BackgroundThe most prominent feature of neurologic dysfunction in the neonatal period is the occurrence of seizures. Determining the underlying etiology for neonatal seizures is critical. Etiology determines prognosis and outcome and guides therapeutic strategies.[1] (See Etiology, Prognosis, Treatment, and Medication.) The neonatal period is limited to the first 28 days of life in a term infant. For premature infants, this term usually is applied until gestational age 44 weeks; ie, the age of the infant from conception to 44 weeks (ie, 4 wk after term). Seizure characteristics

Most neonatal seizures occur over only a few days, and fewer than half of affected infants develop seizures later in life. Such neonatal seizures can be considered acute reactive (acute symptomatic), and therefore the term neonatal epilepsy is not used to describe neonatal seizures.[2] Seizures in neonates are relatively common, with variable clinical manifestations. Their presence is often the first sign of neurologic dysfunction, and they are powerful predictors of long-term cognitive and developmental impairment. (See Prognosis.) Most seizures in the neonate are focal, although generalized seizures have been described in rare instances.Subtle seizures are more common in full-term than in premature infants. Video electroencephalogram (EEG) studies have demonstrated that most subtle seizures are not associated with electrographic seizures. Examples of subtle seizures include chewing, pedaling, or ocular movements.[3] Neonatal seizure classificationClonic seizuresThese movements most commonly are associated with electrographic seizures. They often involve 1 extremity or 1 side of the body. The rhythm of the clonic movements is usually slow, at 1-3 movements per second. Tonic seizuresThese may involve 1 extremity or the whole body. Focal tonic seizures involving 1 extremity often are associated with electrographic seizures. Generalized tonic seizures often manifest with tonic extension of the upper and lower limbs and also may involve the axial musculature in an opisthotonic fashion. Generalized tonic seizures mimic decorticate posturing; the majority are not associated with electrographic seizures. Myoclonic seizuresThese may occur focally in 1 extremity or in several body parts (in which case they are described as multifocal myoclonic seizures). Focal and multifocal myoclonic seizures typically are not associated with electrographic correlates. Generalized myoclonic jerks are possibly the clinical equivalent of infantile spasms. PathophysiologyThe biochemical effects of neonatal seizures include derangements of energy metabolism. Energy-dependent ion pumps are compromised, and adenosine diphosphate (ADP) levels rise. The rise in ADP stimulates glycolysis with the ultimate increase in pyruvate, which accumulates as a result of compromised mitochondrial function.Patient educationFor patient education information, see the Brain and Nervous System Center, as well as Seizures in Children and Seizures Emergencies.Etiology Seizures occur when a large group of neurons undergo excessive, synchronized depolarization. Depolarization can result from excessive excitatory amino acid release (eg, glutamate) or deficient inhibitory neurotransmitter (eg, gamma amino butyric acid [GABA]). Hypoxic-ischemic encephalopathyAnother potential cause is disruption of adenosine triphosphate (ATP) dependent resting membrane potentials, which cause sodium to flow into the neuron and potassium to flow out of the neuron. Hypoxic-ischemic encephalopathy disrupts the ATP-dependent sodium-potassium pump and appears to cause excessive depolarization. It is an important cause of neonatal seizures.[1, 4] Seizures resulting from hypoxic-ischemic encephalopathy may be seen in term and premature infants. They frequently present within the first 72 hours of life. Seizures may include subtle, clonic, or generalized seizures. HemorrhageIntracranial hemorrhage occurs more frequently in premature than in term infants. Distinguishing infants with pure hypoxic-ischemic encephalopathy from those with intracranial hemorrhage often is difficult. Subarachnoid hemorrhage is more common in term infants. This type of hemorrhage occurs frequently and is not clinically significant. Typically, infants with subarachnoid hemorrhage appear remarkably well. Germinal matrix-intraventricular hemorrhage is seen more frequently in premature than in term infants, particularly in infants born prior to 34 weeks' gestation. Subtle seizures are seen frequently with this type of hemorrhage. Subdural hemorrhage is seen in association with cerebral contusion. It is more common in term infants.Metabolic disordersMetabolic disturbances include hypoglycemia, hypocalcemia, and hypomagnesemia. Less frequent metabolic disorders, such as inborn errors of metabolism, are seen more commonly in infants who are older than 72 hours. Typically, they may be seen after the infant starts feeding. Intracranial infectionsIntracranial infections (which should be ruled out vigorously) that are important causes of neonatal seizures include meningitis, encephalitis (including herpes encephalitis), toxoplasmosis, and cytomegalovirus (CMV) infections. The common bacterial pathogens include Escherichia coli and Streptococcus