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Introduction
Neonatal seizures are a common problem in the newborn nursery and can occur in infants
at any gestational age. Seizures in a newborn infant evoke a sense of urgency among
neonatologists because they often indicate a disturbance of the central nervous system
(CNS). Causes of neonatal seizures encompass virtually the entire spectrum of neurologic
disorders of infancy, but most neonatal seizures today are due to hypoxic-ischemic brain
injury and intracranial hemorrhage.
The proper treatment of neonatal seizures depends on the cause. For example, neonatal
seizures due to a transient metabolic disturbance, such as hypocalcemia or hypoglycemia,
are treated by correcting the underlying metabolic derangement. However, seizures due to
such transient disturbances are relatively infrequent today because of improved neonatal
care. For neonates who have seizures caused by a systemic infection (sepsis) or CNS
infection (meningitis and encephalitis), the underlying infection must be treated appro-
priately. The specific cause also has prognostic implications.
More common etiologies of neonatal seizures are discussed in this review (Table 1). As
discussed in the review on neonatal electroencephalography (EEG) in this issue of
NeoReviews, proper identification of epileptic seizures is important. The most common
seizure types are: focal or multifocal clonic, tonic, and myoclonic and subtle. Subtle
seizures comprise a variety of motor and autonomic phenomena and are more common in
neonates who have severe encephalopathies. However, neonates often have abnormal
paroxysmal motor activity, such as oral-buccal-lingual movements, pedaling, stepping, and
rotatory arm movements, that are not associated with ictal EEG patterns. These nonepi-
leptic events do not require treatment with anticonvulsants. The EEG is of particular value
for detecting subclinical seizures (EEG seizures without clinical manifestations) and for
distinguishing subtle seizures from nonepileptic behaviors.
Hypoxic-Ischemic Encephalopathy
In today’s neonatal intensive care units, hypoxic-ischemic encephalopathy is the most
common cause of neonatal seizures. Approximately two thirds of all neonatal seizures are
due to this cause.
Infants who have a mild degree of encephalopathy often experience variable levels of
consciousness in which periods of lethargy alternate with periods of irritability and
“hyperalertness.” They manifest jitteriness, which is described best as a spontaneous or
stimulus-induced myoclonus (nonepileptic). Muscle tone is normal or increased, and the
deep tendon reflexes are hyperactive. Mild encephalopathy usually lasts for fewer than
24 hours. (1)(2)
*Departments of Neurology and Neurological Sciences and of Pediatrics, Stanford University, School of Medicine, Lucile
Packard Children’s Hospital, Stanford, Calif.
Within the first postnatal day, the term newborn may common bacterial pathogens are group B Streptococcus,
progress to moderate encephalopathy with an altered Escherichia coli, and other gram-negative rods. Approxi-
level of consciousness (lethargy or stupor with reactivity) mately 25% of neonates who have bacterial sepsis develop
and hypotonia. Seizures that may occur during this stage meningitis. (4) Lumbar puncture for cerebrospinal fluid
must be differentiated from other abnormal movements, analysis and culture is performed when meningitis is
such as spontaneous myoclonus, hyperactive tendon suspected. The degree of EEG background abnormalities,
stretch reflexes with clonus, and jaw clonus. the presence of EEG-documented seizures, and the level of
Severe encephalopathy is characterized by coma, flac- consciousness are strong predictors of outcome. (5)
cidity, and unresponsiveness to noxious stimuli. (1)(2)
Seizures are very common during this stage and occur Encephalitis
within the first 24 hours after birth, often within 12 hours. Various viruses, such as herpes simplex virus (HSV) and
(3) Focal clonic or multifocal clonic seizures often are enteroviruses, may cause acute encephalitis and seizures.
present. Furthermore, subtle seizures, consisting of eye Congenital infections, such as toxoplasmosis and cyto-
deviation, subtle posturing, or autonomic changes, fre- megalovirus infection, may cause seizures, but such sei-
quently accompany more overt seizures. Infants also may zures tend to occur later in the neonatal period or early
have nonepileptic events, such as decerebrate posturing, infancy.
which is believed to represent a “brainstem release phenom- HSV encephalitis is one of the common severe viral
enon” due to forebrain dysfunction. The seizures usually encephalitides in the neonatal period. Seizures due to
last for several days and may be difficult to control. HSV infection occur in 57% of newborns who have CNS
The frequency and severity of neonatal seizures due to disease and 22% of those who have the disseminated form
hypoxic-ischemic encephalopathy usually parallel the of disease, but rarely in the skin-eye-mouth (SEM) dis-
grade of the encephalopathy. Seizures are most common ease group. (6) The mean age of patients who have CNS
during the first week after birth. As the acute encepha- disease at initiation of antiviral therapy is 15 to 20 days.
