Neonatal seizure

Seizures in the neonatal population often present differently than in other age groups due to brain immaturity. Electroclinical seizures are defined by evidence of seizure activity on electroencephalogram as well as clinical signs or symptoms. However, in neonates there may be no clinical movement abnormality (either because the seizures are subclinical or because they were not witnessed), so the only symptom may be abnormal level of consciousness. When motor movements due occur, they cannot be suppressed by gentle restraint by a nurse or caregiver. Classification systems have been developed based on neonatal seizure motor manifestations, summarized below.[5] For more information about seizure classification, see page seizure types.

Neonatal seizures have a number of causes. Determining the cause of a confirmed seizure is important because treatment and prognosis vary based on underlying etiology of the seizure. In contrast to seizures that occur in other age groups, seizures that occur during the neonatal period are most often caused by the following processes:

• Hypoxic-Ischemic Encephalopathy: This is the most common cause of seizures in the neonatal period.[7]
• Perinatal Arterial Stroke: Arterial stroke can be caused by intra-arterial thrombosis or embolism from the heart or placenta. The risk for perinatal arterial stroke increases with a variety of conditions that occur due to material factors during birth (oligohydramnios, chorioamnionitis, placental abnormalities) or neonatal factors (clotting disorders, congenital heart defects)[7]
• Intraventricular hemorrhage
• Central Nervous System Infection: CNS Infection are found in 3-10% of neonates who seize, though exact incidence varies between studies.[7] Bacterial meningitis and viral meningoencephalitis are most prevalent, though fungal infections can occur.
• Congenital central nervous system malformations: Lissencephaly, polymicrogyria, and tuberous sclerosis are specific entities known to cause seizures due to defects in brain tissue development. Since prognosis is poor and often these disorders are genetic, identification of this etiology is of utmost importance to be able to counsel parents appropriately.
• Inborn Errors of Metabolism: Inborn errors of metabolism can cause physiologic conditions that result in seizures. These errors are genetic and often are accompanied by other symptoms such as lethargy, poor feeding, and low tone.[7] Diagnosis often involves specific laboratory tests of metabolic products as well as genetic tests. Several classification systems exist for seizures caused by inborn errors of metabolism, one of which separates causes into problems with neurotransmitter metabolism, energy production, and biosynthetic substances crucial for brain formation.[8]
• Electrolyte abnormalities: Metabolic abnormalities such as hypoglycemia, hyponatremia, and hypocalcemia can manifest as seizures.
• Substance-Related: Neonatal abstinence syndrome occurs when maternal drug use before birth results in a fetal withdrawal syndrome. Substances include alcohol, cocaine, narcotics, tricyclclic antidepressants, or other sedatives. Seizures can be prevented from occurring if the symptoms of withdrawal are recognized and treated early.[7]

A normal amplitude integrated EEG trace in a term infant who is several days old. The amplitude-integrated trace is in the top half of the screen displaying left- and right-sided traces. There is a normal baseline and upper limit, sleep-wake cycling, and no seizures.

Seizure activity in a neonate is difficult to diagnose, as many seizures have no clinical correlate. Altered level of consciousness is often the only clue, and in a neonate this can be difficult to accurately assess. Thus, diagnosis relies on attempting to directly measurement the abnormal electrical activity in the brain with electroencephalography (EEG). EEG is combined with video recording of the infant to correlate any seizure movements with EEG recordings.

There are several modes of EEG that are commonly used in the NICU to diagnose neonatal seizures. Conventional continuous multichannel conventional EEG is the gold standard for diagnosis of epileptiform activity, but requires expert interpretation. Newer amplitude integrated EEG (aEEG) (also termed cerebral function monitoring, or CFM) allows easier monitoring of brain activity, but may not allow identification of short duration, low amplitude, or very high frequency seizure activity.[9] Often, both modes are displayed concurrently.

Once diagnosis is made, the goals of management are to identify the cause of the seizure, stop the seizure activity, and maintain physiologic parameters such as oxygenation, ventilation, blood glucose, and temperature.

Treatment greatly depends on the cause of the seizure. For example, infectious causes of seizures (meningitis, meningoencephalitis), are often treated with antimicrobials (antibiotic, antifungal, or antiviral medications). Similarly, electrolyte or glucose abnormalities are treated by repleting or lowering the offending electrolyte or sugar.

If the cause of the seizures are unlikely to be easily or quickly corrected, once diagnosis of a seizure is made, the mainstay of treatment is pharmacotherapy with anti-epileptic drugs. A 2013 systematic review found that most practitioners use phenobarbital or phenytoin.[11] This study found that phenobarbital has the safest side effect profile and longest history of use in neonates. Benzodiazepines are often used as second line treatment if treatment with phenobarbital does not result in clinical improvement. Research is ongoing on use of other anti-epileptics that are commonly used in older children and adults are safe or efficacious to use in neonates. Part of the challenge of anticonvulsant drug treatment during the neonatal period is that the immature excitatory and inhibitory neurotransmitter system results in few effective drug targets.[10]

With earlier diagnosis and increasingly prompt diagnosis, mortality after diagnosis of neonatal seizures has decreased dramatically from an estimated 33% in the 1990s to around 10% in the 2010s.[12] Underlying cause of the seizure remains the greatest predictor of ongoing seizures and neurologic problems later in life. Controversy remains with the extent of damage the seizures themselves cause. Clinician consensus is that frequent or intractable seizures (status epilepticus) leads to neuronal damage and are associated with later neurodevelopment problems.[13]

Developmental delay, cerebral palsy, and problems with vision and hearing are the most common poor outcomes following neonatal seizures.[12] Severity of impairment ranges greatly and many infants develop normally once the initial seizure cause is treated.

Studies have identified risk factors for poor outcomes after neonatal seizures. Infants that are premature, have hypoxemic ischemic encephalopathy, CNS infection, severe intraventricular hemorrhage, structural central nervous system defect, or severely abnormal EEG tracings tend to do worse than infants with focal strokes, transient metabolic issues (hypoglycemia, hypocalcemia), or clinical seizures without EEG abnormalities.[12]

Risk of epilepsy later during childhood is a common question asked by parents in the neonatal intensive care unit (NICU). Unfortunately, the answer is rarely clear cut as it depends greatly on the underlying cause. For all infants with neonatal seizures  regardless of cause, the rate of subsequent seizures during childhood is estimated between 10 and 20%.[14] Infants who survive severe global HIE have the highest rate of epilepsy later in life.[12]

It is difficult to determine the incidence of seizures in the neonatal period. Estimations range between 1-5 per 1,000 live-births,[10] though the actual rate of seizures during this period may be higher due to lack of accurate diagnosis of sub-clinical seizure activity without continuous EEG monitoring. Acute causes of seizures (hypoxemic ischemic encephalopathy, infection, intracranial hemorrhage, stroke, etc) are more common than first-episode of neonatal epilepsy syndromes.

Seizures occur during the neonatal period at a higher rate than in any other period of life. Seizures in the developing brain are more common than in a mature brain for several reasons. First, the developing brain is hyperexcitable due to excess in excitatory glutaminergic neurons and immaturity of inhibitory gamma-amino butyric acid (GABA) neurons. Preterm infants are at especially high risk for seizures for this reason.[12]

Since interpretation of continuous EEG monitoring requires a trained neurologist, automated interpretation software has been proposed. Algorithms and machine learning have been studied, however logistical and mathematic challenges remain.

• Epilepsy in children