ARTICLE

Neonatal Seizures
Alan Hill, MD, PhD*
OBJECTIVES: After completing this article, readers should be able to: 1. 2. 3. 4. State the most common cause of neonatal seizures in the term infant. Compare and contrast the clinical features of neonatal seizures with those of epilepsy in older children. Describe the relationship of clinically suspected neonatal seizures with findings on surface electroencephalography. Delineate the most important determinant of prognosis for neonatal seizures.

Introduction
Neonatal seizures often are a manifestation of significant neurologic disease and a major predictor of adverse neurologic outcome in the newborn. The clinical features and electroencephalographic (EEG) characteristics of neonatal seizures differ considerably from those associated with epilepsy in older infants and children, an observation that reflects the immature stage of development of the newborn brain. Another major difference relates to the fact that neonatal seizures rarely are idiopathic. Prompt diagnosis, investigation to establish the underlying etiology, and rapid intervention are essential to minimize the possibility of associated cardiorespiratory instability and to correct treatable causes. Furthermore, experimental data suggest that ongoing or prolonged seizures may cause additional cerebral injury and have detrimental longterm effects.

passes both clinical phenomena that correlate temporally with epileptiform EEG abnormalities and stereotypical, paroxysmal clinical activities that are not associated clearly with EEG alterations.

Epidemiology
The reported incidence of neonatal seizures varies widely. Based on clinical observation, they are thought to occur in approximately 0.5% of term newborns and 20% of preterm newborns. However, long-term EEG recordings in pharmacologically paralyzed term newborns suggest that the incidence may be as high as 40% in some high-risk populations.

the speculation that some of these clinical events represent brainstem release phenomena rather than true epileptic seizures (ie, primitive brainstem and spinal motor patterns that are dissociated from normal cortical inhibition). In addition to the interest surrounding the origins of seizure-like activity in the newborn (which may determine whether treatment with conventional anticonvulsant medications is used), the physiologic and metabolic consequences of neonatal seizures are of major clinical significance. These include interference with respiration, alterations in blood pressure, and cerebral perfusion (even in the absence of abnormal motor activity), which in turn may exacerbate hemorrhagic or ischemic brain injury. In addition, experimental data suggest that ongoing neonatal seizures may deplete cerebral glucose levels and impair synthesis of cerebral DNA and proteins, which could contribute to the extent of cerebral injury.

Etiology
Neonatal seizures rarely are idiopathic, and immediate attention should be focused on identifying an underlying etiology to permit appropriate intervention and to enable accurate decisions regarding prognosis. Although there are numerous possible underlying etiologies of neonatal seizures, a relatively small number account for the majority of cases (Table 1). The time of onset and characteristics of neonatal seizures may suggest the most probable cause (Table 2). Clearly, a number of concomitant etiologic factors may be operative in the same infant. For example, hypoglycemia and hypocalcemia may occur as a result of catabolic stress in certain situations, such as hypoxic-ischemic encephalopathy or meningitis.
HYPOXIC-ISCHEMIC ENCEPHALOPATHY

Pathogenesis
A detailed discussion of the physiologic and metabolic mechanisms underlying neonatal seizures is beyond the scope of this article. However, several concepts that have important clinical implications deserve amplification. Generalized tonic-clonic seizures or an orderly progression of seizures is uncommon in the newborn because of the immature organization of the cerebral cortex and incomplete myelination of the interhemispheric connections. In contrast, oral-buccal-lingual movements, oculomotor disturbances, and autonomic dysfunction are frequent clinical manifestations and are considered to reflect the relatively more advanced development of brainstem and diencephalon in this age group. Alternatively, the observed lack of correlation of clinical events with epileptiform activity recorded by surface EEG has raised

Definition
A seizure is defined generally as an excessive, synchronous electrical discharge (ie, depolarization of neurons in the brain). However, this definition may be too restrictive when applied to seizures in the newborn. Neonatal seizures may be defined more aptly as paroxysmal alterations in neurologic function (eg, behavioral, motor, or autonomic function). This definition encom*Professor and Head, Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. Pediatrics in Review

Moderate or severe acute hypoxicischemic encephalopathy accounts

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NEUROLOGY Neonatal Seizures

TABLE 1. Causes of Neonatal Seizures

ETIOLOGY TERM INFANTS PRETERM INFANTS OUTCOME

Hypoxic-ischemic encephalopathy Intraventricular hemorrhage (severe) Subarachnoid hemorrhage (severe) Hypoglycemia Hypocalcemia Intracranial infection Cerebral dysgenesis Drug withdrawal

Most common Uncommon Common Common Uncommon Common Common Uncommon

Common Common Uncommon Common Uncommon Common Common Uncommon

Variable Poor Good Variable Good Variable Poor Variable

for approximately two thirds of all cases of neonatal seizures. Such seizures may be of any type, usually begin at any time during the first 24 hours of life, and frequently are difficult to control effectively with anticonvulsant medications. Often there are associated abnormalities of brainstem responses and muscle tone. Hypoxic-ischemic cerebral injury sustained earlier during gestation may be asymptomatic in the newborn period. Consistently unilateral, focal seizures often are indicative of localized brain lesions, especially focal cerebral infarction. However, focal or multifocal seizures in the newborn also may occur in the context of diffuse cerebral injury.