lopathy resolves, the seizures also remit spontaneously. (6) However, approximately 10% of patients exhibit on-
Approximately one third of affected infants experience set of symptoms within the first 24 hours after birth,
postneonatal seizures (ie, epilepsy). suggesting in utero acquisition of HSV infection. In the
CNS and disseminated forms of the infection, typical skin
Infections vesicles are absent in approximately 40% of infants. (6)
Meningitis The neonatal form of HSV encephalitis is caused more
Bacterial meningitis can cause seizures that usually occur often by type 2 HSV that the newborn acquires during
in the latter part of the first postnatal week. (3) The most delivery from maternal genital lesions. Fetal scalp moni-
toring may be a risk factor for acquiring the virus. Neu- which usually are the result of trauma. CT and MRI
roimaging studies in neonatal HSV encephalitis often reveal subdural collections of blood over the convexities
show diffuse brain abnormalities. In severe CNS disease, and along the tentorium. There also may be a compo-
EEG may show a characteristic multifocal periodic or nent of subarachnoid hemorrhage. Seizures occur within
pseudoperiodic pattern. (7) The periodic sharp activity the first 48 postnatal hours. (3)
(recurring at 1- to 4-sec intervals) appears in the tempo-
ral, frontal, and central regions. It usually does not vary Cerebrovascular Infarction (Stroke)
and is interrupted only by focal seizures. Since the intro- Cortical injury may result from occlusion of an artery that
duction of acyclovir therapy, severe CNS disease occurs causes necrosis of all cellular elements in the distribution
rarely, and more nonspecific EEG abnormalities usually of a single vessel. The middle cerebral artery is involved
are recorded. (8) HSV encephalitis should be considered most frequently. Most injuries are believed to be due to
in the differential diagnosis of acutely ill newborns who embolic or thrombotic processes. Although the actual
have seizures. If the presentation is compatible with cause is found infrequently, coagulopathy, congenital
neonatal HSV infection, appropriate diagnostic studies heart disease, and trauma are common associated disor-
should be obtained and acyclovir treatment initiated. ders. As the infarction evolves, brain parenchyma dissolve
HSV cultures from the conjunctivae provide the greatest and a cavity (porencephalic cyst) forms. If multiple ves-
yield, although skin and oropharyngeal samples often sels are involved, multicystic encephalomalacia or hydra-
also are obtained. (6) HSV DNA polymerase chain reac- nencephaly may result. Clinical features are understand-
tion (PCR) of CSF specimens appears to be sensitive for ably variable because the time of the infarction and the
CNS involvement, but CSF viral cultures have a low location are the primary determinants of physical find-
yield. ings.
Seizures frequently are described in infants who have
Intracranial Hemorrhage neonatal strokes. (10) Focal clonic seizures are common.
Subarachnoid hemorrhages may cause neonatal seizures Hemiparesis may be present on neurologic examination,
in the term infant. This often occurs in the context of a but it often is subtle. The EEG usually demonstrates
vaginal delivery of an infant who otherwise appears fairly lateralized abnormalities and allows assessment of the
healthy. Seizures often begin during the second day after severity of the encephalopathy in other cortical regions.
birth. Computed tomography (CT) and magnetic reso- CT and MRI show a wedge-shaped area of abnormal
nance imaging (MRI) may show subarachnoid blood in signal that is in the distribution of a single artery. MRI
the posterior fossa, over the cerebral convexities, or both. sequences using diffusion-weighted images may provide
Blood collections also may be present along the tento- a sensitive method of detecting infarcts early in the
rium. These seizures are usually self-limited and have a course before CT or routine MRI sequences reveal the
good prognosis. lesion.
