures. Clin Perinatol 2009 Dec;36(4):901-14. 12. Shah DK, Wusthoff CJ, Clarke P, Wyatt JS, Ramaiah SM, Dias RJ, et al. Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2014 May;99(3):F21924. 13. 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 Nov;136(5):e1302–9. 14. Painter M, Scher M, Stein A, Armatti S, Wang Z, Gardiner J, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999 Aug;341(7):485–489. 15. Gutherz SB, Kulick CV, Soper C, Kondratyev A, Gale K, Forcelli PA. Brief postnatal exposure to phenobarbital impairs passive avoidance learning and sensorimotor gating in rats. Epilepsy Behav 2014 Aug;37:265–9. 16. Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004 Oct 18;(4):CD004218. 17. Glass H, Kan J, Bonifacio S, Ferriero D. Neonatal seizures: treatment practices among term and preterm infants. Pediatr Neurol 2012;46(2):111–115. 18. Shellhaas RA, Chang T, Wusthoff CJ, Soul JS, Massey SL, Chu CJ, et al. Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study. J Pediatr 2017;181:298-301.e1. 19. Thibeault-Eybalin MP, Lortie A, Carmant L. Neonatal seizures: do they damage the brain? Pediatr Neurol 2009 Mar;40(3):175-80. 20. Bassan H, Bental Y, Shany E, Berger I, Froom P, Levi L, et al. Neonatal seizures: dilemmas in workup and management. Pediatr Neurol 2008;38(6):415–421. 21. Kahn I, Helman G, Vanderver A, Wells E. Anti-N-Methyl-d-Aspartate (NMDA) receptor encephalitis. J Child Neurol 2017 Feb;32(2):243-245. 22. Plioplys S, Siddarth, Asato MR, Caplan R. Clinicians' views on antiepileptic medication management in nonepileptic seizures. J Child Neurol 2014 Jun;29(6):746-50. 23. Clancy RR, Legido A. The exact ictal and interictal duration of
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14 electroencephalographic neonatal seizures. Epilepsia 1987;28:537-41. 24. 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 May;93(3):F187-91. 25. Shellhaas R, Chang T, Tsuchida T, Scher M, Riviello J, Abend N, et al. The American Clinical Neurophysiology Society’s guideline on continuous electroencephalography monitoring in neonates. J Clin Neurophysiol 2011;28(6):611. 26. Hellstrom-Westas L, Boylan G, Agren J. Systematic review of neonatal seizure management strategies provides guidance on anti-epileptic treatment. Acta Paediatr 2015 Feb;104(2):123-9. 27. 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 Jan;17(1):55-63.
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15 Table 1. Survey Respondent Demographics n (%) Fellowship Training Child Neurology Epilepsy/Neurophysiology Neonatal Neurology Neonatology
177 (100) 65 (36.7) 8 (4.5) 2 (1.1)
Clinical Setting Academic Hospital Private Hospital Rural Hospital Outpatient Clinic
140 (79.1) 21 (11.9) 8 (4.5) 8 (4.5)
Clinical Time with Neonates 0% 1-25% 26-50% 51-75% 76-100%
7 (4.0) 151 (85.3) 13 (7.3) 3 (1.7) 3 (1.7)
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16 Table 2. Preferred Management n (%) Length of ESz to Initiate Treatment 5 seconds 10 seconds 20 seconds 60 seconds 5 minutes Any amount No amount
6 (3.4) 90 (51.1) 18 (10.2) 23 (13.0) 11 (6.3) 22 (12.5) 6 (3.4)
Case 1 (Mild HIE, Single ESz) Observe ASD Load* ASD Load + Maintenance**
41 (23.2) 65 (36.7) 71 (40.1)
Case 2 (Moderate HIE, Recurrent ESzs on PB) Observe Increase PB PHT Load LEV Load LEV Load + Maintenance Case 3 (Severe HIE, Recurrent ESzs on PB#) Observe Increase PB Add PHT Add LEV
5 (3.0) 126 (74.6) 8 (4.7) 8 (4.7) 22 (13) 23 (14.3) 39 (24.2) 66 (41.0) 33 (20.5)
* 60 (92.3%) with PB, 4 (6.2%) with LEV, 1 (1.5%) with PHT ** 52 (73.3%) with PB, 19 (26.7%) with LEV
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17 Supplementary Material: Survey Text Demographics: 1) What is your specialty? a. Neurology b. Neonatology 2) Have you completed fellowship training in any of the following specialties? Select any that apply, leave blank if none. a. Clinical Neurophysiology and/or Epilepsy b. Neonatology c. Neonatal Neurology 3) How many years have you been practicing your specialty? 4) Which of the following most closely describes the setting in which you have spent most of your time working? a. Academic hospital b. Private hospital c. Rural/Community hospital d. Outpatient clinic only 5) Approximately how much of your clinical time is spent taking care of neonates in the neonatal intensive care unit? a. 0% b. 1-25% c. 25-50% d. 50-75% e. 75-100% CASE 1: A 38.6 weeks gestation male infant was born by emergent C-section for nonreassuring fetal heart tones. Apgars were 4 and 7 at 1 and 5 minutes, respectively. The initial cord gas had a pH=6.91 with a base deficit of 16. The infant was passively cooled in the delivery room until arrival in the neonatal intensive care unit where whole body hypothermia was started and a neonatal montage continuous video EEG was placed. The initial head ultrasound and EEG background were normal. At 8 hours of life, his EEG showed 20 seconds of rhythmic left temporal sharp activity with an ictal evolution (an electrographic seizure) but no clinical correlate. 1) Which of the following options most closely resembles how you would manage this electrographic seizure? a. Continue observation, no medication at this point b. Load infant with 20 mg/kg of phenobarbital and continue to monitor c. Load infant with 20 mg/kg of fosphenytoin and continue to monitor d. Load infant with 30 mg/kg of levetiracetam and continue to monitor
