Etiology and prognosis of neonatal seizures

INTRODUCTION — Identifying the etiology of seizures is a primary clinical objective in the management of neonatal seizures. Accurate determination of the cause can lead to etiology-specific therapy and may limit central nervous system (CNS) dysfunction that would otherwise occur if the underlying condition was left untreated. Treatment of the underlying cause of seizures may also be necessary to control the seizures themselves.

While there has been much discussion of the potential adverse effect of seizures on the immature brain, the most likely overriding factors that affect long-term outcome are the etiology of the seizures and the degree and distribution of brain injury caused by the underlying disturbance.

This topic review will discuss neonatal seizures in terms of their etiologies and will focus on acute symptomatic seizures. The much less common neonatal epilepsy syndromes are discussed separately. (See "Overview of neonatal epilepsy syndromes".)

The clinical features, diagnosis, etiologic evaluation, and treatment of neonatal seizure are reviewed separately. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Treatment of neonatal seizures".)

CLASSIFICATION — Almost all neonatal seizures may be categorized as "symptomatic" or "provoked" seizures, occurring as a consequence of a specific identifiable etiology (table 1) [1]. Such seizures are considered acute and reactive and are therefore distinct from neonatal epilepsy. (See 'Acute provoked (symptomatic) seizures' below.)

Although the majority (approximately 85 percent) of neonatal seizures occur as acute reactive events in response to identifiable etiologic factors, additional rare but distinct neonatal epilepsy syndromes are well recognized. These include:

●Self-limited (familial) neonatal epilepsy

●Early infantile developmental and epileptic encephalopathy (EIDEE)

●Additional etiology-specific epilepsies (eg, KCNQ2 developmental and epileptic encephalopathy)

The International League Against Epilepsy (ILAE) has classified epilepsy syndromes with the purposes of standardizing terminology and developing a more uniform understanding of the clinical features and consequences of these disorders [2-5]. In the ILAE scheme, epilepsy syndromes are characterized by a cluster of clinical signs, symptoms, and laboratory findings that include seizure type, age of onset, etiology, precipitating factors, severity, ictal and interictal electroencephalography (EEG) findings, duration of the disorder, associated clinical features, chronicity, response to antiseizure medication therapy, and prognosis. (See "ILAE classification of seizures and epilepsy".)

Neonatal seizures associated with these ILAE-designated syndromes are relatively rare. However, their identification is important in the management and prognosis of affected infants. (See "Overview of neonatal epilepsy syndromes" and "Overview of infantile epilepsy syndromes".)

ACUTE PROVOKED (SYMPTOMATIC) SEIZURES — Symptomatic neonatal seizures (also called provoked neonatal seizures) may result from a wide range of possible etiologies [6-9]. These can be organized by frequency (table 1) as well as relative acuity (table 2). Most etiologies can be broadly categorized as:

●Neonatal encephalopathy and hypoxic-ischemic encephalopathy

●Acquired structural brain lesions, including ischemic and hemorrhagic stroke

●Metabolic disturbances

●Central nervous system (CNS) or systemic infections

In a prospective multicenter study of 426 consecutive neonates with seizures in the United States, hypoxic ischemic encephalopathy was the most common etiology (38 percent), followed by ischemic stroke (18 percent) and intracranial hemorrhage (11 percent) [9]. A similar etiologic distribution was reported in a separate European study [10].

Neonatal encephalopathy — Neonatal encephalopathy occurring as the result of hypoxia-ischemia is the most common cause of neonatal seizures [9-11]. (See "Etiology and pathogenesis of neonatal encephalopathy".)

The diagnosis of neonatal encephalopathy and hypoxic-ischemic encephalopathy (HIE) can sometimes be difficult to make. Diagnostic criteria from the large therapeutic hypothermia trials [12-14] are adopted by many institutions and include markers such as Apgar scores, need for resuscitation in the delivery room, recognition of clinical aspects of encephalopathy, altered state of alertness, acidosis, multisystem organ dysfunction, and seizures (table 3). These are reviewed in detail separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Evaluation' and "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Markers of acute hypoxia-ischemia'.)

