LEARNING OBJECTIVES

Introduction

The majority of neonatal seizures (NS) are symptomatic, and they are often the first sign of neurologic injury in the newborn. Their early recognition provides an opportunity to diagnose and treat, or ameliorate, the underlying disorder. While it remains controversial whether NS confer additional neurologic injury, they can disrupt cardiorespiratory control in already unstable infants. In addition to management of the underlying etiology, treatment with antiseizure medication (ASM) is undertaken in all but rare cases.

Establishing the incidence of NS has been complicated by varying methods of seizure diagnosis, (e.g., clinical diagnosis alone vs. electrographic diagnosis), varying modalities used to detect NS electrographically (e.g., amplitude integrated EEG [aEEG] vs. continuous video EEG [cvEEG]), and the impracticality of routinely monitoring all neonates at high risk. General estimates suggest that NS occur in 1% to 8% of patients in the neonatal intensive care unit (NICU) and in 1 to 3.5 per 1,000 live births.^1,2 A recent population-based study in Parma, Italy using EEG confirmation for diagnosis of NS yielded an incidence of 2.29/1,000 live births, with 1.10/1,000 in full term and 14.28/1,000 in preterm births. Incidence increased with decreasing gestational age (up to 85.6/1,000 live births <28 weeks gestation).³

In high-risk neonates undergoing EEG monitoring in the NICU, electrographic seizures (ES) are found in 26% to 82% of patients.⁴ Hypoxic-ischemic encephalopathy (HIE) is the most common cause of NS, followed by arterial ischemic stroke and intracranial hemorrhage.⁵ Seizures associated with HIE typically start within the first 24 hours of life in infants with clinical evidence of encephalopathy, whereas seizures associated with infectious or metabolic etiologies often occur after an initial period of apparent well-being. In recent cohort studies, males show a higher incidence of seizures than females for unknown reasons.⁵

Historically, NS have been considered a marker of the severity of the underlying brain injury and have not been thought to have an independent deleterious effect. However, in HIE and other types of acute brain injury, there is the potential for additional seizure-related excitotoxic injury in vulnerable penumbral regions.^6,7 Accumulating clinical evidence suggests that NS may independently worsen neurodevelopmental outcome and play a role in later epileptogenesis.^8,9 The increased availability of continuous bedside video EEG monitoring in the NICU is now making it possible to accurately characterize the frequency, duration, and topography of NS. This should lead to a better understanding of the relationship of NS to neurodevelopmental outcome.

NS are associated with an overall mortality of ~17%, and neonates who do not respond to first-line medications are twice as likely to die as neonates who do respond.⁵ In addition, survivors of NS have a high rate of neurodevelopmental disability including cerebral palsy (~30%), intellectual disability (~35%), and epilepsy (~15%), with the underlying etiology most predictive of outcome.³

Treatment of NS can be challenging, as up to two-thirds of neonates with seizures do not respond to first-line medications and one-half do not respond to second-line medications.⁵ Treatment strategies have not changed substantially over decades despite the availability of many new antiseizure medications.^10,11 Phenobarbital and phenytoin/fosphenytoin remain standard choices. Newer drugs, such as levetiracetam, have failed to show superiority over the traditional agents. The search for new medications and treatment strategies is an area of active research with the goal of early seizure cessation and improved long-term neurodevelopmental outcomes. The natural history of acute symptomatic seizures, which tend to resolve after a few days, complicates the assessment of the efficacy of new agents as any medication added second line may coincide with the natural decline in seizure frequency.