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18 e. Load infant with 20 mg/kg of phenobarbital, start 3 mg/kg/day phenobarbital maintenance therapy, and continue to monitor f. Load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor 2) How long would a single electrographic-only seizure have to last in this patient before you would initiate any treatment in this patient (please select the answer closest to your typical practice)? a. 5 seconds b. 10 seconds c. 20 seconds d. 60 seconds e. 5 minutes f. I would treat any epileptiform activity found in this patient regardless of presence or absence of a corresponding clinical event. g. I would not treat electrographic activity in the absence of a clinical event. 3) If this patient went on to develop three more 20-second electrographic-only seizures over the next two hours, which of the following most closely resembles your management? a. Continue observation, no medication at this point b. Load infant with 20 mg/kg of phenobarbital and continue to monitor c. Load infant with 20 mg/kg of fosphenytoin and continue to monitor d. Load infant with 30 mg/kg of levetiracetam and continue to monitor e. Load infant with 20 mg/kg of phenobarbital, start 3 mg/kg/day phenobarbital maintenance therapy, and continue to monitor f. Load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor 4) If these recurrent electrographic seizures were associated with clinical correlates (eg. clonic extremity jerking, eye deviation, tachycardia, etc), would your management change? a. No, my management would not change. b. Yes, I would continue observation and not start medication. c. Yes, I would load infant with 20 mg/kg of phenobarbital and continue to monitor. d. Yes, I would load infant with 20 mg/kg of fosphenytoin and continue to monitor e. Yes, I would load infant with 30 mg/kg of levetiracetam and continue to monitor. f. Yes, I would load infant with 20 mg/kg of phenobarbital, start 3 mg/kg/day phenobarbital maintenance therapy, and continue to monitor. g. Yes, I would load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor.
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19 CASE 2: A 38.0 weeks gestation male infant was born by emergent C-section for placental abruption. He was pale and hypotonic in the delivery room. Apgars were 2, 2, and 6 at 1, 5, and 10 minutes, respectively. The initial cord gas showed a pH=6.89 with a base deficit of 14. He was passively cooled in the delivery room until arrival in the neonatal intensive care unit where whole body hypothermia was started and a neonatal montage continuous video EEG was placed. The initial head ultrasound showed white matter echogenicities and decreased resistive indices. The EEG background at initiation was mildly suppressed and discontinuous for gestational age. At 6 hours of life, he developed multifocal clonic seizures with clear electrographic seizure correlates. He was loaded with 20 mg/kg of phenobarbital twice and 3 mg/kg/day maintenance dosing was started. By 18 hours of life, his electro-clinical seizures had stopped, but he continued to have intermittent 30-60 second electrographic-only seizures independently from the left frontal or right temporal regions a few times per hour. A serum phenobarbital level at this time was 28. 1) Which of the following options most closely resembles how you would manage these electrographic-only seizures? a. They do not change my medical management at this time. b. Load with an additional 10 mg/kg of phenobarbital and increase maintenance dosing to 4 mg/kg/day c. Load with 20 mg/kg of fosphenytoin and continue to monitor d. Load with 30 mg/kg of levetiracetam and continue to monitor e. Load with 30 mg/kg of levetiracetam and start maintenance dosing at 20 mg/kg/day 5) If these recurrent electrographic seizures were associated with clinical correlates (eg. clonic extremity jerking, eye deviation, tachycardia, etc), would your management change? a. No, my management would not change. b. Yes, I would continue observation and not start medication. f. Yes, I would load with an additional 10 mg/kg of phenobarbital and increase maintenance dosing to 4 mg/kg/day c. Yes, I would load infant with 20 mg/kg of fosphenytoin and continue to monitor d. Yes, I would load infant with 30 mg/kg of levetiracetam and continue to monitor. e. Yes, I would load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor. CASE 3: A 39.2 weeks gestation female infant was born by spontaneous vaginal delivery. The delivery was prolonged and she required extraction with forceps. She was initially limp and apneic. Apgars were 1, 2, and 6 at 1, 5, and 10 minutes, respectively. The initial cord gas had a pH=6.78 with a base deficit of 20. She was transferred to the NICU and started on the therapeutic hypothermia protocol. When the video EEG was placed, she was noted to be in electrographic status epilepticus with no clinical correlate. She required a total of 40 mg/kg of phenobarbital and 20 mg/kg of
