atypical presentation of neonatal seizures

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Neonatal seizure.

Conrad Krawiec ; Maria Rosaria Muzio .

Affiliations

Last Update: January 2, 2023 .

Continuing Education Activity

Neonatal seizures are a commonly encountered neurologic condition in neonates. They are defined as sudden, paroxysmal, abnormal alteration of electrographic activity from birth to the end of the neonatal period. During this period, the neonatal brain is developmentally immature. Thus, neonatal seizures have unique pathophysiology and electrographic findings resulting in clinical manifestations that can be different (and more difficult to identify) compared to older age groups. This activity reviews the evaluation and treatment of neonatal seizures and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Identify the etiology of neonatal seizures.
Assess the appropriate evaluation of neonatal seizures.
Evaluate the management options available for neonatal seizures.
Communicate interprofessional team strategies for improving care coordination and outcomes in neonates with seizures.
Introduction

Neonatal seizures are a commonly encountered neurologic condition in neonates. [1] [2] [3] They are defined as sudden, paroxysmal, abnormal alterations of electrographic activity from birth to the end of the neonatal period. [3] During this period, the neonatal brain is developmentally immature. [4] [5] Thus, neonatal seizures have unique pathophysiology and electrographic findings resulting in clinical manifestations that can be different (and more difficult to identify) compared to older age groups. [3] [4] When a patient with neonatal seizures is encountered, it may be the first clinical sign of a serious neurologic disorder. [6] Thus, rapid recognition and evaluation are required to identify and treat the underlying etiology, prevent further brain injury, and extinguish the seizure activity. [7] [8] [9] The following topic provides an overview of the etiologies, clinical features, evaluation, and approach to managing a patient with neonatal seizures.

When a neonate presents with seizure activity, a correctable underlying cause may be identified. [10]

Diagnoses that require priority evaluation and urgent treatment are categorized as follows:

Hypoglycemia [12]
Hypocalcemia [10] [13]
Hypomagnesemia [13] [14]
Hyponatremia [13]
Hypernatremia [13]
Hypoxic-ischemic encephalopathy
Perinatal asphyxia
Intraventricular
Intraparenchymal
Subarachnoid
Bacterial meningitis (Group B Streptococcus, Escherichia coli, Listeria monocytogenes) [4] [16]
Viral encephalitis (Herpes simplex encephalitis, Enteroviruses) [6] [17]
Intrauterine infection (Cytomegalovirus, Toxoplasmosis, Varicella, Zika virus) [18] [19]
Urea cycle defects [20]
Peroxisomal disorders [20]
Organic acidemias [20]
Amino acid disorders [20]
Pyroxidine deficiency [20]
Molybdenum cofactor deficiency [20]
Arterial ischemic stroke [21]
Sinus venous thrombosis [22]

Other conditions that should be considered include:

Benign neonatal seizures [23]
Benign familial neonatal epilepsy [23]
Early myoclonic encephalopathy [23]
Early infantile epileptic encephalopathy [24]
Genetic epilepsy syndromes [25]
Schizencephaly [26]
Lissencephaly [26]
Holoprosencephaly [26]
Hydranencephaly [26]
Epidemiology

Neonatal seizures are a commonly encountered neurologic emergency. [27] [28] The incidence has been reported between 1 and 5.5 per 1000 live births in term infants, with higher incidences reported in preterm infants. [27] [29] [30] [31] The incidence in the United States is estimated to be between 80 and 120 cases per 100,000 neonates yearly.

Pathophysiology

The neonatal brain is unique when compared to different age groups. Upon birth, it is in a state of continued brain development; thus, some areas are immature. [4] This creates a state where if the neonatal brain is pathologically provoked, a manifestation of this provocation can be seizures. [4] Seizures are abnormal, synchronous neuronal discharges within the cerebral cortex. This can be due to excessive excitatory or deficient inhibitory neuronal discharges. [1] [4] Due to its immature state, the neonatal brain is prone to seizures due to an imbalance of neuronal excitation over inhibition. [1] Several factors result in this imbalance. The primary factor is the developmental state of the neonatal neuron. In mature brains, the GABA receptor creates a synaptic potential that makes the postsynaptic neuron less likely to generate an action potential. This is achieved by establishing a decreased cellular membrane potential through its modulation of chloride and potassium channels. [4] By ensuring an influx of chloride intracellularly, the cellular membrane potential is decreased, counteracting excitatory postsynaptic potentials generated by glutamate-modulated stimuli. [32] [33] In the neonatal brain, however, the chloride concentration intracellularly is high, with a reversal of the chloride ion gradient. Thus, when the GABA receptor is stimulated, chloride ion channels open, there is an efflux of chloride ions, and depolarization of the neuron occurs through an influx of sodium and calcium ions. [4] Other factors involved in this imbalance include the development of excitatory synapses before inhibitory synapses and the early maturation of voltage-gated ion channels specific to depolarization. [4]

History and Physical

When a neonate presents with seizures, a thorough history and physical examination are required. As there is often an underlying provoking cause, the clinical history should focus on identifying risk factors and the likely etiologies. [1] This can determine prognosis and can guide treatment strategies. The history should include an investigation of the timing of seizure onset, maternal, birth, and family history. Seizures that occur within 12 to 24 hours after birth suggest hypoxic-ischemic encephalopathy, while seizures that occur after this timeframe indicate infection, hemorrhage, or stroke. [11] Maternal history should focus on the presence of genetic as well as acquired conditions that can provoke seizures in the neonate. [10] This may include obtaining a history of previous miscarriages (suggesting an underlying genetic syndrome), gestational diabetes (suggesting a possible difficult delivery with a birth injury or the possibility of fetal thrombotic vasculopathy), infections (sexually transmitted or maternal-fetal transmission of infection), prenatal exposure to prescription or illicit drugs, the withdrawal of prescription or illicit drugs, and the presence of inherited thrombophilias or bleeding disorders. [34] [35] Birth history should focus on ruling out the possibility of anoxic brain injury and intracranial hemorrhage. For anoxic brain injury, the provider should investigate for the presence of cord prolapse, cord thrombosis, non-reassuring fetal heart rates, meconium, low APGAR scores, placental abnormalities, and if it was a planned home birth. [35] [36] [37] For the possibility of intracranial hemorrhage, it should be inquired if the birth placed the neonate at an increased risk of birth injuries. This includes determining if operative vaginal delivery was necessary to complete the birth or if the neonate was macrosomic or had an abnormal fetal presentation, which placed the patient at higher risk for birth injuries. [35] [38] Family history is important to ensure there were no early sibling deaths that may suggest the presence of a genetic syndrome, inborn errors of metabolism, or a family history of epilepsy. [39]

