Neonatal seizures are one of the few neonatal neurologic conditions that require immediate medical attention. Although prompt diagnostic and therapeutic plans are needed, multiple challenges impede the physician’s evaluation of the newborn with suspected seizures (Box 62-1). Clinical and electroencephalographic (EEG) manifestations of neonatal seizures vary dramatically from those in older children, and recognition of the seizure state remains the foremost challenge. This dilemma is underscored by the brevity and subtlety of the clinical repertoire of the neonatal neurologic examination. Environmental restrictions of the sick infant in an intensive care setting, who may be confined to an incubator, intubated, and attached to multiple catheters, limit accessibility. Medications alter arousal and muscle tone and limit the clinician’s ability to distinguish clinical neurologic signs reflective of the underlying disease state. Brain injury from antepartum factors may precipitate neonatal seizures as part of an encephalopathic clinical picture during the intrapartum and neonatal periods, well beyond when brain injury occurred. Overlapping medical conditions from fetal through neonatal periods must be factored into the most appropriate etiologic algorithm to explain seizure expression before applying the most accurate prognosis. Medication options to treat seizures effectively remain elusive and may need to be applied on a specific etiologic basis. Potential neuroresuscitative strategies proposed for the encephalopathic neonate with seizures must consider maternal, placental/cord, and fetal as well as neonatal diseases that cause or contribute to neonatal seizure expression. Fetal and neonatal brain disorders vary in timing and etiology. Neonatal seizures are usually brief and subtle in clinical appearance, sometimes comprising unusual behaviors that are difficult to recognize and classify. Medical personnel vary significantly in their ability to recognize suspect behaviors, contributing to both overdiagnosis and underdiagnosis. The most common practice has been to classify clinical behaviors as seizures without EEG confirmation. However, abnormal motor or autonomic behaviors may represent age- and state-specific behaviors in healthy infants, or nonepileptic paroxysmal conditions in symptomatic infants. For these reasons, confirmation of suspect clinical events with coincident EEG recordings is now more widely recommended. Although for patients with few seizures, these may be missed as brief random events on routine EEG studies. Synchronized video/EEG/polygraphic recordings potentially establish more reliable start and end points for electrically confirmed seizures before the consideration of treatment intervention.15 Rigorous physiologic monitoring better integrates the diagnosis of the seizures with etiology, treatment, and prognosis. Neonatal seizures are listed separately from the traditional classification of seizures and epilepsy during childhood. The International League Against Epilepsy’s Classification adopted by the World Health Organization considers neonatal seizures in an unclassified category because symptomatic seizures may resolve and not constitute a chronic epileptic condition. Another classification scheme suggests a strict distinction of clinical seizure (nonepileptic) events from electrographically confirmed (epileptic) seizures before considering treatment interventions.64 Refinement of novel classifications will be required to better reconcile clinical and EEG criteria for establishing a seizure diagnosis,9, 109 given that nonepileptic movement disorders can be caused by the same acquired diseases, malformations, or medications. Several caveats (Box 62-2) may be useful in the identification of suspected neonatal seizures, yet continue to raise questions regarding our diagnostic acumen. Clinical criteria for neonatal seizure diagnosis were historically subdivided into five clinical categories: focal clonic, multifocal or migratory clonic, tonic, myoclonic, and subtle seizures.106 A subsequent classification expands the clinical subtypes, adopting a strict temporal occurrence of specific clinical events with coincident electrographic seizures to distinguish neonatal clinical “nonepileptic” seizures from “epileptic” seizures (Box 62-3).64 Subtle seizure activity is the most frequently observed category of neonatal seizures and includes repetitive buccolingual movements, orbital-ocular movements, unusual bicycling or pedaling, and autonomic findings (Figure 62-1A). Any subtle paroxysmal event that interrupts the expected behavioral repertoire of the newborn infant and appears stereotypical or repetitive should heighten the clinician’s level of suspicion for seizures. However, alterations in cardiorespiratory regularity, body