Etiology of Neonatal Seizures

After completing this article, readers should be able to: Neonatal seizures are a common problem in the newborn nursery and can occur in infants at any gestational age. Seizures in a newborn infant evoke a sense of urgency among neonatologists because they often indicate a disturbance of the central nervous system (CNS). Causes of neonatal seizures encompass virtually the entire spectrum of neurologic disorders of infancy, but most neonatal seizures today are due to hypoxic-ischemic brain injury and intracranial hemorrhage.The proper treatment of neonatal seizures depends on the cause. For example, neonatal seizures due to a transient metabolic disturbance, such as hypocalcemia or hypoglycemia, are treated by correcting the underlying metabolic derangement. However, seizures due to such transient disturbances are relatively infrequent today because of improved neonatal care. For neonates who have seizures caused by a systemic infection (sepsis) or CNS infection (meningitis and encephalitis), the underlying infection must be treated appropriately. The specific cause also has prognostic implications.More common etiologies of neonatal seizures are discussed in this review (Table 1). As discussed in the review on neonatal electroencephalography (EEG) in this issue of NeoReviews, proper identification of epileptic seizures is important. The most common seizure types are: focal or multifocal clonic, tonic, and myoclonic and subtle. Subtle seizures comprise a variety of motor and autonomic phenomena and are more common in neonates who have severe encephalopathies. However, neonates often have abnormal paroxysmal motor activity, such as oral-buccal-lingual movements, pedaling, stepping, and rotatory arm movements, that are not associated with ictal EEG patterns. These nonepileptic events do not require treatment with anticonvulsants. The EEG is of particular value for detecting subclinical seizures (EEG seizures without clinical manifestations) and for distinguishing subtle seizures from nonepileptic behaviors. In today’s neonatal intensive care units, hypoxic-ischemic encephalopathy is the most common cause of neonatal seizures. Approximately two thirds of all neonatal seizures are due to this cause. Infants who have a mild degree of encephalopathy often experience variable levels of consciousness in which periods of lethargy alternate with periods of irritability and “hyperalertness.” They manifest jitteriness, which is described best as a spontaneous or stimulus-induced myoclonus (nonepileptic). Muscle tone is normal or increased, and the deep tendon reflexes are hyperactive. Mild encephalopathy usually lasts for fewer than 24 hours. (1)(2)Within the first postnatal day, the term newborn may progress to moderate encephalopathy with an altered level of consciousness (lethargy or stupor with reactivity) and hypotonia. Seizures that may occur during this stage must be differentiated from other abnormal movements, such as spontaneous myoclonus, hyperactive tendon stretch reflexes with clonus, and jaw clonus.Severe encephalopathy is characterized by coma, flaccidity, and unresponsiveness to noxious stimuli. (1)(2) Seizures are very common during this stage and occur within the first 24 hours after birth, often within 12 hours. (3) Focal clonic or multifocal clonic seizures often are present. Furthermore, subtle seizures, consisting of eye deviation, subtle posturing, or autonomic changes, frequently accompany more overt seizures. Infants also may have nonepileptic events, such as decerebrate posturing, which is believed to represent a “brainstem release phenomenon” due to forebrain dysfunction. The seizures usually last for several days and may be difficult to control.The frequency and severity of neonatal seizures due to hypoxic-ischemic encephalopathy usually parallel the grade of the encephalopathy. Seizures are most common during the first week after birth. As the acute encephalopathy resolves, the seizures also remit spontaneously. Approximately one third of affected infants experience postneonatal seizures (ie, epilepsy).Bacterial meningitis can cause seizures that usually occur in the latter part of the first postnatal week. (3) The most common bacterial pathogens are group B Streptococcus, Escherichia coli, and other gram-negative rods. Approximately 25% of neonates who have bacterial sepsis develop meningitis. (4) Lumbar puncture for cerebrospinal fluid analysis and culture is performed when meningitis is suspected. The degree of EEG background abnormalities, the presence of EEG-documented seizures, and the level of consciousness are strong predictors of outcome. (5)Various viruses, such as herpes simplex virus (HSV) and enteroviruses, may cause acute encephalitis and seizures. Congenital infections, such as toxoplasmosis and cytomegalovirus infection, may cause seizures, but such seizures tend to occur later in the neonatal period or early infancy.HSV encephalitis is one of the common severe viral encephalitides in the neonatal period. Seizures due to HSV infection occur in 57% of newborns who have CNS disease and 22% of