Treatment of Seizures in the Neonate: Guidelines and Consensus-based Recommendations
The ILAE clinical practice guideline development group for neonatal seizures has developed guidelines and expert-based consensus recommendations for the treatment of neonatal seizures. These recommendations were informed by an extensive systematic review and, where no sufficient evidence was available, on expert-based consensus via Delphi. We are seeking your comments prior to submitting to a journal for peer review.
The systematic review identified 218 studies. The proposal includes guidelines and consensus-based recommendations on first and second line treatment, when to stop antiseizure medication, the impact of therapeutic hypothermia on seizure burden, and use of pyridoxine and pyridoxal 5´-phosphate. An example of a suggested treatment pathway including doses and adverse events based on current evidence and expert recommendations is given.
Draft: Treatment of Seizures in the Neonate: Guidelines and Consensus-based Recommendations – Special Report from the ILAE Task Force on Neonatal Seizures
Appendix A | Appendix B | Appendix C
Public comments are now closed and available for review below.
16 January 2023
Thank you very much for the work done, the evidence presented indicates that phenobarbital continues with the first option, leaving different options in the second line. What is not clear is whether using electroencephalographic monitoring when treating seizures what is referred to in some bibliography as seizure burden.
Rosa Y Alvarado M
13 January 2023
Thank you for compiling this important guidance. We would like to suggest some comments for your consideration.
- There is no caveat included for the caution regarding the use phenytoin or carbamazepine as a second-line agent if a channelopathy is suspected (page 11) and further, for the incorporation of genetic testing in the treatment decision. While genetic variants in SCN1A and the associated Dravet Syndrome are unlikely to present in the neonatal period, we found that nearly 1% of the 800 neonates with seizures evaluated by a tested by a commercial genetic testing laboratory had a positive molecular diagnosis in SCN1A, for which the use of sodium-channel agents may not be appropriate (poster presented at the 2022 AES meeting by Grayson et al.)
- On page 12, the information regarding the rates of success with the second-line agents is presented in a rather confusing manner. We suggest perhaps clarifying this section further. For example:
- For Ref 32: Painter et al 1997; Phenobarbital and Phenytoin met criteria for success in 13/30 (43%) and 13/29 (45%) as the initial agent, and when the other agent was added to the regimen for neonates whose seizures persistent, seizures were controlled with phenobarbital in 5/13 (39%) and phenytoin in 4/15 (27%) neonates.
- For Ref 33: Sharpe et al 2020; Phenobarbital and Levetiracetam met criteria for success with dose escalation in 24/30 (80%) and 15/53 (28%) patients as the initial agent, and when the other agent was added to the regimen for neonates whose seizures persistent, seizures were controlled with phenobarbital in 20/37 (54%) and levetiracetam in 1/6 (17%) neonates, again with dose escalation in this second-line treated group.
- Further, the information presented argues for phenobarbital to be considered in the list of second-line agents as well. Phenobarbital was the only ASM evaluated in the Delphi process that was not recommended by the experts as second-line treatment. Given that it is the choice of first line agent, we feel there should be a comment on why it wasn’t recommended, particularly as there may be patients started on a sodium channel agent (as recommended in the guidelines) and did not respond. These would be highly appropriate patients for phenobarbital use.
- The recommendation (#3) to discharge babies whose seizures resolved off ASMs regardless of EEG and MRI findings is supported by the paper cited (ref 58). However, we think the response should be modulated somewhat, in that if seizures recur, obviously ASMs should be resumed. There is a chance that this recommendation could be taken too literally and could potentially obviate good clinical judgement.
- Finally, the guidance states that the research priorities for the treatment of neonatal seizures includes dose finding, pharmacokinetic and safety studies in neonates, however, there are no recommendations regarding the preferred formulation of these ASMs. If an intravenous formulation is recommended, this should be specifically mentioned in addition to the acceptability of other routes of administration including intranasal and rectal use of ASMs.
Celene Grayson, PhD and Cynthia Harden, MD
11 January 2023
Dear ILAE Task Force:
Thank you for drafting this important document - these guidelines will be helpful to clinicians managing seizures in neonates. We would like to offer several points for your consideration.