Many neonatal seizures are not recognized clinically, and clinical features are poorly predictive of seizures in neonates with HIE. In a rigorous multicenter EEG monitoring study, approximately 50 percent of neonates who received therapeutic hypothermia for HIE had EEG-confirmed seizures, and the most accurate predictor of seizures was a severely abnormal interictal EEG background during the first hour of recording [15]. Seizures in this setting usually occur within the first one to two days of birth and often remit after a few days [11,15-18].

Neonatal encephalopathy is discussed in detail separately. (See "Etiology and pathogenesis of neonatal encephalopathy" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

Structural brain lesions — Structural brain lesions associated with neonatal seizures include hemorrhage (intracerebral, subarachnoid, intraventricular), ischemic stroke (arterial, watershed, and venous distributions), and congenital anomalies of the brain. Hemorrhage and infarction may occur in isolation or may be the consequence of other etiologies such as CNS infection. Seizures are the most common sign of arterial ischemic stroke in newborn infants [19]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome" and "Stroke in the newborn: Classification, manifestations, and diagnosis".)

Neonatal seizures may also occur after infant heart surgery and are associated with increased risk for abnormalities on brain magnetic resonance imaging (MRI) and adverse neurodevelopmental outcomes [20-22]. In two large series of infants who were monitored with video EEG in the postoperative period, the rate of electrographic neonatal seizures (85 to 100 percent of which were subclinical) ranged from 8 to 11 percent [23,24]. Brain abnormalities, including diffuse periventricular leukomalacia or global hypoxic-ischemic injury, were found in 15 of 16 who had MRI [23]. By contrast, another study utilizing specific anesthetic and surgical protocols reported a much lower seizure occurrence, 1 of 68 infants following cardiac surgery and cardiopulmonary bypass [25].

Congenital, developmental brain anomalies (particularly disorders of neuronal migration and organization) may cause neonatal seizures [26]. Cerebral dysgenesis has become more widely recognized with increasing use of high-resolution MRI. These include both focal (eg, focal cortical dysplasia or schizencephaly) and diffuse (eg, lissencephaly) dysgenesis. Such seizures are most properly characterized as being due to neonatal-onset epilepsy. However, it is important to recognize that neonates with congenital brain malformations are also at risk for acute illnesses that predispose them to acute symptomatic seizures [27]. Thus, any neonate with seizures should be evaluated for acute, treatable etiologies (even if epilepsy is suspected).

Metabolic disturbances — Potentially treatable metabolic etiologies include hypocalcemia, hypomagnesemia, and hypoglycemia. All newborns with suspected seizures should have a bedside glucose measurement, as well as laboratory testing for metabolic (electrolyte) disturbances. Typically, reversal of these abnormalities is sufficient to treat the acute symptomatic seizures, and anticonvulsant medications are not necessary. (See "Neonatal hypocalcemia" and "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

CNS infections — Bacterial and viral infections of the CNS are important causes of seizures and other adverse sequelae [28]. In addition, prenatal infections are potential risk factors for seizures. Any neonate with suspected seizures should be considered to have a systemic and/or CNS infection until proven otherwise and should have an immediate evaluation for infection. Often, empiric treatment is indicated until appropriate testing and cultures are completed. (See "Bacterial meningitis in the neonate: Neurologic complications" and "Bacterial meningitis in children: Neurologic complications" and "Overview of TORCH infections", section on 'Clinical features of TORCH infections'.)

Drug withdrawal or intoxication — Neonates exposed to chronic opioids, alcohol, selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, benzodiazepines, and/or barbiturates may suffer a withdrawal syndrome in the first days of life that can include seizures.

The clinical features and management of these syndromes are discussed in detail separately. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Clinical features and diagnosis" and "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

Inborn errors of metabolism — Many of the inborn errors of metabolism can manifest seizures, especially in the neonatal and infantile period.

