Table of Contents

 

Seizures in neonates can be difficult to diagnose because they often present with subtle signs and symptoms. Patient stabilization, seizure cessation, and determination of the etiology are key aspects of emergency department management. This issue reviews common presentations and causes of neonatal seizures, provides recommendations for management in the emergency department, and evaluates existing evidence regarding antiepileptic medications for treatment of neonatal seizures. You will learn:

Common presentations of neonatal seizures, and how to distinguish those from benign mimics of seizures

Various etiologies for neonatal seizures, and which are the most common

How the timing of presentation can help determine the cause of the seizure

Key components of the physical examination that should be conducted for neonates with seizure activity

What types of diagnostic studies are indicated, and which are highest yield

Which antiepileptic drugs have the most evidence supporting their use in neonates, as well as which are recommended as first-line, second-line, and third-line choices

Recommendations for non–antiepileptic drug management of neonatal seizures

Which neonates should be admitted, when admission to a pediatric or neonatal intensive care unit is warranted, and under which circumstances a neonate can be discharged

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Etiology
   1. Infectious Etiologies
   2. Vascular Etiologies
   3. Metabolic Etiologies
      1. Inborn Errors of Metabolism
   4. Other Etiologies
   5. Timeline for Seizure Onset
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. Initial Stabilization
   2. History
   3. Physical Examination
9. Diagnostic Studies
   1. Laboratory Studies
   2. Imaging Studies
   3. Electroencephalography
10. Treatment
    1. Antiepileptic Drugs
       1. Phenobarbital
       2. Phenytoin/Fosphenytoin
       3. Levetiracetam
       4. Benzodiazepines
       5. Lidocaine
       6. Other Antiepileptic Drugs
    2. Non–Antiepileptic-Drug Management
11. Special Populations
    1. Premature Neonates
    2. Patients With Recurrent Brief Resolved Unexplained Events
    3. Patients Who Have Not Had Standard Prenatal Care/Patients With Risk of Exposure to Infectious Agents
    4. Patients Born Outside a Medical Facility
12. Controversies and Cutting Edge
    1. Medication Choices
    2. Amplitude-Integrated Electroencephalography
    3. Genetic Testing
13. Disposition
14. Summary
15. Time- and Cost-Effective Strategies
16. Risk Management Pitfalls for Neonatal Seizures
17. Case Conclusions
18. Clinical Pathway for Management of Neonatal Seizures
19. Tables and Figures
    1. Table 1. Risk Factors for Neonatal Seizures
    2. Table 2. Seizure Etiologies
    3. Table 3. Antiepileptic Drugs
    4. Table 4. Medications to Correct Metabolic Derangements
    5. Figure 1. Seizure Onset Timeline: Seizure Etiology By Postnatal Age
20. References

Abstract

Neonatal seizures are associated with high morbidity and mortality, but they can be difficult to diagnose because they often present with subtle signs and symptoms. Initial management goals in the emergency department include patient stabilization, seizure cessation, and determination of the etiology; identification of life-threatening treatable causes of the seizures should be prioritized. Further management depends on the history and physical examination findings, laboratory testing results, and imaging studies. This issue reviews common presentations and causes of neonatal seizures, considerations for emergency department management, and the evidence regarding antiepileptic medications for neonates.

Case Presentations

An EMS team brings in a 5-day-old boy with a history of a rhythmic, left-arm-shaking episode at home. The parents tell you the pregnancy was normal and the birth was a full-term, normal spontaneous vaginal delivery. The baby had been doing well until yesterday, when he started eating less and not waking up for feeds. The baby has low tone with a tense anterior fontanelle, and his temperature is 35.8˚C (96.4˚F). What workup is warranted at this time?

