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 left untreated. In addition, etiology-specific therapy may 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 overriding factor that affects long-term outcome is the etiology of the seizures and the degree and distribution of brain injury caused by the underlying disturbance.

Most neonatal seizures are due to acute symptomatic causes. However, there is increasing recognition of neonatal-onset epilepsy syndromes. This topic review will discuss recognized neonatal epilepsy syndromes.

●Acute symptomatic neonatal seizures are discussed separately. (See "Etiology and prognosis of neonatal seizures".)

●The characterization of various types of neonatal seizures, with an emphasis upon clinical features and electrodiagnosis, is discussed elsewhere, as is their treatment. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Treatment of neonatal seizures".)

OVERVIEW — Although the majority of neonatal seizures occur as acute reactive events in response to identifiable etiologic factors (table 1), additional rare but distinct neonatal epilepsy syndromes are well recognized. These include:

●Self-limited (benign) neonatal epilepsy

●Self-limited (benign) familial neonatal epilepsy

●Early myoclonic encephalopathy (EME)

●Early infantile epileptic encephalopathy (EIEE)

●KCNQ2 encephalopathy

●DEND syndrome (Developmental delay, Epilepsy, and Neonatal Diabetes)

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, diagnosis, and consequences of these disorders [1-5]. In the ILAE scheme, the 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 electroencephalogram (EEG) findings, duration of the disorder, associated clinical features, response to antiseizure medication therapy, and prognosis (table 2). (See "ILAE classification of seizures and epilepsy".)

SELF-LIMITED SYNDROMES — Two rare but well-recognized neonatal seizure syndromes are associated with a relatively good prognosis: self-limited (benign) neonatal epilepsy and self-limited (benign) familial neonatal epilepsy. These are mainly distinguished by family history.

Self-limited (benign) neonatal epilepsy — There are a number of terms that have been used to designate self-limited (benign) neonatal epilepsy, including "benign neonatal convulsions," "benign idiopathic neonatal seizures," and "fifth-day fits" (because of their peak day of onset). No studies clearly link the diagnosis to a specific etiology, although several hypotheses have been investigated: acute zinc deficiency in cerebrospinal fluid [6] and rotavirus in stool of affected infants [7]. However, the findings of these studies have not been confirmed. Some affected infants are found to have de novo pathogenic variants in the KCNQ2 gene [8].

Clinical features — Seizures occur within the first seven days of life, with 90 percent occurring between days 4 and 6, and they typically resolve within two weeks. These seizures occur in term or late preterm infants after an uneventful pregnancy, labor, and delivery, with no family history of seizures, and with normal neurologic examinations between seizures.

The most frequent seizure type is unifocal clonic, and associated apnea has sometimes been reported. Rarely, the seizures have been characterized as focal tonic. There are no reports of generalized tonic seizures. The seizures are typically brief and last from one to three minutes, though some do evolve into prolonged seizures. In addition, the seizures usually recur during a period of 24 to 48 hours; only rarely do they persist beyond that period.

The ictal electroencephalogram (EEG) is not distinctive from other electrical or electroclinical seizure types.

The interictal EEG background can be normal or abnormal with excessive discontinuity and/or multifocal negative sharp waves. The EEG pattern most closely associated with self-limited neonatal epilepsy is referred to as "theta pointu alternant" [9], and is characterized by nonreactive rhythmic slow activity, discontinuity, interhemispheric asynchrony, and multifocal sharp waves. While this EEG pattern is associated with self-limited neonatal epilepsy, it is not specific; it is found in only about 60 percent of neonates with self-limited neonatal epilepsy and has also been described in other disorders.

Diagnosis — Self-limited neonatal epilepsy is currently considered a diagnosis of exclusion, since the initial clinical presentation may mimic that of infants with acute symptomatic seizures. Thus, an extensive evaluation for an acute symptomatic seizure etiology is necessary even when the suspicion for benign neonatal convulsions is considered high. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

Proposed diagnostic criteria include the following:

●Apgar score greater than seven at one minute

●Typical interval between birth and seizure onset (four to six days)

●Normal neurologic examination before seizure onset and during the interictal periods

●Normal laboratory and imaging findings (eg, metabolic studies, neuroimaging, and cerebrospinal fluid analysis)

●No family history of neonatal seizures or post neonatal epilepsy

Treatment and prognosis — The therapy for self-limited neonatal epilepsy is similar to that for other neonatal seizures, with antiseizure medications acutely administered (see "Treatment of neonatal seizures"). Some experts suggest that the use of antiseizure medications be reserved for those infants who have prolonged seizures in light of the typical self-limited nature and brief duration of the seizures, as well as the generally good outcome associated with the natural history. However, the diagnosis generally cannot be made until after treatment is initiated, since a full evaluation for sepsis and other more common, and treatable, causes of neonatal seizures is required. If antiseizure medications are used, and the diagnosis is clear, they can often be stopped once the infant is beyond the usual 24- to 48-hour period of recurrence risk.