When to suspect a metabolic defect — A metabolic defect should be suspected when seizures and encephalopathy begin several days postpartum following a normal pregnancy and delivery, absent postpartum complications [29]. Other clues include a family history of consanguinity or early sibling death, physical signs such as organomegaly, cardiomyopathy, or hematologic abnormalities, and certain MRI and EEG findings (table 4). Selected laboratory tests may be useful in identifying a specific etiology (table 5). (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Seizures'.)

While the typical presentation usually includes poor feeding, lethargy, and respiratory distress after an initial symptom-free period of a few to several days, some infants present with isolated seizures. Inborn errors of metabolism should be suspected in the following settings [29,30]:

●Prepartum fetal seizures (although this is a rare and difficult-to-determine finding)

●Myoclonic seizure semiology

●Seizures refractory to conventional treatment

●Seizures associated with progressive deterioration of the infant's clinical status and worsening of the EEG background pattern

●Imaging findings of prominent brain atrophy, apparent hypoxic-ischemic injury without a history of insult, or diffuse cerebral edema

The associated clinical features typical of inborn errors of metabolism are discussed separately. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

A variety of pathogenic mechanisms may be responsible for seizures in these disorders [29]. Those that involve accumulation of metabolites or deficiency of a vitamin or cofactor are most relevant in the neonatal period, and some have specific therapies available that may improve clinical outcomes significantly. (See 'Cofactor and vitamin deficiencies' below.)

In disorders resulting from enzyme deficiencies, seizures may be caused by toxic substrates that accumulate proximal to the block or through activation of an alternate metabolic pathway. Examples include urea cycle defects, nonketotic hyperglycinemia, organic acidurias, and aminoacidopathies. Some of these disorders are included in newborn screening panels, but the composition of the panel varies from state to state and country to country. (See "Inborn errors of metabolism: Identifying the specific disorder".)

Other inborn errors of metabolism commonly manifest seizures but the onset is typically later, in infancy or early childhood. These include disorders of energy deficiency (eg, glucose transporter-1 [GLUT1] deficiency, mitochondrial disorders, brain creatine deficiency) and those associated with structural brain changes causing neuronal dysfunction (eg, lysosomal diseases, disorders of glycogen metabolism, peroxisomal disorders, congenital disorders of glycosylation) [29]. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn", section on 'Inborn errors of metabolism' and "Inborn errors of metabolism: Classification".)

Cofactor and vitamin deficiencies — Disorders that result in a cofactor or vitamin deficiency are important to recognize because they represent rare but treatable metabolic causes of refractory neonatal seizures. Examples include pyridoxine-dependent epilepsy (PDE) due to antiquitin deficiency, pyridoxamine 5’-phosphate oxidase (PNPO) deficiency, and biotinidase deficiency. Molybdenum cofactor deficiency is another rare cofactor deficiency with an emerging treatment option.

●Pyridoxine-dependent epilepsy – Most cases of PDE are due to alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase (also known as antiquitin, or ATQ) deficiency, an autosomal recessive inborn error of metabolism caused by defects in the ALDH7A1 gene that lead to accumulation of alpha-AASA and pipecolic acid in plasma, urine and CSF [31-34]. PNPO deficiency due to pathogenic variants in the PNPO gene is a related condition that lacks a biomarker aside from medically refractory neonatal seizures that are responsive to pyridoxine or pyridoxal 5’-phosphate (PLP) [35-37].

Antiquitin deficiency and PNPO deficiency have overlapping phenotypes. Most patients present with seizures in the neonatal period that can be focal, generalized, tonic, or myoclonic; some patients have infantile spasms [34,38,39]. Up to half of children with PNPO deficiency are born at ≤37 weeks gestation [35,36]. Most children have excellent seizure control with pyridoxine or PLP supplementation but have a wide variety of neurodevelopmental problems [40-43]. Lysine restricted diets, combined with arginine supplementation, may also be associated with milder neurodevelopmental phenotypes in affected children [44,45]. Some children with antiquitin deficiency and pyridoxine-refractory seizures may respond to leucovorin (folinic acid) [46]. This has led to a sequence of empirical therapies and biochemical evaluation in infants with medically refractory neonatal seizures (algorithm 1). (See "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures'.)

