In neonates, the International 10–20 system for EEG is simplified to approximately 20 scalp electrodes accompanied by an electrocardiogram lead and respiratory belt.¹² Interpretation requires specialized education to learn preterm and term neonates’ normal patterns in wakefulness and sleep and the appearance of important pathologies, including seizures. EEG technologists and bedside nursing staff are essential to help identify the plethora of potential artifacts commonly observed on cEEG recordings.

aEEG is a widely available bedside tool that is easy to apply and interpret at the bedside.¹⁴ It uses a limited montage (usually 1–3 channels to cover the frontal and central or parietal regions). The maximum and minimum amplitude recorded during a specified time epoch are plotted on a compressed time scale and semilogarithmic y-axis for amplitude to display a trend tracing for each electrode pair.¹⁵ A seizure is suspected when a sudden and sustained increase in amplitude is noted on both upper and lower margins of the aEEG tracing. A concurrent review of the raw EEG signal is helpful to confirm an evolving, monomorphic waveform consistent with seizure.¹⁶ Limitations of aEEG include low sensitivity to detect low amplitude, brief, or very focal seizures occurring in an area not directly adjacent to the electrodes. In 125 neonates greater than 34 weeks postmenstrual age who were evaluated with concurrent cEEG and aEEG, neonatologists were able to use aEEG to identify between 12% and 38% of the individual seizures seen on cEEG, and overall aEEG use identified between 22% and 57% of neonates with seizures.¹⁷

Common EEG and aEEG artifacts include patting, sucking, intravascular line drips, ventilation artifact, and extracorporeal membrane oxygenation artifact.^15,18 Artifacts may be more difficult to distinguish from seizures on aEEG due to limited channels, lack of video, and absent technologist input to resolve electrical artifacts. Prospective cohort studies have found dramatically differing rates of events concerning for seizures depending on the type of neurophysiology monitoring used, particularly in the preterm neonatal population. In two similar prospective cohorts of preterm neonates, 48% of children had seizures when aEEG was used for diagnosis¹⁹ compared with 5% of children when gold standard cEEG was used for diagnosis.²⁰ Such divergent results suggest that, while aEEG may serve as an excellent screening tool (especially in resource-limited settings), gold-standard cEEG is necessary for optimal seizure management.^21,22

For most monitoring systems, aEEG can be displayed at the bedside (using the leads placed for the full montage recording) while the cEEG is recorded and made available for remote access by the neurophysiologist.²¹ This approach has the advantage of providing both a bedside tool for immediate use by the neonatology team and the gold-standard recording for definitive seizure identification. Furthermore, using the same machine and recording for both the aEEG and traditional EEG display can facilitate communication between teams as annotations regarding clinical condition or medication administration by the bedside team can be communicated easily with the neurophysiologist and vice versa.

Quantitative EEG (qEEG) has been increasingly used to predict and aid in identifying neonatal seizures. qEEG analysis, including relative and absolute spectral analysis, has been used to evaluate neonatal EEG seizure risk in neonates with encephalopathy.²³ Ongoing work is focused on translating qualitative use of EEG background to predict seizure risk^24,25 into quantified and more easily applied metrics.

Seizure detection algorithms developed in adults have low accuracy for detecting seizures in neonates.²⁶ Recent efforts to develop neonatal-specific seizure detection algorithms have demonstrated decreased time to treatment and seizure burden when partnered with physician review.²⁷ Initial neonatal qEEG development has focused on term and near-term neonates, but efforts are underway to develop qEEG techniques specific for preterm neonates.¹⁸

Neonatal seizures are sequential when the ictal pattern progresses through a series of phases associated with EEG changes.¹³ Within the individual ictal event, the lateralization and composition of ictal features may vary. This type of seizure is associated with genetic epilepsies, particularly KCNQ2 encephalopathy.^45,49–52

Tremor and jitteriness can occur in both ill and healthy neonates. The movements are characterized by rhythmic oscillation of varying amplitudes and stereotypy. Tremor may be asymmetric and either spontaneous or induced by stimulation or movement.⁵³ Tremor and jitteriness may be differentiated from seizure by suppression with flexion, restraint, or repositioning. Tremor and jitteriness can occur in neonates with hypothermia, or secondary to metabolic derangements, particularly hypoglycemia and hypocalcemia. Tremor and jitteriness are also seen in neonates exposed to some maternal medications classes, including selective serotonin reuptake inhibitors (SSRI), cocaine, and marijuana.^54–56