METABOLIC DERANGEMENTS

The most common metabolic disturbances associated with seizures are hypoglycemia, hypocalcemia, and derangements of serum sodium levels. Early hypoglycemia and hypocalcemia occur most commonly following gestational diabetes and in infants who are preterm, small for gestational age, or both. Hypo- or hypernatremia may result from dehydration, inappropriate fluid administration, or inappropriate secretion of antidiuretic hormone. Rarely, inborn errors of metabolism present with seizures and an evolving, catastrophic neurologic and systemic deterioration, usually after several days of age. Pyridoxine

dependency is a rare, autosomal recessive cause of neonatal or even intrauterine seizures that can be excluded based only on the response to several weeks of treatment with pyridoxine. The response to intravenous pyridoxine during EEG monitoring no longer is considered to be diagnostic of this disorder. Accordingly, it has been recommended that all newborns who have seizures of unknown etiology receive a trial of oral pyridoxine.
INTRACRANIAL INFECTION

In infants who have intracranial bacterial infection, seizures often begin during the latter part of the first week of life, usually in the context

TABLE 2. Correlation of Timing and Etiology of Neonatal Seizures

MOST COMMON TIME OF ONSET ETIOLOGY DAYS 1 TO 2 DAYS 3 TO 7 DAYS 7 TO 10

Intracranial hemorrhage Hypoxic-ischemic encephalopathy Hypoglycemia Hypocalcemia Inborn errors of metabolism Intracranial infection Cerebral dysgenesis Anesthetic injection Drug withdrawal Neonatal epilepsy syndromes
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X X X X (early)

X (late) X X

X X

X X
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NEUROLOGY Neonatal Seizures of systemic sepsis. The time of onset of seizures following congenital viral infection varies.
INTRACRANIAL HEMORRHAGE

Seizures associated with intracranial hemorrhage vary considerably, depending on the type of hemorrhage. Germinal matrix-intraventricular hemorrhage, which occurs most commonly in the preterm newborn, may present with tonic seizures. Seizures associated with subarachnoid hemorrhage usually begin during the first day of life in term newborns. Characteristically, infants appear healthy between seizures, and the long-term prognosis is good. Subdural hemorrhage or cerebral contusion often presents with focal or subtle seizures of early onset.
DEVELOPMENTAL CEREBRAL ABNORMALITIES

or short-acting barbiturates. In addition, focal seizures may occur in association with cerebral infarction following prenatal exposure to cocaine. Rarely, inadvertant injection of a local anesthetic agent into the fetal scalp during delivery may result in transient seizures during the first hours of life.
NEONATAL EPILEPSY SYNDROMES

The most common neonatal epilepsy syndrome is autosomal dominant benign familial neonatal seizures, which usually begin on the third day of life and resolve after several months. In contrast, early myoclonic epileptic encephalopathy and Ohtahara syndrome are associated with progressive neurologic deterioration.

Table 3. It is important to remember that seizures may manifest as isolated alterations in autonomic function, especially abnormal heart rate or change in blood pressure or oxygenation. Apnea alone rarely represents a seizure unless it occurs in the context of other clinical seizure activity. Several common movement disorders may be mistaken for seizures in the newborn (Table 4). Accurate diagnosis of nonepileptic movements is important to avoid the inappropriate use of anticonvulsant medications and to permit more accurate prediction of outcome.
EVALUATIONS

Clinical Aspects
SYMPTOMS AND SIGNS

Seizures associated with cerebral dysgenesis or genetic syndromes have variable onset. Dysmorphic features, microcephaly, or cutaneous lesions may suggest these diagnoses.
DRUG WITHDRAWAL AND INTOXICATION

Infants who are exposed prenatally to alcohol and heroin rarely present with seizures. However, tremors and irritability, which may be mistaken for seizures, are a common manifestation. Seizures may occur in the context of withdrawal from cocaine

In most instances, neonatal seizures are identified by clinical observation. Any unusual repetitive and stereotypic event may represent a clinical seizure. The relationship between such abnormal movements and abnormal electrical/epileptiform activity on EEG may be inconsistent. Furthermore, neonatal seizures must be distinguished from nonepileptic movements, which may mimic seizures. A clinical classification of neonatal seizures is summarized in