pneumoniae. Malformation syndromesWhile most cerebral malformations present with seizures at a later age, major malformation syndromes are important to consider. Lissencephaly, pachygyria, polymicrogyria, and linear sebaceous nevus syndrome can present with seizures in the neonatal period. Benign neonatal seizuresBenign neonatal seizure syndromes can be characterized by familial or idiopathic seizures. Benign familial neonatal seizures typically occur in the first 48-72 hours of life; the seizures disappear by age 2-6 months. A family history of seizures is usual. Development is typically normal in these infants. Benign idiopathic neonatal seizures typically present at day 5 of life (ie, fifth day fits), with the vast majority presenting between days 4 and 6 of life. Seizures are often multifocal. Cerebrospinal fluid (CSF) analysis is usually unremarkable.EpidemiologyThe incidence of neonatal seizures in the United States has not been clearly established, although an estimated frequency of 80-120 cases per 100,000 neonates per year has been suggested. The incidence of seizures is higher in the neonatal period (ie, the first 4 wk after birth) than at any other time of life.[5] Age-related demographicsNeonatal seizures by definition occur within the first 4 weeks of life in a full-term infant and up to 44 weeks from conception for premature infants. Seizures are most frequent during the first 10 days of life. Prognosis Prognosis is determined by etiology for neonatal seizures. If the EEG background is normal, the prognosis is excellent for seizures to resolve; normal development is likely.[6, 7] Severe EEG background abnormalities indicate poor prognosis; such patients frequently have cerebral palsy and epilepsy. The presence of spikes on EEG is associated with a 30% risk of developing future epilepsy. The prognosis following neonatal seizures that result from isolated subarachnoid hemorrhage is excellent, with 90% of children not having residual neurologic deficits. Scoring systemPisani et al devised a scoring system for early prognostic assessment after neonatal seizures. Analysis of 106 newborns who had neonatal seizures and were followed prospectively to 24 months' postconceptional age identified 6 independent risk factors for adverse outcome: (1) birth weight, (2) Apgar score at 1 minute, (3) neurologic examination at seizure onset, (4) cerebral ultrasonogram, (5) efficacy of anticonvulsant therapy, and (6) presence of neonatal status epilepticus. Each variable was scored from 0 to 3 to represent the range from normal to severely abnormal; these were then added together to produce a total composite score, ranging from 0 to 12. A cutoff score of 4 or higher provided the greatest sensitivity and specificity for prediction of adverse neurologic outcome.[8] Morbidity and mortalityNeonatal seizures are a risk factor that markedly increases rates of long-term morbidity and neonatal mortality. The presence of neonatal seizures is the best predictor of long-term physical and cognitive deficits. Complications of neonatal seizures may include the following: Cerebral palsy Cerebral atrophy Hydrocephalus ex-vacuo Epilepsy Spasticity Feeding difficulties HistoryInfants with neonatal seizures are frequently lethargic between seizures and often appear ill. Findings of the neurologic examination between seizures may be normal. However, neurologic examination abnormalities may be seen correlating with a focal or generalized neurologic syndrome. The clinical history provides important clues to the likely etiology of neonatal seizures.[1] Family historyA family history of neonatal convulsions may suggest that the infant has a genetic syndrome. Many of these syndromes are considered benign and frequently disappear within the neonatal period. In the absence of other etiologies, a family history of neonatal seizures may suggest a good prognosis.[9] Pregnancy historyA detailed pregnancy history is important. Search for a history that supports TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes) infections. The presence of kittens may suggest toxoplasmosis as an etiology. A history of fetal distress, preeclampsia, or maternal infection also can provide etiologic clues.Delivery historyDelivery history is also important. The type of delivery and the antecedent events should be documented. Apgar scores may offer some guidance concerning etiology, although a low Apgar score without the need for resuscitation and subsequent neonatal intensive care is unlikely to be associated with neonatal seizures.Postnatal historyThe postnatal history is also significant. Neonatal seizures in infants with an uneventful antenatal history and delivery may result from a postnatal cause. A history of tremulousness may suggest drug withdrawal or neonatal hypocalcemia. Temperature and/or blood pressure instability may suggest an infection; a sepsis workup may be required. A history of rubella or the absence of immunization against rubella may offer a diagnostic clue. In the United States, rubella immunization typically is given during the toddler years to both sexes and the degree of immunity is high. In countries where only teenage girls are immunized for rubella, neonatal seizures resulting from central nervous system (CNS) rubella involvement is a greater threat.