●Biotinidase deficiency – Biotinidase deficiency due to pathogenic variants in the biotinidase gene may result in medically refractory neonatal seizures that are responsive to oral biotin supplementation. In areas where biotinidase enzyme activity is not included in the newborn screening panel, a trial of biotin may be considered in addition to pyridoxine, PLP, and/or leucovorin. (See "Treatment of neonatal seizures", section on 'Biotinidase deficiency'.)

●Molybdenum cofactor deficiency – Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disorder that results from one of several single gene defects in the biosynthetic pathway of molybdenum cofactor [47]. Approximately two-thirds of patients have MoCD type A, in which pathogenic variants in molybdenum cofactor synthesis gene 1 (MOSC1) result in the inability to synthesize the first intermediate in the pathway, cyclic pyranopterin monophosphate (cPMP), and the toxic accumulation of sulfites in blood and urine [48]. Most patients present during the first few days of life with exaggerated startle, lethargy, intractable seizures, and autonomic dysfunction, a complex of symptoms that may resemble hypoxic ischemic encephalopathy. The disorder can be diagnosed by urine dipstick showing elevated sulfite levels and confirmed with urinary cPMP testing and mutational analysis. Supplementation of cPMP by daily intravenous infusions is a promising therapy in patients with MoCD type A (but not type B) with the potential to greatly improve neurodevelopmental outcomes when started sufficiently early and continued chronically [49-52].

NEONATAL EPILEPSY SYNDROMES — One of the neonatal epilepsy syndromes recognized by the International League Against Epilepsy (ILAE) is considered self-limited, as its name implies, and is associated with a relatively good prognosis: self-limited (familial) neonatal epilepsy [5]. By contrast, early infantile developmental and epileptic encephalopathy (EIDEE) is categorized as a severe neonatal epilepsy syndromes because of its poor prognosis. Genetic etiologies are being increasingly recognized in patients with these syndromes [27]. These syndromes are discussed separately. (See "Overview of neonatal epilepsy syndromes" and "Overview of infantile epilepsy syndromes".)

PROGNOSIS — The consequences of acute symptomatic seizures in neonates are determined mainly by the etiology of the seizures [53,54]. Seizure burden and use of antiseizure medications may also have some impact, but this has yet to be fully defined [55]. (See "Overview of neonatal epilepsy syndromes".)

Mortality and neurologic impairment — There is a high incidence of early death (15 to 20 percent) associated with neonatal seizures [9,56]. Risk factors for early death include hypoxic-ischemic etiology and high seizure burden. Mortality is even more common among preterm neonates, with mortality rates ranging from 25 to 35 percent [57-59]. Even among survivors, there is an elevated risk of death throughout childhood, particularly for those who develop cerebral palsy and global developmental delay.

Neurologic impairment, developmental delay, and postneonatal epilepsy are common among survivors [54,60-66]. In studies with follow up ranging from 17 months to 10 years of age, the following long-term outcomes have been reported:

●Abnormalities on neurologic examination (42 to 59 percent)

●Global developmental delay (55 percent) [61]

●Intellectual disability (20 to 40 percent) [62,63]

●Cerebral palsy (25 to 43 percent) [62,63,67]

●Learning disabilities (27 percent) [63]

●No neurologic abnormalities (22 to 35 percent) [60]

●Epilepsy (13 to 27 percent) as discussed in the section that follows

Postneonatal epilepsy — Postneonatal epilepsy occurs in 13 to 27 percent of survivors of neonatal seizures [60-64,68-71], and rates as high as 56 percent have been reported among populations with relatively high risk factors for central nervous system (CNS) dysfunction, such as more frequent seizures or status epilepticus [72,73]. When seizures do occur in the postneonatal period, they most often emerge within the first six to nine months of life [63,68,69]. However, the risk continues through early childhood [74].

