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Neonatal Seizure

Author: Conrad Krawiec Editor: Maria Rosaria Muzio Updated: 7/7/2025 10:37:08 AM

Introduction

Neonatal seizures constitute a commonly encountered neurologic condition in neonates.[1] Defined as sudden, paroxysmal, and abnormal alterations of electrographic activity from birth to the end of the neonatal period, these seizures reflect the developmental immaturity of the neonatal brain. This immaturity contributes to a unique pathophysiology and electrographic pattern, resulting in clinical manifestations that can be different and more difficult to identify than in older age groups.[2]

In some cases, seizure activity serves as the first clinical sign of a serious neurologic disorder.[3] Rapid recognition and evaluation are required to identify and treat the underlying etiology, prevent further brain injury, and extinguish the seizure activity.[4][5] This activity provides an overview of the etiologies, clinical features, evaluation, and approach to managing neonatal seizures.

Etiology

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Etiology

When seizure activity occurs in a neonate, identifying an underlying and potentially reversible cause is a critical first step in evaluation.[6] Etiologies requiring prompt recognition and urgent intervention fall into the following categories:

  • Metabolic disturbances [7]
    • Hypoglycemia [8]
    • Hypocalcemia [9]
    • Hypomagnesemia [10]
    • Hyponatremia
    • Hypernatremia
  • Hypoxic conditions [11]
    • Hypoxic-ischemic encephalopathy
    • Perinatal asphyxia
  • Intracranial hemorrhage
    • Intraventricular
    • Intraparenchymal
    • Subarachnoid
    • Subdural
  • Infections
    • Bacterial meningitis (eg, group B Streptococcus, Escherichia coli, Listeria monocytogenes) [12][13]
    • Viral encephalitis (eg, herpes simplex encephalitis, enteroviruses) [14]
    • Intrauterine infection (eg, cytomegalovirus, toxoplasmosis, varicella, Zika virus) [15][16]
  • Inborn errors of metabolism
    • Selected enzyme deficiencies 
      • Urea cycle defects
      • Peroxisomal disorders
      • Organic acidemias
      • Amino acid disorders
    • Vitamin and cofactor deficiencies
      • Pyroxidine deficiency
      • Molybdenum cofactor deficiency[17]
  • Thromboembolic events
    • Arterial ischemic stroke [18]
    • Sinus venous thrombosis [19]

Other conditions to consider include the following:

  • Neonatal epilepsy syndromes 
    • Benign neonatal seizures
    • Benign familial neonatal epilepsy
    • Early myoclonic encephalopathy [20]
    • Early infantile epileptic encephalopathy [21]
    • Genetic epilepsy syndromes [22]
  • Congenital brain malformations 
    • Schizencephaly
    • Lissencephaly
    • Holoprosencephaly
    • Hydranencephaly [23]

Accurate etiologic classification informs both acute treatment and long-term care planning. Clinical, laboratory, and neuroimaging data integration is critical to this process.

Epidemiology

Neonatal seizures are a commonly encountered neurologic emergency.[24][25] Reported incidence in term infants ranges from 1 to 5.5 per 1000 live births, with substantially higher rates observed in preterm populations.[26][27][28] In the United States, the annual incidence is estimated at 80 to 120 cases per 100,000 neonates.

Pathophysiology

The neonatal brain differs significantly from that in older age groups. At birth, the brain enters a phase of continued maturation, with many neural structures remaining developmentally immature. This immaturity renders this vital organ vulnerable to pathologic provocation, often manifesting as seizure activity. Seizures involve abnormal, synchronous neuronal discharges within the cerebral cortex. These discharges may result from excessive excitatory input or insufficient inhibitory signaling. An imbalance favoring excitation over inhibition contributes to the increased susceptibility of the neonatal brain to seizures.[29]

Several factors contribute to the excitatory-inhibitory imbalance observed in the neonatal brain. The most significant is the developmental state of the neonatal neuron. In mature brains, stimulation of the γ-aminobutyric acid (GABA) receptor produces an inhibitory postsynaptic potential that reduces the likelihood of action potential generation. This effect is achieved by decreasing the cellular membrane potential by modulation of chloride and potassium channels. Chloride influx lowers the membrane potential, counteracting excitatory postsynaptic potentials mediated by glutamate.[30][31]

In contrast, the neonatal brain maintains a high intracellular chloride concentration, reversing the chloride ion gradient. Under these conditions, stimulation of the GABA receptor leads to chloride efflux and subsequent neuronal depolarization due to sodium and calcium influx. Additional contributors to this imbalance include the earlier development of excitatory synapses relative to inhibitory synapses and the premature maturation of voltage-gated ion channels that promote depolarization.