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20 fosphenytoin before the electrographic seizure activity stopped. She was started on phenobarbital maintenance dosing at 3 mg/kg/day. However, her EEG continued to show electrographic-only seizures that were 20-30 seconds in duration, 4-5 times per day during cooling and rewarming despite a serum phenobarbital level of 42. Her brain MRI on day 5 of life showed sequelae of severe hypoxic-ischemic injury with diffuse subcortical white matter hyperintensity on T2-weighted imaging. 1) Which of the following most closely reflects your preferred management? She was otherwise clinically stable. a. No change to medical management. b. Increase maintenance phenobarbital to a target serum level of 50-60 c. Add levetiracetam 20 mg/kg/day to her regimen d. Load with 20 mg/kg of fosphenytoin and start phenytoin maintenance at 4 mg/kg/day e. Keep her on the EEG for a few days after rewarming to see if the electrographic seizure frequency decreases before adjusting her antiseizure medications 2) If there were clinical correlates (eg. clonic extremity jerking, eye deviation, tachycardia, etc) with the patient’s electrographic seizures, would that change your management? a. No, my management would not change b. Yes, I would increase maintenance phenobarbital to a target serum level of 50-60 c. Yes, I would load with 20 mg/kg of fosphenytoin and start phenytoin maintenance at 4 mg/kg/day d. Yes, I would add levetiracetam 20 mg/kg/day to her regimen e. Yes, I would keep her on the EEG for a few days after rewarming to see if the electrographic seizure frequency decreases before adjusting her antiseizure medications
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S0887-8994(17)30455-1 http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.006 PNU 9176
To appear in:
Pediatric Neurology
Received date: Revised date: Accepted date:
3-5-2017 5-6-2017 13-6-2017
Please cite this article as: Melanie A. McNally, Adam L. Hartman, Variability in Preferred Management of Electrographic Seizures in Neonatal Hypoxic Ischemic Encephalopathy, Pediatric Neurology (2017), http://dx.doi.org/doi: 10.1016/j.pediatrneurol.2017.06.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Variability in preferred management of electrographic seizures in neonatal hypoxic ischemic encephalopathy Melanie A. McNally* MD, Adam L. Hartman*† MD *Division of Pediatric Neurology, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland Division of Clinical Research, National Institute of Neurological Disorders and Stroke Corresponding author: Adam L. Hartman, MD Division of Clinical Research National Institute of Neurological Disorders and Stroke 6001 N. Executive Blvd Rockville, MD 20852 Funding Source: No funding was secured for this study. Financial disclosures: The authors have no financial relationships relevant to this article to disclose. Conflict of Interest: The authors have no conflicts of interest to disclose. This article was prepared while Adam L. Hartman, MD was employed at Johns Hopkins University. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Short Title: Survey of seizure management in HIE Word Count: 2,281
Abstract: Objective: Seizures occur commonly in neonates and growing evidence suggests they may cause added harm in neonates with hypoxic ischemic encephalopathy (HIE). However, specific recommendations about when and how to treat seizures in this context are lacking. The objective of this study was to determine the scope of practice
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2 nationally regarding management of non-status epilepticus electrographic-only seizures (ESzs) in neonates with HIE. Study Design: A case-based survey was distributed to members of the Child Neurology Society. Providers were asked about their preferred management strategy for sequential clinical scenarios. Results: 177 child neurologists responded to the survey. 77% of providers would treat 20 seconds or less of electrographic seizure activity. In a neonate with mild HIE and an ESz, there was no agreement among providers regarding whether to start maintenance therapy in addition to a one-time anti-seizure drug (ASD) load. In a neonate with moderate HIE on phenobarbital (PB) for early electro-clinical seizures, the majority of providers would escalate treatment for ongoing ESzs and would do so by increasing PB dosing. In a neonate with severe HIE complicated by status epilepticus on PB who subsequently develops recurrent ESzs, providers varied significantly in their management preferences. For all three cases, 75-85% of providers would not change their management preferences based on the presence or absence of a clinical correlate with the electrographic seizure. Conclusions: We found marked variability among providers regarding preferred management of non-status epilepticus ESzs after HIE. Our results identified specific aspects of ESz management in neonatal HIE where there is limited consensus. These discrepancies may serve as opportunities for future investigation.