- The most recent search was done on 28 June 2020, and these guidelines are being drafted in 2023. We would suggest consideration of an updated search to ensure the most recent evidence is considered for these guidelines, and we have cited some of these publications.1,2
- The search strategy focusing on studies that include only electrographic seizures could potentially exclude studies that evaluated seizure response based on other important outcomes related to their safety. We understand this is important when evaluating the efficacy of seizure treatment on seizure burden and to avoid including seizure mimics. However, it excludes studies that provide insight into other relevant factors related to ASM treatment, such as adverse effects that may impact important outcomes such as mortality and neurodevelopment. Safety studies typically require large numbers of patients, and neonatal studies that only include patients with electrographic seizures are not sufficient powered to detect safety related issues. Phenobarbital and phenytoin have been shown to be neurotoxic in animal models.3-5 Additionally, phenobarbital has been associated with decreased cognitive and motor scores in some studies of infants and young children.6-8 As the ultimate goal of ASM treatment is not simply seizure cessation but long term outcome, a search strategy that excludes studies evaluating adverse effects ASM does not provide a complete picture of long-term outcome. We would suggest that future search strategies consider real-world evidence, where not all infants will undergo continuous EEG monitoring, into consideration of evidence. Access to continuous EEG monitoring that is interpreted by trained pediatric neurologists may be limited, even in high-resource settings. This is especially important if these guidelines are to be utilized in low and middle income countries.
- The second-line treatment recommendations should consider risks such as mortality and neurodevelopmental outcome in recommendations between agents such as a phenytoin/fosphenytoin and levetiracetam. The current guideline draft states the level of evidence was very low for this recommendation and expert opinion was sought (with mixed results). As stated above, the authors’ search strategy limited to electrographic seizures excluded studies that could provide helpful information on adverse effects of ASMs. Adverse effects of phenytoin include arrhythmias, respiratory depression, and hypotension, which are serious and potentially lethal side-effects.9 For example, a recent large US cohort study examined phenytoin compared to levetiracetam as second-line treatment following phenobarbital failure.2 The comparative safety of these two medications in this study favors levetiracetam as second-line treatment.
Thank you for the opportunity to provide points for your consideration.
Dr. Elizabeth Sewell, Dr. Ravi Patel and Dr. Kaashif Ahmad
- Glass HC, Shellhaas RA. Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures-Reply. JAMA Neurol. 2022;79(1):91-92.
- Sewell EK, Hamrick SEG, Patel RM, Bennett M, Tolia VN, Ahmad KA. Association between anti-seizure medication and outcomes in infants. J Perinatol. 2021.
- Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A. 2002;99(23):15089-15094.
- Forcelli PA, Kim J, Kondratyev A, Gale K. Pattern of antiepileptic drug–induced cell death in limbic regions of the neonatal rat brain. Epilepsia. 2011;52(12):e207-e211.
- Kaushal S, Tamer Z, Opoku F, Forcelli PA. Anticonvulsant drug–induced cell death in the developing white matter of the rodent brain. Epilepsia. 2016;57(5):727-734.
- Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. Journal of Perinatology. 2013;33(11):841-846.
- Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. New England Journal of Medicine. 1990;322(6):364-369.
- Sulzbacher S, Farwell JR, Temkin N, Lu AS, Hirtz DG. Late cognitive effects of early treatment with phenobarbital. Clinical pediatrics. 1999;38(7):387-394.
- El-Dib M, Soul JS. The use of phenobarbital and other anti-seizure drugs in newborns. Semin Fetal Neonatal Med. 2017;22(5):321-327.
10 January 2023
Thanks to all for the wonderful work.
I think is accessible and affordable even in LMIC. Anyway only levet we’re preferred in cardiac condition so if there’s no levet in the case of seizure due to channel channelopathy what could be the anti seizure choice.
10 January 2023
Dear ILAE Task force,
We congratulate for the efforts made in providing advances in neonatal seizures management; in particular, we appreciate with enthusiasm your efforts in underlining the importance of the EEG/aEEG as indispensable tools for seizure detection and believe that such inputs from the scientific community are needed to strengthen the possibility to have 24-7 skilled personnel available in all settings; furthermore, we believe it is fundamental, as you did, to underline the need to withdraw ASMs as soon as possible, ideally before discharge home (recommendation 3).