Nonepileptic myoclonus, like myoclonic seizures, is characterized by rapid (<100 msec) jerks of one or more areas of the body.⁵⁷ In the preterm neonate, benzodiazepines may cause medication-induced myoclonus thought to be due to developmental differences in the γ-aminobutyric acid (GABA) receptors, which abate as neonates mature.^58,59 Nonepileptic myoclonus has been described in the setting of intracranial infection, intracranial hemorrhage, periventricular leukomalacia, and genetic and metabolic disorders.^41,42,60,61

In an otherwise healthy neonate with a normal neurologic exam and jerking movements occurring only during sleep, benign neonatal sleep myoclonus should be considered. Benign neonatal sleep myoclonus is arrhythmic, may increase with attempts to physically suppress the movements, occurs at all sleep stages, and stops when the child is wakened.⁶² Benign neonatal sleep myoclonus will typically resolve by 3 months of age, although a few infants may have movements up to a year of age.⁶²

Dystonia is a sustained involuntary contraction of opposing muscle groups, often resulting in a twisted or abnormal posture.⁵⁷ In neonates, dystonia or opisthotonic posturing is most commonly seen in encephalopathic neonates who have sustained an injury to the basal ganglia.⁶³ Less common causes include inborn error of metabolism (e.g., monoamine neurotransmitter disorders, maple syrup urine disease^64,65). Nonepileptic bilateral tonic extension not having a correlate on EEG may represent “brainstem release” in the setting of extensive cortical dysfunction or posterior fossa pathology.²⁹

Hyperekplexia is a rare but important cause of hyperkinetic paroxysmal events in neonates that is characterized by nonextinguishable exaggerated startle reflex accompanied by hyperreflexia and hypertonia. Hyperekplexia is most commonly associated with mutations of the glycine receptor, but can also be seen in molybdenum cofactor deficiency.^66,67 Untreated hyperekplexia is associated with death secondary to apneic spells, which can be mitigated using scheduled benzodiazepines.^68,69

HIE is the most common cause of seizures in neonates, accounting for 38% in a recent prospective cohort.²⁸ The frequency of seizure in neonates with moderate HIE has decreased by approximately half since therapeutic hypothermia was established as the standard of care by multiple randomized controlled trials.^73–75 The onset of seizures in HIE varies but is typically within the first 24 hours⁷⁴ after birth, with recent data suggesting it is rare to have seizure onset after 24 hours in the setting of a normal or mildly abnormal EEG background.²⁴ The majority of seizures in neonates due to HIE will abate within 72 hours.⁷⁶

Ischemic stroke of either venous or arterial origin and intracranial hemorrhage are common and important causes of seizures in neonates. Up to 90% of neonates with perinatal arterial ischemic infarct present with seizures,⁷⁷ most often focal clonic seizures.³¹ Neonates with perinatal arterial ischemic infarcts may be otherwise well appearing. Bland and hemorrhagic infarcts associated with neonatal cerebral venous sinus thrombosis are more commonly seen after complicated pregnancy or delivery, sepsis, or dehydration and frequently have seizures as a presenting symptom.⁷⁸ Intraventricular hemorrhage is the most common cause of seizures in the very preterm neonate (<32 weeks).⁷⁹ Term neonates with intraventricular hemorrhage should be evaluated for cerebral venous sinus thrombosis.

Neonates requiring early repair of congenital heart defects or extracorporeal membrane oxygenation have unique risk factors for cerebrovascular injury leading to seizures.⁸⁰ Approximately 10% of neonates monitored with cEEG after repair of the congenital heart defect have clinical or subclinical seizures.^81–83 Up to 30% of children undergoing extracorporeal membrane oxygenation have seizures.^84,85 Imaging suggests that seizures are secondary to a mix of injuries, including hypotensive hypoxic injuries, embolic infarction, and an increased risk of intracranial hemorrhage in the setting of anticoagulation.^82–84

Viral and bacterial meningitis are important causes of neonatal encephalopathy and seizures. Neonatal herpes encephalitis^86,87 and enteroviruses (and particularly parechovirus)^88,89 are the most common causes of seizures due to viral infection. Bacterial meningitis is also directly implicated in seizures and is frequently complicated by arterial stroke, cerebral venous sinus thrombosis, and cerebral abscess, which may further contribute to seizure burden and injury.⁹⁰