movements, and other behaviors during active (rapid eye movement [REM]) sleep, quiet (non-REM) sleep, or waking segments must be recognized before proceeding to a seizure evaluation.85 Within the subtle category of neonatal seizures are stereotypical changes in heart rate, blood pressure, oxygenation, or other autonomic signs, particularly during pharmacologic paralysis for ventilatory care. Other unusual autonomic events include penile erections, skin changes, salivation, and tearing. Autonomic expressions may be intermixed with motor findings. Isolated autonomic signs such as apnea, unless accompanied by other clinical findings, are rarely associated with coincident electrographic seizures23 (see Figure 62-1B). Because subtle seizures are both clinically difficult to detect and only variably coincident with EEG seizures, synchronized video/EEG/polygraphic recordings are recommended to document temporal relationships between clinical behaviors and coincident electrographic events.11, 15, 64 Despite the “subtle” expression of this seizure category, these children may have suffered significant brain injury. Rhythmic movements of muscle groups in a focal distribution that consist of a rapid phase followed by a slow return movement are clonic seizures, to be distinguished from the symmetric “to-and-fro” movements of tremulousness or jitteriness. Gentle flexion of the affected body part easily suppresses the tremor, whereas clonic seizures persist. Clonic movements can involve any body part such as the face, arm, leg, and even diaphragmatic or pharyngeal muscles. Generalized clonic activities can occur in the newborn but rarely consist of a classic tonic followed by clonic phase, which is characteristic of the generalized motor seizure noted in older children and adults. Focal clonic and hemiclonic seizures have been described with localized brain injury, usually from cerebrovascular lesions,15 but can also be seen with generalized brain abnormalities. As in older patients, focal seizures in the neonate may be followed by transient motor weakness, historically referred to as a transient Todd paresis or paralysis, to be distinguished from a more persistent hemiparesis over days to weeks. Clonic movements without EEG-confirmed seizures have been described in neonates with normal EEG backgrounds, and their neurodevelopmental outcome can be normal.11 Multifocal or migratory clonic activities spread over body parts either in a random or anatomically appropriate fashion. Such seizure movements may alternate from side to side and appear asynchronously between the two halves of the child’s body. The word fragmentary was historically applied to distinguish this event from the more classic, generalized tonic-clonic seizure seen in the older child. Multifocal clonic seizures may also resemble myoclonic seizures, consisting of brief, shocklike muscle twitching of the midline or extremity musculature. Neonates with this seizure description either die or suffer significant neurologic morbidity.79 Tonic seizures refer to a sustained flexion or extension of axial or appendicular muscle groups. Tonic movements of a limb or sustained head or eye turning may also be noted. Tonic activity with coincident EEG needs to be carefully documented because 30% of such movements lack a temporal correlation with electrographic seizures (Figure 62-2). “Brainstem release” resulting from functional decortication after severe neocortical dysfunction or damage is one physiologic explanation for this nonepileptic activity (discussed later). Extensive neocortical damage or dysfunction permits the emergence of uninhibited subcortical expressions of extensor movements.82 Tonic seizures may also be misidentified when the nonepileptic movement disorder of dystonia is the more appropriate behavioral description. Both tonic movements and dystonic posturing can also simultaneously occur. Myoclonic movements are rapid, isolated jerks that can be generalized, multifocal, or focal in an axial or appendicular distribution. Myoclonus lacks the slow return phase of the clonic movement complex described previously. Healthy preterm infants commonly exhibit myoclonic movements without seizures or a brain disorder. Therefore, EEG is recommended to confirm the coincident appearance of electrographic discharges with these movements (Figure 62-3). Pathologic myoclonus in the absence of EEG seizures also can occur in severely ill preterm or full-term infants after severe brain dysfunction or damage.84 As with older children and adults, myoclonus may reflect injury at multiple levels of the neuroaxis from the spine, brainstem, and cortical regions. Stimulus-evoked myoclonus with either coincident single spike discharges or sustained electrographic seizures has been reported.89 An extensive evaluation must