Unfortunately, we are concerned that more than one point needs to be further assessed.
With regard to recommendation 6, the authors state that a trial of pyridoxine should be provided as add-on to ASM in neonates with seizures unresponsive to second-line ASM without an identified etiology. Both our experience and various reports from the literature, though, support the possibility that patients with vitamin B6-dependent epilepsy might show an initial response to common ASMs to, later, relapse with status epilepticus.1,2 We believe updated guidelines should look deeper into this matter and suggest considering a trial of pyridoxine in all patients with seizures of unknown etiology as first-line treatment, even before ASMs’ administration, especially in neonates presenting with clinical features or EEG characteristics suggestive of vitamin B6- dependent epilepsy.
Furthermore, the authors’ enthusiasm in providing 'high' consensus-based evidence that Phenobarbital should always be administered as first-line ASM seems a bit incautious (recommendation 1). Historically, Phenobarbital has been largely used and this unavoidably justifies the high amount of literature available on its efficacy rates and side-effects. On the other hand, though, the scientific community has pronounced for decades on Phenobarbital’s long-term detrimental side effects on neurodevelopment. We believe the fact that to date there’s no 'universally' more effective alternative does not justify Phenobarbital’s administration in all patients, as suggested in your paper, even in those with low seizure burden, electrical only seizures or short, self-limiting seizures. It would probably be more prudent to at least address this issue in the paper and to underline the need to consider Phenobarbital’s side effects and inform parents when the decision to prescribe it is made. Furthermore, in your paper Phenobarbital is suggested as first choice in all cases but its’ overall efficacy remains quite unsatisfactory; this, unavoidably raises doubts and questions in readers. What the scientific community and clinicians worldwide expect is not anymore the 'holy grail' of neonatal seizures treatment, a medication that works for all patients, regardless of the underlying etiology and seizures features but the possibility to point towards a targeted, precision medicine; in 2021 our group published a systematic review on ASMs’ efficacy in treating neonatal seizures from different etiologies and found, among 66 included studies, that the same ASM provided different efficacy rates in different population of newborns, that were grouped altogether not by the ASM used, as in your paper, but by the underlying etiology.3 In particular, some data pointed towards an overall satisfactory efficacy of Lidocaine for stroke, SCB for genetic channelopathies – as you well underlined – Lev for HIE and found that Lev was safe both in term and preterm newborns and in terms of both short- and long-term outcomes, not only in patients with cardiac comorbidities as you underlined based mainly on expert opinions. Indeed, the small number of patients enrolled and the not-so rigid methodology of most studies included both in our and in your work probably does not allow to replace current protocols but we feel the need for updated guidelines, such as yours, to support the efforts made by clinicians worldwide to point towards a precision therapy and feel concerned that the paper you provided does not completely follow the trend that clinical practice has conquered in the last years and risks perpetuating management strategies that have been shown to be unsatisfactory and in some cases even harmful.
Raffaele Falsaperla & Bruna Scalia
- Kluger G, Blank R, Paul K, Paschke E, Jansen E, Jakobs C, Wörle H, Plecko B. Pyridoxine-dependent epilepsy: normal outcome in a patient with late diagnosis after prolonged status epilepticus causing cortical blindness. Neuropediatrics. 2008 Oct;39(5):276-9. doi: 10.1055/s-0029-1202833. Epub 2009 Mar 17. PMID: 19294602.
- Lin J, Lin K, Masruha MR, Vilanova LC. Pyridoxine-dependent epilepsy initially responsive to phenobarbital. Arq Neuropsiquiatr. 2007 Dec;65(4A):1026-9. doi: 10.1590/s0004-282x2007000600023. PMID: 18094870.
- Falsaperla R, Scalia B, Giugno A, Pavone P, Motta M, Caccamo M, Ruggieri M. Treating the symptom or treating the disease in neonatal seizures: a systematic review of the literature. Ital J Pediatr. 2021 Apr 7;47(1):85. doi: 10.1186/s13052-021-01027-2. PMID: 33827647; PMCID: PMC8028713.