Postneonatal epilepsy syndromes in survivors of neonatal seizures generally reflect the underlying etiology of the symptomatic seizures. As an example, a child with a focal brain lesion is most likely to develop focal epilepsy, while a child with diffuse brain injury may develop a generalized epilepsy syndrome [75]. A relatively high rate of West Syndrome (infantile spasms, hypsarhythmia, and developmental disability) has been reported among survivors [63,67,76].

Risk factors for postneonatal epilepsy include:

●Neonatal status epilepticus

●Requirement for more than one antiseizure medication to control neonatal seizures

●Seizure semiology other than focal clonic or focal tonic

●Abnormal neuroimaging

●Low birth weight

●Multifocal (versus focal) neonatal seizures

●Seizure spread to the contralateral hemisphere

●Persistently abnormal interictal EEG background

●Diagnosis of cerebral palsy during early childhood

Specific risk factors for infantile spasms after acute symptomatic seizures are:

●Severely abnormal neonatal EEG background or ≥3 days of EEG-confirmed neonatal seizures [77]

●Deep gray or brainstem injury on neonatal brain MRI

●Abnormal tone on discharge neurologic exam

To date, the only potentially protective intervention to prevent post-neonatal epilepsy is therapeutic hypothermia for neonates with hypoxic-ischemic encephalopathy (HIE). One study reported significantly lower post-neonatal epilepsy rates among neonates treated with therapeutic hypothermia compared with normothermia (19 versus 40 percent) [78]. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

Mechanisms of brain injury — It is difficult to assess the relative contribution of various factors that may determine long-term outcome of those who have experienced neonatal seizures. Contributing factors may include the direct effect of seizures on the developing brain, the indirect effect of seizures, direct or indirect effects of antiseizure medications, and the effect of the underlying cause of seizures [79]. Immature animals are more resistant to some types of seizure-induced brain injury than are older animals [80]. However, animal models suggest that early-life seizures can lead to altered neuronal circuitry and may manifest as impaired learning and memory.

Abnormalities that have been observed in animal models after induced neonatal seizures include reduced dendritic spine density in hippocampal pyramidal neurons, decreased neurogenesis, and altered hippocampal plasticity (eg, diminished capacity for long-term potentiation, reduced susceptibility to kindling and enhanced paired-pulse inhibition) [81-84].

In clinical practice it may appear that seizure duration influences outcome, since infants who experience brief and infrequent seizures can have relatively good long-term outcomes, while those with prolonged seizures may not do as well. However, transient causes (eg, glucose or electrolyte disturbances that have no associated permanent brain injury) may result in easily controlled seizures or self-limited seizures, while medically refractory neonatal seizures may be the result of more sustained, less treatable, or more severe brain disorders [85]. Therefore, it is difficult to be certain about causation.

Nonetheless, survivors of HIE who experienced severe neonatal seizures were reported to have a 30-point (2 standard deviations) lower full-scale intelligence quotient (IQ) at age four years, compared with those who were seizure-free in the neonatal period [86]. Those with milder seizure burden still had lower IQs (by a full standard deviation) than children who were seizure free. These associations persisted after adjustment for neonatal MRI injury severity.

Another study found that a greater burden of electrographic seizures correlated with a relative increase in mortality and morbidity in at-risk infants in general, and also in infants with perinatal asphyxia [87]. Other investigations utilizing proton magnetic resonance spectroscopy (H-MRS) in neonates have found associations between seizure severity and both impaired cerebral metabolism (measured by lactate/choline) and compromised neuronal integrity (measured by N-acetylaspartate/choline) [88]. These results suggest that brain injury is not limited to structural damage detected by MRI.