be initiated to exclude metabolic, structural, and genetic causes. Rarely, healthy sleeping neonates exhibit abundant myoclonus that subsides with arousal to the waking state,22 termed benign sleep myoclonus of the newborn. Specific nonepileptic neonatal movement repertoires continually challenge the physician’s attempt to reach an accurate diagnosis of seizures and avoid the unnecessary use of antiepileptic medications. Coincident paper or synchronized video/EEG/polygraphic recordings are now the suggested diagnostic tool to confirm the temporal relationship between the suspect clinical phenomena and electrographic expression of seizures. The following three examples of nonepileptic movement disorders incorporate a classification scheme,64 based on the absence of coincident EEG seizures. Tremors are frequently misidentified as clonic activity. Unlike the unequal phases of clonic movements described earlier, the flexion and extension phases of tremor are equal in amplitude. Children are usually alert or hyperalert but may also appear somnolent. Passive flexion and repositioning of the affected tremulous body part diminishes or eliminates the movement. Such movements are usually spontaneous but can be provoked by tactile stimulation. Metabolic or toxin-induced encephalopathies, including mild asphyxia, drug withdrawal, hypoglycemia, hypocalcemia, intracranial hemorrhage, hypothermia, and growth restriction, are common clinical scenarios when such movements occur. Neonatal tremors usually decrease with age; for example, in 38 full-term infants, excessive tremulousness resolved spontaneously over a 6-week period, with 92% being neurologically normal at 3 years of age.97 Medications are rarely considered to treat this particular movement disorder.72 Myoclonic movements are either (1) bilateral and synchronous or (2) asymmetric and asynchronous. Clusters of myoclonic activity occur predominantly during active (REM) sleep, more so in the preterm infant,32 but also in healthy term infants. These benign movements are not stimulus sensitive and have no coincident electrographic seizure activity or changes in EEG background rhythms. When this movement occurs in the healthy term neonate, it is usually suppressed during wakefulness. This clinical entity of benign neonatal sleep myoclonus is a diagnosis of exclusion after an extensive consideration of pathologic diagnoses.22 Some infants with severe central nervous system dysfunction present with nonepileptic spontaneous or stimulus-evoked myoclonus. Metabolic encephalopathies (e.g., glycine encephalopathy), cerebrovascular lesions, brain infections, or congenital malformations may present with nonepileptic myoclonus.84 Encephalopathic neonates may respond to tactile or painful stimulation by either isolated focal, segmental, or generalized myoclonic movements. Rarely, cortically generated spike or sharp-wave discharges as well as seizures may also be noted on the EEG coincident with these myoclonic movements84 (Figure 62-4). Medication-induced myoclonus as well as stereotypic movements have also been described.94 Dystonia or dyskinesia is a third commonly misdiagnosed movement disorder that is often misrepresented as tonic or subtle seizures, or may be expressed with nonepileptic tonic movements. These movements can be associated with either acute or chronic disease states involving basal ganglia structures or extrapyramidal pathways, commonly injured after antepartum or intrapartum severe asphyxia (termed status marmoratus),106 or rarely with specific inherited metabolic diseases 54 or drug toxicity from neuropsychiatric medications given to the mother. Alternatively, posturing reflects subcortical motor pathways that remain functionally unopposed because of a diseased or malformed neocortex.82 Electrographic/polysomnographic studies have become invaluable tools for the assessment of suspected seizures.15,19,64,76,108 Technical and interpretative skills of normal and abnormal neonatal EEG sleep patterns must be mastered before the clinician develops a confident visual analysis style for seizure recognition.85,101 For the epileptic older child and adult, it is generally accepted that the epileptic seizure is a clinical paroxysm of altered brain function with the simultaneous presence of an electrographic event on an EEG recording. Some advocate the use of single-channel computerized devices for prolonged monitoring, given the multiple logistical problems using conventional multichannel recording devices. This device, however, may not detect focal or regional seizures because recording from a single channel will not detect localized disease processes distant from the channel.76 Neonatal EEG seizure patterns commonly consist of a repetitive sequence of waveforms that evolve in frequency, amplitude, electrical