Keywords: Neonatal seizures, phenobarbital, levetiracetam, phenytoin, survey
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3 Abbreviations: neonatal intensive care unit (NICU), neonatal seizures (NSs), hypoxic ischemic encephalopathy (HIE), therapeutic hypothermia (TH), anti-seizure drug (ASD), electrographic-only seizures (ESzs), continuous video electroencephalogram (cEEG), phenobarbital (PB), head ultrasound (HUS), phenytoin (PHT), levetiracetam (LEV)
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4 Introduction Seizures occur regularly in neonates with an incidence 1-5 per 1,000 life births in population-based studies and are associated with significant mortality and short and long-term morbidity, including developmental delay and postnatal epilepsy.1-5 40-60% percent of all neonatal seizures (NSs) occur after hypoxic ischemic encephalopathy (HIE), a common neonatal brain injury also associated with significant mortality and poor neurologic outcomes.6-9 The role of NSs in brain injury pathogenesis and their impact on long-term neurodevelopmental outcomes is an area of ongoing research.10 There is growing preclinical and clinical evidence suggesting that NSs after HIE may cause added harm to the neonatal brain independent of the original injury.3,11 In these neonates with HIE receiving therapeutic hypothermia (TH), recent clinical evidence shows that (1) electrographic seizure burden during TH and rewarming correlates with degree of brain injury on MRI regardless of initial clinical severity, (2) treating electrographic seizures with or without clinical correlates decreases seizure burden, and (3) decreased electrographic seizure burden correlates with improved long-term outcomes.3,12,13 These data suggest that optimizing treatment of electrographic seizures in neonates with HIE may improve outcomes. Management of NSs is challenging due to the known side effects and poor efficacy of available anti-seizure drugs (ASDs) in this patient population.10,14,15 Current treatment strategies remain largely based on expert opinion, rather than evidencebased guidelines.16,17 While there is general consensus in the field that treating status epilepticus in these patients is warranted, in developing a neonatal seizure
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5 management protocol for our hospital as part of a quality improvement initiative, we noted that preferred treatment regimens (including selection of medicines, dosing, and timing of administration) for non-status NSs remain controversial. Similarly, significant variability has also been demonstrated in clinical practice among other academic medical centers in terms of duration of treatment after neonatal seizures.18 Historically, an important discussion among neonatal providers was whether electro-clinical and electrographic-only seizures (ESzs) should be treated similarly. There was much debate regarding the effect of ESzs on the developing brain.19 When pediatric neurologists and neonatologists were surveyed in 2006, only one-third felt that ESzs could harm the brain and would treat ESzs.20 However, when providers were surveyed in 2010, three-quarters stated they would always or usually recommend treating ESzs in the neonatal population.17 This observed shift in provider attitude towards ESzs in the neonate was in line with guidelines from the American Clinical Neurophysiology Society published in 2011 stating that electroencephalography is the gold standard to identify NSs.25 However, specific recommendations about what ESz duration or frequency warrants treatment and in what clinical context remain unclear. The objective of this study was to determine the scope of practice nationally regarding management of non-status ESzs in neonates with HIE. We hypothesized that significant variability exists in determining which ASD to use, time to initiate treatment, and when to start maintenance therapy. Results of this study may guide future investigations into the optimal treatment of NSs. Methods
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6 A case-based survey (http://ictr.johnshopkins.edu/clinical/clinicalresources/clinical-research-informatics-core/qualtrics-survey/) was distributed through the Child Neurology Society email listserv and a reminder e-mail to optimize survey participation was sent four weeks later. The Johns Hopkins Institutional Review Board approved the survey. Prior to participating in the survey, providers were informed that by completing the survey they were giving consent to use their anonymous responses for research purposes. Descriptive statistics were used to report the percentage of respondents for each selection and open responses (e.g., number of years in practice). Three clinical cases and management options for sequential scenarios were presented. The full survey can be found in the supplementary materials. The first case described a male infant with mild HIE who underwent TH. His initial head ultrasound (HUS) and continuous video electroencephalography (cEEG) recording were normal. The infant developed a 20 second electrographic-only seizure at eight hours of life. The second case described a male infant with moderate HIE who underwent TH. His initial HUS revealed white matter echogenicities and decreased resistive indices and his cEEG showed a mildly suppressed background with increased discontinuity for gestational age. At six hours of life he developed electro-clinical seizures requiring two phenobarbital (PB) loads to stop and he was subsequently started on maintenance PB. At eighteen hours of life he was having a few 30-60 second ESzs per hour despite a PB level of 28 mg/L. The third case described a female infant with severe HIE who underwent TH. Her initial vEEG revealed electrographic status epilepticus (no clinical correlate) requiring termination with PB and phenytoin (PHT). She was started on PB maintenance therapy, but her vEEG continued to show 20-30 second ESzs four to five
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7 times per day during cooling and rewarming despite a serum PB level of 42 mg/L. Chisquared analyses were used to compare proportions of respondents for each choice.
Results Demographics Survey responses were received from 177 attending child neurologists, of 1100 total listserv recipients, with a median of ten years in practice (1st quartile four years, 3rd quartile 25 years). Our response rate is similar to previously published surveys in this field.21,22 65 providers also had fellowship training in epilepsy or neurophysiology, eight in neonatal neurology, and three in neonatology. Most of the responding providers work in an academic hospital and spend 1-25% of their clinical time taking care of neonates (Table 1).