Diagnostic ConsiderationsBenign sleep myoclonus The clinician should be familiar with this benign condition, in which rhythmic movements (which occur only during sleep) mimic seizures. The condition can be alarming and may occur focally during nonrapid eye movement (non-REM) sleep. Video EEG monitoring shows no electrographic seizures.Jitteriness Jitteriness must be differentiated from seizures in neonates. Jitteriness is not associated with ocular deviation. It is stimulus sensitive (eg, easily stopped with passive movement of the limb). The movement resembles a tremor, and no autonomic changes are associated with it. Seizures often are associated with ocular deviation and are not stimulus sensitive. Autonomic changes frequently accompany them. The movements are clonic, unlike the tremorlike movements of jitteriness. Other conditions to consider in the differential diagnosis of neonatal seizures include the following: Anoxia Benign epilepsy syndromes Mitochondrial cytopathies Myoclonic epilepsy Myoclonus Organic acidurias Pyridoxine-dependent epilepsy Subarachnoid hemorrhage Subdural hematoma Tuberous sclerosis Vein of Galen malformation Viral encephalitis Viral meningitis Differential Diagnoses Abnormal Neonatal EEG Benign Neonatal Convulsions Cerebellar Hemorrhage Early Myoclonic Encephalopathy Epilepsy and Seizures Epileptiform Discharges Herpes Simplex Encephalitis Neonatal Injuries in Child Abuse Neonatal Meningitis Shuddering AttacksImaging StudiesCranial ultrasonographyCranial ultrasonography is performed readily at the bedside; it is a valuable tool for quickly ascertaining whether intracranial hemorrhage, particularly intraventricular hemorrhage, has occurred. A limitation of this study is the poor detection rate of cortical lesions or subarachnoid blood.Cranial CT scanningCranial computed tomography (CT) scanning is a much more sensitive tool than ultrasonography in detecting parenchymal abnormalities. The disadvantage is that the sick neonate must be transported to the imaging site. A distinct advantage is that with modern CT scan techniques, a study can be obtained in approximately 10 minutes.Cranial CT scan can delineate congenital malformations. Subtle malformations may be missed on CT scan, requiring a magnetic resonance imaging (MRI) study.MRICranial MRI is the most sensitive imaging study for determining the etiology of neonatal seizures, particularly when electrolyte imbalance has been excluded as the seizures cause.[16] A major disadvantage is that MRI cannot be performed quickly and, in an unstable infant, it is best deferred until the acute clinical situation resolves. EchocardiographyThis study can rule out cardiac hypomotility as a result of more diffuse hypoxia.Approach ConsiderationsTests to ascertain the cause of neonatal seizures include the following: Serum glucose and electrolytes - Transient neonatal hypocalcemia is a cause of neonatal seizures during the first 3 weeks of life; hypocalcemia associated with chromosome 22q11 deletion syndrome may also be a consideration TORCH (toxoplasmosis, rubella, CMV, herpes) infection studies Urine organic acids Serum amino acid assay Renal function tests - These tests rule out posthypoxic renal dysfunction; hypoxic damage to multiple organ systems may also be suggested by elevated liver transaminase levels. Cerebrospinal fluid analysisThis should include tests checking for the following: Pleocytosis Xanthochromia - Suggestive of blood breakdown products, particularly if jaundice is not present Lactic acid and pyruvate - For evidence of mitochondrial cytopathies Herpes virus - Using a polymerase chain reaction (PCR) assay Glucose concentration - Low glucose concentration is suggestive of bacterial meningitis In the absence of bacterial meningitis, persistently low CSF glucose concentrations may suggest a glucose transporter defect.ElectroencephalographyElectroencephalography plays a vital role in properly identifying and differentiating neonatal seizures from nonepileptic events.[10, 11] Video EEG monitoring may be helpful when infrequent neonatal seizures persist.[12] (See the images below.)Onset of neonatal seizure demonstrating a focal onset in the right frontal (FP4) region. At this point, the child had head and eye deviation to the left. Twenty seconds into a seizure that had focal onset in the right frontal (FP4) region, the seizure shows a rhythmic buildup of activity in the right frontocentral region. This seizure had focal onset in the right frontal (FP4) region and subsequent buildup of activity in the right frontocentral region. As the seizure evolves, the electroencephalogram shows diffuse involvement of both cerebral hemispheres. Neonatal brain cooling for hypoxic ischemic encephalopathy[13, 14, 15] Infants undergoing brain cooling for hypoxic ischemic encephalopathy are unable to undergo an EEG for 48 hours or longer following initiation of brain cooling. This renders concern for neonatal seizures. Amplitude-integrated EEG (aEEG) may be useful for monitoring such infants. Therapeutic hypothermias (rectal temperature of 34C) in infants older than conceptual age 36 weeks initiated within the first 6 hours following