field, and morphology. Four types of ictal patterns have been described: focal ictal patterns with normal background, focal patterns with abnormal background, multifocal ictal patterns, and focal monorhythmic periodic patterns of various frequencies. It is generally suggested that a minimal duration of 10 seconds with the evolution of discharges is required to distinguish electrographic seizures from repetitive but nonictal epileptiform discharges.15,21 Clinical neurophysiologists usually classify brief or prolonged repetitive discharges with a lack of evolution as nonictal patterns, but some argue that simply the presence of epileptiform discharges is confirmatory of seizures.95 The specific features of electrographic seizure duration and topography are unique to the neonatal period. Few studies have quantified minimal or maximal seizure durations in neonates.14,21,91 Most notably, the definition of the most severe expression of seizures that potentially promotes brain injury, status epilepticus, can be problematic. For the older patient, status epilepticus is defined as at least 30 minutes of continuous seizures or two consecutive seizures with an interictal period during which the patient fails to return to full consciousness. This definition is not easily applied to the neonate for whom the level of arousal may be difficult to assess, particularly if sedatives are given. One study arbitrarily defined neonatal status epilepticus as continuous seizure activity for at least 30 minutes, or 50% of the recording time91; 33% (11 of 34 term infants) had status epilepticus with a mean duration of 29.6 minutes before antiepileptic drug use, and an additional 9% (3 of 34 preterm infants) also had status epilepticus with an average duration of 5.2 minutes per seizure (i.e., 50% of the recording time). The mean seizure duration was longer in the full-term infant (i.e., 5 minutes) compared with the preterm infant (i.e., 2.7 minutes). Given that more than 20% of this study group fit the criteria for status epilepticus based on EEG documentation, concerns must be raised regarding the underdiagnosis of the more severe form of seizures that potentially contribute to brain injury. Uncoupling of the clinical and electrographic expressions of neonatal seizures after antiepileptic medication administration also contributes to an underestimation of the true seizure duration, including status epilepticus (Figure 62-5). One study estimated that 25% of neonates expressed persistent electrographic seizures despite resolution of their clinical seizure behaviors after receiving antiepileptic medications,90 termed electroclinical uncoupling. Other pathophysiologic mechanisms besides medication effect also might explain uncoupling.9 Most neonatal electrographic seizures arise focally from one brain region. Generalized synchronous and symmetric repetitive discharges can also occur. In one study, 56% of seizures were seen in a single location at onset; specific sites included temporal-occipital (15%), temporal-central (15%), central (10%), frontotemporal-central (6%), frontotemporal (5%), and vertex (5%). Multiple locations at the onset of the electrographic seizures were noted in 44%.15 Electrographic discharges may be expressed as specific EEG frequency ranges from fast to slow, including beta, alpha, theta, or delta activities. Multiple electrographic seizures can also be expressed independently in anatomically unrelated brain regions. At the opposite end of the spectrum from periodic discharges, brief rhythmic discharges that are less than 10 seconds in duration have also been addressed with respect to an association with seizures and outcome (Figure 62-6). Neonates with electrographic seizures may also exhibit these brief discharges; other neonates express only isolated discharges without seizures. Neonates with brief discharges can suffer from hypoglycemia or periventricular leukomalacia, which carries a higher risk for neurodevelopmental delay.68 Based on 415 clinical seizures in 71 infants, clonic seizure activity had the best correlation with coincident electrographic seizures. “Subtle” clinical events, on the other hand, had a more inconsistent relationship with coincident EEG seizure activity, suggesting nonepileptic brainstem release phenomena for at least a proportion of such events. Functional decortication resulting from neocortical damage without coincident EEG seizures has therefore been suggested, such as with tonic posturing, as illustrated in Figure 62-2A. Newborns with nonseizure brainstem release activity may express a different functional pattern of metabolic dysfunction, detected as altered glucose uptake on single-photon emission computed tomography studies, than neonates with seizures.4 A suggestion to document increased prolactin levels