258Sharp Waves and Brief Rhythmic Discharges

Sharp Wave Transients

In the newborn, unlike at other stages of development, sporadic sharp wave transients occur as a normal developmental EEG feature during brain maturation. They are most abundant at 32 to 34 weeks, decreasing gradually in frequency through term, at which point they should be rare (≤2–3/hour), of modest amplitude and duration (<75 µV, 100–200 ms), located in the central, temporal, or centro-temporal region, and only seen during quiet sleep.¹² When they are more frequent than normal, they are considered a manifestation of encephalopathy and not an indication of a lowered seizure threshold. The American Clinical Neurophysiology Society (ACNS) guideline on EEG terminology in neonates states that sharp wave transients are excessive when there are >11/hour in the term newborn and >13/hour in the preterm newborn.¹² There are other features of neonatal sharp wave transients that suggest they are abnormal, and in some cases the argument can be made that they may in fact be epileptiform or suggestive of a structural lesion. These features include high amplitude (>150 mV), positive polarity, focal persistence, occurrence in focal runs, complex morphology with a large after-going slow wave, and presence in continuous portions of the record (e.g., active sleep and waking) (Figure 7.1A–D).¹²

Positive Sharp Waves

Positive sharp wave transients (PSW) located in the central or vertex region (also referred to as positive rolandic sharp waves) in the preterm infant have classically been associated with intraventricular hemorrhage (IVH)^13,14 (Figure 7.2A–D). PSW are seen in 30% to 78% of patients with IVH.^15,16 An association between PSW and periventricular leukomalacia has also been described.¹⁷ Location outside of the rolandic area, particularly in the temporal region, may also offer insight into cerebral injury; Chung and Clancy found an association of positive temporal sharp waves in preterm neonates with cerebral injury.¹⁸ Others have suggested that they represent a benign pattern similar to the temporal theta bursts seen in the premature infant.¹⁹

Brief Rhythmic Discharges

Brief rhythmic discharges (BRDs) may be indicative of a lowered seizure threshold. These are also referred to as B(I)RDs—the “(I)” meant to convey either ictal or interictal occurrence and a degree of controversy as to their significance. In the newborn, they are currently defined as evolving rhythmic discharges of >2 µV amplitude and <10 seconds duration¹² (Figure 7.3A–F). The requirement for evolution of the waveform has not always been included in the definition, however it is required as per the ACNS guideline definition. In 1990, Shewmon first characterized BRDs as a possible epileptiform pattern distinct from other physiologic (e.g., temporal theta/alpha bursts, delta “brushes”) or pathologic rhythmic discharges in the neonate.²⁰ This and subsequent studies have indicated a prevalence in neonatal EEG recordings of up to 20% and have described associations with neonatal brain injury (particularly leukomalacia), electrographic seizures, increased mortality, and long-term neurodevelopmental disability.^21,22 While they are generally not expected to have a clinical correlate, Oliveira et al. described a clinical correlate (focal clonic movements, focal tonic events, convulsive apnea, or motor automatisms) in ~16% of BRDs.²² Although less well-studied in adults, BRDs were reported to occur in a case-controlled series at a frequency of 2% in critically ill adult patients.²³ In the critically ill adult population, BRDs were strongly associated with seizure occurrence and were more likely to occur in the first hour of monitoring than were seizures (75% vs. 25%), leading to a recommendation to continue monitoring in those in whom BRDs were noted early in the recording.²³ While the same data do not exist regarding the timing of BRDs in newborn EEGs, the presence of BRDs should be noted and, depending on the clinical circumstances, their association with seizure and brain injury may suggest the advisability of continued monitoring.

Neonatal Seizures

Historically, clinical NS included events with or without associated electrographic seizure patterns. Now, and for the purposes of this chapter, only those clinical events that are associated with electrographic seizure patterns are considered NS.¹² It is nonetheless possible that clinical seizures occur in the absence of detectable scalp EEG activity, as can occur in older children and adults.

