Overview of neonatal epilepsy syndromes

INTRODUCTION — Identifying the cause is a primary clinical objective in the management of neonatal seizures, in part because accurate determination can lead to more precise therapy. Most neonatal seizures are acute symptomatic seizures, but approximately 10 percent are due to epilepsy and have been relabeled by the International League Against Epilepsy (ILAE) (table 1) with the purposes of standardizing terminology and developing a more uniform understanding of the clinical features, diagnosis, and consequences of these disorders [1-6]. (See "ILAE classification of seizures and epilepsy".)

This topic review will discuss recognized neonatal epilepsy syndromes. Infantile onset epilepsy syndromes are reviewed elsewhere. (See "Overview of infantile epilepsy syndromes".)

Importantly, infants with neonatal-onset seizures can have comorbid illnesses that predispose to acute provoked seizures, thereby requiring a search for those causes in all neonates [7]. (See "Etiology and prognosis of neonatal seizures".)

The characterization of distinct types of neonatal seizures and their treatment is reviewed elsewhere. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Treatment of neonatal seizures".)

OVERVIEW OF EVALUATION — Neonates with suspected seizures should first be evaluated for immediately treatable, provoked (symptomatic) causes of seizures (table 2 and table 3). First-line diagnostic testing includes electroencephalography (EEG) to confirm the diagnosis of seizures and brain magnetic resonance imaging (MRI), which may help narrow the differential diagnosis and tailor the subsequent workup. Serum, urine, and cerebrospinal fluid (CSF) studies are obtained on a case-by-case basis. This evaluation is discussed in more detail separately. (See "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Etiologic evaluation'.)

A complete evaluation for acute provoked seizures (eg, due to hypoxic-ischemic injury, stroke, infection, or metabolic causes) remains necessary even when a familial epilepsy syndrome is suspected. This is critical, since acute provoked seizures are far more common than neonatal epilepsies and require early, effective treatment to mitigate the underlying brain injury and address treatable causes. This is particularly true for seizures associated with metabolic disturbances (eg, hypoglycemia, hypocalcemia, and hypomagnesemia) or central nervous system (CNS) or systemic infections.

A therapeutic trial of intravenous pyridoxine administration should be performed if seizures are unresponsive to standard treatments. (See "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures' and 'PD-DEE and P5PD-DEE' below.)

Genetic testing is recommended in neonates with epilepsy and for those who do not have an acute provoked seizure cause identified on initial history, examination, and neuroimaging [7]. Mandatory newborn screening identifies many treatable causes, but the composition of the screens varies based upon location.

Specific investigations for the diagnosis of the neonatal syndromes are discussed in the sections that follow.

SELF-LIMITED (FAMILIAL) NEONATAL SYNDROMES — Familial, now considered "self-limited” epilepsies by the ILAE [6], are syndromes in which there is likely to be spontaneous remission of the seizures, but this is not invariably the case [6]. Depending upon the associated gene, up to 30 percent of individuals will have epilepsy in later life [8]. Although the majority of neonatal seizures occur as acute reactive (provoked) events in response to identifiable etiologic factors (table 2), additional rare but distinct neonatal epilepsy syndromes are well recognized (table 1).

Self-limited (familial) neonatal epilepsy — Self-limited (familial) neonatal epilepsy (SeLNE) is rare, with an estimated incidence of 5.3 per 100,000 live births [9]. The familial and nonfamilial forms of SeLNE are distinguished by family history; the genetic, clinical, and EEG features are similar.

●Terminology – SeLNE was previously known by several terms, including:

•Benign familial neonatal epilepsy

•Benign neonatal convulsions

•Benign idiopathic neonatal seizures

•"Fifth-day fits" (because of their peak day of onset)

●Genetics – SeLNE is one of several epilepsies characterized as a channelopathy, caused in most cases by pathogenic variants in voltage-gated potassium channel genes (KCNQ2 and KCNQ3) [6,10-21]. The nonfamilial form of SeLNE is due to de novo pathogenic variants in these genes. The familial form of the disorder is inherited in an autosomal dominant pattern. The penetrance of these pathogenic variants is approximately 85 percent [22]; 15 percent of those who carry a variant may not have recognized 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 [23,24].

KCNQ2 variants have also been identified in patients with more severe developmental and epileptic encephalopathy syndromes. (See "Overview of infantile epilepsy syndromes", section on 'Early infantile developmental and epileptic encephalopathy' and 'KCNQ2-DEE' below.)

●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 six weeks to six months, although about 30 percent of individuals with KCNQ2-SeLNE develop epilepsy later in life [8]. These seizures occur in term or late preterm infants after an uneventful pregnancy, labor, and delivery, with no family history of seizures (in the case of the nonfamilial form), and with normal neurologic examinations between seizures. The incidence is similar for males and females.