A mother brings in her newborn daughter, with concern for abnormal movements. The girl was born at 34 weeks' gestation; she is now 3 weeks old. The mother says the baby will often stiffen and arch her back, and she is worried because there is a family history of epilepsy. The baby has no chronic lung disease or severe complications from prematurity. There have been no recent fevers or sick contacts. The baby has been falling off the growth curve despite high-calorie formula. She often spits up, which seems to make her uncomfortable. The mother brought in a video that captures one of the episodes. You watch the video and see 10 seconds of full-body stiffening, reddening of the face, and significant back arching. The baby has a normal neurologic examination with normal tone, reflexes, and a soft, flat anterior fontanelle. Could this be a seizure disorder? What other diagnoses are on your differential?

Your next patient is a 6-day-old full-term baby boy. His parents brought him in because he was vomiting. He has not been feeding well and is still below birth weight. He started vomiting intermittently several days ago, but now he is vomiting after every feeding. The state newborn screen has not yet resulted. While you are examining him, he starts to have repetitive blinking, followed by staring. After this, he fell asleep. A few minutes later, his right arm stiffens, and it progresses to generalized shaking. What could be causing this baby’s behavior? What kinds of medications may be required?

Introduction

The incidence of seizures in children is highest in the neonatal period (defined as up to age 28 days, or 44 weeks of gestational age for premature infants). Seizures affect 3 to 5 of every 1000 children, with an increased risk among premature infants (2-3/1000 full-term neonates; 10-15/1000 preterm neonates).¹ Neonatal seizures are associated with high mortality and risk for adverse neurodevelopmental outcomes,^2,3 and often confer a poorer prognosis compared to seizures in older children. Seizure activity in this age group can be subtle, as they are typically focal seizures, and only rarely generalized, tonic-clonic seizures. Neonates who exhibit seizure-like activity often present to the emergency department (ED), especially if activity is severe. Neonatal seizures most often present in the first 2 days of life, with 80% of neonatal seizures presenting within the first week of life.⁴

Most neonatal seizures are secondary in etiology, rather than representing a primary epilepsy syndrome. Because of neonates’ immature nervous systems, seizures can be difficult to diagnose, as they often present as subtle movements with a range of clinical appearances. Seizures in neonates present most commonly as subtle focal automatisms, such as lip-smacking, tongue protrusion, sucking, chewing, paddling, arm or leg bicycling, swimming, boxing, or ocular movements.^5,6 Overall, abnormal eye movements are the most common manifestation and can include deviation, repetitive blinking, or staring.⁵ Seizures can also be clonic, characterized by repetitive, rhythmic, jerking movements; or tonic, with stiffness (often with extension in all extremities or extension of legs with flexion of arms), and may be focal or generalized.⁵ Myoclonic seizures with isolated or nonrhythmic jerking movements can also be focal, multifocal, or generalized.^4,6,7 Status epilepticus is defined as continuous or repetitive seizure activity for more than 5 minutes, or a series of seizures between which there is no return to baseline.^5,8 High seizure burden and status epilepticus have been associated with worse outcomes.¹

Early seizure cessation is important for improved patient outcomes. However, even with prompt treatment, the overall prognosis for neonates with seizures remains poor. Diagnosis of neonatal seizures is often made definitively by electroencephalography (EEG), as both electroclinical dissociation (when seizure activity on EEG is not observable clinically) and benign mimics (events that clinically appear to be seizures without abnormal EEG activity) are both common in this age.⁹ With this in mind, this issue will focus on clinical neonatal seizures, as these cases are most likely to present to the ED for evaluation and can be diagnosed clinically. The treatment of neonatal seizures depends on the etiology, but most often includes an antiepileptic drug or correction of the inciting pathology.

This issue of Pediatric Emergency Medicine Practice reviews common presentations and causes of neonatal seizures, provides recommendations for management in the ED, and evaluates existing evidence regarding antiepileptic medications for treatment of neonatal seizures.

Critical Appraisal of the Literature

A PubMed search was conducted for literature on neonatal seizures using the search terms: neonatal seizure[s], infantile seizures, infant seizure, and neonate[s] and seizure[s]. The search yielded 760 initial results and was limited to infants aged < 1 month, English language or available English-language translation, and non–neonatal intensive care unit (NICU) or non–postoperative cardiac surgical studies. Abstracts were reviewed for relevance, and a total of 80 articles were identified. A review of the citations expanded the total to 110 articles, of which, 78 were chosen for inclusion.