Physical examination should focus on findings that may indicate an underlying etiology. This includes the general appearance of the neonate, vital signs, head circumference, mental status (and level of alertness), and the quality of the fontanelle to identify if the patient has bacterial meningitis (with or without septic shock) or acute intracranial hemorrhage. [40] If the patient is stable, a full neurologic examination should be performed focusing on the neonate’s cranial nerves, motor exam, tone, and presence of facial dysmorphisms to identify if the patient has a structural brain lesion associated with thrombosis or an underlying genetic condition. [35] A skin examination should ensure the patient has no findings suggestive of a congenital infection and an assessment of the patient’s perfusion. [40] [41] Patients with inborn errors of metabolism may present with acute metabolic acidosis; thus, neonates should be evaluated for the presence of lethargy or respiratory distress, which are usual sequelae to this condition. [39] Suppose the patient has seizure activity during the examination. In that case, the provider should focus on assessing the physical features to ensure it is a true seizure and to assist in identifying the etiology. [11] The location of seizure activity may indicate a focal ischemic stroke or hemorrhage if there is focal activity or hypoxic-ischemic injury, infection, or multifocal stroke or hemorrhage if it is generalized. [7] [11]

The classification of neonatal seizure types and their significant features are as follows:

Manifests as repetitive rhythmic contractions
It can involve the face, upper or lower extremities, neck, or trunk
The physical suppression of movement or limb repositioning cannot extinguish it
May migrate to other areas of the body within the same seizure (most commonly contralaterally but can occur ipsilaterally as well)
If generalized, the seizure activity is diffuse, bilateral, and synchronous
Manifests as a continuous but transient extremity posturing or asymmetric posturing of the trunk or neck
This may include horizontal eye deviation
If generalized, it may mimic decerebrate posturing (upper and lower extremity tonic extension) or decorticate posturing (upper extremity flexion and lower extremity extension)
Manifests as nonrepetitive contractions
Involves flexor muscle groups of the extremity (commonly upper extremity), trunk, diaphragm, or face
If generalized, the seizures may appear as bilateral jerking of the flexor muscles of the upper and lower extremities

Abrupt autonomic vital sign changes, while rare in otherwise healthy neonates, can be associated with subclinical seizure activity in neonates at risk for seizures. [44]

The suspected etiology directs the evaluation of neonatal seizures. Acutely, the provider should immediately rule out hypoglycemia (via blood glucose); hyponatremia, hypomagnesemia, hypocalcemia (via an electrolyte panel); (3) sepsis/meningitis/encephalitis (via a complete blood count, C reactive protein, blood cultures, and cerebral spinal fluid studies). [13] Other diagnostic studies may include computed tomography, ultrasound, or magnetic resonance imaging of the brain to determine the presence of a stroke, intracranial hemorrhage, or structural defects of the brain. [1] Laboratory work consisting of a meconium analysis may be obtained to determine the presence of illicit substances. [45] Electroencephalography (EEG) may be performed to confirm the occurrence of seizures, as it may be difficult for a bedside observer to identify clinical or subclinical seizures. [46] [47] If the patient appears to have seizures that are difficult to control or other symptoms, the patient may be evaluated for inborn errors of metabolism. [48] This consists of a blood gas analysis to evaluate the metabolic state of the patient and the following additional laboratory studies: pyruvate, lactic acid, urine amino, and organic acids. [48] Another consideration is an underlying genetic or epilepsy syndrome, which can be evaluated with specific blood testing. [39] [49]

Treatment / Management

After ensuring the patient has a patent airway, is hemodynamically stable, and has intravenous access, therapy should be targeted to treat the underlying condition identified. This can include therapeutic hypothermia for hypoxic-ischemic encephalopathy [50] , antibiotics for sepsis/meningitis, providing dextrose if the patient is severely hypoglycemic, correction of electrolyte abnormalities, or referral to neurosurgery if the patient has evidence of an intracranial hemorrhage. If the patient is suspected of having an inborn error of metabolism, halting of feeds, correcting metabolic derangements, and empiric therapy with vitamin and cofactor replacement may be initiated. [39] [48] [51]

If the seizure is clinically evident and prolonged, phenobarbital is the most common first-line agent. [15] [52] If seizures do not resolve after the first loading dose, repeat boluses of this medication should be given. The next agent commonly utilized is fosphenytoin. [53] Other agents include levetiracetam and lidocaine in selected settings. [52] Short-acting benzodiazepines (ie, midazolam) can be utilized if there is a delay in administering these agents. Following the initiation of the acute treatment for neonatal seizures, pediatric neurology should be contacted urgently to assist with management. Pediatric neurology can arrange for continuous electroencephalography monitoring that can confirm the presence of neonatal seizures, assist with identifying subclinical seizure activity, and participate in treating refractory seizures. [54] Pediatric neurologists can also participate in the management of long-term antiepileptic maintenance therapy in inpatient and outpatient settings. The duration of treatment is dependent on the underlying etiology.

Differential Diagnosis

Non-epileptic behaviors must be distinguished from neonatal seizures. [55] Due to the known difficulty of distinguishing these behaviors from epileptic clinical events, electroencephalography monitoring is recommended. [56] Normal newborn behaviors that could resemble seizures include sucking movements, hiccuping, and benign neonatal sleep myoclonus (physiologic myoclonus that occurs during sleep). [55] Other behaviors that occur in the presence of a systemic disease that may trigger consideration for neonatal seizures include startle disease (hyperekplexia), apnea, jitteriness, infantile spasms, clonus, and tremors. [55] [57] [58] Motor automatisms (ie, repetitive eye-opening, eye deviation, repetitive mouth and tongue movements, bicycling of the lower extremities, tonic posturing) can resemble seizure activity but can be distinguished by the ability to provoke them with tactile stimulation and suppress them by restraint or repositioning of the limb(s) affected. [59] [60] They are considered non-epileptic but may be indicative of an underlying neurologic disease process; thus, a systematic neurologic workup may be necessary, especially if associated with other clinical signs or symptoms. [29]

Benign epilepsy syndromes
Mitochondrial cytopathies
Myoclonic epilepsy
Organic acidurias
Pyridoxine-dependent epilepsy
Subdural hematoma
Subarachnoid hemorrhage
Tuberous sclerosis
Viral encephalitis
Viral meningitis
Vein of Galen malformation
Benign neonatal convulsions
Cerebellar hemorrhage
Herpes simplex encephalitis
Child abuse
Neonatal meningitis
Shuddering attacks

The prognosis of neonatal seizures depends on the underlying etiology. If EEG is normal, the prognosis is excellent, but if EEG has many abnormalities, such neonates have a poor prognosis and may develop cerebral palsy and epilepsy. The presence of spikes on EEG has a 30% risk of developing future epilepsy. The mortality rate of neonatal seizures is reported to be as high as 20%. [15] In survivors, neurologic impairment, disability, developmental delay, and epilepsy are common. [9] [61] [62] [63]

Complications

A majority of neonatal seizure complications are associated with the adverse effects that can occur with antiepileptic medication administration. Thus, the provider should be vigilant for loss of airway with hypoxemia or hypercarbia, especially when a benzodiazepine or phenobarbital is administered. [64] This is of paramount importance as hypoxemia can commonly result in cardiac arrest in pediatric patients. [65] Medication administration of phenobarbital is associated with myocardial depression, while phenytoin is associated with cardiac dysrhythmias; thus, hemodynamic instability can occur. [64] [66] The provider should be prepared to administer inotropic cardiovascular support and consider using fosphenytoin to avoid the adverse effects of phenytoin administration. [67] Antiepileptic medications can cause hepatic and renal dysfunction; therefore, close monitoring of drug levels is necessary during the acute phase as well as when the patients are prescribed maintenance drug dosing. [1] [68] Other complications include:

Cerebral palsy/spasticity
Cerebral atrophy/hydrocephalus ex-vacuo
Feeding difficulties
Deterrence and Patient Education

First and foremost, if the patient has a seizure that lasts longer than 5 minutes or if he or she has repeated seizures over a few minutes, emergency services must be contacted. The patient may be prescribed an emergency antiepileptic medication (ie, rectal diazepam); thus, the parents may be counseled on its use. [69] Parents should also be counseled on the prognosis of neonatal seizures, particularly the possibility of neurologic impairments in patients who survive and the importance of referral to early rehabilitation services. [70] In patients who develop long-term epilepsy, the parents should have higher vigilance in situations (ie, ensure adequate supervision) where if seizure activity should occur, the dangers can be compounded (ie, scuba diving). [71] A child with seizures should have routine clinical follow up with pediatric neurology, and the parents should be advised of the importance of medication adherence. [72]

Enhancing Healthcare Team Outcomes

The diagnosis and management of neonatal seizures require an interprofessional approach to avoid complications from the underrecognition of clinical seizures and the adverse effects of the medications administered. Referral to critical care services (neonatal or pediatric) should be performed early to place the patient under the care of neurocritical care experts and to ensure that the patient is stabilized from an oxygenation and hemodynamic standpoint. [73] Pediatric neurology should be consulted to evaluate the patient and confirm the diagnosis of neonatal seizures. [54] Electroencephalography technicians need to be readily available to initiate monitoring and screen for electrographic seizure activity that may be subclinical. [54] [74] The medications utilized to control seizures must be ordered, obtained, and administered promptly. Pharmacists with pediatric expertise should be available to safely provide these medications and assist providers in understanding specific pharmacological characteristics concerning the unique renal and hepatic physiology of the pre-term or term neonate. [1] Finally, the bedside nurses are vital to helping providers identify clinically evident seizure activity, annotate pertinent events, and help ensure the patient is safe from the adverse effects some antiepileptic agents have. [75]

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Disclosure: Conrad Krawiec declares no relevant financial relationships with ineligible companies.

Disclosure: Maria Rosaria Muzio declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Cite this Page Krawiec C, Muzio MR. Neonatal Seizure. [Updated 2023 Jan 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Seizures in Neonates: Diagnosis and Management in the Emergency Department

*new* quick search this issue.

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, case presentations, introduction, critical appraisal of the literature, infectious etiologies.

Vascular Etiologies
Inborn Errors of Metabolism
Other Etiologies
Timeline for Seizure Onset
Differential Diagnosis
Prehospital Care
Initial Stabilization
Physical Examination
Laboratory Studies
Imaging Studies
Electroencephalography
Phenobarbital
Phenytoin/Fosphenytoin
Levetiracetam
Benzodiazepines
Other Antiepileptic Drugs
Non–Antiepileptic-Drug Management
Premature Neonates
Patients With Recurrent Brief Resolved Unexplained Events
Patients Who Have Not Had Standard Prenatal Care/Patients With Risk of Exposure to Infectious Agents
Patients Born Outside a Medical Facility
Medication Choices
Amplitude-Integrated Electroencephalography
Genetic Testing
Disposition
Time- and Cost-Effective Strategies

Risk Management Pitfalls for Neonatal Seizures

Case Conclusions
Clinical Pathway for Management of Neonatal Seizures
Table 1. Risk Factors for Neonatal Seizures
Table 2. Seizure Etiologies
Table 3. Antiepileptic Drugs
Table 4. Medications to Correct Metabolic Derangements
Figure 1. Seizure Onset Timeline: Seizure Etiology By Postnatal Age

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.

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?

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.

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).

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.)

Table 1. Risk Factors for Neonatal Seizures

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

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

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

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 .

Sands TT, McDonough TL. Recent advances in neonatal seizures . Curr Neurol Neurosci Rep . 2016;16(10):92. (Review)
Glass HC, Wirrell E. Controversies in neonatal seizure management . J Child Neurol . 2009;24(5):591-599. (Systematic review)
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)
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)
Stafstrom CE. Neonatal seizures . Pediatr Rev. 1995;16(7):248-255. (Review)
Co JP, Elia M, Engel J Jr, et al. Proposal of an algorithm for diagnosis and treatment of neonatal seizures in developing countries . Epilepsia . 2007;48(6):1158-1164. (Special report)
Sharma D, Pandita A, Murki S, et al. Neonatal seizures: an emergency condition commonly seen in neonatal intensive care unit. BMJ Case Rep . 2014;2014. (Case series; 2 patients)
Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus--report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia . 2015;56(10):1515-1523. (Special report)
Jacobs J, Spelbrink EM. Seizures in preterm infants. J Clin Neurophysiol . 2016;33(5):382-393. (Review)
Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures . N Engl J Med . 1999;341(7):485-489. (Randomized controlled trial; 59 neonates)
Pathak G, Upadhyay A, Pathak U, et al. Phenobarbitone versus phenytoin for treatment of neonatal seizures: an open-label randomized controlled trial . Indian Pediatr . 2013;50(8):753-757. (Randomized controlled trial; 109 neonates)
Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study . Neurology . 2004;62(3):486-488. (Randomized controlled trial; 22 neonates)
Slaughter LA, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a systematic review. J Child Neurol . 2013;28(3):351-364. (Systematic review)
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Neonatal seizures: diagnostic updates based on new definition and classification

Eun-hee kim , md, phd, jeongmin shin , md, byoung kook lee , md.

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Corresponding author: Eun-Hee Kim, MD, PhD. Department of Pediatrics, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine, 20, Bodeum 7-ro, Sejong 30099, Korea Email: [email protected]

Received 2021 Aug 31; Revised 2021 Oct 10; Accepted 2021 Nov 5; Collection date 2022 Aug.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/ ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Neonatal seizures are the most common neurological symptoms caused by various etiologies in the neonatal period, but their diagnosis and treatment are challenging because their pathophysiology and electroclinical manifestations differ from those of patients in older age groups. Many seizures present as electrographic-only events without clinical signs or as obscure clinical manifestations that are difficult to distinguish from other neonatal behaviors. Accordingly, a new definition and classification of neonatal seizures was recently proposed by the International League Against Epilepsy Task Force on neonatal seizures, highlighting the role of electroencephalography in diagnosing and treating neonatal seizures. Neonatal seizures are defined as electrographic events with sudden, paroxysmal, and abnormal alteration of activity and divided into electroclinical seizures and electrographic-only seizures according to their clinical signs, thus excluding clinical events without an electrographic correlation. Seizure types are described by their predominant clinical features and divided into motor (automatisms, clonic, epileptic spasms, myoclonic, tonic, and sequential), nonmotor (autonomic and behavioral arrest), and unclassified. Although many neonatal seizures are acute reactive events caused by hypoxic-ischemic encephalopathy or vascular insults, structural, genetic, or metabolic etiologies of neonatal-onset epilepsy should also be thoroughly evaluated to determine their appropriate management.