those who have the disseminated form of disease, but rarely in the skin-eye-mouth (SEM) disease group. (6) The mean age of patients who have CNS disease at initiation of antiviral therapy is 15 to 20 days. (6) However, approximately 10% of patients exhibit onset of symptoms within the first 24 hours after birth, suggesting in utero acquisition of HSV infection. In the CNS and disseminated forms of the infection, typical skin vesicles are absent in approximately 40% of infants. (6)The neonatal form of HSV encephalitis is caused more often by type 2 HSV that the newborn acquires during delivery from maternal genital lesions. Fetal scalp monitoring may be a risk factor for acquiring the virus. Neuroimaging studies in neonatal HSV encephalitis often show diffuse brain abnormalities. In severe CNS disease, EEG may show a characteristic multifocal periodic or pseudoperiodic pattern. (7) The periodic sharp activity (recurring at 1- to 4-sec intervals) appears in the temporal, frontal, and central regions. It usually does not vary and is interrupted only by focal seizures. Since the introduction of acyclovir therapy, severe CNS disease occurs rarely, and more nonspecific EEG abnormalities usually are recorded. (8) HSV encephalitis should be considered in the differential diagnosis of acutely ill newborns who have seizures. If the presentation is compatible with neonatal HSV infection, appropriate diagnostic studies should be obtained and acyclovir treatment initiated. HSV cultures from the conjunctivae provide the greatest yield, although skin and oropharyngeal samples often also are obtained. (6) HSV DNA polymerase chain reaction (PCR) of CSF specimens appears to be sensitive for CNS involvement, but CSF viral cultures have a low yield.Subarachnoid hemorrhages may cause neonatal seizures in the term infant. This often occurs in the context of a vaginal delivery of an infant who otherwise appears fairly healthy. Seizures often begin during the second day after birth. Computed tomography (CT) and magnetic resonance imaging (MRI) may show subarachnoid blood in the posterior fossa, over the cerebral convexities, or both. Blood collections also may be present along the tentorium. These seizures are usually self-limited and have a good prognosis.In the preterm infant, intraventricular hemorrhages may result from bleeding in the subependymal germinal matrix. Large hemorrhages often are associated with periventricular ischemic lesions and may cause seizures. Seizures may manifest as generalized tonic posturing or subtle seizure phenomena. (3) In one study, seizures due to intraventricular hemorrhages accounted for 45% of the preterm infants who had EEG-documented seizures. (9) However, in our experience, seizures due to catastrophic intraventricular hemorrhages in preterm infants seem to be less common.Intraventricular hemorrhage in term infants may result from trauma, hypoxic-ischemic injury, or venous sinus thrombosis. In term infants, the hemorrhages usually originate in the choroid plexus. Seizures may occur in affected infants, and the duration of seizures and prognosis appear to be related to the cause of the hemorrhage.Seizures may occur from subdural hemorrhages, which usually are the result of trauma. CT and MRI reveal subdural collections of blood over the convexities and along the tentorium. There also may be a component of subarachnoid hemorrhage. Seizures occur within the first 48 postnatal hours. (3)Cortical injury may result from occlusion of an artery that causes necrosis of all cellular elements in the distribution of a single vessel. The middle cerebral artery is involved most frequently. Most injuries are believed to be due to embolic or thrombotic processes. Although the actual cause is found infrequently, coagulopathy, congenital heart disease, and trauma are common associated disorders. As the infarction evolves, brain parenchyma dissolve and a cavity (porencephalic cyst) forms. If multiple vessels are involved, multicystic encephalomalacia or hydranencephaly may result. Clinical features are understandably variable because the time of the infarction and the location are the primary determinants of physical findings.Seizures frequently are described in infants who have neonatal strokes. (10) Focal clonic seizures are common. Hemiparesis may be present on neurologic examination, but it often is subtle. The EEG usually demonstrates lateralized abnormalities and allows assessment of the severity of the encephalopathy in other cortical regions. CT and MRI show a wedge-shaped area of abnormal signal that is in the distribution of a single artery. MRI sequences using diffusion-weighted images may provide a sensitive method of detecting infarcts early in the course before CT or routine MRI sequences reveal the lesion.Infants may develop spastic hemiparesis (“hemiplegic cerebral palsy”) as a long-term sequela. Because of the frequent involvement of the middle cerebral artery, the upper extremity is more impaired. The extent and location of the pathologic lesion are important factors in determining whether intellectual impairment and epilepsy also