Infants with this disorder are classically described to have a uniformly good outcome in terms of neurologic status, development, and post-neonatal epilepsy. However, some studies suggest a more variable outcome [10,11]; one meta-analysis found abnormalities in about 15 percent of infants followed from six months to six years, most with a transient "psychomotor delay" [12]. Thus, the disorder may not always be benign, suggesting that either there is an underlying etiology that has not yet been characterized, or that the seizures themselves may adversely affect the infant.

Self-limited (benign) familial neonatal epilepsy — Since the first description of a family with neonatal seizures in several generations [13], there has been great progress made in the characterization of the syndrome of self-limited (benign) familial neonatal epilepsy, its genetics, and biology [12]. This syndrome has been reported to occur in 14 per 100,000 live births [14]. Self-limited (benign) familial neonatal epilepsy is also known as benign familial neonatal convulsions and benign familial neonatal seizures.

Genetics — Self-limited familial neonatal epilepsy is considered to be one of several epileptic disorders characterized as a channelopathy, caused in most cases by pathogenic variants in voltage-gated potassium channel genes (KCNQ2 and KCNQ3) [15-18]. The disorder is inherited in an autosomal dominant pattern. The penetrance of these pathogenic variants is approximately 85 percent [19]. Fifteen percent of those who carry a variant may fail to show seizures. In addition, there may be some families with undetected variants, or with variants in genes more commonly associated with later-onset seizures or more severe epilepsy syndromes, such as SCN2A [20,21]. (See "Epilepsy syndromes in children", section on 'Benign familial infantile epilepsy'.)

●In the EBN1 syndrome, which is the most frequently encountered, there are deletions in the gene that encodes a voltage-gated potassium channel referred to as KCNQ2 on chromosome 20q [13,22-26]. KCNQ2 variants have also been identified in patients with more severe epileptic encephalopathy syndromes. (See 'Early infantile epileptic encephalopathy' below.)

●There is a less frequently encountered EBN2 syndrome, with a deletion of chromosome 8q24 that encodes another voltage-gated potassium channel referred to as KCNQ3 [27,28].

Genetic testing is available and may be helpful in cases in which there is not a clear family history [29]. Further information is available at https://www.ncbi.nlm.nih.gov/gtr/. Counseling for genetic testing is discussed separately. (See "Genetic testing".)

Clinical features — Self-limited familial neonatal epilepsy is characterized by focal or multifocal clonic or tonic seizures, a family history of neonatal seizures, and no other neurologic abnormalities. The seizures typically occur within a few days to one week of life, although there is some variability in age at onset. Seizures are usually brief and resolve spontaneously in early infancy, but may continue until age two to three months. The interictal EEG is usually normal.

Treatment and prognosis — The initial evaluation and treatment for self-limited (benign) familial neonatal epilepsy is similar to that for other neonatal seizures. A complete evaluation for acute symptomatic neonatal seizures remains necessary even when self-limited familial neonatal epilepsy is suspected. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

As with the more severe phenotype of KCNQ2 encephalopathy (see 'KCNQ2 developmental and epileptic encephalopathy (KCNQ2 DEE)' below), observational data suggest that seizures may respond preferentially to carbamazepine or oxcarbazepine [30-32].

The syndrome had been considered to be "benign" or self-limited because initial reports suggested a relatively good outcome and no long-term neurologic sequelae. However, subsequent studies have found a higher incidence of post neonatal epilepsy than in those without self-limited familial epilepsy [33]. Seizures after age six months occur in up to one third of patients with pathogenic KCNQ2 variants, and those with higher neonatal seizure burden appear to be the most likely to have persistent epilepsy [20].

SEVERE SYNDROMES — A severe neonatal epilepsy syndrome should be suspected in newborns who lack an obvious cause for acute symptomatic seizures, especially if the interictal electroencephalogram (EEG) shows a burst suppression pattern. The severe syndromes are often associated with refractory seizures and poor neurodevelopmental outcomes.

