Neonatal Seizure Disorders
(See also Seizure Disorders.)
Seizures occur in up to 1.4% of term infants and 20% of premature infants. Seizures may be related to a serious neonatal problem and require immediate evaluation. Most neonatal seizures are focal, probably because generalization of electrical activity is impeded in neonates by lack of myelination and incomplete formation of dendrites and synapses in the brain.
Some neonates undergoing electroencephalography (EEG) to assess seizures or other symptoms of encephalopathy (eg, hypoactivity, decreased responsiveness) are found to have clinically silent seizures (≥ 20 seconds of rhythmic epileptiform electrical activity during an EEG but without any clinically visible seizure activity). Occasionally, clinically silent electrical activity is continuous and persists for > 20 minutes; at that point, it is defined as electrical status epilepticus.
The abnormal central nervous system (CNS) electrical discharge may be caused by a
Seizures resulting from an intracranial process usually cannot be differentiated from seizures resulting from a systemic problem by their clinical features (eg, focal vs generalized).
Hypoxia-ischemia, the most common cause of neonatal seizures, may occur before, during, or after delivery (see Overview of Perinatal Respiratory Disorders). Such seizures may be severe and difficult to treat, but they tend to abate after about 3 to 4 days. When neonatal hypoxia is treated with therapeutic hypothermia (usually whole-body cooling), seizures may be less severe but may recur during rewarming.
Ischemic stroke is more likely to occur in neonates with polycythemia, thrombophilia due to a genetic disorder, or severe hypotension but may occur in neonates without any risk factors. Stroke occurs typically in the middle cerebral artery distribution or, if associated with hypotension, in watershed zones. Seizures resulting from stroke tend to be focal and may cause apnea.
Neonatal infections such as meningitis and sepsis may cause seizures; in such cases, seizures are usually accompanied by other symptoms and signs. Group B streptococci and gram-negative bacteria are common causes of such infections in neonates. Encephalitis due to cytomegalovirus, herpes simplex virus, rubella virus, Treponema pallidum, Toxoplasma gondii, or Zika virus can also cause seizures.
Hypoglycemia is common among neonates whose mothers have diabetes, who are small for gestational age, or who have hypoxia-ischemia or other stresses. Seizures due to hypoglycemia tend to be focal and variable. Prolonged or recurrent hypoglycemia may permanently affect the CNS.
Intracranial hemorrhage, including subarachnoid, intracerebral, and intraventricular hemorrhage, may cause seizures. Intraventricular hemorrhage, which occurs more commonly in premature infants, results from bleeding in the germinal matrix (an area that is adjacent to the ventricles and that gives rise to neurons and glial cells during development).
Hypernatremia can result from accidental oral or IV sodium chloride overload.
Hyponatremia can result from dilution (when too much water is given orally or IV particularly in the setting of hypovolemia, which, when severe enough, leads to increased antidiuretic hormone [ADH] levels despite the low serum osmolarity [nonosmotic ADH release]) or may follow sodium loss in stool or urine.
Hypocalcemia (serum calcium level < 7.5 mg/dL [< 1.87 mmol/L]) is usually accompanied by a serum phosphorus level of > 3 mg/dL (> 0.95 mmol/L) and can be otherwise asymptomatic. Risk factors for hypocalcemia include prematurity and a difficult birth.
Hypomagnesemia is a rare cause of seizures, which may occur when the serum magnesium level is < 1.4 mEq/L (< 0.7 mmol/L). Hypomagnesemia often occurs with hypocalcemia and should be considered in neonates with hypocalcemia if seizures continue after adequate calcium therapy.
CNS malformations can also cause seizures.
Maternal substance abuse (eg, cocaine, heroin, diazepam) is an increasingly common problem; seizures can accompany acute withdrawal after birth.
Neonatal seizures may be familial; some have genetic causes. Benign familial neonatal convulsions is a potassium channelopathy inherited in an autosomal dominant pattern. Early infantile epileptic encephalopathy (Ohtahara syndrome) is a rare disorder associated with a variety of mutations.
Neonatal seizures are usually focal and may be difficult to distinguish from normal neonatal activity because they may manifest as chewing or bicycling movements. Common manifestations include migratory clonic jerks of extremities, alternating hemiseizures, and primitive subcortical seizures (which cause respiratory arrest, chewing movements, persistent eye deviations or nystagmoid movements, and episodic changes in muscle tone). Generalized tonic-clonic seizures are uncommon.
Clinically silent electrical seizure activity is often present after a hypoxic-ischemic insult (including perinatal asphyxia or stroke) and in neonates with CNS infections, especially after initial antiseizure drug treatment, which is more likely to stop clinical manifestations than electrical seizure activity.
Evaluation begins with a detailed family history and a physical examination.
Jitteriness (alternating contraction and relaxation of opposing muscles in the extremities) must be distinguished from true seizure activity. Jitteriness is usually stimulus-induced and can be stopped by holding the extremity still; in contrast, seizures occur spontaneously, and motor activity is felt even when the extremity is held still.
EEG is essential, and at times recording may need to be prolonged, especially when it is difficult to determine whether the neonate is having seizures. EEG is also helpful for monitoring response to treatment.
EEG should capture periods of active and quiet sleep and thus may require ≥ 2 hours of recording. A normal EEG with expected variation during sleep stages is a good prognostic sign; an EEG with diffuse severe abnormalities (eg, suppressed voltage or burst suppression pattern) is a poor one.
Bedside EEG with video monitoring for ≥ 24 hours may detect ongoing clinically silent electrical seizures, particularly in the first few days after a CNS insult.