develop. (11)Cerebral venous thrombosis often presents in newborns who have seizures, respiratory distress, and lethargy. (12)(13) In one study, 68% of neonates who had cerebral venous thrombosis experienced seizures. (13) The occlusions usually occur in the superior sagittal sinus, sigmoid/transverse sinus, or multiple venous sinuses. Venous occlusions may lead to focal cerebral injury (ie, strokes), which frequently are hemorrhagic. MRI has been particularly useful for diagnosing venous sinus thrombosis and focal injury due to venous occlusions. (12) Venous sinus thrombosis also may cause secondary intraventricular (choroid plexus) hemorrhages in the term newborn. Risk factors for venous thrombosis include persistent pulmonary hypertension, infection, dehydration, and thrombophilic disorders.Extracorporeal membrane oxygenation (ECMO) is associated with various cerebrovascular disturbances in addition to the underlying hypoxemic condition that necessitates its use. (14) Posterior fossa hemorrhages have been noted in infants receiving ECMO, presumably due to disturbance of cerebral venous return. Seizures are relatively common in infants undergoing ECMO. (15)Cerebral malformations are well-recognized causes for seizures during infancy and the newborn period. Those that typically present in the neonatal period are discussed here.With holoprosencephaly, there is failure of complete separation of cerebral hemispheres and deep gray nuclei, often associated with a fluid-filled dorsal cyst. Seizures occur in approximately 50% of patients who have holoprosencephaly, and more severe epilepsies occur in those who have additional dysplastic cortical abnormalities. (16) EEG recordings from scalp regions overlying the abnormal telencephalon often appear grossly abnormal, displaying multifocal spikes and polyspikes; prolonged runs of rhythmic alpha, theta, or delta activity; asynchrony; and a fast beta activity that probably represents subclinical seizures.Lissencephaly (agyria-pachygyria) is a developmental malformation in which the cortical surface of the brain is smooth or contains broad, thick gyri. Seizures are common and often become refractory to medical treatments. EEG readings in affected infants and children show a characteristic “major fast dysrhythmia” that consists of rapid, very high-amplitude, alpha-beta activity. (17)Certain types of cerebral dysgenesis may be caused by a specific inborn error of metabolism that disturbs early fetal development. For example, nonketotic hyperglycinemia, pyruvate dehydrogenase deficiency, and maternal hyperglycinemia frequently are associated with corpus callosal dysgenesis. (18) Peroxisomal disorders and fatty acid oxidation defects have been associated with migration abnormalities. Therefore, when these types of malformations are encountered, further metabolic investigation should be pursued. The recognition of a metabolic disorder as the cause of the brain malformation is important for both the care of the patient and for genetic counseling.Seizures due to hypoglycemia occur most commonly in infants of diabetic mothers or infants who are small for gestational age. Seizures may be focal and often begin on the second postnatal day. The hypoglycemia may be due to other conditions, such as hypoxic-ischemic encephalopathy or infections. Correction of the hypoglycemia treats the seizures and concomitant neurologic symptoms such as jitteriness, hypotonia, and lethargy. In cases of persistent hypoglycemia, further metabolic and endocrinologic evaluations should be considered.Hypocalcemia was a commonly reported cause of seizures in the past, constituting 20% to 34% of neonatal seizures in the 1960s and early 1970s. (19) Most affected infants experienced late-onset (age 4 to 14 d) hypocalcemic seizures that were due to the high phosphate content of cow milk formulas. This nutritional problem has become rare as careful attention is paid to the calcium: phosphorous ratio in infant formulas. Today, hypocalcemic seizure are uncommon (constituting approximately 3% of the total) and are of early onset (first 3 d). (20) The cause of hypocalcemia also has changed, with approximately 50% of cases being associated with congenital cardiac defects. (19) Prematurity and endocrine dysfunctions (maternal hyperparathyroidism or idiopathic hypoparathyroidism) are some of the causes of hypocalcemia. Hypomagnesemia often is associated with hypocalcemia, but it does not seem to cause seizures in isolation without hypocalcemia.A diagnostic evaluation for DiGeorge or velocardiofacial syndrome (22q11.2 deletion syndrome) should be considered for patients who present with hypocalcemia and cardiac disorders. A fluorescent in situ hybridization test for deletion in 22q11.2 is the diagnostic method of choice. Affected patients also have craniofacial abnormalities, hypoparathyroidism, and immune deficiencies.Hypocalcemia also may be induced after cardiopulmonary bypass and blood transfusion. (19) It is important to provide adequate supplementation of calcium postoperatively in patients who have undergone open-heart surgery.Similarly to seizures due to