delivery may decrease mortality and neurodevelopmental disabilities. This period is also one during which neonatal seizures may occur, rendering diagnosis by EEG inaccessible, specially when cooling is isolated to the head by means of a Cool Cap". The neonatal EEG can be initiated only after completion of Cool Cap therapy, when the core temperature has been normalized. Otherwise, the EEG would assess a brain that is hypothermic and appear more suppressed than actual brain EEG activity.ConsultationsNeurology consultation is recommended to help with the evaluation of seizures, electroencephalography, video EEG monitoring, and management of anticonvulsant medications.TransferMothers in premature labor ideally should be transferred to a facility with a tertiary neonatal intensive care unit. This is more desirable than transfer after birth, since later transfers more commonly result in morbidity.MonitoringNeurology outpatient evaluation and follow-up are needed to decide when to discontinue seizure medications. Orthopedic evaluations may be appropriate in infants with joint deformities. Patients require developmental evaluation for early identification of physical or cognitive deficits. Enrollment in a "birth to 3" program may be indicated. Patients must be monitored carefully for development of contractures; strongly consider a physical medicine/physical therapy referral.Medical CareAcute neonatal seizures should be treated aggressively, although controversy exists as to the optimal treatment for them.[10, 17] When clinical seizures are present, a rigorous workup to determine an underlying etiologic cause should be initiated quickly. Electrolyte imbalances should be corrected through a central venous site. Hypocalcemia should be treated cautiously with calcium, since leakage of calcium into subcutaneous tissue can cause scarring. When an inborn error of metabolism is suspected, discontinue feeding, since feeding may exacerbate the seizures and encephalopathy. Institute intravenous solutions. Once these issues have been addressed, antiepileptic drug (AED) therapy should be considered. Phenobarbital is the initial drug of choice. If seizures persist, the use of phenytoin should be considered. Patients with seizures resulting from intracranial hemorrhage should have head circumference measurements performed daily. A rapid increase in head circumference may indicate hydrocephalus. Seizure MedicationsSeizure medication concentrations should be monitored during the acute period. These drugs often are discontinued between ages 3 and 6 months if further seizures have not occurred. A trend toward earlier discontinuation has met with good results. A general recommendation is to use AEDs for 3 months, but electroencephalography may be helpful in deciding when to stop AEDs.If the patient remains seizure free, then medications may be tapered gradually. If the patient is on 2 AEDs, then one should be tapered first before considering withdrawal of the other. If seizures recur, then the patient should be placed back on AEDs. The patient may be placed on the original AED, or carbamazepine may be considered. Medication SummaryAdministration of antiepileptic medications should be instituted in an orderly and efficient manner.[18] Initial treatment with phenobarbital should be considered. If seizures persist, phenytoin should be added. Persistent seizures may require the use of an intravenous benzodiazepine, such as lorazepam or midazolam. As previously stated, seizure medication concentrations should be monitored during the acute period. These drugs often are discontinued between ages 3 and 6 months if further seizures have not occurred. A trend toward earlier discontinuation has met with good results. Hypoglycemia, if present, should be corrected. Anticonvulsants, OtherClass SummaryThese agents prevent seizure recurrence and terminate clinical and electrical seizure activity.View full drug information Phenobarbital It is important to use the minimal amount of phenobarbital required and to wait for the anticonvulsant effect to develop before a second dose is given. Start with the loading dose and continue with the maintenance dosage. View full drug information Phenytoin (Dilantin, Phenytek) Phenytoin should be added to phenobarbital if seizures persist. Phenytoin may act in the motor cortex, where it may inhibit the spread of seizure activity. The activity of brain-stem centers responsible for the tonic phase of grand mal seizures also may be inhibited. View full drug information Lorazepam (Ativan) Lorazepam is a benzodiazepine anticonvulsant. It is used in cases refractory to phenobarbital and phenytoin. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including the limbic and reticular formations. Vitamins, Water-SolubleClass SummaryPyridoxine may be effective in seizures that are refractory to the medications already discussed. It is essential for normal deoxyribonucleic acid (DNA) synthesis and cell function. View full drug information Pyridoxine (Aminoxin, Pyri-500) Pyridoxine should be tried in patients not responding to the above regimen. Patients with pyridoxine-dependent seizures respond immediately to pyridoxine.