History and Physical

A thorough history and physical examination are essential in neonates presenting with seizures. An underlying provoking cause is frequently present. Therefore, the clinical history should aim to identify relevant risk factors and probable etiologies. These findings help guide both prognosis and treatment strategies. Key historical elements include the timing of seizure onset and maternal, birth, and family history.

Seizures occurring within the first 12 to 24 hours of life are often associated with hypoxic-ischemic encephalopathy, while those presenting later may indicate infection, hemorrhage, or stroke. The maternal history should be assessed for acquired and genetic conditions that increase seizure risk. Important considerations include prior miscarriages, suggestive of a genetic syndrome; gestational diabetes, raising the possibility of birth injury or fetal thrombotic vasculopathy; sexually transmitted infections or other vertically transmitted pathogens; prenatal exposure to prescription or illicit drugs; drug withdrawal; and inherited thrombophilias or bleeding disorders.[32][33]

The birth history should be evaluated for evidence of anoxic brain injury and intracranial hemorrhage. Clues suggesting anoxic injury include cord prolapse, cord thrombosis, nonreassuring fetal heart rates, meconium-stained amniotic fluid, low Apgar scores, placental abnormalities, and planned home birth.[34][35] Risk factors for intracranial hemorrhage include birth trauma, operative vaginal delivery, macrosomia, and abnormal fetal presentation, all of which may increase the likelihood of mechanical injury during delivery.[36] The family history should be investigated for early sibling deaths, inborn errors of metabolism, or familial epilepsy syndromes, any of which may suggest an underlying genetic predisposition.[37]

Physical examinations should emphasize findings that may suggest an underlying etiology. Key elements include general appearance, vital signs, head circumference, mental status, level of alertness, and fontanelle contour, particularly when evaluating for bacterial meningitis (with or without septic shock) or acute intracranial hemorrhage.[38] In stable neonates, a complete neurologic examination should focus on cranial nerve function, motor activity, tone, and facial dysmorphisms that may suggest a structural brain lesion, thrombotic event, or genetic disorder. Skin examination should evaluate for stigmata of congenital infection and assess overall perfusion status.[39]

Patients with an inborn error of metabolism may exhibit acute metabolic acidosis, often presenting with lethargy or respiratory distress. Physical findings should be carefully assessed during an active seizure to confirm seizure activity and possibly identify the underlying cause. Focal motor activity may suggest ischemic stroke or localized hemorrhage, whereas generalized activity raises concern for hypoxic-ischemic injury, infection, or multifocal stroke or hemorrhage.

Neonatal seizures are classified into several electroclinical types, each with distinct physical features. Accurate recognition of seizure semiology is essential for diagnosis, especially when electroencephalographic correlation is limited. The major seizure types and their characteristic features are as follows:

  • Focal clonic seizures present with repetitive, rhythmic contractions involving the face, limbs, neck, or trunk. These movements cannot be suppressed by repositioning or physical restraint. Seizure activity may migrate during the same ictal event, most commonly to the contralateral hemisphere, though ipsilateral migration can also occur.
  • Generalized clonic seizures are characterized by diffuse, bilateral, and synchronous motor activity.
  • Focal tonic seizures involve sustained, transient posturing of an extremity, the trunk, or the neck. These seizures may be associated with horizontal eye deviation.
  • Generalized tonic seizures may mimic decerebrate posturing (extension of both upper and lower extremities) or decorticate posturing (flexion of the upper extremities with extension of the lower extremities).[40]
  • Myoclonic seizures are abrupt, nonrepetitive muscle contractions that typically involve the flexor muscle groups of the upper extremities, trunk, diaphragm, or face.
  • Generalized myoclonic seizures manifest as bilateral, synchronous jerks affecting the upper and lower extremities.[41]