The clinical events most often associated with electrographic seizures include focal clonic, focal tonic, and myoclonic seizures. Neonates may also have electroclinical spasms.²⁴ Orolingual and ocular movements can be seen at the onset or during seizure evolution.²⁵ Autonomic phenomena, including apnea, tachycardia, hypertension, sialorrhea, and piloerection, often accompany NS or can themselves be the primary clinical manifestations of a seizure. As it is not possible to confidently assess awareness in newborns, seizures cannot be designated as with or without impaired awareness as in older children and adults. It is believed that, due to the immaturity of myelination, dendritic arborization, and synaptic development, the immature brain is unable to support “generalized” seizures;²⁶ therefore, all NS are considered focal. Seemingly generalized clinical patterns are usually, in fact, multifocal with asynchronous bilateral semiology and may represent different seizures occurring simultaneously but 259independently over the left and right hemisphere. Exceptions include spasms and myoclonic seizures that are associated with diffuse voltage attenuation²⁴ or an ictal burst-suppression pattern,²⁷ respectively.

The clinical seizure can be subtle, fragmentary, and brief compared to the electrographic seizure or may be lacking entirely (electrographic-only/subclinical). This is particularly true in neonates who have received anti-seizure medication. Electroclinical uncoupling/decoupling, a phenomenon in which treated electroclinical seizures lose their clinical correlate and become solely subclinical, has been well studied in neonates. Scher and colleagues found this to occur in 58% of a cohort of 59 neonates.²⁸ The term electroclinical dissociation has been used interchangeably with uncoupling. We note that in some early studies the term electroclinical dissociation was used to refer to the lack of an EEG correlate of a clinical seizure due to the electrophysiologic characteristics of the seizure generator.²⁹ Infants receiving neuromuscular blockers will also manifest solely EEG-only/subclinical seizures. Similarly, in an encephalopathic infant, all electrographic seizures may be subtle or subclinical (~16% in a recent cohort).⁵ For these reasons, conventional video EEG is the gold standard for the diagnosis of neonatal seizures.^12,30,31

An electrographic NS is defined as a sudden EEG change lasting at least 10 seconds characterized by a repetitive, usually rhythmic, pattern with unequivocal evolution in frequency, voltage, waveform, and/or location (in contrast to older patients where evolution of all parameters is required), with a clear beginning, middle, and end, and a minimum voltage of 2 µV (peak to peak)¹² (Figure 7.4A–C). Ictal patterns include rhythmic or semirhythmic spikes and sharp waves (Figure 7.5A–C) and/or sinusoidal waves of alpha, theta, or delta frequency (Figure 7.6A–F). Ictal discharges can be relatively monomorphic or can involve multiple patterns (Figure 7.7A–B). Different patterns may predominate in seizures from different regions in an individual patient.²⁶ Unlike in children and adults, in neonates there is no minimum required frequency of discharges. Recurrent electrographic seizures should be separated by at least 10 seconds to be considered separate seizures. NS typically show less electrographic spread than seizures in children and adults, thought to be due to the immature state of myelination.³² Seizures usually arise from a single focus, but multiple foci discharging asynchronously can also occur (Figures 7.8A–E, 7.9, and 7.10). Location(s) and lateralization of seizure onset, frequency, pattern of spread, and presence or absence of a clinical correlate should be reported.

Just as it remains uncertain whether NS confer additional brain injury in settings such as hypoxic-ischemic injury, it is also unclear how best to express seizure “burden.” Previously, and often in clinical practice, counting the number of seizures occurring during the period of monitoring has been the primary means of quantification. However, the duration of seizures (expressed as total duration/unit time), the maximum seizure frequency (maximum number of seizures/hour), proportion of the record in which seizures occur, and/or the temporal and spatial evolution (expressed in channels/seconds) may be more relevant to the potential for seizure-related injury. Each of these measures has been used in studies of NS and their treatment, though not all are practical in the clinical setting. Regardless of the method used, serial evaluation and quantification may be useful in assessing the temporal progression of seizure burden and/or the response to treatment.