Metabolic derangements that cause seizures include hypoglycemia, hypocalcemia, hyponatremia, and hypernatremia. Hypoglycemia is associated with seizures, jitteriness, and abnormal tone. Profound hypoglycemia can result in parieto-occipital predominant injury, particularly if prolonged.⁹¹ Parenchymal injury may lead to seizures even after reversing the initial hypoglycemia.⁹² Symptomatic hypocalcemia can occur at an ionized calcium level of less than 4.8 mg/dL (1.2 mmol/L) in term infants and less than 4.0 mg/dL (1 mmol/L) in premature infants.⁹³ Symptomatic neonates may experience myoclonic jerks, exaggerated startle, and seizures until calcium is appropriately repleted.^94,95 Both hypo and hypernatremic seizures are rare in the neonate and are typically seen in the setting of excess maternal water intake during labor, endocrine abnormalities, infection, dehydration, or iatrogenic causes and are treated with judicious correction of the electrolyte abnormality and the underlying cause.⁹⁶

Prenatal exposure to a variety of substances can put neonates at risk for seizures and common seizure mimics. Maternal opiate and alcohol ingestion can both result in seizures due to substance withdrawal.^54,97 Maternal cocaine use can cause seizures through several mechanisms, including acute intoxication, withdrawal, and increased risk of neonatal stroke.^55,98

Maternal SSRI use has been associated with neonatal withdrawal syndrome, that includes neonatal convulsions, tremor, jitteriness, and disturbed state regulation, which can also mimic seizures.⁹⁹ Most children with convulsions due to maternal SSRI use do not have EEG seizures and do not require treatment with ASM therapy. A common clue that the etiology is SSRI withdrawal is the presence of very early convulsions, within the first hours after birth. Similarly, withdrawal from prenatal exposure to methamphetamines is associated with tremor, jitteriness, and exaggerated startle, which may be easily mistaken for seizures.⁵⁶

Neonatal-onset familial genetic epilepsies and epileptic encephalopathies are individually rare, but collectively account for more than half of neonatal-onset epilepsy.¹⁰⁰ They are clinically heterogeneous, and can be associated with myoclonic seizures, tonic seizures, epileptic spasms, or sequential seizures,^{13,31,35–37,101} with at least one study citing tonic seizures as a key seizure semiology.¹⁰¹

Benign neonatal familial seizures are associated with a normal interictal EEG and neurological examination, and seizures that respond readily to ASM. Neonatal-onset epileptic encephalopathies present with a severely abnormal EEG background, neurological examination,⁵¹ and limited response to phenobarbital (PB). Mutations in potassium and sodium channels can cause both benign familial and epileptic encephalopathy phenotypes. KCNQ2, KCNQ3, and SCN2A are among the most common channelopathies presenting in the neonatal period.^102–104 Neonates with early-onset genetic epilepsies often respond favorably to sodium channel blockers such as oxcarbazepine.¹⁰⁵

For neonates without an acute provoked etiology for seizures, genetic testing is increasingly considered standard of care.^106,107 Although specific EEG patterns and physical findings may suggest a particular genetic etiology, neonatal-onset genetic epilepsies as a whole have a high degree of phenotypic overlap. Therefore, broad genetic testing with an infantile epilepsy panel, or whole exome/genome testing is warranted.^108–110

Between 4% and 9% of neonates diagnosed with seizures have an underlying brain malformation.^28,111 Of these, a subset may be identified on prenatal ultrasound and referred for advanced prenatal imaging and neurological counseling. Malformations that are readily identified on prenatal imaging include holoprosencephaly, Dandy Walker-associated malformations, and some disorders of neuronal migration and organization.^100,112 Many malformations associated with seizures go undetected prenatally and are diagnosed after birth. Cerebral malformations that are associated with epilepsy include polymicrogyria, focal cortical dysplasias, schizencephalies, and grey matter heterotopias.¹⁰⁰ Brain malformations may accompany additional physical findings, including congenital heart disease and ophthalmologic findings¹⁰⁰ but are more commonly isolated alterations in neuronal proliferation and migration unique to the brain. Neonatal encephalopathy secondary to diffuse malformations may be mistaken for or accompanied by hypoxic-ischemic injury, but magnetic resonance neuroimaging is well suited for differentiating between these etiologies.

Inborn errors of metabolism are identified in only 1% to 4% of neonates with seizures^28,113 but are crucial to identify promptly due to the availability of specific treatments for some disorders.¹¹⁴ An inborn error of metabolism may initially be diagnosed as (or coexist with) HIE.¹¹⁵ Clinicians should maintain a high level of suspicion, particularly in the setting of consanguinity or family history of neonatal-onset seizures, prenatal onset of seizures, or progressive worsening of seizures and EEG background without explanation.¹¹⁶ Examples of inborn errors of metabolism that present with seizures in the neonatal period include glycine encephalopathy,^41,42 pyridoxine-dependent epilepsy,¹¹⁵ glucose transporter type 1 deficiency,¹¹⁷ and molybdenum cofactor deficiency.¹¹⁸