with clinical seizures has also been reported,42 but such levels have not yet been correlated with electrographic seizures. Electroclinical dissociation is one proposed mechanism by which subcortical seizures may appear only intermittently on surface-recorded EEG studies.109 Electroclinical dissociation has been defined as a reproducible clinical event that occurs both with and without coincidental electrographic seizures. In one group of 51 infants with electroclinical seizures, 33 infants simultaneously expressed both electrical and clinical seizure phenomena. Extremity movements were more significantly associated with synchronized electroclinical seizures. However, a subset of 18 of 51 neonates (35%) also expressed electroclinical dissociation on EEG recordings. For neonates who expressed electroclinical dissociation, the clinical seizure component always preceded the electrographic seizure expression, suggesting that a subcortical focus initiated the seizure state. Some of these children also expressed synchronized electroclinical seizures, even on the same EEG record. Clearly EEG is required to document the electrographic phase after the initial behavioral event. Controversy remains over whether subcortical seizures versus nonictal functional decortication best categorizes suspect clinical behaviors without coincident EEG documentation. This dilemma should encourage the clinician to use the EEG as a neurophysiologic yardstick by which more exact seizure start points and endpoints can be assigned, before offering pharmacologic treatment with antiepileptic drugs. Neonates certainly exhibit electrographic seizures that go undetected unless EEG is used.67 This is best shown in neonates who are pharmacologically paralyzed for ventilatory assistance, or in infants with clinical seizures that are suppressed by the use of antiepileptic drugs.15,88,90 In one cohort of 92 infants, 60% of whom were pretreated with antiepileptic medications, 50% of neonates had electrographic seizures with no clinical accompaniment.90 Both clinical and electrographic seizure criteria were noted for 45% of 62 preterm and 53% of 33 full-term infants. Seventeen infants were pharmacologically paralyzed when the EEG seizure was first documented. A later cohort of 60 infants, none of whom were pretreated with antiepileptic medications, included 7% with only electrographic seizures before antiepileptic drug administration,90 and 25% who expressed electroclinical uncoupling after antiepileptic drug use. Overestimation and underestimation of neonatal seizures are consequently reported whether clinical or electrical criteria are used. Using clinical criteria, seizure incidences ranged from 0.5% in term infants to 22.2% in preterm neonates.78 Discrepancies in incidence reflect not only varying postconceptional ages of the study populations chosen, but also poor interobserver reliability45 and the hospital setting in which the diagnosis was made. Hospital-based studies that include high-risk deliveries generally report a higher seizure incidence. Population studies that include less medically ill infants from general nurseries report lower percentages.46 Incidence figures based only on clinical criteria without EEG confirmation include “false-positive” results, consisting of the neonates with either normal or nonepileptic pathologic neonatal behaviors. Conversely, the absence of scalp-generated EEG seizures may include a subset of “false-negative” results from subjects who express seizures only from subcortical brain regions without expression on the cortical surface. Consensus between those relying on clinical and EEG criteria is still required. Interictal EEG abnormalities (including nonictal repetitive epileptiform discharges) have important prognostic implications for both preterm and full-term infants. Severely abnormal bihemispheric patterns include the burst suppression pattern (Figure 62-7), electrocerebral inactivity, low-voltage invariant pattern, persistently slow background pattern, multifocal sharp waves, and marked asynchrony.14 For infants with hypoxic-ischemic encephalopathy (HIE), subclassifications of specific EEG patterns such as burst suppression with or without reactivity may give a more accurate prediction of outcome.99 Dysmaturity of the EEG sleep background for a child’s corrected age has also been an important feature to recognize; discordance between cerebral and noncerebral components of sleep state or immaturity of EEG patterns for the given postconceptional age of the infant predict a higher risk for neurologic sequelae.86,88,106 Even focal or regional patterns have prognostic significance, such as with preterm infants who express repetitive positive sharp waves at the midline or central regions, often noted with intraventricular hemorrhage and