Because neonatal seizures rarely are idiopathic, immediate attention must be directed toward identifying an underlying etiology. Clearly, a detailed history, especially about maternal risk factors and complications of pregnancy, labor, and delivery, and physical examination are of paramount importance. In addition, initial screening investigations that should be considered include measurement of serum glucose, calcium, magnesium, pH, sodium bicarbonate, sodium, blood urea nitrogen, and ammonia. Lumbar puncture should be performed to determine the presence of infection or intracranial hemorrhage. If these investigations fail to identify a specific etiology, additional studies may include neuroimaging; measurement of serum

TABLE 3. Classification of Neonatal Seizures

SEIZURE TYPE CLINICAL MANIFESTATIONS

EEG ABNORMALITIES

Subtle

Oral-buccal-lingual movements Ocular movements Stereotypic pedalling, swimming, stepping Autonomic dysfunction Rhythmic, slow jerking Focal or multifocal Involves facial, extremity, or axial structures Sustained posturing of limbs Asymmetric position of trunk/neck Focal or generalized Rapid, isolated jerks Involves limbs or trunk Generalized, multifocal, or focal

Variable

Clonic

Common

Tonic

Focal: common Generalized: uncommon Variable

Myoclonic

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NEUROLOGY Neonatal Seizures

TABLE 4. Nonepileptic Behaviors of Newborns

MOVEMENT DISORDER BRIEF DESCRIPTION

Jitteriness

Spontaneous or stimulus-sensitive Flexion and extension of equal amplitude Diminished by repositioning/flexion of extremity No associated abnormal eye movements Bilateral or unilateral, synchronous or asynchronous myoclonus Occurs during active sleep Not stimulus-sensitive Occurs with severe central nervous system dysfunction Focal or generalized myoclonus May have cortical spike-wave discharge on electroencephalography Rare familial disorder Hyperactive startle, generalized myoclonus Severe hypertonia May have apnea and bradycardia Responds to benzodiazepines the underlying physiologic and metabolic derangements (if present) and controlling ongoing or recurrent seizures. If necessary, immediate support of ventilation and perfusion must be ensured. When the cause is not a particular correctable metabolic derangement (eg, intracranial infection, hemorrhage, inborn errors of metabolism), appropriate specific treatment should be initiated in conjunction with symptomatic treatment with anticonvulsant medications. A scheme for treatment of neonatal seizures is outlined in Table 5. Serial blood levels of anticonvulsants (eg, phenobarbital, phenytoin) often must be obtained to determine maintenance dosages because of the variable pharmacokinetics in this age group. Enteric absorption of phenytoin is especially unpredictable. There are anecdotal reports of the use of other anticonvulsants, including primidone, lamotrigine, thiopentone, paraldehyde (no longer available in the United States, but available in Canada), and carbamazepine, for treatment of refractory seizures. Several major issues remain unresolved, including optimal maintenance doses of anticonvulsants, the importance of eliminating electrographic seizures, and the optimal duration of anticonvulsant therapy. The duration of therapy must be guided by the underlying etiology. Recent reports suggest that unnecesVol. 21 No. 4 April 2000

Benign neonatal sleep myoclonus

Stimulus-evoked myoclonus

Hyperekplexia (stiff-man syndrome)

amino acids, lactate, and urine organic acids; investigation for congenital viral infections; chromosome karyotype; and toxic drug screen. Assessment of other organ systems (eg, renal, hematologic, hepatic) may support a diagnosis of hypoxicischemic encephalopathy or an inborn error of metabolism. Confirmation of neonatal seizures often depends on the use of EEG, especially in infants who are paralyzed pharmacologically. Although routine interictal EEG is a noninvasive and portable procedure, interpretation of the findings in this age group is difficult and requires special expertise. Further, its diagnostic

value often is limited. In an attempt to improve diagnostic accuracy, some modifications of the EEG technique have been developed, such as serial or prolonged studies, continuous EEG monitoring, cerebral function monitoring, and synchronized video/EEG recording. EEG rarely is helpful for identifying a specific etiology, but interictal abnormalities, especially the background electrical activity, may have significant prognostic value.
MANAGEMENT

The treatment of neonatal seizures should be directed toward correcting

TABLE 5. Acute Treatment of Neonatal Seizures

Ensure respiration Ensure cardiac support If hypoglycemic: Glucose 10% solution: 2 mL/kg IV followed by continuous infusion at 5 to 7 mg/kg per minute Other specific treatments (as indicated): Calcium gluconate 5% solution: 4 mL/kg IV Magnesium sulfate 50% solution: 0.2 mL/kg IM Pyridoxine 50 to 100 mg IV Symptomatic treatment: Phenobarbital loading dose: 20 mg/kg IV; additional doses: 5 mg/ kg IV (10 to 15 min) to maximum of 20 mg/kg Phenytoin 20 mg/kg (1 mg/kg per minute) Lorazepam 0.05 to 0.10 mg/kg IV
intravenous; IM intramuscular.