4 January 2023
The authors are to be congratulated for going forward on the path of preventing overtreatment by advocating discontinuation of antiseizure medication (ASM) before discharge home in infants who showed cessation of acute symptomatic seizures (recommendation 3). However, their enthusiasm for phenobarbital as a first-line ASM (recommendation 1) and treatment of all neonatal seizures including electrographic-only seizures (recommendation 5) cause concern.
Phenobarbital has been shown to display considerable neurotoxicity in numerous animal models both in rodents and in monkeys. In newborn mice, a dosage of phenobarbital that reduces seizure burden in hypoxia-induced seizures (25 mg/kg) lacks any positive effect on histopathological injury, behavioral abnormality, or impaired memory function.1 In neonatal rats with status epilepticus, phenobarbital and midazolam even worsen neuronal injury.2 In neonatal rhesus monkeys, extensive degeneration of neurons and oligodendrocytes has been observed in various brain regions following the administration of phenobarbital and midazolam3 that is not ameliorated by hypothermia.4 A retrospective study of 280 human infants who were given ASM for neonatal seizures, a cumulative exposure of 100 mg phenobarbital/kg was associated with 8-9 points decrease of the Bayley Scales of Infant Development scores at 2 years of age, while the probability of cerebral palsy increased more than 2-fold.5 Furthermore, low-dose phenobarbital (5 mg/kg/d) given prophylactically to infants and young children was associated with a decline of the intelligence quotient by 5-8 points in a large placebo-controlled randomized controlled trial.6 Thus, phenobarbital may be the most efficacious ASM but its administration exerts considerable damage to the developing brain. Possibly, this is the price to pay for infants with heavy seizure burden, but for infants with short, self-limiting seizures, the remedy may be more dangerous than the disease.
Seizures by themselves have not been found to be linked to impaired neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy.7,8 As overall seizure burden is a marker of the extent of brain damage, the association between high seizure burden and neurodevelopmental impairment is trivial. Prolonged seizures appear to herald rather than cause poor outcome, at least in the setting of hypoxic-ischemic encephalopathy. Data from two prospective randomized controlled trials involving 33 infants9 and 172 infants,10 respectively, failed to suggest that treatment of subclinical seizures improves outcome in newborns with acute symptomatic seizures, contravening recommendation 5. Efforts aimed at stopping all seizures as rapidly and effectively as possible may do more harm than good.
- Quinlan SMM, Rodriguez-Alvarez N, Molloy EJ, Madden SF, Boylan GB, Henshall DC, Jimenez-Mateos EM. Complex spectrum of phenobarbital effects in a mouse model of neonatal hypoxia-induced seizures. Sci Rep 2018;8(1):9986. doi: 10.1038/s415980‑18‑28044-2.
- Torolira D, Suchomelova L, Wasterlain CG, Niquet J. Phenobarbital and midazolam increase neonatal seizure-associated neuronal injury. Ann Neurol 2017;82(1):115-120. doi: 10.1002/ana.24967.
- Noguchi KK, Fuhler NA, Wang SH, Capuano S 3rd, Brunner KR, Larson S, Crosno K, Simmons HA, Mejia AF, Martin LD, Dissen GA, Brambrink A, Ikonomidou C. Brain pathology caused in the neonatal macaque by short and prolonged exposures to anticonvulsant drugs. Neurobiol Dis2021;149:105245. doi:10.1016/j.nbd.2020.105245.
- Ikonomidou C, Wang SH, Fuhler NA, Larson S, Capuano S 3rd, Brunner KR, Crosno K, Simmons HA, Mejia AF, Noguchi KK. Mild hypothermia fails to protect infant macaques from brain injury caused by prolonged exposure to antiseizure drugs. Neurobiol Dis2022;171:105814. doi: 10.1016/j.nbd.2022.105814.
- 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):841-6. doi: 10.1038/jp.2013.116.
- 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 Med1990;322(6):364‑9. doi: 10.1056/NEJM199002083220604.