Autonomic manifestations, such as abrupt changes in vital signs, are uncommon in otherwise healthy neonates. However, these features may indicate subclinical seizure activity in neonates at increased risk for seizures.[42]

Evaluation

The suspected etiology should guide the diagnostic evaluation of neonatal seizures. Initial assessment must include immediate exclusion of hypoglycemia (via bedside blood glucose) and electrolyte disturbances—specifically hyponatremia, hypomagnesemia, and hypocalcemia—through an electrolyte panel. Evaluation for sepsis, meningitis, or encephalitis should include a complete blood count, C-reactive protein, blood cultures, and cerebrospinal fluid analysis. Using cranial ultrasound, computed tomography, or magnetic resonance imaging, neuroimaging may identify intracranial hemorrhage, stroke, or structural brain abnormalities. Meconium analysis can be useful in detecting prenatal exposure to illicit substances.[43]

Electroencephalography is critical to confirm seizure activity, particularly in cases where seizures are subclinical or difficult to detect by bedside observation.[44][45] Evaluation for inborn errors of metabolism should be considered if seizures are refractory or accompanied by other concerning features. Assessments should include blood gas analysis and targeted metabolic testing such as serum pyruvate, lactic acid, and urine amino and organic acids.[46] Genetic epilepsy syndromes may also be investigated through molecular testing and epilepsy gene panels as clinically indicated.[47]

Treatment / Management

After confirming a patent airway, hemodynamic stability, and intravenous access, treatment should be directed toward the underlying cause. Interventions may include therapeutic hypothermia for hypoxic-ischemic encephalopathy, empiric antibiotics for suspected sepsis or meningitis, intravenous dextrose for severe hypoglycemia, correction of electrolyte abnormalities, or neurosurgical referral in cases of intracranial hemorrhage.[48] For suspected inborn errors of metabolism, initial management includes cessation of feeds, correction of metabolic derangements, and empiric administration of vitamin and cofactor replacements.[49](B3)

In the setting of clinically apparent, prolonged seizures, phenobarbital remains the most commonly used first-line antiseizure medication.[50] Additional boluses may be administered if seizures persist following an initial loading dose. Fosphenytoin is typically used as a second-line agent.[51] Other pharmacologic options include levetiracetam or lidocaine, depending on the clinical context. Short-acting benzodiazepines, such as midazolam, may be administered when definitive treatment is delayed.(A1)

Pediatric neurology consultation should be obtained promptly to guide further management. Neurologists can initiate continuous electroencephalography to confirm seizure activity, detect subclinical seizures, and assist in treating refractory seizures.[52] Pediatric neurologists also provide recommendations regarding long-term antiepileptic maintenance therapy during both inpatient care and postdischarge follow-up. The duration of treatment depends on the underlying etiology.(B2)

Differential Diagnosis

Nonepileptic behaviors must be carefully distinguished from neonatal seizures.[53] These movements can closely resemble epileptic events. Thus, electroencephalography is recommended for accurate characterization.[54] Normal neonatal behaviors that may mimic seizures include sucking motions, hiccuping, and benign neonatal sleep myoclonus, which is physiologic myoclonic activity that occurs during sleep. Other nonepileptic movements, often seen in neonates with systemic illness, include jitteriness, apnea, clonus, tremors, and exaggerated startle responses, such as hyperekplexia.[55][56]

Motor automatisms, including repetitive eye-opening, eye deviation, oral-buccal movements, bicycling of the limbs, and tonic posturing, may resemble seizure activity but are often triggered by tactile stimulation and suppressed by repositioning or restraint.[57][58] These findings are considered nonepileptic but may reflect underlying neurologic pathology. Further evaluation is warranted if additional concerning features are present.