There are limited randomized controlled trials (RCTs) evaluating neonatal seizures, with 3 RCTs focusing on treatment.^10-12 Additionally, there are 3 systematic reviews on treatment.^13-15 The existing body of evidence consists largely of retrospective studies and a few prospective studies, as well as many case reports, case series, and reviews. Many studies are limited by small sample size and inconsistent diagnostic and treatment success criteria (ie, EEG-confirmed vs clinical seizures).

Etiology

The neonate is susceptible to seizures due to an imbalance of excitatory and inhibitory pathways in the immature neonatal brain.¹⁶ Additionally, complications in the birthing process, such as trauma or hypoxia, may result in seizures.¹⁶ Risk factors for seizures include maternal influences, perinatal factors, infant characteristics, and family history.^17,18 (See Table 1.)

There is a wide range of causes of neonatal seizures (see Table 2), with the leading etiologies being hypoxic ischemic encephalopathy (HIE), vascular disorders, infections, and acquired metabolic derangements.⁵ HIE is the most common cause of seizures and is often related to a complicated birthing process.¹⁹

Infectious Etiologies

Infections cause up to 20% of neonatal seizures and may present later than other etiologies.²⁰ Infectious causes can range from generalized sepsis to primary neurologic infections such as meningitis, encephalitis, or meningoencephalitis. Organisms to consider include a variety of bacteria, viruses, and parasites, as outlined in Table 2.^6,21 Herpes simplex virus (HSV) may be found in the temporal lobe and is often associated with focal seizures, although this is more common in older patients.²² Maternal history or typical HSV lesions are often absent, as the risk of transmission is highest with the initial outbreak. Rubella can cause intracranial lesions, and toxoplasmosis and cytomegalovirus classically cause intracranial calcifications, all of which can lead to seizures. Rotavirus can cause leukoencephalopathy and repetitive seizures; a retrospective study of 32 neonates with presumed postnatal rotavirus infection showed that only 25% of patients experienced diarrhea and none had fever or rash.²¹

Risk Management Pitfalls for Neonatal Seizures

2. “The mother said the baby was feeding normally, 3 ounces of formula every 3 hours. I didn’t think to ask about the contents or how she was preparing it.”

Hypoglycemia, hypocalcemia, and hyponatremia are easily treatable causes for neonatal seizures, so do not fail to consider these. A thorough feeding history that includes formula mixing should be obtained for all infants. Some parents water down formula to conserve powder or because they don’t know the appropriate ratio. Point-of-care glucose monitoring, as well as electrolyte levels should be obtained immediately for all neonates with seizure activity.

6. “We could not obtain IV access even though our best nurses tried, so we were not able to give medication for the seizure.”

Do not forget about alternative routes for antiepileptics and other medications if vascular access is not available. Many medications can be administered through IN, IM, or rectal routes, and intraosseous access should always be considered for a critical patient in whom IV access cannot be established. Many antibiotics can also be given IM.

7. “The described event sounded a bit suspicious, but the baby looked great on exam in the ED, so I thought maybe it was nothing serious.”

Any neonate with witnessed or current seizure activity should be admitted for monitoring. Think twice about discharging, and only do so if it is certain that the event was a benign mimic or there is comfortable, reliable follow-up in place with the primary care provider and/or neurologist, as the event may warrant an EEG in the near future. Remember that electroclinical dissociation is common, and seizures in the neonatal population are always worrisome.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study is included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

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3. Glass HC, Glidden D, Jeremy RJ, et al. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr. 2009;155(3):318-323. (Prospective cohort; 143 patients)
4. Plouin P, Kaminska A. Neonatal seizures. In: Dulac O, Lassonde M, Sarnat HB, eds. Handbook of Clinical Neurology: Pediatric Neurology Part I. Neonatal seizures. Amsterdam: Elsevier; 2013:467-476. (Textbook chapter)
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