The most frequent seizure type is focal tonic, involving the head, face, and limbs [6]. Focal clonic seizures may also occur [7]. Seizures may alternate sides and may progress to bilateral tonic seizures but do not have generalized/bilateral features at onset; associated apnea has sometimes been reported. The seizures are typically brief and last from one to three minutes, though some do evolve into prolonged seizures and the individual seizures may occur in clusters.

●Evaluation and diagnosis – SeLNE is a diagnosis of exclusion since the initial clinical presentation may mimic that of infants with acute provoked seizures. Thus, an extensive evaluation for an acute provoked seizure etiology (table 2) is necessary even when the suspicion for SeLNE is high. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

Diagnostic criteria (table 4) for SeLNE require focal tonic seizures at onset and a nonlesional brain MRI [6] in an infant delivered after a normal pregnancy and labor. The infant's head circumference and neurologic examination must be normal, and causes of acute provoked seizures must be excluded.

The ictal EEG is not distinctive from other electrical or electroclinical seizure types, and an ictal EEG is not required to make the diagnosis [6]. The interictal EEG background can be normal or may be mildly abnormal due to mildly excessive discontinuity (ie, periods of continuous activity alternating with brief, seconds-long periods of suppression) and/or excessive multifocal negative sharp waves.

Neuroimaging is mandatory, and a normal MRI is required to confirm the diagnosis of SeLNE. Where available, genetic testing should confirm a pathogenic variant in KCNQ2 or KCNQ3; lack of variants in these genes suggests a different diagnosis is more likely.

●Treatment – The therapy for SeLNE is similar to that for other neonatal seizures, with antiseizure medications acutely administered (see "Treatment of neonatal seizures"). 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 the diagnosis of SeLNE is clear, case reports and case series suggest that carbamazepine (10 mg/kg per day) or oxcarbazepine (35 mg/kg per day) can be effective treatments [25]. Antiseizure medications can often be stopped once the infant is beyond the usual six-week period of recurrence risk.

●Clinical course and outcomes – In most cases, seizures abate by age six months, typically by age six weeks. Development is typically normal. Seizures after age six months occur in up to one-third of patients, and those with higher neonatal seizure burden appear to be the most likely to have persistent epilepsy [6,23].

Self-limited familial neonatal-infantile epilepsy — Self-limited familial neonatal-infantile epilepsy (SeLFNIE) is characterized by focal tonic or focal clonic seizures and no other neurologic abnormalities. The incidence is undetermined [6].

●Terminology – SeLFNIE has also been known as benign familial neonatal-infantile seizures.

●Genetics – SeLFNIE is inherited in an autosomal dominant pattern and is caused by pathogenic variants in the SCN2A gene [26]; rare cases are associated with pathogenic variants of the KCNQ2 gene [18].

●Clinical features – SeLFNIE is characterized by focal tonic or focal clonic seizures, a family history of neonatal seizures, and no other neurologic abnormalities (normal physical examination and neuroimaging are required). At onset, seizures are focal tonic with head and eye deviation. The seizures typically occur within a few days to several months of life, with a mean onset at 11 weeks (median 13 weeks) [26]. Seizures may last from 20 seconds to 4 minutes, but often occur in clusters [27]. The interictal EEG is typically normal.

●Evaluation and diagnosis – A complete evaluation for acute provoked seizures (table 2) remains necessary even when SeLFNIE is suspected. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

Diagnostic criteria for SeLFNIE (table 5) require the onset, from age 1 day to 21 months, of focal tonic seizures with head and eye deviation, followed by seizures with other tonic and clonic features, which may evolve to bilateral tonic-clonic seizures [6].

A brain MRI is required to exclude other causes of seizures. The interictal EEG is usually normal. EEG slowing or focal discharges in central and posterior regions may be seen during periods of active seizures [6,27]. However, an ictal EEG is not required to confirm the diagnosis.

●Treatment – Seizures are responsive to treatment with antiseizure medications [6]. Carbamazepine is considered a first-line agent for SeLFNIE [25].

●Clinical course and outcomes – Seizure frequency is variable (some infants have only a few seizures while others have frequent seizures in clusters), but the seizures cease by 12 to 24 months and do not recur later in life [6], though a subset of patients with early onset SCN2A-associated seizures will develop episodic ataxia and may remain on medication treatment [28].

DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES — Developmental and epileptic encephalopathies (DEEs) are severe syndromes associated with refractory seizures and abnormal neurodevelopmental outcomes, which are related to both the underlying syndrome etiology and the seizures or epileptiform abnormalities [6].

A severe neonatal epilepsy syndrome should be suspected in newborns who lack an obvious cause for acute seizures, especially if the interictal EEG shows a burst suppression pattern or if the seizures do not respond as expected to initial treatments.