periventricular leukomalacia.85 Screening infants at risk for neonatal seizures with a routine EEG soon after birth allows identification of more severe interictal EEG background abnormalities that more likely predict seizure occurrence on subsequent neonatal records.47 Interictal EEG findings are not pathognomonic for particular etiologies, pathophysiologic mechanisms, or timing.88 History, physical examination, and laboratory findings need to be integrated with the electrographic interpretation of both ictal and interictal pattern abnormalities for the particular child. Serial EEG studies better assist the clinician in diagnostic and prognostic interpretations.103 As with abnormal examination findings into the second week of life, the persistence of electrographic abnormalities also raises prognostic concerns. For example, the newborn who expresses severe EEG abnormalities into the second week of life implies a greater likelihood for neurologic impairment, even despite the resolution of clinical dysfunction. Conversely, the child who rapidly recovers from a significant brain disorder, with the reemergence of normal EEG features during the first few days after birth, may experience comparatively fewer neurologic sequelae. Interictal EEG pattern abnormalities also reflect fetal brain disorders that preceded labor and delivery. The depth and severity of the neonatal brain disorder (defined by clinical and electrographic criteria), therefore, may reflect chronic injury to the fetus, who subsequently becomes symptomatic after a stressful intrapartum period, with or without more recent injury (see Chapter 61). Neonatal seizures are not disease specific and can be associated with a variety of medical conditions that occur before, during, or after parturition. Seizures may occur as part of an asphyxial brain disorder that is expressed after birth from intrapartum, peripartum or antepartum causes (see Chapter 61). The epidemiology of neonatal encephalopathy with a subset with hypoxic-ischemic encephalopathy should be recognized.44 Hypoxic-ischemic events can be further subdivided as modifiable sentinel events such as a prolapsed umbilical cord causing acute intrapartum hypoxic-ischemic encephalopathy versus nonmodifiable causes such as clinically silent fetal thrombotic vasculopathy resulting in chronic uteroplacental vascular insufficiency, leading to both chronic and acute asphyxial conditions Alternatively, neonatal encephalopathies without asphyxia may also occur.2,51 Importantly, neonatal seizures can also present as an isolated clinical sign from a remote antepartum disease or injury without other signs of a postnatal encephalopathy. A logistic model to predict seizures emphasizes the accumulation of both antepartum and intrapartum factors to increase the likelihood of neonatal seizure occurrence.73 Although separately these factors had low positive predictive values, a significant cumulative risk profile included antepartum maternal anemia, bleeding, asthma, meconium-stained amniotic fluid, abnormal fetal presentation, fetal distress, and shoulder dystocia. Hypoxia-ischemia (i.e., asphyxia) is traditionally considered the most common causal factor associated with neonatal seizures.83,107,109 However, children suffer asphyxia either before or during parturition, and only 10% of cases of asphyxia result from postnatal causes.1,107 When asphyxia is suspected during the labor and delivery process, biochemical confirmation can be attempted. Intrauterine factors in the hours to days before labor can result in antepartum fetal asphyxia without later documentation of acidosis at birth or immediately before birth. Maternal illnesses such as thrombophilia or preeclampsia, or specific uteroplacental abnormalities such as abruptio placentae or cord compression may contribute to fetal asphyxial stress without providing the opportunity to document in utero acidosis at the end of parturition.87 Antepartum maternal trauma and chorioamnionitis are additional acquired conditions that cause or contribute to intrauterine asphyxia secondary to uteroplacental insufficiency. Intravascular placental thromboses, infarction of the placenta (fetal or maternal surfaces), or umbilical cord thrombosis noted on placenta/cord examinations postnatally are additional surrogates for remote peripartum or intrapartum fetal asphyxia (see Chapter 27). Meconium passage into the amniotic fluid may also promote an inflammatory response in the placental membranes, causing vasoconstriction and additional asphyxia. Neuroimaging, preferably with magnetic resonance imaging (MRI), may later define the destructive brain lesions that resulted from in utero asphyxia, even without HIE expressed at birth. Diffusion-weighted MRI provides a shorter time window that may or may not extend before the