hypoglycemia, those due to hypocalcemia may be focal.Inborn errors of metabolism of the newborn often are associated with encephalopathy and seizures. A variety of such disorders may cause neonatal seizures, including urea cycle defects, organic acidurias, and aminoacidopathies. Hyperammonemia and metabolic acidosis are signs of such disorders. Rare causes include disorders of biotin metabolism, peroxisomal disorders, molybdenum cofactor deficiency, sulfite oxidase deficiency, and disorder of fructose metabolism. (21) These disorders should be suspected when an encephalopathy develops in a healthy infant who deteriorates after the initiation of feedings. The goal is to identify the metabolic problem and correct the underlying defect whenever possible while administering anticonvulsants.In the neonatal form of maple syrup urine disease and propionic acidemia, a characteristic EEG pattern is evident in the first few postnatal weeks. (22) Runs and bursts of 5 to 7 Hz, primarily monophasic negative (mu-like or comblike) activity in the central and midline central regions are present during all states, with the most abundant bursts occurring in non-rapid eye movement sleep. The pattern gradually disappears after the institution of dietary therapy.Classic nonketotic hyperglycinemia (glycine encephalopathy) is due to a defect in cleavage of the excitatory amino acid glycine. This lifelong condition usually causes neonatal seizures characterized by early myoclonic encephalopathy and severe static encephalopathy. Transient nonketotic hyperglycinemia is a very rare disorder characterized by clinical and biochemical findings similar to those seen in classic nonketotic hyperglycinemia. (23) Abnormalities in amino acids resolve partially or completely in days to months. Nearly all patients who have the classic nonketotic hyperglycinemia develop severe neurologic sequelae; most patients who have the transient form exhibit normal development. Therefore, distinguishing the transient from the classic form of nonketotic hyperglycinemia is important for prognosis. CSF analysis of glycine may be needed to diagnose either form.Pyridoxine-dependent epilepsy (PDE) is caused by an inborn abnormality in pyridoxine-dependent synthesis of the inhibitory neurotransmitter GABA. This is a rare autosomal recessive disorder. Children present with frequent seizures or status epilepticus in the newborn period or early infancy. Seizures are refractory to conventional anticonvulsants. The seizures may develop in utero. The seizures are controlled only with the administration of high-doses of pyridoxine (vitamin B6). In between the seizures, the infants are hypotonic, agitated, and irritable. They have exaggerated startle responses. The seizures often are partial in onset and generalize secondarily. Myoclonic seizures and infantile spasms also may occur. The interictal EEG shows a burst-suppression pattern and generalized rhythmic slow waves. (24)No routine diagnostic tests are available to confirm this diagnosis. For newborns and infants who have medically refractory seizures, PDE should be considered in the differential diagnosis. The diagnostic test (and treatment) consists of a trial of pyridoxine (100 mg, intravenous bolus). This usually is infused over several minutes because a rapid bolus may induce apnea, bradycardia, and severe hypotonia. Simultaneous EEG monitoring during administration is helpful to determine a response, which may require 5 to 10 minutes. If there is a response to pyridoxine, the infant should be treated with daily therapy of 200 mg/d orally. Other antiepileptic medications can be withdrawn gradually. A pyridoxine withdrawal challenge can confirm the diagnosis. If the child has PDE, seizures recur in 7 days to 3 weeks, and pyridoxine should be restarted.Although the seizures may be controlled with pyridoxine, psychomotor retardation is common in children who have PDE. The spectrum of dysfunction varies from mild to severe. Even early diagnosis and treatment does not seem to prevent the development of mental deficiencies. In some children, progressive ventricular enlargement has been noted in serial neuroimaging studies. (25)Infants who have glucose transporter type 1 deficiency syndrome (GLUT-1 DS) may have neonatal seizures, but seizures appear more frequently during infancy (usually between 6 and 12 wk). This disease is due to GLUT-1 deficiency, which in of glucose at the and This defect of glucose the brain in glucose are very usually that causes developmental and a motor disorder in early have been in the GLUT-1 The diagnosis should be suspected when there is low CSF glucose to glucose GLUT-1 can be by an that the of in to is treatment for GLUT-1 as an for the The appears to epilepsy in affected children, although the long-term is not recognition of this disorder is important because there appears be a between in treatment and severity of seizures of neonatal usually begin during the first week after birth. other cause is found for the seizures. on the neurologic and interictal EEG are The child may have several seizures during infancy, but they resolve spontaneously. There