In the preterm infant, intraventricular hemorrhages Infants may develop spastic hemiparesis (“hemiplegic
may result from bleeding in the subependymal germinal cerebral palsy”) as a long-term sequela. Because of the
matrix. Large hemorrhages often are associated with frequent involvement of the middle cerebral artery, the
periventricular ischemic lesions and may cause seizures. upper extremity is more impaired. The extent and loca-
Seizures may manifest as generalized tonic posturing or tion of the pathologic lesion are important factors in
subtle seizure phenomena. (3) In one study, seizures due determining whether intellectual impairment and
to intraventricular hemorrhages accounted for 45% of epilepsy also develop. (11)
the preterm infants who had EEG-documented seizures. Cerebral venous thrombosis often presents in new-
(9) However, in our experience, seizures due to cata- borns who have seizures, respiratory distress, and leth-
strophic intraventricular hemorrhages in preterm infants argy. (12)(13) In one study, 68% of neonates who had
seem to be less common. cerebral venous thrombosis experienced seizures. (13)
Intraventricular hemorrhage in term infants may re- The occlusions usually occur in the superior sagittal
sult from trauma, hypoxic-ischemic injury, or venous sinus, sigmoid/transverse sinus, or multiple venous si-
sinus thrombosis. In term infants, the hemorrhages usu- nuses. Venous occlusions may lead to focal cerebral
ally originate in the choroid plexus. Seizures may occur in injury (ie, strokes), which frequently are hemorrhagic.
affected infants, and the duration of seizures and prog- MRI has been particularly useful for diagnosing venous
nosis appear to be related to the cause of the hemorrhage. sinus thrombosis and focal injury due to venous occlu-
Seizures may occur from subdural hemorrhages, sions. (12) Venous sinus thrombosis also may cause
such disorders may cause neonatal seizures, including The seizures often are partial in onset and generalize
urea cycle defects, organic acidurias, and aminoacidopa- secondarily. Myoclonic seizures and infantile spasms also
thies. Hyperammonemia and metabolic acidosis are signs may occur. The interictal EEG shows a burst-suppression
of such disorders. Rare causes include disorders of biotin pattern and generalized rhythmic slow waves. (24)
metabolism, peroxisomal disorders, molybdenum cofac- No routine diagnostic tests are available to confirm
tor deficiency, sulfite oxidase deficiency, and disorder of this diagnosis. For newborns and infants who have med-
fructose metabolism. (21) These disorders should be ically refractory seizures, PDE should be considered in
suspected when an encephalopathy develops in a healthy the differential diagnosis. The diagnostic test (and treat-
infant who deteriorates after the initiation of feedings. ment) consists of a trial of pyridoxine (100 mg, intrave-
The goal is to identify the metabolic problem and correct nous bolus). This usually is infused over several minutes
the underlying defect whenever possible while adminis- because a rapid bolus may induce apnea, bradycardia, and
tering anticonvulsants. severe hypotonia. Simultaneous EEG monitoring during
In the neonatal form of maple syrup urine disease and administration is helpful to determine a response, which
propionic acidemia, a characteristic EEG pattern is evi- may require 5 to 10 minutes. If there is a response to
dent in the first few postnatal weeks. (22) Runs and pyridoxine, the infant should be treated with daily ther-
bursts of 5 to 7 Hz, primarily monophasic negative apy of 200 mg/d orally. Other antiepileptic medications
(mu-like or comblike) activity in the central and midline can be withdrawn gradually. A pyridoxine withdrawal
central regions are present during all states, with the most challenge can confirm the diagnosis. If the child has
abundant bursts occurring in non-rapid eye movement PDE, seizures recur in 7 days to 3 weeks, and pyridoxine
sleep. The pattern gradually disappears after the institu- should be restarted.