- Kharoshankaya L, Stevenson NJ, Livingstone V, Murray DM, Murphy BP, Ahearne CE, Boylan GB. 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.
- Basti C, Maranella E, Cimini N, Catalucci A, Ciccarelli S, Del Torto M, Di Luca L, Di Natale C, Mareri A, Nardi V, Pannone V, Di Fabio S. Seizure burden and neurodevelopmental outcome in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia: A single center observational study. Seizure 2020;83:154-159. doi: 10.1016/j.seizure.2020.10.021.
- van Rooij LG, Toet MC, van Huffelen AC, Groenendaal F, Laan W, Zecic A, de Haan T, van Straaten IL, Vrancken S, van Wezel G, van der Sluijs J, Ter Horst H, Gavilanes D, Laroche S, Naulaers G, de Vries LS. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics 2010;125(2):e358-66. doi: 10.1542/peds.2009-0136.
- Hunt RW, Liley HG, Wagh D, Schembri R, Lee KJ, Shearman AD, Francis-Pester S, de Waal K, Cheong JYL, Olischar M, Badawi N, Wong FY, Osborn DA, Rajadurai VS, Dargaville PA, Headley B, Wright I, Colditz PB; Newborn Electrographic Seizure Trial Investigators. Effect of treatment of clinical seizures vs electrographic seizures in full-term and near-term neonates: a randomized clinical trial. JAMA Netw Open2021;4(12):e2139604. doi: 10.1001/jamanetworkopen.2021.39604.
25 December 2022
Nice work from the ILAE task Force.
Dr Sameer Zuberi visited Aga Khan University Hospital a month ago. Since then, we have started collecting data regarding recurrence of seizures in HIE noenatal age groups.
Although the majority of RCTs mentioned in this report are based on clinical seizures, electroclinical and specifically electrographic seizures are still topics of concern in a major part of world.
I question that in developing countries the majority of HIE neonates are Grade III, and suddenly withdrawing ASMs may result in recurrence.
Data from developing countries are still lacking. Early discontinuation of ASMs should be individualized in certain conditions.
Dr. Farhan Ali
20 December 2022
Thank you for this excellent work.
20 December 2022
Dear Madam or Sir,
The draft mentions sodium channel blockers as a treatment options, but lists only phenytoin and carbamazepine as possible choices. Are there any reasons not to mention oxcarbazepine (which is, at least in Germany, nowadays much more widely used than carbamazepine) and lacosamide?
20 December 2022
This is a valuable effort. The sentence on page 10 of the introduction [Electroencephalography (EEG or aEEG) is required for seizure diagnosis since most seizures in neonates have no clinical manifestations (electrographic-only)...] is very important.
EEG is not yet provided in many NICUs at point of diagnosis. I suggest more emphasis on need for EEG for certain diagnosis and to determine AED treatment duration in neonatal seizures.
19 December 2022
I have great worries about consensus based guidelines as they risk perpetuating treatments or management protocols that may ultimately be shown to be harmful or ineffective. A non-evidenced based guideline risks imposing a harmful or dangerous treatment on ALL infants; this was the case for example with routine use of 100% oxygen for newborn resuscitation, a practice that was enshrined in consensus/expert opinion based guidelines which harmed countless babies. However, I recognise that all too often, evidence to support clinical practice is insufficient and also that consistency of practice within a centre has some benefits. Therefore when evidence is insufficient for an evidence-based guideline I strongly recommend that the authors include the following statements in their document: 1) the treatment uncertainties should be explained to parents; 2) it should be made explicit to neonatal centres that the existence of a guideline does not mean they cannot take part in a randomised controlled trial to address the treatment uncertainty; 3) all neonatal centres should be strongly advised to join high quality randomised studies to resolve such uncertainties; and 4) it should be explained to parents that in the face of uncertainty, randomisation is the most fair and ethical approach as it is the only way to provide every baby with an equal chance of receiving the (unknown) best treatment.
19 December 2022
I appreciate the great effort from the authors to provide us with this recommendations. I would like to ask, if it is possible to address the following concerns:
- Treatment as a rescue-option in newborns with CNS insult and seizure-like activity that are being transported or waiting for transport to a specialized NICU center (an agent that will not interfere with the exam/EEG or with a short half-life).