onset of labor or when the mother entered the hospital, depending on the length of hospitalization before birth and the postnatal age when the MRI was obtained. Therefore, asphyxia-induced brain injuries may result from in utero maternal-fetal-placental diseases that later are expressed in part as neonatal seizures, independent of the biochemical marker of acidosis at birth, as well as the evolving HIE syndrome in the days after birth.1 A case-control study of term infants with clinical seizures reported a fourfold increase in the risk of unexplained early-onset seizures after intrapartum fever. All known causes of seizures were eliminated, including meningitis or sepsis. These 38 newborns, compared with 152 control subjects, experienced intrapartum fever as an independent risk factor on logistic regression that predicted seizures. The authors speculated on the role of circulating maternal cytokines that triggered “physiologic events” contributing to seizures.50 The American College of Obstetricians and Gynecologists1 has published guidelines that suggest essential or collective criteria to define postasphyxial neonatal encephalopathy (i.e., HIE) after significant clinical depression noted at birth. The report acknowledges that as many as 90% of children have antepartum timing to a brain injury, with the caveat that more recent asphyxial injury may occur either in the intrapartum or peripartum periods up to 48 hours before delivery. Postasphyxial encephalopathy refers to an evolving clinical syndrome over days after birth depression during which neonatal seizures may occur, usually in children who also exhibit severe early metabolic acidosis, hypoglycemia or hypocalcemia, and multiorgan dysfunction.70,90 Other epiphenomena around asphyxia may contribute to seizures. Seizures after asphyxia may be associated with trauma, intracranial hemorrhage, or other brain damage based on neurologic diagnoses besides asphyxia. The physical examination findings of the infant with HIE and seizures include coma, hypotonia, brainstem abnormalities, and loss of fetal reflexes. Postasphyxial seizures usually occur within the first 3 days of life, depending on the length and degree of asphyxial stress during the intrapartum period.102 An early occurrence of seizures, within several hours after delivery, sometimes suggests antepartum or peripartum occurrence of a fetal brain disorder when associated with specific fetal heart rate patterns. However, seizure onset is not a reliable indicator of timing of fetal brain injury. Earlier seizure onset, within 4 hours of birth, in encephalopathic newborns may predict a particularly adverse outcome independent of etiology for asphyxia.27 Asphyxia is conventionally diagnosed based on the association of several metabolic parameters with hypoxia and acidosis. The duration of asphyxia is difficult to assess based on either single or even multiple Po2 values, and pH levels of less than 7.2 are considered of greater clinical concern for predicting HIE, although the suggested guideline of a pH of less than 7.0 is one criterion by which the clinical entity of HIE might be predicted.1 A metabolic definition of asphyxia should also include a base deficit of more than 12 mmol/L, although specific researchers suggest a base deficit of more than 16 mmol/L because of its higher predictive power for the emergence of the HIE syndrome, including clinical seizures.52 One caveat should always be considered before assigning a relative risk to a pH value; elevated Pco2 values introduce a superimposed respiratory acidosis secondary to hypercarbia. Elevated Pco2 with respiratory acidosis is comparatively less harmful to brain tissue and is more rapidly corrected by aggressive ventilatory support. Alternatively, metabolic acidosis suggests a more profound alteration of intracellular function that better predicts an evolving brain disorder, which may include seizures as part of HIE. Low Apgar scores traditionally are associated with infants with suspected neurologic depression after delivery, with possible evolution to HIE and seizures (see Chapter 32). Low 1- and 5-minute Apgar scores indicate the continued need for resuscitation, but only low scores at 10, 15, and 20 minutes more accurately predict sequelae. Normal Apgar scores, however, do not eliminate the possibility of severe antepartum brain injury, either from asphyxia or other causes. As many as two thirds of neonates who exhibit cerebral palsy at older ages had normal Apgar scores at birth without HIE.66 Placental findings may reflect disease states at any time before birth either with or without metabolic acidosis and evolving HIE after birth. Although in utero meconium passage commonly occurs in otherwise healthy newborns, meconium staining of the child’s skin may be correlated with