Keywords: Neonatal seizures, Diagnosis, Classification, Electroencephalography, Etiology

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Graphical abstract

Introduction

Neonates are most susceptible to seizure development due to their brain immaturity and high risk of injury [ 1 , 2 ]. Neonatal seizures, a most common neurological condition, are associated with high mortality rates of up to 20% [ 1 , 2 ]. Neonatal seizures can lead to long-term outcomes such as epilepsy, cerebral palsy, developmental disabilities, and psychomotor impairments depending on their etiologies and clinical courses [ 3 - 5 ]. The incidence of neonatal seizures is reportedly 1.5–5.5 per 1,000 live births among term infants but tends to be higher in preterm or very low birth weight infants [ 6 , 7 ]. Most neonatal seizures are acute, symptomatic, and provoked by severe brain insults such as hypoxic-ischemic encephalopathy (HIE) or intracranial hemorrhages (ICHs), but some may involve neonatal-onset epilepsy related to structural, metabolic, or genetic disorders [ 2 , 8 , 9 ]. In all cases, the rapid identification and acute management of the seizure and its etiology are imperative, although long-term treatment and prognosis vary widely depending on the underlying etiologies [ 3 , 4 , 10 ]. However, these goals are not always easy to achieve because of the variable and subtle presentations of neonatal seizures and the need to differentiate epileptic events from nonepileptic movements [ 11 , 12 ]. In addition, the widespread use of continuous electroencephalographic monitoring in the neonatal intensive care unit (NICU) has led to the recognition that electrographic-only seizures with no clinical correlation are frequent, especially in critically ill neonates [ 13 - 15 ]. The role of electroencephalography (EEG) in the diagnosis of neonatal seizures has been increasingly emphasized, and this recognition has led the International League Against Epilepsy (ILAE) Task Force on Neonatal Seizures to propose a new definition and classification of neonatal seizures [ 16 ]. This review discusses the new definitions and classifications of neonatal seizures based on its pathophysiology, electroclinical relationship, behavioral patterns, and diagnosis through advanced testing of multiple etiologies.

Pathophysiology

The immature brain in the neonatal period has multiple age-related pathophysiologic mechanisms that increase an individual’s risk of acute seizures [ 17 , 18 ]. The fundamental mechanism is the neurophysiologic condition in which the excitatory neural circuits mature early while the inhibitory circuits mature late in the developing brain [ 11 , 19 , 20 ]. This amplified excitation is an important physiological condition in many activity or use-dependent developmental processes such as neurogenesis, cell migration and differentiation, synaptogenesis, and circuit development [ 17 - 19 , 21 ]. Enhanced excitatory neurotransmission and the paucity of inhibitory mechanisms by maturational changes in excitatory glutamate and gamma-aminobutyric acid receptor function, developmental alterations or modulation of neuronal ion channels and neuropeptides, and age-dependent early microglial activation in early central nervous system (CNS) development increases the risk of seizures during the neonatal period [ 17 , 18 , 22 ].

In addition, due to the incomplete arborization of axons and dendritic processes and unmyelination of the neonatal brain, electrical activities are less quickly propagated, resulting in fragmented seizures [ 17 ]. Because of these neurophysiological conditions, neonatal seizures are usually focal, often short-lasting, and generalized tonic-clonic seizures are rare or absent in neonates [ 15 , 23 , 24 ].

Other characteristics of the neonatal brain include more advanced development of the limbic system with connections to the midbrain and brainstem than cerebral cortical organization, which leads to a high frequency of mouthing, eye deviation, and apnea as neonatal seizures and uncoupled/dissociated electroclinical seizures for which treatment with antiseizure medication may control clinical events but electrographic seizures persist regardless [ 15 , 23 , 24 ]. These physiological characteristics are more pronounced in preterm than in term neonates, so the more mmature they are, the shorter the seizures and the higher the proportion of subclinical or electrographic-only seizures. Thus, EEG is essential for diagnosis [ 10 , 15 , 24 ].

Many etiologies can cause neonatal seizures, although only a few account for most seizures [ 2 , 8 , 25 , 26 ]. In contrast to seizures in older age groups, most neonatal seizures are acute symptomatic seizures with suspected specific etiologies that are distinct from neonatal epilepsy [ 10 , 12 ]. Relatively few seizures are idiopathic or neonatal epilepsy syndromes related to structural abnormalities, genetic syndromes, or inborn errors of metabolism, but their identification is important in their management and prognosis. The relative frequency of each etiology differs in term versus preterm infants due to differences in brain maturity and physiologic conditions [ 2 , 23 ]. In term infants, HIE is the most common cause, and HIE-related seizures typically occur–6–8 hours after insult and within the first 24 hours of life [ 9 , 23 ]. On the other hand, cerebrovascular diseases such as infarction or hemorrhage are the most common cause in preterm infants [ 10 , 15 ]. Seizures related to meningitis, inborn errors of metabolism, or brain malformations can occur at any gestational age [ 8 , 12 , 23 ]. The timelines of occurrence and etiologies of reactive seizures in term versus preterm infants are shown in Fig. 1 .

Etiologies of neonatal seizures according to seizure onset timing. The most common causes of seizures occurring within the first 24 hours of life are hypoxic-ischemic encephalopathy or vascular etiologies, followed by acute metabolic disturbances such as hypoglycemia or inborn errors of metabolism such as pyridoxine dependency. Within the next 24–72 hours, the main etiologies include infection, cortical malformations, cerebral infarction, inborn errors of metabolism such as glycine encephalopathy, urea cycle disturbances, pyridoxine dependency, and benign familial neonatal seizures. Over the next 72 hours to a week, causes include cortical malformations, cerebral infarction or hemorrhage, or inborn errors of metabolism, such as urea cycle disturbances. In the next 1–4 weeks, the differential includes cortical malformations, viral infections such as herpes simplex, or genetic epilepsy syndromes.

1. Acute symptomatic neonatal seizures

Acute symptomatic seizures in the neonatal period occur as acute reactive events to HIE, stroke, hemorrhage, infection, hypoglycemia, or electrolyte imbalance [ 9 , 12 ]. The most common cause is HIE, which accounts for 35%–45% of all neonatal seizures, typically developing seizures in the first 12–24 hours of life [ 9 , 12 , 27 , 28 ]. In HIE patients, seizure semiology varies among brain injury regions, but there is a high prevalence of subclinical or electrographic-only seizures in neonates [ 14 ]. The second most common cause of neonatal seizures is cerebrovascular events such as infarction or hemorrhage, which may occur in isolation or be the consequence of a CNS infection [ 12 ]. Perinatal arterial ischemic strokes are commonly caused by embolism form the placenta or umbilical cord, carotid artery, or heart, and the most common sign in newborn infants with strokes is seizures, often occurring within the first 24–72 hours of life or later [ 29 - 31 ]. In such cases, perinatal arterial ischemic strokes should be considered the cause of neonatal seizures, especially if the mother has oligohydramnios, chorioamnionitis, premature rupture of the membranes, preeclampsia, diabetes, or a smoking history and the infant has risk factors such as congenital heart disease, systemic infection, coagulopathy, or male sex [ 8 , 25 , 29 , 31 ]. Since most perinatal strokes occur in the motor cortex in the middle cerebral artery territory, the seizures often present as focal clonic seizures [ 29 , 31 ]. ICH, which can also cause acute symptomatic seizures, is the second most common etiology of seizures in preterm infants [ 30 ]. Hemorrhage size and location determine seizure severity and semiology [ 29 , 31 , 32 ]. While parenchymal hemorrhages, often caused by underlying vascular malformations, often make an individual prone to seizures, intraventricular hemorrhages rarely progress to seizures unless the amount of bleeding is significant and parenchymal damage occurs [ 12 , 32 ].

