AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

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 weeks after term).

The most prominent feature of neurological dysfunction in the neonatal period are seizures. Determining the underlying etiology for neonatal seizures is critical. Etiology determines prognosis and outcome and guides therapeutic strategies.¹ 

Most neonatal seizures occur over only a few days, and fewer than half of affected infants develop seizures later in life. Such neonatal seizures could be considered acute reactive (acute symptomatic), thus 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 neurological dysfunction, and they are powerful predictors of long-term cognitive and developmental impairment. 

For related information, see Medscape's Neonatal Medicine Resource Center.

Pathophysiology

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]). Another potential cause is disruption of ATP-dependent resting membrane potentials, which causes a flow of sodium into the neuron and potassium 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, 3}

The biochemical effects of neonatal seizures include derangements of energy metabolism. Energy-dependent ion pumps are compromised, and ADP levels rise. The rise in ADP stimulates glycolysis with the ultimate increase in pyruvate, which accumulates as a result of compromised mitochondrial function. 

Frequency

United States

The incidence of neonatal seizures has not been established clearly, 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 weeks after birth) than in any other age group.⁴

International

Incidence is unknown.

Mortality/Morbidity

• Neonatal 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.

Race

No racial preponderance is known.

Sex

Sex-based frequency differences have not been described.

Age

• Neonatal 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

The clinical history provides important clues to the likely etiology of neonatal seizures.¹ 

• A 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.⁵
• A 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 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.
• The 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 CNS rubella involvement is a greater threat.
• Neonatal seizures are classified as follows:
• • 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 EEG studies have demonstrated that most subtle seizures are not associated with electrographic seizures. Examples of subtle seizures include chewing, pedaling, or ocular movements.
  • Clonic seizures: These movements most commonly are associated with electrographic seizures. They often involve one extremity or one side of the body. The rhythm of the clonic movements is usually slow, 1-3 movements per second.
  • Tonic seizures: These may involve one extremity or the whole body. Focal tonic seizures involving one extremity often are associated with electrographic seizures.
  • • Generalized tonic seizures often manifest with tonic extension of both 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 seizures: These may occur focally in one 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.
• 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.

Physical

• Infants 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.

Causes

The differential diagnosis for neonatal seizures is voluminous. Important causes include the following:

• Seizures resulting from hypoxic-ischemic encephalopathy may be seen in both term and premature infants. They frequently present within the first 72 hours of life. Seizures may include subtle, clonic, or generalized seizures.
• Intracranial 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 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 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.
• While 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 seizure syndromes are characterized by the following:
• • 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.
  • Benign 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 non-rapid eye movement (REM) sleep. Video EEG monitoring shows no electrographic seizures.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Anoxia
Benign epilepsy syndromes
Mitochondrial cytopathies
Myoclonic epilepsy
Myoclonus
Organic acidurias
Pyridoxine-dependent epilepsy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• Serum glucose and electrolytes, including calcium: 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.
• CSF analysis: This should include tests checking for pleocytosis, xanthochromia (suggestive of blood breakdown products, particularly if jaundice is not present), lactic acid and pyruvate (for evidence of mitochondrial cytopathies), polymerase chain reaction (PCR) for herpes virus, and 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.
• 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.

Imaging Studies

• Cranial ultrasonography
• • Cranial ultrasonography is performed readily at the bedside; it is a valuable tool to quickly ascertain 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 scan
• • Cranial CT scan is a much more sensitive tool than ultrasound 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 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 an MRI study.
• MRI
• • MRI is the most sensitive imaging modality to determine etiology for neonatal seizures.² 
  • Cranial MRI is the most sensitive test in determining the etiology of neonatal seizures, particularly when electrolyte imbalance has been excluded as a cause for seizures.
  • A major disadvantage is that it cannot be performed quickly and, in an unstable infant, it is best deferred until the acute clinical situation resolves.

Other Tests

• EEG plays a vital role in properly identifying and differentiating neonatal seizures from nonepileptic events.⁶ See Media files 1-3.
• Video EEG monitoring may be helpful when infrequent neonatal seizures persist.⁷
• Echocardiography: This study can rule out cardiac hypomotility as a result of more diffuse hypoxia.

TREATMENT

Section 6 of 10  

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• Workup
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• Follow-up
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Medical Care

Acute neonatal seizures should be treated aggressively.⁶ Controversy exists as to what is the optimal treatment for neonatal seizures.⁸ 

When clinical seizures are present, a rigorous workup to determine an underlying etiologic cause should be initiated quickly. The following points should be attended to:

• 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.
• Obtain EEG when uncertain as to whether the observed events are epileptic or nonepileptic.
• 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.