Once immediately treatable symptomatic causes of neonatal seizures are excluded, first-line diagnostic testing should include brain magnetic resonance imaging (MRI), which may help narrow the differential diagnosis and tailor the subsequent workup. A therapeutic trial of intravenous pyridoxine administration should be performed. Serum, urine, and cerebrospinal fluid (CSF) studies are obtained on a case-by-case basis. Genetic testing is recommended in neonates with epilepsy who do not have an acute symptomatic cause identified on initial history, examination, and neuroimaging [34]. This evaluation is discussed in more detail separately. (See "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures' and "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Etiologic evaluation'.)

Early myoclonic encephalopathy (EME) and early infantile epileptic encephalopathy (EIEE) are the classic neonatal epileptic encephalopathy syndromes (table 3) [35-37]. Although EME and EIEE are considered distinct syndromes, they both exhibit a burst suppression pattern on EEG. In addition, there may be considerable overlap between EME and EIEE in terms of diagnostic criteria and prognosis. Additional severe neonatal epilepsy syndromes include KCNQ2 encephalopathy [38] and DEND syndrome (Developmental delay, Epilepsy, and Neonatal Diabetes) due to disease-causing variants in the KCNJ11 gene.

Early myoclonic encephalopathy — EME has been referred to in the literature as myoclonic encephalopathy with neonatal onset, early myoclonic encephalopathy, and neonatal myoclonic encephalopathy.

Etiology — EME has most often been associated with inborn errors of metabolism, including:

●Non-ketotic hyperglycinemia

●D-glyceric acidemia

●Methylmalonic acidemia (see "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia')

●Hyperammonemia due to carbamyl phosphate synthetase (see "Urea cycle disorders: Clinical features and diagnosis")

●Pyridoxine dependency (see "Etiology and prognosis of neonatal seizures", section on 'Inborn errors of metabolism')

●Propionic acidemia (see "Organic acidemias: An overview and specific defects", section on 'Propionic acidemia')

●Molybdenum cofactor deficiency (see "Etiology and prognosis of neonatal seizures", section on 'Inborn errors of metabolism')

●Sulfite oxidase deficiency

●Menkes disease (see "Overview of dietary trace elements", section on 'Menkes disease')

●Zellweger syndrome (see "Peroxisomal disorders", section on 'Zellweger syndrome')

Congenital (developmental) brain anomalies are thought to be an uncommon etiology for EME. There are a few reports of EME occurring in families.

The clinical picture of erratic myoclonus in an encephalopathic neonate with an EEG characterized as burst suppression during sleep should prompt an evaluation for these etiologies.

Clinical features — The age of onset is in the early neonatal period; there is no sex preponderance. The neurologic examination is very abnormal at onset, and all affected neonates have an altered state of consciousness (encephalopathy).

In addition to the encephalopathy, seizure types are the basis of initial syndrome identification.

●Segmental, fragmentary, or erratic myoclonic seizures are the earliest seizure type expressed, usually within the first few hours of life. These seizures are characterized by random, asynchronous, twitching of limb muscles, most often involving distal musculature.

●Focal clonic seizures may develop shortly after the appearance of the fragmentary myoclonic seizures, and may occur in association with the myoclonus or independently. The infant may eventually also experience generalized myoclonus.

●Repetitive tonic spasms may develop late in the course, between three and four months of age, after resolution of these other seizure types.

The EEG is helpful in diagnosis of EME. The burst suppression pattern may be present only in sleep, but it can also occur in all sleep-wake stages. The bursts are typically short (one to three seconds) and the periods of suppression are relatively long (two to 10 seconds). There is sometimes no associated EEG seizure pattern when myoclonus is present, but clear seizures are recorded when focal-clonic or tonic seizures occur. Later in the disease course, in early infancy, the EEG evolves to a modified hypsarhythmia pattern or to multifocal spikes and sharp waves.

Treatment and prognosis — The encephalopathy and the associated fragmentary myoclonus are treated with etiology-specific therapies when available. Seizures are treated with standard antiseizure medications (see "Treatment of neonatal seizures"). Although the fragmentary myoclonus may eventually resolve over weeks or months, the focal motor seizures, if they do occur, tend to become refractory to antiseizure medication therapy. The infants do not develop neurologically and tend not to acquire any developmental milestones. Approximately 50 percent of affected infants die, most within the first year of life.

Early infantile epileptic encephalopathy — Early infantile epileptic encephalopathy (EIEE) has also been referred to as Ohtahara syndrome [36]. It is a rare disorder characterized by frequent tonic spasms in neonates and infants, with burst-suppression pattern on EEG. In contrast to EME, the burst suppression pattern in EIEE is seen across all sleep-wake stages. There are some features of EIEE that are similar to EME, and there are also some distinctive characteristics (table 3). The emerging consensus is that two syndromes have significantly overlapping features, and may be considered points along a spectrum of a single disorder.