Predictive variables

Clinical features — The dominant factor that predicts outcome appears to be the underlying cause of the seizures rather than the presence, duration, or degree of brain involvement of the seizures themselves. In clinical studies, normal developmental outcomes are more likely when seizures are associated with hypoglycemia or hypocalcemia than when seizures occur in association with HIE, severe infection, or hemorrhage [6,54,89-96].

Seizure type may also predict outcome, due in part to the degree of CNS dysfunction typically associated with various categories of seizures [62,63,97]. The presence of focal clonic and focal tonic seizures may suggest a relatively good outcome, primarily because these are typically associated with brain injury confined to one region, with spared CNS function in the remaining brain regions. However, focal tonic seizures are often associated with neonatal epilepsies that can portend significant neurodevelopmental impairment [27]. Generalized tonic posturing, motor automatisms, and myoclonus suggest a poor outcome, since they are associated with diffuse CNS dysfunction. Similarly, multifocal seizures are associated with worse outcomes than unifocal seizures.

A number of clinical variables in addition to etiology and character of the seizures may be predictors of outcome; these include [9,53,54,63,96-100]:

●Seizure burden, including the number of sites of seizure onset and seizure duration

●Status epilepticus

●Neurologic examination at the time of seizures and at the time of hospital discharge

●Number of drugs required to treat seizures

●Findings on neuroimaging

●Gestational age (term versus preterm)

●Birth weight

Multiple, rather than single, factors appear to be most accurate in predicting outcome. However, all of these variables ultimately are related to the degree of brain injury at the time of seizure occurrence, and, in turn, the seizure etiology.

EEG features — The character of the interictal background EEG can be helpful in the determination of long-term outcome of infants who have experienced seizures.

It is generally thought that the greater the EEG abnormality, the worse the prognosis. In making this determination, however, it is critical to take into consideration both the timing of the EEG in relation to the suspected time of injury and the rate of resolution of EEG abnormalities over time. An EEG performed early in the course of illness can be repeated several days later. The persistence of a diffuse EEG abnormality can suggest a poor prognosis, while its resolution suggests a better outcome. On the other hand, a normal initial EEG within 24 hours of birth reliably suggests a good prognosis.

For newborns who receive therapeutic hypothermia for HIE, the recovery of EEG patterns may be delayed, with emergence of sleep-wake cycling in the second day of life [101]. Still, persistent severe background abnormalities confer a high risk for adverse outcomes.

Features of the ictal EEG that predict worse outcome include multifocal seizure onset and ictal spread to the contralateral hemisphere.

SUMMARY

●Almost all neonatal seizures may be categorized as "symptomatic" (acute and reactive) seizures, occurring as a consequence of a specific identifiable etiology (table 1 and table 2). (See 'Classification' above.)

●Neonatal encephalopathy occurring as the result of hypoxia-ischemia is the most common cause of symptomatic neonatal seizures. Other common causes are ischemic or hemorrhagic stroke, metabolic disturbances, and central nervous system infection. Inborn errors of metabolism, although rare, are important to identify, since disease-modifying therapy may be available. (See 'Acute provoked (symptomatic) seizures' above.)

●Three rare but distinct neonatal epilepsy syndromes are well recognized: benign familial neonatal epilepsy, early myoclonic encephalopathy, and early infantile epileptic encephalopathy. Genetic etiologies for these syndromes are being increasingly recognized. (See "Overview of neonatal epilepsy syndromes".)

●There is a high incidence of early death (15 to 20 percent; higher for preterm infants) associated with neonatal seizures, as well as a high incidence of neurologic impairments (20 to 60 percent), cerebral palsy (up to 35 percent), developmental delay (up to 55 percent), and postneonatal epilepsy (13 to 27 percent) among survivors. (See 'Prognosis' above.)

●The most likely overriding factors that affect long-term outcome are the etiology of the seizures and the degree and distribution of brain injury caused by the underlying disturbance. The interictal EEG can also be useful in helping to predict long-term outcome. (See 'Predictive variables' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Eli Mizrahi, who contributed to an earlier version of this topic review.