meconium-laden macrophages in placental membranes in a depressed newborn. Meconium staining through the chorionic layer to the amnion suggests a longer-standing asphyxial stress, such as over 4 to 6 hours (see Chapter 27). Placental weight below the 10th or above the 90th percentile suggests chronic perfusion abnormalities to the fetus. Microscopic evidence of lymphocytic infiltration, altered villous maturation, chorangiosis, and erythroblastic proliferation of placental villi each support chronic asphyxial stresses to the fetus. In a study of preterm and term neonates (23 to 42 weeks of corrected age) with EEG-confirmed seizures, a significant association between seizures and chronic (with or without acute) placental lesions was noted, increasing to a factor of 12.1 (p < .003) by term age. Odds ratios were not significant for infants with seizures and exclusively acute placental lesions, presumably from events closer to labor and delivery.92 Specific clinical findings in the depressed neonate with suspected HIE may reflect antepartum disease states.58 Intrauterine growth restriction, hydrops fetalis, or joint contractures (including arthrogryposis) are findings that suggest remote in utero diseases that may have been associated with antepartum asphyxia and later express as intrapartum fetal distress or neonatal depression. Hypertonicity, often with cortical fisting, in a previously depressed child who rapidly recovers after a resuscitative effort also commonly reflects longer-standing fetal neurologic dysfunction before labor or the mother’s admission to the hospital. Sustained hypotonia and unresponsiveness for 3 to 7 days are the expected signs of HIE after asphyxial stress during labor, with or without brain injury. Hypoglycemia is usually defined as glucose levels of 35 to 40 mg/dL (see Chapter 95). No clear consensus exists concerning a direct cause-and-effect relationship of hypoglycemia with seizure occurrence. Also, associated disturbances may coexist, such as hypocalcemia, craniocerebral trauma, cerebrovascular lesions, and asphyxia, which may also contribute to lowering the infant’s threshold for seizures. Infants born of diabetic or toxemic mothers, particularly infants who were small for gestational age, are also at risk for hypoglycemia. Jitteriness, apnea, and altered tone are clinical signs that may appear in children with hypoglycemia but are not representative of a seizure state. Cerebrovascular lesions in posterior brain regions have been reported in children with hypoglycemia. Vulnerability of brain to ischemic insults is enhanced by concomitant hypoglycemia. Total serum calcium levels below 7.5 to 8 mg/dL generally define hypocalcemia (see Chapter 96). The ionized fraction is a more sensitive indicator of seizure vulnerability. As with hypoglycemia, the exact level of hypocalcemia at which seizures occur is debatable. An ionized fraction of 0.6 mg/dL or less may have a more predictable association with the presence of seizures. Hypocalcemia owing to high-phosphate infant formula has been previously cited as a cause of late-onset seizures.79 However, hypocalcemia now more commonly occurs with a variety of nonspecific problems or asphyxia, and may coexist with hypoglycemia or hypomagnesemia. Rarely, congenital hypoparathyroidism in association with other genetic abnormalities such as DiGeorge syndrome (i.e., velocardiofacial syndrome, or 22q11 deletion with cardiac and brain anomalies) must be considered. These infants may have severe congenital heart disease as well as a hypoparathyroid state with hypocalcemia and hypomagnesemia that precipitates seizures.53 In infants with hypocalcemia of unknown etiology, the condition may be the result of maternal hypercalcemia. Ascertainment of the mother’s calcium status should be considered because maternal hypercalcemia can suppress fetal parathyroid development.
Seizures in Neonates
Diagnosis: Clinical Versus Electroencephalographic
Clinical Seizure Criteria
Subtle Seizure Activity
Clonic Seizures
Multifocal (Fragmentary) Clonic Seizures
Tonic Seizures
Myoclonic Seizures
Nonepileptic Behaviors of Neonates
Tremulousness or Jitteriness Without Electrographic Correlates
Neonatal Myoclonus Without Electrographic Seizures
Neonatal Dystonia/Dyskinesia Without Electrographic Seizures
Electrographic Seizure Criteria
Ictal Electroencephalographic Patterns: A More Reliable Marker for Seizure Onset, Duration, and Severity
Seizure Duration and Topography
Brainstem Release Phenomena
Subcortical Seizures and Electroclinical Dissociation
Incidence of Neonatal Seizures
Interictal Electroencephalographic Pattern Abnormalities
Major Etiologies for Seizures
Asphyxia-Related Events
Metabolic Derangements
Hypoglycemia
Hypocalcemia
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Seizures in Neonates