IV

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NEUROLOGY Neonatal Seizures sary prolongation of therapy for transient disorders should be avoided because of unresolved concerns about the possible adverse effects of anticonvulsants on the developing nervous system. There is no evidence that prolongation of anticonvulsant therapy decreases the risk for developing epilepsy in later childhood. The most important determinant of prognosis is the underlying etiology. Thus, infants who have cerebral dysgenesis have uniformly poor outcomes, and 50% to 100% of those who have moderate or severe hypoxic-ischemic encephalopathy develop sequelae. In contrast, infants who have transient metabolic derangements and are treated promptly or who have only subarachnoid hemorrhage usually have a good outcome. Intracranial infection and inborn errors of metabolism are associated with a variable prognosis. Characteristics of the clinical seizures and the EEG often are useful predictors. Early-onset seizures and frequent or prolonged seizures that are refractory to multiple anticonvulsants generally have a poor prognosis. In the term newborn, the interictal EEG may be useful for predicting outcome. A normal interictal EEG is associated with an 85% chance of normal development compared with isoelectric, low-voltage, or paroxysmal burst-suppression background activity, which generally is associated with a poor outcome. However, caution must be exercised in predicting outcome based on EEG findings because of technical and interpretive difficulties with the procedure. This applies especially to preterm newborns and term infants who have mild or moderate abnormalities on EEG.
SUGGESTED READING
Clancy RR. The management of neonatal seizures. In: Stevenson KD, Sunshine P, eds. Fetal and Neonatal Brain Injury: Mechanisms, Management and the Risks of Practice. Oxford, United Kingdom: Oxford University Press; 1997:432 461 Holmes GL. Epilepsy in the developing brain: lessons from the laboratory and clinic. Epilepsia. 1997;38:1230 Holmes GL. Neonatal seizures. Semin Pediatr Neurol. 1994;1:72 82 Massingale TW, Buttross S. Survey of treatment practices for neonatal seizures. J Perinatol. 1993;13:107110 Mizrahi EM. Consensus and controversy in the clinical management of neonatal seizures. Clin Perinatol. 1989;16:485500 Sher MS. Seizures in the newborn infant. Diagnosis, treatment and outcome. Clin Perinatol. 1997;24:735772 Volpe JJ. Neonatal seizures. In: Volpe JJ, ed. Neurology of the Newborn. 3rd ed. Philadelphia, Penn: WB Saunders Co; 1995: 172207 Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics. 1989;84:422 428

Prognosis
The mortality rate for clinical seizures in term newborns has decreased considerably in recent years to approximately 15%. However, mortality rates in preterm infants who have seizures remain high and may be increased as much as fourfold compared with that of term infants. In addition, adverse neurologic sequelae are common and have been reported in approximately two thirds of survivors. Mental retardation and motor deficits (cerebral palsy) are more common sequelae following neonatal seizures than epilepsy. In many instances, these sequelae may be the result of the underlying cause of the neonatal seizures.
PIR QUIZ
Quiz also available online at www.pedsinreview.org. 4. A mother brings her 3-week-old infant to you because she is concerned about twitching movements of the lower extremities that he has exhibited for 2 weeks. She has observed these movements when he is asleep. Physical examination reveals a sleeping infant who has an occasional twitching movement in the right leg similar to what the mother has observed. Upon arousal the infant appears vigorous, and findings on the neurologic examination are normal. Which of the following is the most likely diagnosis? A. Benign neonatal myoclonus. B. Cerebral palsy. C. Hyperekplexia. D. Inborn error of metabolism. E. Infantile spasm.

5. You are called to examine a 1-day-old infant who exhibits repeated sucking movements interspersed with facial twitching and rhythmic horizontal movements of the eyes. You suspect the infant is having seizures. Which of the following is a true statement regarding neonatal seizures? A. Electroencephalography is a sensitive and specific method of detecting seizures. B. Generalized tonic-clonic activity is the most common clinical manifestation. C. Most neonatal seizures are idiopathic. D. Subarachnoid hemorrhage is a more common cause of seizures in preterm infants than in term infants. E. The underlying cause of the seizure activity is the most important determinant of outcome.

6. A 2-day-old girl presents with generalized tonic/clonic movements and facial twitching lasting for 15 minutes. Respirations appear irregular. After ensuring the adequacy of airway and ventilation, 0.1 mg/kg lorazepam is administered intravenously. Which of the following drugs should be administered next? A. Carbamazepine. B. Clonazepam. C. Paraldehyde. D. Phenobarbital. E. Valproic acid.

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