Acute metabolic disturbances in calcium, glucose, or sodium can also cause various types of neonatal seizures [ 9 , 10 , 12 ]. In most cases of metabolic disturbance, acute seizures are resolved by the correction of transient metabolic disturbances without antiseizure medication. However, antiseizure medication can be used in cases of severe and prolonged metabolic disturbances, and it is important to identify and treat their underlying cause to prevent recurrence [ 33 , 34 ]. Acute symptomatic seizures can also be caused by bacterial or viral infection of the CNS [ 9 , 10 , 12 ]. It is important to recognize and diagnose seizures early to minimize CNS or systemic sequelae of severe infection. Acute seizures caused by infections, such as late group B streptococcal infection or herpes simplex virus infection, can occur at any time during the neonatal period [ 9 , 10 , 12 ]. Seizure semiology and severity can vary depending on the infection region and severity. In all neonates with a suspected infective etiology, CNS infection should be evaluated through cerebrospinal fluid (CSF) tests and neuroimaging to ensure accurate and prompt treatment. In addition, as infection-related seizures are often longer than those associated with stroke or hemorrhage, prolonged EEG monitoring is recommended to provide adequate treatment with antiseizure medications [ 12 , 35 , 36 ].

2. Neonatal epilepsy

Although acute symptomatic seizures are more common in the neonatal period, they may be the first presentation of an epilepsy syndrome, with approximately 13% of neonatal seizures [ 2 , 23 ]. It is important to identify epilepsy syndrome and its etiology to determine its treatment and prognosis. Brain malformations, genetic variants, and inborn errors of metabolism can cause neonatal-onset epilepsy syndromes.

3. Developmental structural brain abnormalities

Congenital and developmental structural brain abnormalities may cause neonatal seizures and have become more widely recognized with increasing use of head ultrasound (HUS) and high-resolution magnetic resonance imaging (MRI). Malformations of cortical development, including lissencephaly, hemimegalencephaly, focal cortical dysplasia, tuberous sclerosis, and polymicrogyria, may be due to disorders of neuronal and glial proliferation or apoptosis, neuronal migration, or cortical organization and are often related to gene mutation, but they can also be caused by congenital infection, prenatal ischemia, or exogenous or endogenous toxins. Genetic etiologies that cause brain malformations and neonatal-onset epilepsy are pathogenic variants of ARX , TSC1/TSC2 , DCX , and DEPDC5 , and more genes are being identified by advanced technology. Depending on lesion location and severity, various types of seizures can occur, and many are resistant to treatment.

In some cases, additional congenital anomalies of other organs may be associated; therefore, a thorough clinical evaluation and early consultation for genetic diagnosis and proper treatment are required.

4. Genetic neonatal epilepsies

Genetic etiologies are being increasingly recognized in neonatal seizures using advanced genetic evaluation [ 37 - 39 ]. Once strucural abnormalities or reversible metabolic abnormalities are excluded as the etiologies of neonatal seizures, neonatal epilepsy should be considered another etiology as it is important for determining treatment and predicting prognosis and comorbidities [ 38 ]. Genetic neonatal epilepsies are largely divided into self-limited and benign epilepsy and severe epilepsy according to clinical course and outcome but display phenotypic and genetic heterogeneity [ 37 , 40 ]. Neonatal epilepsy syndromes include self-limited familial neonatal epilepsy, self-limited neonatal seizures, early-infantile epileptic encephalopathy (EIEE), early myoclonic encephalopathy (EME), and epilepsy of infancy with migrating focal seizures (EIMFS). The clinical characteristics and genetic variants of the representative genetic neonatal epilepsy are summarized in Table 1 .

Clinical characteristics and genetic variants of neonatal epilepsy syndromes

Self-limited familial neonatal seizures are autosomal dominant channelopathies that present as brief seizures within the first few days of life [ 41 , 42 ]. Common types of seizures are frequent, brief, and clustered focal tonic seizures, which are often associated with apnea, vocalizations, or autonomic symptoms. Self-limited neonatal familial epilepsy can be diagnosed if there are no abnormal findings on neurologic examination and laboratory tests, typical clinical manifestations, and a positive family history of neonatal seizures. Seizures are expected to be in remission by 6 months of age but often require treatment with antiseizure medications [ 41 , 42 ].

Self-limited neonatal seizures typically occurring on the fourth or sixth day of life, often having an onset later than that of self-limited familial neonatal seizures [ 39 , 40 , 43 ]. Self-limited neonatal seizures usually present as unilateral or bilateral clonic seizures that last several minutes, often clustering, migrating, or progressing to status epilepticus, and the background activity of EEG is mostly normal with nonspecific interictal findings. Other acute symptomatic etiologies should be ruled out to ensure an accurate diagnosis, and immediate treatment is typically required, although the seizures tend to decrease spontaneously within 2 days [ 44 ].

EIEE, also known as Ohtahara syndrome and EME, consists of severe neonatal epilepsy syndromes with poor prognosis and suppression-burst patterns on EEG [ 45 ]. Neonates with EIEE usually present with very frequent tonic seizures and/or rarely as epileptic spasms within the first 3 months but often within the first 2 weeks of life. The EEG of these frequent seizures shows a suppression-burst pattern, with the suppression lasting 35 seconds. EIEE is generally associated with congenital structural brain abnormalities but may be due to multiple single-gene mutations [ 40 , 46 , 47 ]. In most patients, the prognosis is poor due to severe developmental disabilities and age-specific progression to West syndrome or Lennox-Gastaut syndrome, and early-life mortality rates are high [ 45 ].

EME may be seen along with metabolic or genetic disorders such as glycine encephalopathy, pyridoxine/pyridoxal 5′-phosphate dependency, or biotinidase deficiency [ 45 ]. Seizures in EME usually begin within the first 3 months, as in EIEE, but typical seizure types are myoclonic, not tonic [ 45 ]. Myoclonic seizures may occur irregularly, clustered, or continuously, and they usually appear as generalized seizures, whereas focal myoclonic seizures may initially manifest on the face or extremities. The EEG background for EME is also characterized by a suppression-burst pattern, which is more apparent during sleep and may evolve to hypsarrhythmia by 3–5 months of age in up to 50% of patients with EME [ 23 , 45 , 48 ]. EME is also associated with pathogenic variants of single genes similar to EIEE, and its prognosis is generally poor with high rates of mortality and severe neurodevelopmental disabilities [ 39 , 40 ].