Survey Results To better understand each provider’s threshold to treat, we asked how long an ESz would have to last to initiate treatment in case #1 (mild HIE). The majority of providers (77%) reported that they would treat 20 seconds or less of ESz activity, whereas the remainder would wait 60 seconds or more before treating (Table 2). The most frequent response was ten seconds, consistent with the arbitrary cutoff that has long been utilized to define an electrographic seizure.23 Responses suggested a low threshold for most providers to treat an ESz. For the infant in case #1, there was general consensus among treating providers to use PB first line (82%; seventeen percent chose levetiracetam (LEV) and one provider chose PHT). These responses did
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8 not differ between providers with fellowship training in epilepsy or neurophysiology (n=65) versus those without (n=112) (Χ2=5.28, p=0.38). Interestingly, however, there was very little agreement among these providers regarding whether or not to start maintenance therapy in addition to the one-time ASD load. There was an almost equal split in terms of management preference among the treating providers (Table 2). These responses also did not differ between providers with fellowship training in epilepsy or neurophysiology (n=65) versus those without (n=112) (Χ2=0.2, p=0.90). In case #2, we presented an infant with moderate HIE on PB maintenance therapy for early electro-clinical seizures (serum level 28 mg/L). With this case, we wanted to assess if providers would escalate therapy for ongoing intermittent ESzs in this clinical context and, if so, how they would do it. We found good consensus among providers that escalating therapy in this scenario was warranted, with only three percent of providers choosing to observe. The majority of treating providers (77%) chose to give a 10 mg/kg load of PB and increase the maintenance dosing to 4 mg/kg/day (Table 2). Notably, similar to the results in the first case, eighteen percent of treating providers would instead utilize LEV in this situation (load or load with maintenance therapy as a second agent). These responses did not differ between providers with fellowship training in epilepsy or neurophysiology (n=62 cases) versus providers without this training (n=107) (X2=6.4, p=0.16). Finally, in case #3, we asked providers how they would manage ongoing intermittent ESzs in an infant with severe HIE on PB maintenance therapy with a higher serum level than case #2 (42 mg/L). Like the prior cases, there was general agreement to escalate treatment, with only fourteen percent of providers choosing to observe.
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9 However, unlike case #2, there was significant variability in how providers chose to escalate therapy in this clinical scenario. Most treating providers (48%) chose to add PHT as a second agent, but approximately quarter of them would increase PB to a serum level of 40-50 mg/L and another quarter would add LEV as a second agent (Table 2). These responses did not differ between providers with fellowship training in epilepsy or neurophysiology (n=62) versus providers without this training (n=99) (Χ2=0.68, p=0.87). Given that detecting neonatal seizures clinically is unreliable and recent guidelines state that the use of cEEG in these patients is considered the gold standard, we inquired whether management decisions would change in the presence of an electro-clinical seizure versus an ESz.24,25 Consistent with these previous studies and guidelines, the majority our responding providers (76% (n=132) for case #1, 84% for case #2 (n=143), 75% (n=122) for case #3) would not change management based on the presence or absence of a clinical correlate (e.g., apnea, limb stiffening, lip smacking).
Discussion In our national survey, we found significant variability among child neurologists regarding some management issues in non-status ESzs in neonates with HIE. Our three cases each involved a neonate with HIE receiving TH, but each neonate differed in his or her injury severity, seizure burden, and ASD regimen in order to identify specific areas where ESz management was or was not disputed. While half of providers agreed that 10 seconds of an ESz should prompt treatment, the other half varied
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10 significantly regarding the duration of an ESz that whould prompt treatment. Additionally, there was marked disagreement in how aggressive providers would be in treating both a first ESz in an neonate with mild HIE or ongoing ESzs in a neonate with severe HIE. In these two cases, there was no consensus regarding when to start maintenance therapy for non-status ESzs, when to add a second ASD, or which agent should be the adjuvant therapy. In our case involving a neonate with moderate HIE, we found more agreement in how to escalate treatment for ongoing ESzs, however there remained a significant portion of providers who chose a different ASD. While we did find many areas of dispute, we also found some important trends in preferred practice. Three-quarters of providers would treat a first ESz in an infant with mild HIE. Of these providers, the majority would use PB first, consistent with expert opinion and surveys of national and international practice.5,18,26 Interestingly, 17% of providers who chose to treat a first ESz (either with a one-time ASD load or with a ASD load and maintenance) would use LEV first line. Additionally, when managing recurrent ESzs, approximately 20% of our respondents would use LEV as a second agent in both the moderate or severe HIE scenarios. When providers were surveyed in 2010, only one percent answered they would use LEV first line and only nine percent would use LEV second line for neonatal seizures.17 However, more recent prospective cohort studies of neonates in the National Seizure Registry found that 28% of neonates with HIE received LEV for seizures at some point in their hospital course and 24% were prescribed LEV at the time of discharge, suggesting that our results reflect current clinical practice and a growing tendency to use LEV in this patient population (although in comparison, 94% of them received PB at some point and 63% were on PB at time of
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11 discharge).5,18 Finally, our results also indicated that providers would treat ESzs the same way as electro-clinical seizures in all the clinical scenarios, congruent with previously published survey data and practice guidelines.17,25 There are limitations to our survey. The responding pediatric neurologists worked primarily in academic medical centers and did not spend a significant amount of their clinical time managing neonates, a common academic model. It is possible that this may have biased our results, however many academic centers have NICUs where a sizeable number of infants are referred for HIE and seizures. Similarly, our results may represent attitudes toward clinical management in a survey scenario but may not represent what is actually clinical practice, given the number of trainees and rotating attending physicians commonly involved in academic environments. Moreover, providers may have made management decisions that were not listed as one of the answer choices in the multiple-choice format. Also, although our survey response rate was similar to that published in previous studies21,22, it still only represents sixteen percent of possible participants introducing possible bias to our results. Finally, this survey represents opinion of pediatric neurologists, who typically are not the clinicians initially managing these patients, although they are often involved in more advanced clinical states reflected in our cases. Neonatologists, who are most commonly prescribing initial management, may have had different responses. Prior surveys have shown that neonatologists and pediatric neurologists agree that PB should be used firstline, however neonatologists were found to use other drugs (e.g., LEV) and, in one study, advocate for shorter duration of ASD treatment in this patient population than pediatric neurologists.17,26,27 Despite these limitations, our results reveal a significant
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12 lack of consensus in how pediatric neurologists approach ESzs in this patient population. Neonatal seizures are common and providers are regularly faced with determining when and how to treat them. Our study found wide variation in some aspects of neonatal ESz management. With growing evidence suggesting that seizures may cause additional harm in neonates with HIE, it is important to generate evidence based guidelines for providers in these situations to optimize outcomes. 3,12,13 Our data have identified specific aspects of neonatal seizure management where there is limited consensus.