Conditions that may present with seizure-like or seizure-associated phenomena include the following:

  • Anoxia
  • Myoclonus
  • Benign epilepsy syndromes
  • Mitochondrial cytopathies
  • Myoclonic epilepsy
  • Organic acidurias
  • Pyridoxine-dependent epilepsy
  • Subdural hematoma
  • Subarachnoid hemorrhage
  • Tuberous sclerosis
  • Viral encephalitis
  • Viral meningitis
  • Vein of Galen malformation
  • Benign neonatal convulsions
  • Cerebellar hemorrhage
  • Herpes simplex encephalitis
  • Myoclonic epilepsy
  • Child abuse
  • Neonatal meningitis
  • Shuddering attacks

Accurate differentiation between epileptic and nonepileptic movements is critical to avoid unnecessary treatment and to identify neonates requiring further evaluation. Electroencephalographic confirmation and thorough clinical assessment are essential for accurate diagnosis and effective management.

Prognosis

The underlying etiology largely determines prognosis in neonatal seizures. A normal encephalogram (EEG) is associated with excellent outcomes, whereas severely abnormal EEG findings correlate with poor prognosis and an increased risk of cerebral palsy and epilepsy. The presence of interictal spikes on EEG is associated with a 30% risk of developing epilepsy later in life. Reported mortality rates reach up to 20%. Neurological impairment, developmental delay, epilepsy, and long-term disability are frequently observed among survivors.[59][60][61][62]

Complications

Complications associated with neonatal seizures are often linked to the adverse events from antiepileptic medications. Clinicians must closely monitor for respiratory compromise, including hypoxemia and hypercarbia, particularly following administration of benzodiazepines or phenobarbital.[63] This vigilance is critical, as hypoxemia is a common precipitant of cardiac arrest in pediatric populations.[64]

Phenobarbital may induce myocardial depression, while phenytoin has been associated with cardiac dysrhythmias, both of which can result in hemodynamic instability.[65] In such cases, clinicians should be prepared to initiate inotropic cardiovascular support and consider the use of fosphenytoin as a safer alternative to mitigate these adverse events.[66] Antiepileptic agents may also impair hepatic or renal function, necessitating close monitoring of drug levels during acute treatment and the maintenance phase of therapy.[67] Beyond medication-related complications, long-term neurologic sequelae may include cerebral palsy with spasticity, epilepsy, cerebral atrophy with hydrocephalus ex vacuo, and persistent feeding difficulties. Affected neonates frequently require long-term neurodevelopmental follow-up and interprofessional care.

Deterrence and Patient Education

Seizures lasting longer than 5 minutes or occurring rapidly over several minutes warrant immediate activation of emergency medical services. Emergency antiepileptic medications, such as rectal diazepam, may be prescribed for out-of-hospital use. Parents should receive clear instructions on administration techniques.[68] Counseling should also address the potential long-term consequences of neonatal seizures, including the risk of neurologic impairment, and emphasize the value of early referral to rehabilitation services.[69] In children who develop epilepsy, caregivers must be especially vigilant in situations where seizure activity could pose additional risk, such as swimming or activities requiring sustained attention or coordination.[70] Ongoing clinical follow-up with pediatric neurology is essential, and parents should be advised of the critical importance of adherence to prescribed antiepileptic therapy.[71]

Enhancing Healthcare Team Outcomes

The diagnosis and management of neonatal seizures require an interprofessional approach to prevent complications arising from underrecognition of clinical seizures and adverse effects of antiseizure medications. Early referral to neonatal or pediatric critical care services ensures timely stabilization of oxygenation and hemodynamics and facilitates evaluation by neurocritical care specialists.[72] Pediatric neurology consultation is essential to confirm the diagnosis and guide the treatment strategy.

EEG technicians must be readily available to initiate monitoring and detect electrographic seizures that may not present with overt clinical signs.[73] Timely access to antiseizure medications is critical. Pharmacists with expertise in pediatric pharmacology play an important role in ensuring the safe preparation and administration of these agents, particularly in neonatal renal and hepatic immaturity. Bedside nurses are equally vital, as they assist in recognizing clinical seizures, annotating events during monitoring, and safeguarding the patient from adverse drug events.[74]

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