tion of dietary therapy. Although the seizures may be controlled with pyri-
Classic nonketotic hyperglycinemia (glycine enceph- doxine, psychomotor retardation is common in children
alopathy) is due to a defect in cleavage of the excitatory who have PDE. The spectrum of dysfunction varies from
amino acid glycine. This lifelong condition usually causes mild to severe. Even early diagnosis and treatment does
neonatal seizures characterized by early myoclonic en- not seem to prevent the development of mental deficien-
cephalopathy and severe static encephalopathy. Tran- cies. In some children, progressive ventricular enlarge-
sient nonketotic hyperglycinemia is a very rare disorder ment has been noted in serial neuroimaging studies. (25)
characterized by clinical and biochemical findings similar
to those seen in classic nonketotic hyperglycinemia. (23) Glucose Transporter Type 1 Deficiency
Abnormalities in amino acids resolve partially or com- Infants who have glucose transporter type 1 deficiency
pletely in days to months. Nearly all patients who have syndrome (GLUT-1 DS) may have neonatal seizures,
the classic nonketotic hyperglycinemia develop severe but seizures appear more frequently during infancy (usu-
neurologic sequelae; most patients who have the tran- ally between 6 and 12 wk). This disease is due to
sient form exhibit normal development. Therefore, dis- GLUT-1 deficiency, which results in decreased transport
tinguishing the transient from the classic form of nonke- of glucose at the blood-brain barrier and across glial cell
totic hyperglycinemia is important for prognosis. CSF membranes. (26) This defect of glucose transport into
analysis of glycine may be needed to diagnose either the brain results in hypoglycorrhachia (CSF glucose con-
form. centrations are very low, usually ⬍40 mg/dL [2.2
mmol/L]) that causes epilepsy, developmental delay,
Pyridoxine-dependent Epilepsy and a complex motor disorder in early childhood. Several
Pyridoxine-dependent epilepsy (PDE) is caused by an mutations have been identified in the GLUT-1 gene. The
inborn abnormality in pyridoxine-dependent synthesis of diagnosis should be suspected when there is unexplained
the inhibitory neurotransmitter GABA. This is a rare low CSF glucose concentrations relative to serum glu-
autosomal recessive disorder. Children present with fre- cose levels. GLUT-1 DS can be confirmed by an assay
quent seizures or status epilepticus in the newborn pe- that measures the uptake of 14C-O-methlyl-D-glucose in
riod or early infancy. Seizures are refractory to conven- erythrocytes. (27)
tional anticonvulsants. The seizures may develop in The ketogenic diet, established to treat intractable
utero. The seizures are controlled only with the admin- childhood epilepsy, is effective treatment for GLUT-1
istration of high-doses of pyridoxine (vitamin B6). In DS. (28) Ketones serve as an alternative fuel for the brain.
between the seizures, the infants are hypotonic, agitated, The diet appears to control epilepsy in affected children,
and irritable. They have exaggerated startle responses. although the long-term outcome is not known. Early
recognition of this disorder is important because there sharp activity. This pattern persists in awake and sleep
appears be a correlation between delay in treatment and states. However, the pattern appears to be somewhat
severity of encephalopathy. nonspecific; similar patterns can be seen in certain inborn
errors of metabolism, such as maple syrup urine disease.
Familial or Idiopathic Epilepsies
Benign Familial Neonatal Convulsions Early-onset Epilepsies Associated With
The seizures of benign familial neonatal convulsions Encephalopathy
usually begin during the first week after birth. No other Early myoclonic encephalopathy is characterized by er-
cause is found for the seizures. Findings on the neuro- ratic, fragmentary myoclonic jerks that begin in the new-
logic examination and interictal EEG are normal. The born period. These jerks are replaced by partial seizures,
child may have several seizures during infancy, but they massive erratic myoclonus, and infrequently, tonic sei-
resolve spontaneously. There usually is a family history of zures. The EEG shows a characteristic burst-suppression
seizures during the neonatal period or infancy. pattern, with periods of suppression (4 to 12 sec) that are
There appears to be a characteristic pattern of electro- seen during sleep. (34) The burst-suppression pattern
clinical seizures. The seizures begin with a diffuse flatten- often evolves into hypsarrhythmia or multifocal sharp
ing of the background accompanied by apnea and tonic waves and spikes. The infants have marked developmen-
motor activity. Seizures subsequently evolve to rhythmic tal delay, abnormal tone, and microcephaly. Known
slow activity that is followed by bilateral spike and sharp causes include inborn errors of metabolism (particularly
wave discharges during bilateral clonic activity. (29)(30) nonketotic hyperglycinemia), pyridoxine dependency,
Vocalizations, chewing, and eyelid movements also are and brain malformations such as hydranencephaly. The
present during this phase. Others have found that the specific cause often is not determined, although familial
seizures in benign familial neonatal convulsions are focal cases have been reported.
in onset, with secondary generalization. (31)(32) Ohtahara syndrome (early infantile epileptic enceph-
Benign familial neonatal convulsions is an idiopathic alopathy with suppression-burst) is characterized by fre-
epileptic syndrome that has an autosomal dominant in- quent tonic spasms that develop in the neonatal period or
heritance with an 85% penetrance. Large familial pedi- early infancy. (35) The burst-suppression pattern is seen
grees have been identified. In 1989, two gene loci were during sleep and wakefulness. The tonic spasms are asso-
identified, one on the long arm of chromosome 20 and ciated with the bursts or abrupt attenuation of cerebral
the other on the long arm of chromosome 8. In 1998, activity (desynchronization). Partial seizures are seen in
two genes were identified in this syndrome, distinguish- one third of the infants, but myoclonic seizures are rare.