Early infantile DEE — Early infantile developmental and epileptic encephalopathy (EIDEE) is reviewed here briefly and discussed in greater detail elsewhere. (See "Overview of infantile epilepsy syndromes", section on 'Early infantile developmental and epileptic encephalopathy'.)

●Terminology – EIDEE incorporates the epilepsies previously classified as Ohtahara syndrome and early myoclonic encephalopathy (EME).

●Etiology and clinical features – EIDEE can be caused by a wide range of etiologies. These include developmental brain anomalies (eg, cortical dysplasia and other types of cerebral dysgenesis) as well as genetic syndromes. EIDEE is characterized by onset within the first three months of life, frequent refractory seizures, developmental impairment, and poor prognosis with reduced life expectancy (table 6). Infants with EIDEE may evolve to develop infantile epileptic spasms syndrome (IESS), and then, in childhood, they may develop Lennox-Gastaut syndrome.

●Diagnostic evaluation – This is reviewed separately. (See "Overview of infantile epilepsy syndromes", section on 'Early infantile developmental and epileptic encephalopathy'.)

●Treatment – Treatment of EIDEE mirrors that of epilepsies in older children, with combinations of antiseizure medications, dietary therapies, and epilepsy surgery in selected infants. Resective epilepsy surgery, in properly selected infants who are referred to highly experienced surgical centers, can be curative [29].

KCNQ2-DEE — In contrast to self-limited familial neonatal epilepsy, some individuals with de novo missense KCNQ2 pathogenic variants develop KCNQ2-DEE. Infants with KCNQ2-DEE present in the first week of life with an abnormal neurologic examination (encephalopathy, hypotonia, and lack of visual attentiveness) and severe, treatment-resistant seizures [6,7,30-33].

●Terminology – Some infants with KCNQ2-DEE present with what previously was termed Ohtahara syndrome [34]. Current terminology refers to Ohtahara syndrome as an EIDEE. (See "Overview of infantile epilepsy syndromes" and "Overview of infantile epilepsy syndromes", section on 'Early infantile developmental and epileptic encephalopathy'.)

●Clinical features – Seizures typically begin in the first days of life in an infant with encephalopathy and an abnormal neurologic examination [6]. The seizures often have a tonic semiology but are not classically tonic spasms; myoclonic and/or focal seizures are also described, as are sequential seizures. Neonates with gain of function KCNQ2 variants may have prominent nonepileptic startle-like myoclonus, in addition to encephalopathy and severely abnormal interictal EEG background patterns [35].

●Evaluation and diagnosis – The interictal EEG can have abundant multifocal negative sharp waves and/or can meet criteria for burst suppression. Brain MRI may reveal subtle abnormalities (T1 and T2 hyperintensity) in the basal ganglia and thalami that can resolve after the neonatal period [31,36]. No other specific imaging abnormalities are reported. Genetic testing for KCNQ2 pathogenic variants is necessary to confirm the diagnosis (table 7).

●Treatment – While seizures are resistant to treatment, limited data suggest that patients with KCNQ2 pathogenic variants may respond best to antiseizure medications that act on sodium channels (eg, oxcarbazepine, carbamazepine, or phenytoin) [30,37].

●Clinical course and prognosis – The seizures resolve within a few months to years in over half of patients, but affected children typically have moderate to severe global neurodevelopmental disabilities [6,38].

PD-DEE and P5PD-DEE — Pyridoxine-dependent (ALDH7A1) developmental and epileptic encephalopathy (PD-DEE) and the related disorder, pyridoxamine 5'-phosphate oxidase deficiency (PNPO) developmental and epileptic encephalopathy (P5PD-DEE), are rare but treatable genetic causes of medically refractory neonatal epilepsy. Both syndromes lead to metabolic defects within the lysine degradation pathway. (See "Etiology and prognosis of neonatal seizures", section on 'Cofactor and vitamin deficiencies'.)

●Terminology – PD-DEE is also known as pyridoxine-dependent epilepsy.

●Clinical features – Most patients with PD-DEE or P5PD-DEE develop seizures in-utero or shortly after birth and have co-occurring encephalopathy. However, a later presentation, typically in the first three years of life, is seen in up to one-quarter of patients, with rare patients presenting in adolescence [39,40]. Seizure types are variable, including multifocal myoclonus, focal seizures, epileptic spasms, and generalized tonic-clonic seizures. Seizures may be frequent and evolve to status epilepticus.

●Evaluation and diagnosis – The interictal EEG is typically markedly abnormal prior to treatment with a burst-suppression pattern and abundant multifocal epileptiform discharges. Brain MRI may be normal or show white matter edema in the setting of severe encephalopathy [39,41]. Other reported MRI abnormalities include ventricular enlargement and corpus callosum hypoplasia. Metabolic testing should not delay treatment, but biochemical evaluation with measurement of urine and plasma alpha-aminoadipic semialdehyde (alpha-AASA) and/or plasma pipecolic acid can aid the diagnosis (table 8). Genetic testing is useful to detect pathogenic variants in the ALDH7A1 or PLPB genes in PD-DEE, or the PNPO gene in P5PD-DEE.