EIMFS develops within the first 6 months of life and often occurs in the neonatal period [ 39 ]. Seizures begin as focal clonic and/or tonic and evolve over time with more prominent autonomic features such as apnea, cyanosis, flushing, or sweating [ 39 , 48 ]. Frequent and multifocal epileptiform discharges in the interictal phase and continuous spike discharges migrating from one cortical area to another in the ictal phase are characteristic of EIMFS [ 39 ].

5. Inborn errors of metabolism

Inborn errors of metabolism are rare causes of neonatal seizures but important causes of intractable neonatal seizures, accounting for 30% of cases [ 49 - 51 ]. Neonatal seizures can occur in a wide variety of inborn errors of metabolism, including various amino acids, disorders of energy metabolism, cofactor-related metabolic diseases, purine and pyrimidine metabolic diseases, congenital disorders of glycosylation, and lysosomal and peroxisomal disorders. It is important to minimize complications by diagnosing treatable inborn errors of metabolism without delay. Pyridoxine-dependent epilepsy is an autosomal recessive disease diagnosed by the intravenous administration of 100 mg of pyridoxine (maximum of 500 mg) while monitoring EEG response or assessing clinical response to a 3-week course of oral pyridoxine [ 52 ]. Pyridoxal-phosphate-responsive epilepsy, an autosomal recessive disorder due to a pyridoxal-5′-phosphate oxidase (PNPO) deficiency, responds to oral treatment with pyridoxal phosphate [ 53 ]. Partial responsiveness to pyridoxine may be seen in other conditions with neonatal seizures such as neonatal hypophosphatasia, familial hypophosphatasia, nutritional vitamin B6 deficiency, and PNPO deficiency [ 52 , 54 ].

Biotinidase deficiency is a rare autosomal recessive inherited disorder that affects the recycling of biotin, an essential B vitamin that presents as intractable neonatal seizures [ 49 ]. Folinicacid-responsive epilepsy leads to intractable seizures due to mutations of the ALDH7A1 (antiquitin) gene resulting in alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency [ 55 ]. Neonates with this condition usually respond to folinic acid within 24–48 hours [ 55 ]. Glucose transporter-1 deficiency is an autosomal dominant disorder usually caused by sporadic mutations in the SLC2A1 gene [ 56 ]. Glycine encephalopathy (neonatal nonketotic hyperglycinemia) typically presents as seizures on the second or third day of life [ 50 ]. Serine deficiency, disorders of creatine biosynthesis, and phenylketonuria should also be considered rare causes of neonatal seizures [ 49 ].

1. New definition and classification of neonatal seizures

Historically, neonatal seizures have been defined as paroxysmal, repetitive, and stereotypical events with any other type of seizures and categorized according to their motor manifestations, such as focal clonic, multifocal-clonic, generalized tonic, myoclonic, and subtle [ 57 ]. It is then further categorized as clinical only, electroclinical, or electrographic-only based on the EEG findings [ 13 , 57 ]. That is, it has been diagnosed based on clinically observed seizures before or regardless of EEG monitoring results. However, neonatal seizures are typically difficult to differentiate them from nonepileptic paroxysmal events, and focal seizures that provoked sensory manifestation cannot be recognized clinically in neonates [ 24 , 58 , 59 ]. In addition, previous studies have shown that most neonatal seizures are electrographic-only events without clinical symptoms, whereas clinical-only seizures without electrographic seizure activity are not epileptic seizures in nature [ 35 , 60 ]. Therefore, to ensure an accurate neonatal seizure diagnosis, the confirmation of electrographic seizures on EEG monitoring along with bedside clinical observation is essential, and the new definition and classification of neonatal seizures were recently proposed by ILAE Task Force on Neonatal Seizures [ 16 ]. The newly proposed definition of neonatal seizures differs from that of infants and children and is based on electrographic events identified by EEG recording rather than clinical events suspicious for seizure [ 16 ]. The electrographic criteria for neonatal seizure recently presented by the American Clinical Neurophysiologic Society are a sudden abnormal EEG event defined by sudden and stereotyped repetitive waveforms that evolve in morphology, frequency, and/or location, with a minimum 2 μV peak-to-peak voltage and ≥10-second duration; no evidence of clinical signs is required ( Figs. 2 , 3A ) [ 61 ].

Approach to diagnosing neonatal seizures. The new definition and classification by the International League Against Epilepsy Task Force on neonatal seizures diagnoses neonatal seizures as events with an electroencephalography (EEG) correlation that are divided into electroclinical seizures and electrographic-only seizures according to clinical signs. Electroclinical seizures are described by their predominant clinical features and divided into motor (automatisms, clonic, epileptic spasms, myoclonic, tonic, and sequential), nonmotor (autonomic and behavioral arrest), and unclassified. Neonatal seizures are largely divided into acute symptomatic seizures and neonatal-onset epilepsies, and the etiologies can be identified as hypoxicischemic encephalopathy, structural, genetic, infectious, and metabolic by laboratory investigation. CRP, C-reactive protein; CSF, tcerebrospinal fluid; cEEG, continuous EEG; HIE, hypoxic-ischemic encephalopathy.

Term newborn presenting with apnea and staring on day 1. (A) Electroencephalography on day 2 showed sharply contoured rhythmic activities over the left central region with onset (red arrow) and change of frequency and amplitude. (B) Findings of head ultrasound on day 2 were normal, (C) but diffusion-weighted magnetic resonance imaging on day 2 presented increased signal intensity in the territory of the left middle cerebral artery representing the extension of acute ischemic stroke.

These preferentially EEG-defined neonatal seizures are classified into electroclinical seizures and electrographic-only seizures depending on whether clinical signs are accompanied, and their clinical signs are classified as motor, nonmotor, and unclassified according to the movement [ 16 ]. The motor seizures are then divided into automatisms, clonic, epileptic spasms, myoclonic, sequential, and tonic seizures by seizure types, and each is divided into foal, multifocal, unilateral, or bilateral (asymmetric or symmetric) depending on the range of symptoms [ 62 ]. While the basic principles of the 2017 ILAE classification of seizure types are the initial division of seizures into those of focal and generalized onset, it is unnecessary to distinguish generalized seizures because most neonatal seizures involve exclusively focal or multifocal onset due to their neurophysiologic condition [ 16 , 62 ]. On the other hand, a clinical sign without a specific movement is considered a nonmotor seizure, which is divided into automatism and behavior arrest [ 16 , 62 ]. Seizure semiology can help the physician recognize the underlying cause early because focal clonic seizures are strongly related to acute symptomatic etiology such as stroke and infectious causes, focal tonic seizures with genetic epileptic encephalopathy, autonomic seizures with hemorrhage, and myoclonic seizures with inborn errors of metabolism [ 36 , 63 ]. A description and clinical considerations of each seizure type are listed in Table 2 .