Effect of Gestational Age

Ictal patterns are generally similar in term and preterm newborns, with some notable exceptions. Some authors have described a greater likelihood of sharp elements (e.g., sharp and slow waves, repetitive sharp waves) in the ictal patterns of term infants, whereas preterm infants are more likely to have seizures comprising rhythmic alpha or delta patterns.^33,34 While seizure onset is focal in both term and preterm infants, regional onset (more than one adjacent electrode) may be more common in preterm infants.³⁴ Centrotemporal location of seizure onset is most common in term and late preterm infants,^33,35 while in preterm infants <32 weeks gestational age, occipital and frontal locations predominate.^33,36 Shorter seizure duration has been described in preterm infants in some,³⁷ but not all, studies³⁴ (Figure 7.11A–D). Propagation of seizure is rare at <28 weeks gestational age³⁴ and, if it occurs, is usually to the homologous contralateral region (i.e., central: central). In more mature newborns, propagation can occur to any region, ipsilateral or contralateral. Subclinical seizures occur at all gestational ages; some studies indicate a similar proportion of subclinical seizures at all gestational ages (~65%),³⁸ while others suggest that a higher proportion of seizures are subclinical in preterm as compared to term neonates (75% vs. 51%).³³ The occurrence of exclusively subclinical seizures was significantly greater in preterm infants (24%) than in term infants (14%) in the multicenter Neonatal Seizure Registry.⁵

Effect of Etiology

Approximately 70% of NS are acute symptomatic due to hypoxic-ischemic injury, arterial ischemic stroke, or intracranial hemorrhage. In HIE, seizure onset is usually within the first 24 hours of life, often within the first 12 hours, with resolution after the first few days of life.^39,40 In infants with severe encephalopathy, seizures are often subclinical. More than half of infants with arterial ischemic stroke present in the neonatal period, often with focal seizures that onset after 12 hours of life. Preterm infants with arterial ischemic stroke are less likely to have seizures but may present, instead, with respiratory difficulties, including apnea.^41,42 Subdural hemorrhage and intraventricular hemorrhage (IVH) are the most common forms of intracranial hemorrhage in term and preterm newborns, respectively.⁴³ Small subdural hemorrhages are common and usually benign; however, large hemorrhages can be associated with 260NS, often occurring on the second day of life.⁴³ IVH with or without parenchymal extension is more common in preterm than in term infants and, when grade III and IV, often causes seizures in the first 3 days of life.⁴⁴ Occurrence of IVH after the immediate postnatal period may also be associated with seizures in neonates;⁴⁵ this is typically accompanied by other clinical signs of IVH. Seizures occurring after a 48-hour period of well-being should raise concern for infection or inborn errors of metabolism, which occur at about equal frequency in neonates.⁵

Little is known about the relationship of etiology to ictal clinical and electrographic patterns. A recent review²⁷ suggested that infection (p =.042) and genetic disorders (p < .001) were associated with clonic seizures, metabolic/vitamin-related disorders with myoclonic seizures (p < .001), and vascular disorders with “sequential” seizures (evolving sequence of clinical features, p = .009). Focal discharges were more prevalent in vascular disorders (stroke and hemorrhage, p < .001) and burst suppression in genetic disorders (p < .001) as compared to other etiologies. Future studies should confirm and/or extend these associations.

Effect of Therapeutic Hypothermia

The reported incidence of seizures in HIE in the pre-versus posthypothermia era is similar, 22% to 64% and 34% to 65%, respectively.^40,46,47 However, seizure burden (total duration of seizures/unit time) has been shown to be significantly reduced in hypothermia- as compared to nonhypothermia-treated infants with HIE, with a reduced seizure burden seen specifically in moderate but not severe HIE.^9,40 Time of initial seizure onset is variable in hypothermia-treated infants. Although more than 50% of hypothermia-treated infants will have their initial seizure in the first 24 hours of life, a subset of infants will have their first seizure as late as 60 to 90 hours of life, some during or after rewarming.^47,48 Seizures may also be shorter and more subtle in hypothermia-treated infants,⁴⁰ making them more difficult to identify clinically; approximately 45% of hypothermia-treated infants in two small series had exclusively subclinical seizures.^46,47 Hypothermia does not prevent status epilepticus, which continues to be documented in approximately 25% of hypothermia-treated infants with seizures.³⁹ Lastly, hypothermia may be one factor, among others, responsible for a possible decrease in the rate of childhood epilepsy in survivors of acute symptomatic NS reported in some recent series.^49,50