Consultations

• Neurology consultation is recommended to help with the evaluation of seizures, EEG, video EEG monitoring, and management of anticonvulsant medications.

MEDICATION

Section 7 of 10  

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Antiepileptic medications should be instituted in an orderly and efficient manner (Painter et all 1999). Correct hypoglycemia, if present. Initial treatment with phenobarbital should be considered. If seizures persist, phenytoin should be added. Persistent seizures may require use of an intravenous benzodiazepine such as lorazepam or midazolam.

Drug Category: Anticonvulsants

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Drug Category: Vitamins

This agent may be effective in seizures refractory to medications already discussed. It is essential for normal DNA synthesis and cell function.

FOLLOW-UP

Section 8 of 10  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
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• References

Further Inpatient Care

• Patients with seizures resulting from intracranial hemorrhage should have head circumference measurements performed daily. A rapid increase in head circumference may indicate hydrocephalus.
• 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.
• EEG may be helpful in deciding when to stop AEDs.
• A general recommendation is to use AEDs for 3 months.
• • 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 withdrawing 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.

Further Outpatient Care

• Neurology outpatient evaluation and follow-up are needed to decide when to discontinue seizure medications.
• 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.
• Orthopedic evaluations may be appropriate in infants with joint deformities.

Transfer

• Mothers 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.

Complications

Complications of neonatal seizures may include the following:

• Cerebral palsy
• Cerebral atrophy
• Hydrocephalus ex-vacuo
• Epilepsy
• Spasticity
• Feeding difficulties

Prognosis

• Prognosis is determined by etiology for neonatal seizures.
• • If EEG background is normal, the prognosis is excellent for seizures to resolve; normal development is likely.
  • 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 neurological deficits.

Patient Education

• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education articles Seizures in Children and Seizures Emergencies.

MULTIMEDIA

Section 9 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  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.
	View Full Size Image
Media type:  Rhythm Strip

Media file 2:  Twenty seconds into a seizure that had focal onset in the right frontal (FP4) region (see Image 1), the seizure shows a rhythmic buildup of activity in the right frontocentral region.
	View Full Size Image
Media type:  Rhythm Strip

Media file 3:  This seizure had focal onset in the right frontal (FP4) region and subsequent buildup of activity in the right frontocentral region (see Images 1 and 2). As the seizure evolves, the EEG shows diffuse involvement of both cerebral hemispheres.
	View Full Size Image
Media type:  Rhythm Strip

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
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• Differentials
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• Follow-up
• Multimedia
• References

1. Volpe JJ. Hypoxic-Ischemic Encephalopathy: Biochemical and Physiological Aspects. In: Neurology of the Newborn. 4^th ed. Philadelphia: WB Saunders; 2000:217-276.
2. Scher MS, Trucco GS, Beggarly ME, et al. Neonates with electrically confirmed seizures and possible placental associations. Pediatr Neurol. Jul 1998;19(1):37-41. [Medline].
3. Silverstein FS, Jensen FE. Neonatal seizures. Ann Neurol. Aug 2007;62(2):112-20. [Medline].
4. Sheth RD, Hobbs GR, Mullett M. Neonatal seizures: incidence, onset, and etiology by gestational age. J Perinatol. Jan 1999;19(1):40-3. [Medline].
5. Vigevano F. Benign familial infantile seizures. Brain Dev. Apr 2005;27(3):172-7. [Medline].
6. Sheth RD, Buckley DJ, Gutierrez AR, et al. Midazolam in the treatment of refractory neonatal seizures. Clin Neuropharmacol. Apr 1996;19(2):165-70. [Medline].
7. Sheth RD. Electroencephalogram in developmental delay: specific electroclinical syndromes. Semin Pediatr Neurol. Mar 1998;5(1):45-51. [Medline].
8. Sankar R, Painter MJ. Neonatal seizures: after all these years we still love what doesn't work. Neurology. Mar 8 2005;64(5):776-7. [Medline].
9. Lombroso CT. Neonatal seizures: gaps between the laboratory and the clinic. Epilepsia. 2007;48 Suppl 2:83-106. [Medline].
10. Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. Aug 12 1999;341(7):485-9. [Medline].
11. Sheth RD. Electroencephalogram confirmatory rate in neonatal seizures. Pediatr Neurol. Jan 1999;20(1):27-30. [Medline].
12. Sheth RD. Frequency of neurologic disorders in the neonatal intensive care unit. J Child Neurol. Sep 1998;13(9):424-8. [Medline].
13. Sheth RD, Bodensteiner JB. Delayed postanoxic encephalopathy: possible role for apoptosis. J Child Neurol. Jul 1998;13(7):347-8. [Medline].

Article Last Updated: Aug 21, 2008