Description and clinical considerations of types of neonatal seizure by the 2017 ILAE Classification of Seizures

ILAE, International League Against Epilepsy; EEG, electroencephalography; aEEG, amplitude-integrated EEG; HIE, hypoxic-ischemic encephalopathy; EMG, electromyography; DEE, developmental and epileptic encephalopathy.

Adapted from Pressler et al. Epilepsia 2021;62:615-28 [ 16 ], with permission of John Wiley and Sons.

Neonatal seizures should also be distinguished from nonepileptic neonatal events. Nonepileptic paroxysmal events include jitteriness, hyperekplexia, benign sleep myoclonus, rapid eye movement sleep behavior, apnea, various motor automatisms, and dystonic or tonic posturing [ 16 , 62 , 64 ]. Nonepileptic movements can often be provoked with stimulation and are typically suppressed by touching or repositioning during the event. Nonepileptic events occur without any EEG changes [ 64 , 65 ]. However, as with epileptic seizures, nonepileptic events can also appear as symptoms of underlying pathology and should be evaluated systematically [ 65 , 66 ].

2. Electroencephalography

Neurophysiological testing is important in the diagnosis and acute treatment of neonatal seizures as emphasized in the new definition and classification [ 16 ]. Noninvasive EEG-based diagnostics are easy to set up, portable, practical for bedside testing, and provide a good temporal solution with minimal risk of scalp irritation in the NICU setting [ 58 , 59 ]. Different EEG techniques can be employed, including routine EEG, continuous EEG monitoring (cEEG), video-EEG monitoring, and amplitudeintegrated EEG (aEEG). Continuous video-EEG monitoring is the gold standard for accurate neonatal seizure detection [ 58 , 67 ]. If conventional EEG monitoring is not available, then aEEG can be useful as an initial or complementary tool [ 58 , 59 ]. It is easily available, readily applied, and an easily interpreted method of assessing brain function [ 68 ]. However, since aEEG is less sensitive and less specific for seizure detection than conventional EEG, it is not recommended if the latter is available [ 68 ].

The relative value of each neurophysiological technique is also dependent upon the availability of hardware and professional staff trained and experienced in interpreting the generated data [ 69 , 70 ]. Polygraphic recordings that concurrently capture ocular, respiratory, and muscle movements in addition to ECG data are preferred [ 59 ]. It is usually recommended that neonates with suspicious symptoms be monitored until several typical episodes are detected on EEG. High-risk neonates are typically monitored for 24 hours to screen for seizures [ 59 ]. In addition, even if seizures are detected and treated with antiseizure medications, the continuation of cEEG monitoring is generally recommended until at least a 24-hour seizure-free period is confirmed [ 58 ]. This is because after the administration of antiseizure medications, electroclinical dissociation often occurs, a period in which clinical seizures are no longer observed despite the EEG-defined events persisting [ 13 , 71 ].

The EEG characteristics of neonatal seizures differ from those of older children and adults. In neonates, interictal epileptiform discharges are rarely present to aid in diagnosis, patterns of electrographic seizure activity vary, and not all electrical seizure activity is accompanied by subclinical signs or evident clinical seizures [ 24 , 59 , 72 ]. The background activity in infants with suspected seizures may be helpful in the diagnosis. The characteristics of background activity help to estimate the extent and degree of brain injury, possible diagnoses, and prognosis. However, interictal focal sharp waves are not generally considered evidence of focal epileptogenic brain abnormalities in neonatal seizures; thus, they do not provide useful information for the diagnosis of electrical seizures in every infant [ 58 ]. As ictal EEG features, electrical seizure activity consists of sustained rhythmic activity with various morphologies, amplitudes, and frequencies. While electrical seizure activity may be present in neonates before 34– 35 weeks after conception (CA), it is less frequent in premature than term infants [ 24 ]. Frequency, voltage, and morphology may vary greatly within the same electrical seizure or from one seizure to the next in each infant [ 24 , 58 ]. All electrical seizure activity in neonates begins focally, except for the generalized activity associated with some types of myoclonic jerks or epileptic spasms. Electrical seizure activity in neonates most often arises in the central or temporal region of one hemisphere or the midline central region. Less common sites of onset include the occipital and frontal regions. The region of cortical involvement of the electrical seizure activity determines the motor manifestations of clinical seizures. In general, the onset, morphology, frequency, or propagation patterns of electrical activity are not related to the etiology, but some characteristic patterns on EEG are known to be related to specific etiologies. Focal discharges may be seen in patients with vascular insult or electrolyte imbalance, multifocal discharges in vitamin-related disorders, and suppression-burst with severe epileptic encephalopathies, suggesting specific associations of ictal EEG patterns with underlying etiologies [ 36 ].

3. Etiologic evaluation

1) history and physical examination.

To identify the risk factors of seizures and clues about the underlying etiology, the birth, maternal, and family histories should be investigated in detail. Risk factors for hypoxic injury, fetal heart rate deceleration, low Apgar scores, abnormal fetal presentation, and the nature of the delivery should be included as gestational and birth history [ 8 , 73 ]. Aspects of maternal history include maternal obesity, gestational diabetes, previous miscarriages, history of illness during pregnancy, placental abnormalities, use of prescription or illegal substances, and coagulopathies [ 25 ]. A detailed family history of inborn errors of metabolism or epilepsy, particularly neonatal, has also been identified. Physical examination may also provide clinical clues associated with the underlying etiology and direct further testing. Head size, birthmarks, facial dysmorphism, somatic abnormalities, and signs of infection should be evaluated. In addition, to identify signs suggestive of a structural brain lesion or neonatal encephalopathy, a thorough neurological examination including mental status assessment, cranial nerve examination, and evaluation of muscle tone and primitive reflexes should be performed.

2) Neuroimaging

Neuroimaging is essential for detecting structural cerebral pathology, including hemorrhage, infarction, or abnormalities of cortical development [ 74 , 75 ]. HUS remains the first-line tool for assessing neonatal seizures because of its ease of use at the bedside of acutely ill neonates. For locating hemorrhages and defining ventricular size, HUS has high sensitivity and specificity, but it can often miss brain lesions [ 74 ]. Lesion yield can be increased by repeating the HUS after several days because some abnormalities are delayed in physical appearance [ 74 ]. Brain MRI may be obtained as a complement to HUS once the neonate is stabilized. Brain MRI is the study of choice and, where available, should be performed in all neonates with seizures. Brain MRI is highly sensitive and has good anatomic resolution for identifying cerebral malformations, ICH, stroke, and ischemic changes [ 74 , 75 ]. Diffusion-weighted imaging (DWI) can identify early infarcts. As shown in Fig. 3 , the infarct that was not visible on early HUS ( Fig. 3B ) could be identified by DWI ( Fig. 3C ); therefore, brain MRI should be performed as early as possible in neonates with seizures. MR angiography and venography should be performed when a vascular etiology is suspected. Magnetic resonance spectroscopy can be valuable for facilitating the diagnosis of inborn metabolic anomalies. Computed tomography is generally avoided in neonates because it involves high exposure to ionizing radiation and has lower resolution than MRI.