- In acute metabolic disturbances and seizures (glycemia or electrolytes) ASM should be started while the metabolic issue is being corrected?
- Lidocaine should not be used if phenytoin was previously used.
- Treatment options/recommendations in refractory-seizures or neonatal status epilepticus after using 1st and 2nd line agents.
17 December 2022
Thank you. The methodology and scope for the recommendations is excellent.
I find some of the recommendations confusing, and I think need to be clearer particularly if aimed at non-neurology neonatal professionals in an acute/emergency setting.
Recommendation 1 implies all should have phenobarbital, but then outlines an exception. This is confusing.
Where citing sodium channel ASMs in a recommendation would be good to always list the examples as many will not think of ASMs in this way. In fact I would simply list the suitable drugs to consider rather than refer to them by this category.
For the first line ASM it implies solely family history of channelopathy is factor, whereas for second line, solely electro-clinical features of channelopathy in index case are important. Is this the intention?
I would like to be guided within the guidance as to the definition of channelopathy and what should make me consider a channelopathy in practice, given is a key determinant of different ASMs. Many will not be familiar with this channelopathy term.
The flow diagram arrows are confusing and is hard to follow the logic. The vertical arrows imply next step or decision. The horizontal arrows imply caveats rather than a next step. I think a decision tree approach might make this much clearer so that you can follow through ASM choices based on presence or absence of the key caveats.
15 December 2022
Dear ILAE Task Force,
I have gone through the consensus based recommendations for treatment of seizures in the neonates. Phenobarbitone is known to have negative neurodevelopmental effect especially on the developing brain, recommending it as first line treatment for seizure control needs further clarification in terms of duration and dosage and what should be our end point, clinical seizure control or electrographic improvement. Also stopping anti-seizure medications before discharge irrespective of neurological and electrographic changes needs further research and recommendations. The role neuroimaging can play an important role. The loading and maintenance dosage of levetiracetam also needs clarification.
Dr Rahul Sinha
Command Hospital Chandimandir Panchkula Haryana India
15 December 2022
The manuscript looks excellent and the recommendations are reasonable.
Dr Shripada Rao
13 December 2022
Role of EEG and aEEG especially in LMIC settings for management of Neonatal seizures should be clarified.
13 December 2022
Indication for midazolam infusion, dose and escalation and tapering protocol.
13 December 2022
Refractory seizures can be the first choice of treatment with oxcarbamazepine in channelopathy.
Rafid Abdulkadhim Atshan Alneghimsh
13 December 2022
Dear ILAE Task force,
I am concerned that the first recommendation - that in neonates with seizures requiring antiseizure medication (ASM), phenobarbital should be the first-line ASM, does not highlight the fact that this is based only on data regarding seizure cessation efficacy, and we do not know if it will ultimately improve neurodevelopmental outcome- the ultimate endpoint we care about.
Although phenobarbital has proven highly effective at achieving seizure cessation, its net effect on neurodevelopment could still be negative, due to its neurotoxic effects.
Rat and primate neonatal studies have shown markedly accelerated neuronal apoptosis following a single standard dose of phenobarbital, (and most other antiseizure medications, phenytoin, midazolam, valproate). Other adverse effects caused by phenobarbital in the animal model include interference with cell proliferation and migration, axonal arborization, synaptogenesis and synaptic plasticity.1-6
Fetal exposure has been shown to reduce cognitive outcomes in 2 case control studies. The magnitude of the effect was about 0.5 standard deviations.7
Young children randomized to PHB for febrile seizure had persistently lower IQ test results after medications tapered.8-11
This month at Neonatal Hot Topics conference, 7 December 2022, Washington DC Professor Rod Hunt, presented additional, yet unpublished, data from his recent study on the impact of aEEG monitoring on neurodevelopmental outcome.12 This showed a dose dependent adverse impact of phenobarbital on IQ, a 3pt IQ drop for every 10 mg/kg phenobarbital received. On average in his cohort, neonates received 38 mg/kg of PHB. This association held after correction for the underlying severity of injury and for seizure burden.