usually is a of seizures during the neonatal period or appears to be a characteristic pattern of seizures. The seizures begin with a diffuse of the background by and tonic motor activity. Seizures to rhythmic slow activity that is by and sharp during clonic activity. and also are present during this have found that the seizures in neonatal are focal in with secondary neonatal is an idiopathic epileptic syndrome that has an autosomal with an Large have been In two were one on the arm of 20 and the other on the arm of In two were in this distinguishing this as the first epilepsy in which a was were found in and for in cause or in by the of the This causes idiopathic neonatal seizures or seizures develop between postnatal days 4 and 6 in of The seizures may include focal clonic activity, apnea, and status Children do not have and development is is The cause of this disorder is interictal EEG in this syndrome shows a pattern. The EEG background consists of to 7 activity that is and with other sharp activity. This pattern in and However, the pattern appears to be similar can be seen in inborn errors of metabolism, such as maple syrup urine myoclonic encephalopathy is characterized by myoclonic that begin in the newborn period. These are by partial seizures, myoclonus, and infrequently, tonic seizures. The EEG shows a characteristic burst-suppression with periods of to 12 that are seen during sleep. The burst-suppression pattern often or multifocal sharp and The infants have developmental abnormal and causes include inborn errors of metabolism nonketotic pyridoxine and brain malformations such as The specific cause often is not although cases have been syndrome infantile epileptic encephalopathy with is characterized by frequent tonic spasms that develop in the neonatal period or early infancy. The burst-suppression pattern is seen during and The tonic spasms are associated with the bursts or of cerebral activity seizures are seen in one third of the infants, but myoclonic seizures are The infants have severe encephalopathy and develop The cause varies but often is related to cerebral abnormalities, including cerebral and diffuse or focal cortical metabolic disorders are associated with of seizure onset the as by findings from a in the (20) Most seizures due to hypoxic-ischemic encephalopathy and intracranial hemorrhage during the first 4 postnatal days. encephalopathy of total) was the most common cause of seizures in both preterm and term infants. Seizures associated with hypoxic-ischemic encephalopathy early in the neonatal period (ie, in the first 2 postnatal Furthermore, of all seizures in the first 2 days after were related to hypoxic-ischemic encephalopathy. Seizures due to hypocalcemia or hypoglycemia also within the first 2 days. Most of the seizures due to cerebral dysgenesis after the first although a small in the first 2 days. There was a distribution to seizure onset due to infections, with the first occurring within the first 4 days and one occurring after the first week. Seizures due to idiopathic neonatal seizures between 5 and 7 days. Those due to neonatal to occur 2 appropriate diagnostic evaluations for a child who neonatal seizures. The diagnostic should be performed in a CSF and a neuroimaging should be obtained in all infants who have neonatal seizures. The goal for determining cause is to any or condition as hypocalcemia and and to determine the prognosis. The of neuroimaging test frequently is If the infant is ill or receiving ECMO, may be the of the child is for CT or However, is in its and to the cerebral CT is helpful for acute intracranial hemorrhages or MRI is the of for of hypoxic-ischemic brain injury and to identify cerebral infection also is very important. Blood and CSF cultures should be and the child should appropriate bacterial are If there is a clinical of viral a and culture for HSV may be obtained while the child is treated with antiviral such as or causes are inborn errors of metabolism should be initiated. A persistent metabolic acidosis an organic for inborn errors of metabolism include for urea cycle abnormalities, for amino and urine organic is to a careful of any seizures in during the neonatal period or early infancy to for or genetic Because the seizures of neonatal remit during infancy, the may not that they had experienced seizures. It is important to both maternal and for this and severity of the neurologic that causes the neonatal seizure is a of prognosis and (Table For example, approximately 50% of children who have had hypoxic-ischemic encephalopathy with seizures have normal development. (3) Infants seizures are due to intraventricular hemorrhages associated with periventricular have a low for normal development. Seizures due to subarachnoid hemorrhages are associated with a in most infants. In bacterial approximately 50% of the neonates who have seizures have a normal outcome. (3) dysgenesis is associated with a outcome. neonatal have a very good prognosis. It important to possible causes of neonatal seizures both to provide prognostic and to determine appropriate In approximately of can be (20)