ing this as the first epilepsy in which a gene was identified. The infants have severe encephalopathy and develop
Mutations were found in KCNQ2 and KCNQ3, genes intractable epilepsy. The cause varies but often is related
for voltage-gated potassium channels. Mutations in to cerebral structural abnormalities, including cerebral
KCNQ2 cause loss or marked reduction in potassium dysgenesis, porencephaly, hemimegalencephaly, Aicardi
M-current by impairing the repolarization of the neuro- syndrome, and diffuse or focal cortical dysplasias. Less
nal cell membrane. (33) This causes neuronal hyperex- commonly, metabolic disorders are associated with Oh-
citability. tahara syndrome.
Benign Idiopathic Neonatal Seizures (Fifth-day Timing of Onset of Seizures and Cause
Fits) The timing of seizure onset gives clues about the cause,
In benign idiopathic neonatal seizures or fifth-day fits, as suggested by findings from a study in the 1980s. (20)
seizures develop between postnatal days 4 and 6 in 80% Most seizures due to hypoxic-ischemic encephalopathy
of patients. The seizures may include focal clonic activity, and intracranial hemorrhage occurred during the first 4
apnea, and status epilepticus. Children do not have sub- postnatal days. Hypoxic-ischemic encephalopathy (65%
sequent epilepsy, and development is normal. Family of total) was the most common cause of seizures in both
history is negative. The cause of this disorder is un- preterm and term infants. Seizures associated with
known. hypoxic-ischemic encephalopathy occurred early in the
The interictal EEG in this syndrome shows a theta neonatal period (ie, 90% in the first 2 postnatal days).
pointu alternant pattern. The EEG background consists Furthermore, 80% of all seizures in the first 2 days after
of predominantly sharply contoured theta (4 to 7 Hz) birth were related to hypoxic-ischemic encephalopathy.
activity that is discontinuous and intermixed with other Seizures due to hypocalcemia or hypoglycemia also oc-
30. Ronen GM, Rosales TO, Connolly M, Anderson VE, Leppert due to a novel mutation in KCNQ2 causes neonatal convulsions.
M. Seizure characteristics in chromosome 20 benign familial neo- Ann Neurol. 1999;46:305–312
natal convulsions. Neurology. 1993;43:1355–1360 34. Lombroso CT. Early myoclonic encephalopathy, early infantile
31. Aso K, Watanabe K. Benign familial neonatal convulsions: epileptic encephalopathy, and benign and severe infantile myo-
generalized epilepsy? Pediatr Neurol. 1992;8:226 –228 clonic epilepsies: a critical review and personal contributions. J Clin
32. Bye AME. Neonate with benign familial neonatal convulsions: Neurophysiol. 1990;7:380 – 408
recorded generalized and focal seizures. Pediatr Neurol. 1994;10: 35. Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalop-
164 –165 athy with suppression-bursts, Ohtahara syndrome; its overview
33. Lerche H, Biervert C, Alekov AK, et al. A reduced K⫹ current referring to our 16 cases. Brain Dev. 2002;24:13–23
NeoReviews Quiz
5. Seizures in newborns can result from several causes. Identifying the cause is important for both treatment
and determination of the prognosis. Of the following, the most common cause of neonatal seizures in
today’s neonatal intensive care units is:
A. Central nervous system infection.
B. Congenital brain malformation.
C. Drug withdrawal.
D. Hypoxic-ischemic encephalopathy.
E. Metabolic disorder.
6. A 2-week-old term newborn has repetitive episodes of myoclonic seizures that are refractory to
conventional anticonvulsants. The infant is irritable and hypotonic and has exaggerated startle responses.
The electroencephalogram shows a burst-suppression pattern and generalized rhythmic slow waves during
the interictal period. After diagnostic testing, you suspect a metabolic disorder. Of the following, the most
likely metabolic cause of seizures in this infant is:
A. Glucose transporter type 1 deficiency.
B. Maple syrup urine disease.
C. Nonketotic hyperglycinemia.
D. Propionic acidemia.
E. Pyridoxine dependency.
7. The neurodevelopmental outcome for a newborn who has seizures is determined largely by the cause of the
seizures. Of the following, a favorable neurodevelopmental outcome is most likely to be associated with:
A. Bacterial meningitis.
B. Cerebral dysgenesis.
C. Hypoxic-ischemic encephalopathy.
D. Periventricular hemorrhagic infarction.
E. Subarachnoid hemorrhage.