Acknowledgements: We would like to acknowledge Roger Larson for helping us access the Child Neurology Society Listserv. We are grateful to the many pediatric neurologists and neonatologists at Johns Hopkins Hospital who provided feedback on initial versions of the survey. This manuscript is dedicated to the memory of Sheila Pakula, a lifelong supporter of neonatal care at Johns Hopkins Hospital.
References 1. Holden KR, Mellits ED, Freeman JM. Neonatal seizures. I. Correlation of prenatal and perinatal events with outcomes. Pediatrics 1982;70(2):165-76. 2. Ronen G, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in Newfoundland: A population-based study. J Pediatr 1999;134(1):71–75. 3. Glass H, Pham T, Danielsen B, Towner D, Glidden D, Wu Y. Antenatal and intrapartum risk factors for seizures in term newborns: A population-based study, California 1998-2002. J Pediatr 2009;154(1):24–28.e1. 4. Pisani F, Facini C, Pavlidis E, Spagnoli C, Boylan G. Epilepsy after neonatal seizures: Literature review. Eur J Paediatr Neurol 2014;19(1):6–14.
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13 5. Glass H, Shellhaas R, Wusthoff C, Chang T, Abend N, Chu C, et al. Contemporary profile of seizures in neonates: A prospective cohort study. J Pediatr 2016;174:98– 103.e1. 6. Levene MI, Traunce JQ. Cause of neonatal convulsions. Towards more precise diagnosis. Arch Dis Child 1986;61(1):78-9. 7. Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117(4):1270–1280. 8. Kurinczuk J, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic–ischaemic encephalopathy. Early Hum Dev 2010;86(6):329–38. 9. Vasudevan C, Levene M. Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med 2013 Aug;18(4):185-91. 10. Rooij L van, Broek M van den, Rademaker C, Vries L de. Clinical Management of Seizures in Newborns. Paediatr Drugs 2013 Feb;15(1):9-18. 11. Holmes GL. The long-term effects of neonatal seizures. Clin Perinatol 2009 Dec;36(4):901-14. 12. Shah DK, Wusthoff CJ, Clarke P, Wyatt JS, Ramaiah SM, Dias RJ, et al. Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2014 May;99(3):F21924. 13. 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 Nov;136(5):e1302–9. 14. Painter M, Scher M, Stein A, Armatti S, Wang Z, Gardiner J, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999 Aug;341(7):485–489. 15. Gutherz SB, Kulick CV, Soper C, Kondratyev A, Gale K, Forcelli PA. Brief postnatal exposure to phenobarbital impairs passive avoidance learning and sensorimotor gating in rats. Epilepsy Behav 2014 Aug;37:265–9. 16. Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004 Oct 18;(4):CD004218. 17. Glass H, Kan J, Bonifacio S, Ferriero D. Neonatal seizures: treatment practices among term and preterm infants. Pediatr Neurol 2012;46(2):111–115. 18. Shellhaas RA, Chang T, Wusthoff CJ, Soul JS, Massey SL, Chu CJ, et al. Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study. J Pediatr 2017;181:298-301.e1. 19. Thibeault-Eybalin MP, Lortie A, Carmant L. Neonatal seizures: do they damage the brain? Pediatr Neurol 2009 Mar;40(3):175-80. 20. Bassan H, Bental Y, Shany E, Berger I, Froom P, Levi L, et al. Neonatal seizures: dilemmas in workup and management. Pediatr Neurol 2008;38(6):415–421. 21. Kahn I, Helman G, Vanderver A, Wells E. Anti-N-Methyl-d-Aspartate (NMDA) receptor encephalitis. J Child Neurol 2017 Feb;32(2):243-245. 22. Plioplys S, Siddarth, Asato MR, Caplan R. Clinicians' views on antiepileptic medication management in nonepileptic seizures. J Child Neurol 2014 Jun;29(6):746-50. 23. Clancy RR, Legido A. The exact ictal and interictal duration of
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14 electroencephalographic neonatal seizures. Epilepsia 1987;28:537-41. 24. 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 May;93(3):F187-91. 25. Shellhaas R, Chang T, Tsuchida T, Scher M, Riviello J, Abend N, et al. The American Clinical Neurophysiology Society’s guideline on continuous electroencephalography monitoring in neonates. J Clin Neurophysiol 2011;28(6):611. 26. Hellstrom-Westas L, Boylan G, Agren J. Systematic review of neonatal seizure management strategies provides guidance on anti-epileptic treatment. Acta Paediatr 2015 Feb;104(2):123-9. 27. 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 Jan;17(1):55-63.