Additionally, the recommendation does not not define when seizures require antiseizure medication.
A summary of the evidence that seizures are harmful per se and the remaining gaps in that evidence should be included in this guideline.
It should be highlighted that our evidence that seizures are harmful is most convincing for prolonged seizures in both animal and human studies.13-16 In patients with low seizure burden, neurodevelopmental outcome is frequently normal. Boylan et al17 demonstrate that a cut off maximal seizure burden of 13 minutes/ hour or total seizure burden of 40 minutes separate patients with abnormal outcomes from those with normal outcomes. In NEOLEV2 more than half the cohort had seizure burdens less than this.
It remains unclear in patients with low seizure burden, whether the risk of neurologic injury from the seizures is greater than the risks of neurotoxic injury from phenobarbital.
Unedited, the draft recommendation will lead to widespread increased use of phenobarbital for all neonatal seizures, potentially doing more harm than good.
Dr Cynthia Sharpe
- Klitgaard H, Matagne A, Gobert J, Wulfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol. 1998;353(2-3):191-206.
- Kim J, Kondratyev A, Gale K. Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther. 2007;323(1):165-73.
- Forcelli PA, Kozlowski R, Snyder C, Kondratyev A, Gale K. Effects of neonatal antiepileptic drug exposure on cognitive, emotional, and motor function in adult rats. J Pharmacol Exp Ther. 2012;340(3):558-66.
- Forcelli PA, Kim J, Kondratyev A, Gale K. Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia. 2011;52(12):e207-11.
- Forcelli PA, Janssen MJ, Vicini S, Gale K. Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development. Ann Neurol. 2012;72(3):363-72.
- Kaindl AM, Asimiadou S, Manthey D, Hagen MV, Turski L, Ikonomidou C. Antiepileptic drugs and the developing brain. Cell Mol Life Sci. 2006;63(4):399-413.
- Reinisch JM, Sanders SA, Mortensen EL, Rubin DB. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA. 1995;274(19):1518-25.
- 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):364-9.
- Sulzbacher S, Farwell JR, Temkin N, Lu AS, Hirtz DG. Late cognitive effects of early treatment with phenobarbital. Clin Pediatr (Phila). 1999;38(7):387-94.
- Calandre EP, Dominguez-Granados R, Gomez-Rubio M, Molina-Font JA. Cognitive effects of long-term treatment with phenobarbital and valproic acid in school children. Acta Neurol Scand. 1990;81(6):504-6.
- Camfield CS, Chaplin S, Doyle AB, Shapiro SH, Cummings C, Camfield PR. Side effects of phenobarbital in toddlers; behavioral and cognitive aspects. J Pediatr. 1979;95(3):361-5.
- Hunt RW, Liley HG, Wagh D, Schembri R, Lee KJ, Shearman AD, et al. Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial. JAMA Netw Open. 2021;4(12):e2139604.
- 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):318-23.
- Yager JY, Armstrong EA, Miyashita H, Wirrell EC. Prolonged neonatal seizures exacerbate hypoxic-ischemic brain damage: correlation with cerebral energy metabolism and excitatory amino acid release. Dev Neurosci. 2002;24(5):367-81.
- 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):e1302-9.
- Zhou KQ, McDouall A, Drury PP, Lear CA, Cho KHT, Bennet L, et al. Treating Seizures after c-Ischemic Encephalopathy-Current Controversies and Future Directions. Int J Mol Sci. 2021;22(13).
- 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):1242-8.
13 December 2022
Thank you for the interesting study and is very needed in practice.
- Page 10 needs to be clarified: 'Only one study with phenobarbital and levetiracetam used standardized adverse events tables and reported that there was a trend towards hypotension being more common with phenobarbital (n=17%) compared to levetiracetam (n=5%)'.
- Why is the Neonatal hypoglycemia not mentioned or included in the draft discussion?
12 December 2022
Clear guidelines need for the management of convulsive non convulsive status epileptics in neonates. Use of anesthetic agents, intranasal and rectal use of ASM can be mentioned.
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