●Treatment – In nearly all cases of PD-DEE and P5PD-DEE, seizures respond rapidly to treatment with pyridoxine and pyridoxal-5'-phosphate, respectively [6]. Due to the risk for cardiorespiratory collapse, the initial intravenous test doses of pyridoxine should occur in a monitored (hospital) setting. Seizures are unresponsive to antiseizure medications. Treatment is discussed in detail separately. Early initiation of a lysine-restricted diet may result in improved long-term outcomes; L-arginine therapy is also a component of therapy for this syndrome [42]. (See "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures'.)

●Clinical course and prognosis – Patients can have a normal neurodevelopmental outcome with early, appropriate treatment, but many will experience neurodevelopmental delays.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

●Evaluation for provoked seizures – A complete evaluation for acute provoked neonatal seizures (eg, due to hypoxic-ischemic injury, stroke, infection, or metabolic causes) remains necessary even when a self-limited neonatal epilepsy syndrome is suspected. (See 'Overview of evaluation' above.)

●Self-limited (familial) syndromes – Self-limited epilepsies are syndromes in which there is likely to be spontaneous seizure remission, though this is far from inevitable. Although most neonatal seizures occur as acute provoked events in response to identifiable causes (table 2), rare but distinct neonatal epilepsy syndromes are well recognized (table 1).

•Self-limited (familial) neonatal epilepsy (SeLNE) – SeLNE, once known as "fifth-day fits," is caused in most cases by pathogenic variants in voltage-gated potassium channel genes (KCNQ2 and KCNQ3). The nonfamilial form of SeLNE is due to de novo pathogenic variants in these genes; the familial form is inherited in an autosomal dominant pattern. Seizures arise in otherwise normal newborn infants within the first seven days of life. The most frequent seizure type is focal tonic, involving the head, face, and limbs. Diagnostic criteria (table 4) for SeLNE require focal tonic seizures at onset and a normal brain MRI. Treatment for SeLNE involves acute administration of antiseizure medications; seizures are typically most responsive to sodium-channel blockers (eg, carbamazepine). Seizures usually resolve within six weeks to six months, but some patients develop persistent epilepsy. Development is typically normal, though some children have learning difficulties and minor motor delays. (See 'Self-limited (familial) neonatal epilepsy' above.)

•Self-limited familial neonatal-infantile epilepsy (SeLFNIE) – SeLFNIE is an autosomal dominant epilepsy that is caused in most cases by pathogenic variants in the SCN2A gene and characterized by focal tonic or focal clonic seizures and no other neurologic abnormalities. Seizure onset occurs within a few days to several months of life. The diagnosis requires the onset of focal tonic seizures between age one day and 21 months (table 5). Seizures are responsive to pharmacologic treatment, especially sodium channel agents (eg, carbamazepine), and typically remit by age one to two years. (See 'Self-limited familial neonatal-infantile epilepsy' above.)

●Developmental and epileptic encephalopathies (DEEs)

•Early infantile DEE (EIDEE) – This syndrome is characterized by early onset, frequent, refractory seizures, developmental impairment, and poor prognosis with reduced life expectancy (table 6). Infants with EIDEE may evolve to develop infantile epileptic spasms syndrome (IESS) and then, in childhood, may develop Lennox-Gastaut syndrome. (See "Overview of infantile epilepsy syndromes", section on 'Early infantile developmental and epileptic encephalopathy'.)

•KCNQ2-DEE – Infants with KCNQ2-DEE present in the first week of life with neurologic abnormalities (encephalopathy, hypotonia, and lack of visual attentiveness) and severe, treatment-resistant seizures. Seizures resolve within a few months to years in over half of patients, but affected children typically have moderate to severe global neurodevelopmental impairments. Genetic testing for KCNQ2 pathogenic variants is necessary to confirm the diagnosis (table 7). (See 'KCNQ2-DEE' above.)

•PD-DEE and P5PD-DEE – Pyridoxine-dependent DEE (PD-DEE) and the related disorder, pyridoxamine 5'-phosphate deficiency DEE (P5PD-DEE), are rare but treatable genetic causes of medically refractory neonatal epilepsy. Metabolic testing should not delay treatment, but biochemical evaluation and genetic testing can aid the diagnosis (table 8). In nearly all cases of PD-DEE and P5PD-DEE, seizures respond rapidly to treatment with pyridoxine and pyridoxal-5'-phosphate, respectively. (See 'PD-DEE and P5PD-DEE' above.)

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