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15 Table 1. Survey Respondent Demographics n (%) Fellowship Training Child Neurology Epilepsy/Neurophysiology Neonatal Neurology Neonatology
177 (100) 65 (36.7) 8 (4.5) 2 (1.1)
Clinical Setting Academic Hospital Private Hospital Rural Hospital Outpatient Clinic
140 (79.1) 21 (11.9) 8 (4.5) 8 (4.5)
Clinical Time with Neonates 0% 1-25% 26-50% 51-75% 76-100%
7 (4.0) 151 (85.3) 13 (7.3) 3 (1.7) 3 (1.7)
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16 Table 2. Preferred Management n (%) Length of ESz to Initiate Treatment 5 seconds 10 seconds 20 seconds 60 seconds 5 minutes Any amount No amount
6 (3.4) 90 (51.1) 18 (10.2) 23 (13.0) 11 (6.3) 22 (12.5) 6 (3.4)
Case 1 (Mild HIE, Single ESz) Observe ASD Load* ASD Load + Maintenance**
41 (23.2) 65 (36.7) 71 (40.1)
Case 2 (Moderate HIE, Recurrent ESzs on PB) Observe Increase PB PHT Load LEV Load LEV Load + Maintenance Case 3 (Severe HIE, Recurrent ESzs on PB#) Observe Increase PB Add PHT Add LEV
5 (3.0) 126 (74.6) 8 (4.7) 8 (4.7) 22 (13) 23 (14.3) 39 (24.2) 66 (41.0) 33 (20.5)
* 60 (92.3%) with PB, 4 (6.2%) with LEV, 1 (1.5%) with PHT ** 52 (73.3%) with PB, 19 (26.7%) with LEV
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17 Supplementary Material: Survey Text Demographics: 1) What is your specialty? a. Neurology b. Neonatology 2) Have you completed fellowship training in any of the following specialties? Select any that apply, leave blank if none. a. Clinical Neurophysiology and/or Epilepsy b. Neonatology c. Neonatal Neurology 3) How many years have you been practicing your specialty? 4) Which of the following most closely describes the setting in which you have spent most of your time working? a. Academic hospital b. Private hospital c. Rural/Community hospital d. Outpatient clinic only 5) Approximately how much of your clinical time is spent taking care of neonates in the neonatal intensive care unit? a. 0% b. 1-25% c. 25-50% d. 50-75% e. 75-100% CASE 1: A 38.6 weeks gestation male infant was born by emergent C-section for nonreassuring fetal heart tones. Apgars were 4 and 7 at 1 and 5 minutes, respectively. The initial cord gas had a pH=6.91 with a base deficit of 16. The infant was passively cooled in the delivery room until arrival in the neonatal intensive care unit where whole body hypothermia was started and a neonatal montage continuous video EEG was placed. The initial head ultrasound and EEG background were normal. At 8 hours of life, his EEG showed 20 seconds of rhythmic left temporal sharp activity with an ictal evolution (an electrographic seizure) but no clinical correlate. 1) Which of the following options most closely resembles how you would manage this electrographic seizure? a. Continue observation, no medication at this point b. Load infant with 20 mg/kg of phenobarbital and continue to monitor c. Load infant with 20 mg/kg of fosphenytoin and continue to monitor d. Load infant with 30 mg/kg of levetiracetam and continue to monitor
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18 e. Load infant with 20 mg/kg of phenobarbital, start 3 mg/kg/day phenobarbital maintenance therapy, and continue to monitor f. Load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor 2) How long would a single electrographic-only seizure have to last in this patient before you would initiate any treatment in this patient (please select the answer closest to your typical practice)? a. 5 seconds b. 10 seconds c. 20 seconds d. 60 seconds e. 5 minutes f. I would treat any epileptiform activity found in this patient regardless of presence or absence of a corresponding clinical event. g. I would not treat electrographic activity in the absence of a clinical event. 3) If this patient went on to develop three more 20-second electrographic-only seizures over the next two hours, which of the following most closely resembles your management? a. Continue observation, no medication at this point b. Load infant with 20 mg/kg of phenobarbital and continue to monitor c. Load infant with 20 mg/kg of fosphenytoin and continue to monitor d. Load infant with 30 mg/kg of levetiracetam and continue to monitor e. Load infant with 20 mg/kg of phenobarbital, start 3 mg/kg/day phenobarbital maintenance therapy, and continue to monitor f. Load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor 4) If these recurrent electrographic seizures were associated with clinical correlates (eg. clonic extremity jerking, eye deviation, tachycardia, etc), would your management change? a. No, my management would not change. b. Yes, I would continue observation and not start medication. c. Yes, I would load infant with 20 mg/kg of phenobarbital and continue to monitor. d. Yes, I would load infant with 20 mg/kg of fosphenytoin and continue to monitor e. Yes, I would load infant with 30 mg/kg of levetiracetam and continue to monitor. f. Yes, I would load infant with 20 mg/kg of phenobarbital, start 3 mg/kg/day phenobarbital maintenance therapy, and continue to monitor. g. Yes, I would load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor.