Laboratory tests to look for underlying treatable disorders should be done immediately; tests include pulse oximetry; measurement of serum glucose, sodium, potassium, chloride, bicarbonate, calcium, and magnesium; and lumbar puncture for CSF analysis (cell count and differential, glucose, protein) and culture. Urine and blood cultures are also obtained.
The need for other metabolic tests (eg, arterial pH, blood gases, serum bilirubin, urine amino or organic acids) or tests for commonly abused drugs (passed to the neonate transplacentally or by breastfeeding) depends on the clinical situation.
Imaging tests are typically done unless the cause is immediately obvious (eg, glucose or electrolyte abnormality). MRI is preferred but may not be readily available; in such cases, head CT is done.
For very sick infants who cannot be moved to radiology, bedside cranial ultrasonography can be done; it may detect intraventricular but not subarachnoid hemorrhage. MRI or CT is done when infants are stable.
Head CT can detect intracranial bleeding and some brain malformations. MRI shows malformations more clearly and can detect ischemic tissue within a few hours of onset.
Magnetic resonance spectroscopy may help determine the extent of an ischemic injury or identify buildup of certain neurotransmitters associated with an underlying metabolic disorder.
Prognosis depends on the etiology:
About 50% of neonates with seizures due to hypoxia-ischemia develop normally.
Most neonates with seizures due to subarachnoid hemorrhage, hypocalcemia, or hyponatremia do well.
Those with severe intraventricular hemorrhage have a high morbidity rate.
For idiopathic seizures or seizures due to malformations, earlier onset is associated with worse neurodevelopmental outcomes.
It is suspected, but not proved, that prolonged or frequent neonatal seizures may cause damage beyond that caused by the underlying disorder. There is concern that the metabolic stress of prolonged nerve cell firing during lengthy seizures may cause additional brain damage. When caused by acute injuries to the brain such as hypoxia-ischemia, stroke, or infection, neonates may have a series of seizures, but seizures typically abate after about 3 to 4 days; they may recur months to years later if brain damage has occurred. Seizures due to other conditions may be more persistent during the neonatal period.
Treatment of neonatal seizures focuses primarily on the underlying disorder and secondarily on seizures.
For low serum glucose, 10% dextrose 2 mL/kg IV is given, and the serum glucose level is monitored; additional infusions are given as needed but cautiously, to avoid hyperglycemia.
For hypocalcemia, 10% calcium gluconate 1 mL/kg IV (9 mg/kg of elemental calcium) is given; this dosage can be repeated for persistent hypocalcemic seizures. Rate of calcium gluconate infusion should not exceed 0.5 mL/minute (50 mg/minute); continuous cardiac monitoring is necessary during the infusion. Extravasation should be avoided because skin may slough.
For hypomagnesemia, 0.2 mL/kg (100 mg/kg) of a 50% magnesium sulfate solution is given IM.
Bacterial infections are treated with antibiotics.
Herpes encephalitis is treated with acyclovir.
Antiseizure drugs are used unless seizures stop quickly after correction of reversible disorders such as hypoglycemia, hypocalcemia, hypomagnesemia, hyponatremia, or hypernatremia.
Phenobarbital is still the most commonly used drug; a loading dose of 15 to 20 mg/kg IV is given. If seizures continue, 5 to 10 mg/kg IV can be given every 15 to 30 minutes until seizures cease or until a maximum of 40 mg/kg is given. If seizures are persistent, maintenance therapy may be started about 24 h later at 1.5 to 2 mg/kg every 12 hours and increased to 2.5 mg/kg every 12 hours based on clinical or EEG response or serum drug levels. Phenobarbital is continued IV, especially if seizures are frequent or prolonged. When the infant is stable, phenobarbital can be given orally at 3 to 4 mg/kg once/day. Therapeutic serum levels of phenobarbital are 20 to 40 mcg/mL (85 to 170 micromol/L), but higher levels are sometimes needed at least temporarily.
Levetiracetam is used to treat neonatal seizures because it is less sedating than phenobarbital. It is given IV as a 20- to 50-mg/kg IV loading dose given at 2 to 5 mg/kg/minute, and therapy may be continued as 10 to 25 mg/kg IV every 12 hours. Therapeutic levels are not well-established in the neonate.
Fosphenytoin can be used if seizures continue despite phenobarbital and levetiracetam. The loading dose is 20 mg PE (phenytoin equivalents)/kg IV. It is given over 30 minutes to avoid hypotension or arrhythmias. A maintenance dose may be started at 2 to 3 mg PE/kg every 12 hours and adjusted based on clinical response or serum levels. Therapeutic serum levels for phenytoin in neonates are 8 to 15 mcg/mL (32 to 60 micromol/L).
Lorazepam 0.1 mg/kg IV may be used initially for a prolonged seizure or for resistant seizures and repeated at 5- to 10-minute intervals, up to 3 doses in any 8-hour period.
Neonates given IV antiseizure drugs are closely observed; large doses and combinations of drugs, particularly lorazepam plus phenobarbital, may result in respiratory depression.
The appropriate duration of therapy is not known for any of the antiseizure drugs, but if seizures come under control, antiseizure drugs may be stopped before discharge from the nursery.
Neonatal seizures usually occur in reaction to a systemic or central nervous system event (eg, hypoxia/ischemia, stroke, hemorrhage, infection, metabolic disorder, structural brain abnormality).
Neonatal seizures are usually focal and may be difficult to recognize; common manifestations include migratory clonic jerks of extremities, chewing movements, persistent eye deviations or nystagmoid movements, and episodic changes in muscle tone.
Electroencephalography is essential for diagnosis; laboratory testing and usually neuroimaging are done to identify the cause.
Treatment is directed at the cause.
Give phenobarbital or levetiracetam if seizures do not stop when the cause is corrected; fosphenytoin and lorazepam may be added for persistent seizures.
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