4. Other investigations

Since the presence of multiple causes of seizures is not uncommon, all neonates with seizures should be thoroughly evaluated to rule out potentially treatable or reversible etiologies, and further evaluations should be made to identify specific etiologies according to individual clinical circumstances. Initial laboratory tests for neonatal seizures should include those to evaluate transient metabolic disturbances such as hypoglycemia, hypocalcemia, or electrolyte imbalance [ 11 ]. Assessments should generally include a complete blood count, blood culture, CSF analysis, urine culture and toxicology, TORCH (toxoplasmosis, rubella cytomegalovirus, herpes simplex, and HIV) screening, metabolic screening, and ophthalmologic evaluation. Additional laboratory studies might include determining the levels of serum amino acids (glycine and serine), ammonia, lactate, pyruvate, very long chain fatty acids, urine organic acid, biotinidase, pipecolic acid, CSF lactate, CSF amino acids, CSF chromatogram for folinic acid/pyridoxine-dependent seizures, and CSF pyridoxal-5-phosphate (active form of vitamin B6).

Genetic testing should be strongly considered in neonates with epilepsy for whom an acute provoked seizure cause is not identified on the initial history, examination, and neuroimaging. Genetic testing can reportedly identify the putative etiology of epilepsy in more than 75% of patients with neonatal epilepsy [ 15 , 40 ]. In addition to treatment implications, the identification of a genetic etiology assists in prognostic determinations and genetic counseling and avoids further extensive etiologic testing. When genetic testing is performed using a gene panel for epileptic encephalopathies and brain malformations, whole exome sequencing is suggested because of the phenotypic overlap of various genetic epilepsies [ 37 , 40 ].

Etiologies and electroclinical manifestations of neonatal seizures differ from those of infants and children. In addition, new definitions and classifications of neonatal seizures were recently proposed by the ILAE Task Force on neonatal seizures since the characteristics of neonatal seizures have been more specifically identified by the advanced application of EEG examination and advanced testing for various etiologies. The new definition and classification reflect the importance of EEG testing in the diagnosis and treatment of neonatal seizures. With the active application of continuous EEG monitoring, a more accurate diagnosis will reduce unnecessary treatment and expect better prognosis through more timely treatment.

Key message

· Neonatal seizures are often electrographic-only seizures without clinical signs; therefore, the identification of electrical seizure activity on electroencephalography is the gold standard for diagnosis.

· Clinical signs of neonatal seizures are divided into motor or nonmotor seizures, and motor seizures are mostly focal or multifocal.

· Most neonatal seizures are caused by acute symptomatic etiologies, but in cases of intractable seizures, structural, genetic, or metabolic etiologies should be investigated.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Clinical manifestations of neonatal seizures

Affiliations.

1 Department of Neurology, Stanford University School of Medicine, Palo Alto, CA, USA.
2 Departments of Neurology and Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.
PMID: 33599034
DOI: 10.1111/ped.14654

Neonatal seizures present a unique diagnostic challenge with clinical manifestations often subtle or absent to the bedside observer. Seizures can be overdiagnosed in newborns with unusual paroxysmal movements and underdiagnosed in newborns without clinical signs of seizures. Electroclinical "uncoupling" also adds to the diagnostic challenge. Reliable diagnosis requires additional tools; continuous electroencephalogram (EEG) monitoring is the gold standard for diagnosis of neonatal seizures. Certain high-risk neonatal populations with known brain injury, such as stroke or hypoxic-ischemic encephalopathy, are most likely to benefit from continuous EEG. Studies have shown that risk stratification for continuous EEG has positive impact on care, including rapid and accurate diagnosis and treatment of neonatal seizures, which leads to reduced use of antiseizure medicines and length of hospital stay. This review describes common clinical manifestations of neonatal seizures, and clinical situations in which EEG monitoring to screen for seizures should be considered.

Keywords: electroencephalogram; epilepsy; neonatal; seizure; subclinical.

Publication types

Electroencephalography
Hypoxia-Ischemia, Brain* / diagnosis
Hypoxia-Ischemia, Brain* / therapy
Infant, Newborn
Infant, Newborn, Diseases*
Seizures / diagnosis
Seizures / etiology

IMAGES

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COMMENTS

Neonatal Seizures and Neonatal Epilepsy
Seizures are common in neonates, particularly in the first month of life. Neonatal seizures can be either provoked or unprovoked. Provoked seizures, also known as acute symptomatic seizures, may result from hypoxic-ischemic injury, cerebral infarction, brain bleeds, metabolic derangements, or infections.
Neonatal Seizure - StatPearls - NCBI Bookshelf
Neonatal seizures are a commonly encountered neurologic condition in neonates. They are defined as sudden, paroxysmal, abnormal alteration of electrographic activity from birth to the end of the neonatal period. During this period, the neonatal brain is developmentally immature.
Clinical features, evaluation, and diagnosis of neonatal seizures
Most neonatal seizures (approximately 85 percent) are acute provoked seizures (previously called acute symptomatic seizures), occurring as a consequence of a specific identifiable etiology . These acute provoked seizure etiologies can be broadly categorized as: Neonatal encephalopathy and hypoxic-ischemic encephalopathy
PEDIATRIC NEWBORN MEDICINE CLINICAL PRACTICE GUIDELINES
Seizures during the neonatal period may impair learning and memory and increase susceptibility to epilepsy later in life (Holmes 2009). Mortality of less than 20% (Ronen 2007).
Seizures in Neonates: Presentations, Etiologies, and ED ...
This issue reviews common presentations and causes of neonatal seizures, provides recommendations for management in the ED, and evaluates the evidence regarding antiepileptic medications for neonates
Seizures in the neonate: A review of etiologies and outcomes
In this review, we address the conundrum of neonatal seizures including acute symptomatic, remote symptomatic, provoked, and unprovoked seizures, evolving to post-neonatal epilepsies, and neonatal onset epilepsies.
Neonatal seizures: diagnostic updates based on new definition ...
Although acute symptomatic seizures are more common in the neonatal period, they may be the first presentation of an epilepsy syndrome, with approximately 13% of neonatal seizures [2,23]. It is important to identify epilepsy syndrome and its etiology to determine its treatment and prognosis.
Neonatal Seizures | NeoReviews - American Academy of Pediatrics
Neonatal seizures are common among patients with acute brain injury or critical illness and can be difficult to diagnose and treat. The most common etiology of neonatal seizures is hypoxic-ischemic encephalopathy, with other common causes including ischemic stroke and intracranial hemorrhage.
Neonatal Seizures | Pediatrics In Review | American Academy ...
Describe the pathophysiology of seizures in neonates and how this differs from seizures in older children and adults. Describe seizure types in neonates and the limitations of clinical diagnosis of neonatal seizures. Explain how to use neurodiagnostic tools to diagnose and manage neonatal seizures.
Clinical manifestations of neonatal seizures - PubMed
Neonatal seizures present a unique diagnostic challenge with clinical manifestations often subtle or absent to the bedside observer. Seizures can be overdiagnosed in newborns with unusual paroxysmal movements and underdiagnosed in newborns without clinical signs of seizures.