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19 CASE 2: A 38.0 weeks gestation male infant was born by emergent C-section for placental abruption. He was pale and hypotonic in the delivery room. Apgars were 2, 2, and 6 at 1, 5, and 10 minutes, respectively. The initial cord gas showed a pH=6.89 with a base deficit of 14. He was passively cooled in the delivery room until arrival in the neonatal intensive care unit where whole body hypothermia was started and a neonatal montage continuous video EEG was placed. The initial head ultrasound showed white matter echogenicities and decreased resistive indices. The EEG background at initiation was mildly suppressed and discontinuous for gestational age. At 6 hours of life, he developed multifocal clonic seizures with clear electrographic seizure correlates. He was loaded with 20 mg/kg of phenobarbital twice and 3 mg/kg/day maintenance dosing was started. By 18 hours of life, his electro-clinical seizures had stopped, but he continued to have intermittent 30-60 second electrographic-only seizures independently from the left frontal or right temporal regions a few times per hour. A serum phenobarbital level at this time was 28. 1) Which of the following options most closely resembles how you would manage these electrographic-only seizures? a. They do not change my medical management at this time. b. Load with an additional 10 mg/kg of phenobarbital and increase maintenance dosing to 4 mg/kg/day c. Load with 20 mg/kg of fosphenytoin and continue to monitor d. Load with 30 mg/kg of levetiracetam and continue to monitor e. Load with 30 mg/kg of levetiracetam and start maintenance dosing at 20 mg/kg/day 5) If these recurrent electrographic seizures were associated with clinical correlates (eg. clonic extremity jerking, eye deviation, tachycardia, etc), would your management change? a. No, my management would not change. b. Yes, I would continue observation and not start medication. f. Yes, I would load with an additional 10 mg/kg of phenobarbital and increase maintenance dosing to 4 mg/kg/day c. Yes, I would load infant with 20 mg/kg of fosphenytoin and continue to monitor d. Yes, I would load infant with 30 mg/kg of levetiracetam and continue to monitor. e. Yes, I would load infant with 30 mg/kg of levetiracetam, start 20 mg/kg/day levetiracetam maintenance therapy, and continue to monitor. CASE 3: A 39.2 weeks gestation female infant was born by spontaneous vaginal delivery. The delivery was prolonged and she required extraction with forceps. She was initially limp and apneic. Apgars were 1, 2, and 6 at 1, 5, and 10 minutes, respectively. The initial cord gas had a pH=6.78 with a base deficit of 20. She was transferred to the NICU and started on the therapeutic hypothermia protocol. When the video EEG was placed, she was noted to be in electrographic status epilepticus with no clinical correlate. She required a total of 40 mg/kg of phenobarbital and 20 mg/kg of
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20 fosphenytoin before the electrographic seizure activity stopped. She was started on phenobarbital maintenance dosing at 3 mg/kg/day. However, her EEG continued to show electrographic-only seizures that were 20-30 seconds in duration, 4-5 times per day during cooling and rewarming despite a serum phenobarbital level of 42. Her brain MRI on day 5 of life showed sequelae of severe hypoxic-ischemic injury with diffuse subcortical white matter hyperintensity on T2-weighted imaging. 1) Which of the following most closely reflects your preferred management? She was otherwise clinically stable. a. No change to medical management. b. Increase maintenance phenobarbital to a target serum level of 50-60 c. Add levetiracetam 20 mg/kg/day to her regimen d. Load with 20 mg/kg of fosphenytoin and start phenytoin maintenance at 4 mg/kg/day e. Keep her on the EEG for a few days after rewarming to see if the electrographic seizure frequency decreases before adjusting her antiseizure medications 2) If there were clinical correlates (eg. clonic extremity jerking, eye deviation, tachycardia, etc) with the patient’s electrographic seizures, would that change your management? a. No, my management would not change b. Yes, I would increase maintenance phenobarbital to a target serum level of 50-60 c. Yes, I would load with 20 mg/kg of fosphenytoin and start phenytoin maintenance at 4 mg/kg/day d. Yes, I would add levetiracetam 20 mg/kg/day to her regimen e. Yes, I would keep her on the EEG for a few days after rewarming to see if the electrographic seizure frequency decreases before adjusting her antiseizure medications
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