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. Motor seizures Classification systems have been developed based on neonatal seizure motor manifestations, summarized below. • Focal or multifocal clonic Clonic seizures are defined by repetitive contractions of groups of muscles, typically of the limbs, face, or trunk. These may involve one group of muscles (focal) or multiple groups of muscles (multifocal). An isolated focal seizure can move or spread, and can even alternate from one side of the body to the other. If they occur on both sides of the body, they may occur simultaneously in an asynchronous manner. If a multifocal seizure, is limited to muscles of one side of the body, it may occur synchronously or asynchronously. Due to the neonatal brain's immaturity, the typical Jacksonian march may not occur. Focal seizures typically have very close correlates on EEG, with measurable EEG abnormalities with each seizure movement. The rhythm of the clonic movements and EEG abnormalities is usually slow, at 1-3 movements per second. • Focal tonic Focal tonic seizures are characterized by sustained muscle contraction of facial, limb, axial, and other muscle groups. It often involves asymmetric positioning of the neck and trunk and appears as abnormal posturing of a single limb. Horizontal eye deviation may or may not be involved. These movements typically occur in the limbs or face. Stimulation can provoke myoclonic seizures. • Spasms Spasms include either flexor or extensor or both flexor and extensor. These occur in clusters and cannot be provoked by stimulation or suppressed by restraint. They may be difficult to diagnose clinically due to the subtleness of symptoms. A benign familial neonatal seizure onsets as early as 3 days of birth and may involve one or both sides of the brain. Recurrent seizure episodes are observed to occur in neonates. Electroencephalogram of infants with BFNS often have normal readings. Sometimes, they may show theta pointy, a specific abnormality. They usually begin with tonic stiffening accompanied by apnea. Later clonic jerks are witnessed. It occurs in 1 in every 1,00,000 newborns. This condition is usually inherited and is passed on in autosomal dominant manner. This condition is also caused due to mutation in KCNQ2 or KCNQ3 gene that may be carried by people bearing no family history of benign familial neonatal seizure. Mutation in these genes lead to excessive excitability of neurons. Most of the infants with BFNS develop normally but some neonates with it may later develop intellectual disability which becomes evident in early childhood. In some patients approximately 15%, epilepsy recurs later in life. Myokymia is also witnessed in a few cases. == Pathophysiology ==

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. This lowered seizure threshold potential makes the neonatal brain susceptible to acute symptomatic seizures. • Seizure risk due to decreased inhibition: Gamma-butyric acid (GABA) is the main inhibitory neurotransmitter in adult humans. Upon binding with its receptor i.e. GABAa, it causes hyperpolarisation of the neuronal membrane by causing the net influx of chloride ions. This hyperpolarisation leads to inhibition of further action potentials. However, in neonates, there is a relatively high expression of NKCC1(sodium-potassium-chloride cotransporter 1) than KCC2(potassium-chloride cotransporter 2). NKCC1 causes net efflux of chloride ions while KCC2 is responsible for causing a net influx of chloride ions. Increased expression of NKCC1 leads to depolarisation of the neuronal membrane. This depolarisation removes voltage-dependent Mg from N-methyl-D-aspartate(NMDA) receptors and triggers calcium influx. The binding of calcium to the receptors causes the generation of secondary messengers that increases the risks of seizures and increase the excitability of the brain. • Seizure risk due to increased activation: Glutamate is the primary excitatory neurotransmitter and the expression of its receptor is developmentally regulated. It binds to NMDA receptors, kainite receptors, and AMPA receptors. In course of the developmental stages, in several parts of the brain, a subunit of NMDA receptor-GluN2B is highly expressed which increases calcium influx. This mechanism increases the duration of postsynaptic currents in the immature brain in comparison to adult brains. == Causes ==

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, causing approximately 33% of neonatal seizures. • 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. == Diagnosis ==

Seizure activity in a neonate is difficult to diagnose, as many seizures have subtle clinical symptoms. Diagnosis relies on a combination of brain monitoring (electroencephalography)(EEG) and observing clinical signs or symptoms of a seizure. Often, both modes are displayed concurrently. Evaluation for infection (often with blood counts, blood cultures, or lumbar puncture) may be done to determine if there is a secondary cause of seizures. Genetic testing may be done with an epilepsy gene panel to determine presence of neonatal primary genetic epilepsy syndromes. Brain injury such as cerebral infarction or hemorrhage can be evaluated with imaging techniques such as magnetic resonance imaging (MRI) and brain ultrasound. Differential diagnosis Infants can exhibit stereotyped movements that may be hard to distinguish from seizure activity. Since many of these non-seizure movements are not dangerous and require no treatment, differentiation from actual seizure activity is useful. Jitteriness is common in the neonatal period and is seen in upwards of 2/3 of neonates. It is characterized by a tremor that is especially prominent during sleep or periods of agitation. Gaze deviation or eye movements do not occur. Benign neonatal sleep myoclonus (BNSM) is another common movement that can be mistaken for a seizure. It is characterized by jerking limb movements only during sleep, and stop with waking of the infant. == Treatment ==

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. Term or near term infants with moderate to severe hypoxic ischemic encephalopathy causing neonatal seizures may be treated with therapeutic hypothermia. == Outcomes ==

With prompt diagnosis, mortality after diagnosis of neonatal seizures has decreased dramatically from an estimated 33% in the 1990s to around 10% in the 2010s. 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. Infants that are premature, have hypoxemic ischemic encephalopathy, CNS infection, severe intraventricular hemorrhage, structural central nervous system defect, or severely abnormal EEG tracings have a worse prognosis.". For all infants with neonatal seizures  regardless of cause, the rate of subsequent seizures during childhood is estimated between 10 and 20%. Infants who survive severe global HIE have the highest rate of epilepsy later in life. Untreated or repeated neonatal seizures, especially prolonged seizures or status epilepticus, are associated with hippocampal sclerosis later in life. == Epidemiology ==

It is difficult to determine the incidence of seizures in the neonatal period. Estimations range between 1-5 per 1,000 live births, with other estimates being 1.1 cases per 1,000 live births in full term infants and 14 cases per 1,000 live births in preterm infants. The actual rate of seizures during the neonatal period may be higher due to a lack of accurate diagnosis of sub-clinical seizure activity without continuous EEG monitoring. The epidemiology moreover varies in high-income countries (HIC) from that in low-income ones (LIC). The incidence is estimated to be 1-3 per 1000 live births in HIC whereas it ranges from 36 to 90 per live birth in LIC. Acute causes of seizures (hypoxemic ischemic encephalopathy, infection, intracranial hemorrhage, stroke, etc.) are more common than the first episode of neonatal epilepsy syndromes. == Research directions ==

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. == See also ==