Neonatal Status Epilepticus

The definition of status epilepticus (SE) presents particular difficulties in the newborn infant. The International League Against Epilepsy defines SE in children and adults as a state of prolonged seizures due to failure of normal termination processes or initiation of processes that lead to abnormally prolonged seizures.⁵¹ There are two clinically important time points: t₁—the time at which a seizure should be considered “prolonged” and treatment should begin; and t₂—the time at which irreversible injury may occur. For convulsive SE, t₁ is 5 minutes and t₂ is 30 minutes. For focal or nonconvulsive status epilepticus, it is less clear when these time points are reached, including in older children and adults. In newborns, where there is controversy as to whether seizures cause additional injury, the determination of these time points is also far from clear. An operational definition of SE as convulsive seizure ≥5 minutes or 2 or more discrete seizures between which there is incomplete recovery of consciousness is also difficult to apply to the neonate in whom convulsive seizures may be infrequent and assessment of consciousness is limited, especially in the presence of neonatal encephalopathy. Recent American Clinical Neurophysiology Society guidelines recommend that neonatal status epilepticus (NSE) be considered present when “the summed duration of (electrographic) seizures comprises ≥50% of an arbitrarily defined 1-hour epoch”¹² (Figure 7.12A–F).

NSE typically occurs in infants with moderate to severe encephalopathy.³⁸ The frequency of electrographic SE in the NICU ranges from 14% to 43%,⁵² depending on the population studied and the definition of SE used. Diagnosis rests on EEG documentation, as the majority of seizures in NSE are subclinical. In the past, it was thought that SE occurred less commonly in neonates than in critically ill children. However, with wider use of prolonged video EEG recordings in critically ill newborns, the rates appear to be similar. SE occurs at about the same frequency (14%–15%) in preterm and term infants.³⁸

In critically ill children, electrographic SE, but not electrographic seizures, has been associated with unfavorable outcome and greater risk of later epilepsy.⁵³ In newborns, the association of NSE with poor outcome is also clearer than for NS. For example, NSE is associated with postneonatal epilepsy, with approximately 33% to 83% of neonates with SE later developing epilepsy.^54,55 In a recent multicenter, prospective cohort of neonates with seizures,⁵ mortality was higher in patients with NSE than those without (26% vs. 15%). In the same study, mortality was higher in preterm than in term infants with SE (32% vs. 15%);⁵ these findings are similar to the results of a study by Pavlidis et al. showing 53% vs. 18% mortality in preterm versus term infants with SE.⁵⁵ A single center study by Kharoshankaya et al. examined seizure burden and outcome in newborns with HIE. In this study, the presence of seizures alone was not associated with a poor outcome; however, the odds of a poor outcome increased ninefold for neonates with a total seizure burden >40 minutes (p = .001) and eightfold for neonates with a maximum 1 hour seizure burden >13 minutes (p = .003).⁵⁶