Etiology — EIEE is typically associated with structural brain abnormalities (in contrast to the classic metabolic disorders associated with EME), in addition to some monogenetic diseases. The following types of abnormalities have been reported to occur in association with EIEE:

●Porencephaly

●Aicardi's syndrome

●Focal or diffuse cerebral dysgenesis

●Hemimegalencephaly

●Dentate-olivary dysplasia

●Migrational defects

●Mitochondrial disorders

●Genetic pathogenic variants

Genetic studies in patients with EIEE have identified a number of pathogenic variants in genes that appear to cause EIEE, including the KCNQ2 gene that has also been associated with self-limited familial neonatal epilepsy [39-49]. In one series, missense variants in KCNQ2 were identified in 10 out of 51 patients (20 percent) with Ohtahara syndrome [47]. (See 'KCNQ2 developmental and epileptic encephalopathy (KCNQ2 DEE)' below.)

There are more than 80 genes with pathogenic variants that are linked to EIEE [50]. Genetic testing with an epilepsy gene panel or whole exome sequencing is appropriate when any of these etiologies is considered likely and no alternative etiology has been identified on initial evaluation. (See "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Genetic testing'.)

Inborn errors of metabolism associated with EIEE are rare; when they do occur, nonketotic hyperglycinemia has most often been identified.

Clinical features — Onset is within the first two to three months of life. At onset the neurologic examination is abnormal with developmental delay, spasticity, and often motor asymmetries. The predominant seizure type is tonic spasm, and within the spasm there is often a marked asymmetry of movement. Additional seizure types include focal motor seizures and hemiconvulsive seizures.

Tonic spasms are the predominant seizure type in EIEE; they may occur in clusters, or they may occur intermittently in some patients. Tonic spasms occur early in the course of EIEE and erratic myoclonus typically does not occur at all. However, other myoclonic seizures may rarely occur in neonates with EIEE. This contrasts with the clinical features of EME, where erratic myoclonus is a characteristic early and tonic spasms a characteristic late seizure type.

The characteristic background EEG pattern in EIEE (similar to EME) is that of burst suppression, with relatively prolonged bursts (two to six seconds) consisting of very high-voltage activity (150 to 350 microvolts) and relatively shorter periods of suppression (three to five seconds). This pattern is seen across all sleep-wake states. The EEG shows associated synchronization when the tonic spasms occur, with an initial high-voltage slow wave and then generalized fast activity.

Treatment and prognosis — The initial approach to the treatment of EIEE is similar to that of other types of neonatal seizures. (See "Treatment of neonatal seizures".)

Treatment of EIEE has generally been disappointing, although as the genetic underpinnings of EIEE are increasingly understood, there is renewed interest and optimism in more tailored therapies. There have been reported trials of steroid therapy (adrenocorticotropic hormone [ACTH] and corticosteroids), antiseizure medications (eg, valproate, zonisamide), and vitamin B6. There have also been case reports of surgical treatment with hemispherectomy and cortical dysplasia resection [51].

The overall outcome of EIEE is poor [52]. Approximately 50 percent of affected patients die in infancy. Survivors have severe neurologic impairment. In most neonates, the EEG evolves to hypsarhythmia, which is typically asymmetrical. In the remainder, the EEG evolves to consist of multifocal or unifocal spikes. Rarely, the EEG evolves to a diffusely slow background.

When considering prognosis, it is worth noting that EIEE (Ohtahara syndrome) is the earliest of the age-dependent encephalopathies that include West syndrome and Lennox-Gastaut syndrome [53]. The three share the following features:

●Specific age of onset

●Severe intellectual disability

●Abundant epileptiform EEG abnormalities

●The potential to evolve sequentially from syndrome to syndrome depending upon the age of the patient

Thus, as the infant with Ohtahara syndrome becomes a few months old, the patient may develop West syndrome and then in childhood develop Lennox-Gastaut syndrome with the associated seizure types and prognosis.

West syndrome (also known as infantile spasms) is discussed in detail separately. (See "Etiology and pathogenesis of infantile spasms" and "Clinical features and diagnosis of infantile spasms" and "Management and prognosis of infantile spasms".)

Lennox-Gastaut syndrome is also discussed separately. (See "Epilepsy syndromes in children", section on 'Lennox-Gastaut syndrome'.)

