Neonatal epilepsy syndromes

Author: Renée Shellhaas, MD, MS

Section Editors: Douglas R Nordli, Jr, MD, Joseph A Garcia-Prats, MD
Deputy Editor: John F Dashe, MD, PhD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Jun 2020. | This topic last updated: Sep 10, 2018.

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. Treatment is also
discussed separately. (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:

● Benign (self-limited) neonatal seizures

● 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 drug therapy, and prognosis (table 2). (See "ILAE
classification of seizures and epilepsy".)

BENIGN SYNDROMES

Two rare but well-recognized neonatal seizure syndromes are associated with a
relatively good prognosis: benign neonatal convulsions and benign familial
neonatal epilepsy.
Benign (self-limited) neonatal seizures — There are a number of terms that have
been used to designate benign neonatal convulsions, including "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
mutations 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. Although most are self-limited, some do
evolve into seizures that are prolonged. 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 benign neonatal convulsions 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 benign neonatal seizures, it is not specific; it is
found in only about 60 percent of neonates with benign neonatal seizures and has
also been described in other disorders.

Diagnosis — Benign neonatal seizures 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 benign neonatal seizures is similar

to that for other neonatal seizures, with antiseizure drugs acutely administered
(see "Treatment of neonatal seizures"). Some experts suggest that the use of
antiseizure drugs 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 drugs 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 as benign as its designation implies, suggesting that
either there is an underlying etiology that has not yet been characterized, or that
the seizures themselves may adversely affect the infant.

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 benign familial neonatal epilepsy
(BFNE), its genetics, and biology [12]. This syndrome has been reported to occur in
14 per 100,000 live births [14]. BFNE is also known as benign familial neonatal
convulsions and benign familial neonatal seizures.

Genetics — Benign familial neonatal epilepsy is considered to be one of several

epileptic disorders characterized as a channelopathy, caused in most cases by
mutations in voltage-gated potassium channel genes (KCNQ2 and KCNQ3) [15-18].
The disorder is inherited in an autosomal dominant pattern. The penetrance of
these mutations is approximately 85 percent [19]. Fifteen percent of those who
carry a mutated gene may fail to show seizures. In addition, there may be some
families with undetected mutations, or with mutations 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 mutations 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 — Benign 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 benign

familial neonatal epilepsy is similar to that for other neonatal seizures. A complete
evaluation for acute symptomatic neonatal seizures remains necessary even when
benign 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

encephalopathy' below), observational data suggest that seizures may respond
preferentially to carbamazepine or oxcarbazepine [30-32].

The syndrome had been considered to be benign 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 benign familial seizures [33]. Seizures after age six months occur
in up to one third of patients with KCNQ2 mutations, 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

gender 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 drugs (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 drug 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 mutations (eg, SLC25A22, ARX, STXBP1, PLCB1, PNKP)

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

Genetic studies in patients with EIEE have identified a number of gene mutations
that appear to cause EIEE, including the KCNQ2 gene that has also been
associated with benign familial neonatal convulsions [39-49]. In one series,
missense mutations in KCNQ2 were identified in 10 out of 51 patients (20 percent)
with Ohtahara syndrome [47]. (See 'KCNQ2 encephalopathy' below.)
Other associated mutations include SLC25A22, encoding a mitochondrial
glutamate carrier; mutations in Aristaless-related homeobox gene (ARX);
mutation/deletions of STXBP1/MUNC18-1 [40]; and mutations in CDKL5 [50,51],
PLCB1 [52], PNKP [53], SCN2A, PNPO, PIGA, SEPSECS [49], and SCN3A [54]. 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'.)

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 uV) 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
drugs (eg, valproate, zonisamide), and vitamin B6. There have also been case
reports of surgical treatment with hemispherectomy and cortical dysplasia
resection [55].

The overall outcome of EIEE is poor [56]. 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 [57]. The three share the following features:

● Specific age of onset

● Severe mental retardation
● 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 encephalopathy — In contrast to benign familial neonatal epilepsy, some

individuals with KCNQ2 mutations 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 [58].

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 mutations may result in a dominant-negative effect on voltage-gated

potassium channels, which in a xenopus model system could be partially reversed
by retigabine [59]. Clinically, patients with KCNQ2 mutations may respond best to
antiseizure drugs that act on sodium channels (eg, oxcarbazepine or
carbamazepine) [38,60]. A similarly positive treatment response has been reported
for infants with SCN2A variants [30,61].

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 [62]. Oral sulfonylurea therapy appears to be more effective than
insulin in controlling hyperglycemia, and can also lead to improved seizure control
and psychomotor development [63-65]. (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, there are additional rare but
distinct neonatal epilepsy syndromes. Many of these epilepsies have clearly
definable genetic etiologies, as well as predictable treatment responses and
long-term prognoses. (See 'Overview' above.)

● Benign (self-limited) neonatal seizures, "fifth-day fits," is a neonatal seizure

syndrome that occurs in normal infants after an uneventful pregnancy, labor,
and delivery. (See 'Benign (self-limited) neonatal seizures' 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 drugs can often be discontinued after about 48 hours, once

acute symptomatic seizure etiologies are ruled-out and seizures remit.

● Benign familial neonatal epilepsy is an autosomal dominant inherited

condition. (See '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 KCNQ2 and KCNQ3 mutations is available and may be
considered in cases in which there is not a clear family history.

• Some infants may require antiseizure drug 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 drugs 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 editorial staff at UpToDate, Inc. would like to acknowledge Dr. Eli Mizrahi, who
contributed to an earlier version of this topic review.

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