Rhythmic and Periodic Patterns of Uncertain Significance

The definitions of rhythmic/periodic patterns that are applied to the critical care EEG in children and adults can be applied to the neonate. We note that this is not explicitly stated in the critical care EEG terminology; however, 261the definitions of rhythmic and periodic patterns applied to the critical care EEG of children and adults are referenced in the ACNS guideline for standardized EEG terminology and description of continuous EEG monitoring in neonates.^12,57 Caution should be taken in cases where a rhythmic pattern is identified in the neonate as slow, evolving patterns are accepted as seizure in the neonatal age group. Also, some normal features of the neonatal EEG (anterior dysrhythmia, monomorphic occipital delta) are both rhythmic and nonevolving. Rhythmic/periodic patterns that do not meet the criteria for seizure are rare in neonates, occurring in only 5% of neonatal EEG recordings⁵⁸ (Figure 7.13A–B). In these cases, the patterns do not evolve in any of the domains required to meet the definition of a seizure. Periodic discharges with uniform morphology occurring at regular intervals are found most commonly in neonates with stroke, but also in neonates with herpes simplex virus encephalitis and hypoxic ischemic encephalopathy.^58,59 Periodic discharges tend to occur in the parasagittal region in preterm neonates and in the temporal region in term neonates. Periodic discharges often occur in neonatal EEGs also containing seizures and are likely to outlast electrographic seizures in infants treated with antiseizure medication.⁵⁸

Artifacts That Mimic Seizure

As in older children, it is important to distinguish artifacts from electrocerebral activity (Figures 7.14 and 7.15). Artifacts due to respiratory movements and pulse and cardioballistic artifacts should be relatively constant and time-locked to the polygraphic monitoring of respiration and heart rate. Difficulty may arise when head or body movements, changes in position, or variations in pulse volume cause the artifact to fluctuate and mimic the evolution seen in ictal patterns. Video recording, when available, can be helpful in clarifying responsible clinical events.

Single electrode artifacts with unusual (e.g., squared off) morphology are usually related to electrode impedance (Figures 7.16 and 7.17). The absence of a field, the lack of evolution, and an unusual persistence and duration are often helpful in distinguishing these patterns as artifact. Artifacts with a completely invariant interval may be due to an intravenous drip, especially when the intravenous line is located in a scalp vein.

In the ICU environment, many different electronic monitoring and treatment devices may generate vibration or other movements that can be transmitted to the EEG wires/electrodes. A bedside assessment by an experienced technologist who can check and repair impedances and assess the impact of changing the head or EEG wire position or a visit by the EEG reader to the bedside may be most helpful in identifying the source of an unresolved artifact.

Conclusion

Seizures are common in the neonatal intensive care unit, and the majority of neonatal seizures are subclinical. Proper identification of seizures is important as it is suggested that neonates with high seizure burden and NSE have poorer developmental outcome and higher rates of postneonatal epilepsy. A strong understanding of the electrographic principles of NS and how they differ from important EEG background patterns and seizure mimics are necessary for proper interpretation of neonatal EEG.

This chapter includes access to several videos with real time EEG that illustrate concepts and patterns. Please follow the following url and click onto the show chapter supplementary tab to access the videos: http://connect.springerpub.com/content/book/978-0-8261-4867-4/chapter/ch07

Video 7.1 (Neonatal subclinical seizure)

Video 7.2 (Neonatal focal clonic seizure)

Video 7.3 (Rocking artifact)

KEY POINTS

  •  In the newborn, sporadic sharp wave transients occur as a normal developmental EEG feature during brain maturation; in contrast, brief rhythmic discharges (BRDs) may be indicative of a lowered seizure threshold.

  •  An electrographic neonatal seizure is defined as a sudden EEG change lasting at least 10 seconds characterized by a repetitive, usually rhythmic, pattern with unequivocal evolution in frequency, voltage, waveform, and/or location, with a clear beginning, middle, and end, and a minimum voltage of 2 µV (peak to peak).

  •  Approximately 70% of neonatal seizures are acute symptomatic due to hypoxic-ischemic injury, arterial ischemic stroke, or intracranial hemorrhage.

  •  The incidence of seizures in hypoxic-ischemic encephalopathy in the pre- as compared to posttherapeutic hypothermia era is similar; however, seizure burden has been shown to be significantly reduced by therapeutic hypothermia.

  •  ACNS guidelines recommend that neonatal status epilepticus be considered present when “the summed duration of (electrographic) seizures comprises ≥50% of an arbitrarily defined 1-hour epoch.”

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