KCNQ2 developmental and epileptic encephalopathy (KCNQ2 DEE) — In contrast to self-limited familial neonatal epilepsy, some individuals with KCNQ2 pathogenic variants have a severe neonatal epileptic encephalopathy. Infants with loss of function KCNQ2 variants present in the first week of life with an abnormal neurologic examination (encephalopathy, hypotonia, and lack of visual attentiveness) and severe, treatment-resistant seizures [38]. Some affected infants can present with what appears to be Ohtahara syndrome [47]. Neonates with gain of function KCNQ2 variants may have prominent nonepileptic startle-like myoclonus, in addition to encephalopathy and abnormal EEG [54].

The seizures often have a tonic semiology, but are not classically tonic spasms. The markedly abnormal EEG can have abundant multifocal negative sharp waves and/or can meet criteria for burst suppression. Brain MRI reveals subtle abnormalities (T1 and T2 hyperintensity) in the basal ganglia and thalami. These imaging findings may resolve after the neonatal period [39]. Although the seizures may resolve by age three years, affected children typically have severe global neurodevelopmental disabilities.

KCNQ2 pathogenic variants may result in a dominant-negative effect on voltage-gated potassium channels, which in a xenopus model system could be partially reversed by retigabine [55]. Clinically, patients with KCNQ2 pathogenic variants may respond best to antiseizure medications that act on sodium channels (eg, oxcarbazepine, carbamazepine, or phenytoin) [38,56]. A similarly positive treatment response to carbamazepine has been reported for infants with SCN2A variants [30,57].

DEND syndrome — A rare form of severe neonatal epilepsy, the DEND syndrome (developmental delay, epilepsy, neonatal diabetes) is caused by an activating mutation in the KCNJ11 gene, which encodes the Kir6.2 subunit of the potassium ion channel [58]. Oral sulfonylurea therapy appears to be more effective than insulin in controlling hyperglycemia, and can also lead to improved seizure control and psychomotor development [59-61]. (See "Neonatal hyperglycemia", section on 'Neonatal diabetes mellitus'.)

SUMMARY AND RECOMMENDATIONS

●Although the majority of neonatal seizures occur as acute symptomatic events in response to identifiable etiologic factors (table 1), there are additional rare but distinct neonatal epilepsy syndromes (table 2). Many of these epilepsies have clearly definable genetic etiologies, as well as predictable treatment responses and long-term prognoses. (See 'Overview' above.)

●Self-limited (benign) neonatal epilepsy, also called "fifth-day fits," is a neonatal seizure syndrome that occurs in normal infants after an uneventful pregnancy, labor, and delivery. (See 'Self-limited (benign) neonatal epilepsy' above.)

•Seizures are usually brief, self-limited, and unifocal clonic. They typically occur between days 4 and 6 of life. They usually recur within 24 to 48 hours, but not usually after that.

•This is a diagnosis of exclusion; other causes of acute symptomatic neonatal seizures must be ruled out.

•Antiseizure medications can often be discontinued after about 48 hours, once acute symptomatic seizure etiologies are ruled-out and seizures remit.

●Self-limited (benign) familial neonatal epilepsy is an autosomal dominant inherited condition. (See 'Self-limited (benign) familial neonatal epilepsy' above.)

•Clinically, this syndrome is characterized by focal or multifocal clonic or tonic seizures, a family history of neonatal seizures, and no other neurologic abnormalities. There are no specific long-term neurologic sequelae except an increased risk for post-neonatal epilepsy.

•Genetic testing for pathogenic variants of KCNQ2 and KCNQ3 is available and may be considered in cases in which there is not a clear family history.

•Some infants may require antiseizure medication therapy.

●Early myoclonic encephalopathy is most often associated with inborn errors of metabolism. (See 'Early myoclonic encephalopathy' above.)

•Neonates are encephalopathic at presentation, with erratic myoclonus and multiple seizures types that typically begin within the first hours of life.

•Electroencephalography shows a burst suppression pattern that is most noticeable during sleep.

•The myoclonus typically subsides over weeks to months; focal motor seizures are often refractory to medical therapy.

•There is little neurologic development and mortality in the first year is approximately 50 percent.

●Early infantile epileptic encephalopathy (EIEE; Ohtahara syndrome) is a rare disorder typically associated with structural developmental brain anomalies. Some genetic syndromes have been associated with EIEE. (See 'Early infantile epileptic encephalopathy' above.)

•Infants present within the first two to three months with developmental delay, spasticity, and seizures, including tonic spasms and focal motor seizures.

•The interictal electroencephalogram shows a burst suppression pattern during all behavioral states.

•Treatment with hormonal therapy or antiseizure medications is often unsuccessful. Resective epilepsy surgery, or hemispherectomy, may be appropriate in some circumstances.

•Half of patients die in infancy; survivors have severe neurologic impairment.

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