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Epilepsy Syndromes
Epilepsy Syndromes
is used by most epileptologists to categorize seizure types and epilepsy syndromes [1]. This
classification system has been revised since its origination in 1981, most recently in 2017
[2-6]. (See "ILAE classification of seizures and epilepsy".)
The ILAE recognizes over twenty epilepsy syndromes, each defined by a distinctive
combination of clinical features, signs and symptoms, and electrographic patterns; many of
these syndromes begin in childhood (table 1). Epilepsy syndrome classification provides
invaluable prognostic, therapeutic, and in the case of familial epilepsies, genetic information
[7]. That being said, as an increasing number of genetic mutations have been identified in
patients with both inherited and seemingly sporadic epilepsy syndromes, it has become
clear that the phenotypic spectrum of various syndromes may be broader than what has
been traditionally recognized, and the classification systems will continue to evolve.
This topic will review the clinical features, diagnosis and treatment of some of the more
common epilepsy syndromes that begin in infancy and childhood. Neonatal seizures and
neonatal epilepsy syndromes are discussed separately. (See "Clinical features, evaluation,
and diagnosis of neonatal seizures" and "Etiology and prognosis of neonatal
seizures" and "Neonatal epilepsy syndromes" and "Treatment of neonatal seizures".)
Additional topics relevant to the clinical features and diagnosis of seizures and epilepsy in
children include the following:
Mutations in the sodium channel genes SCN2A and SCN8A have also been identified in
some families with benign familial infantile convulsions with or without dyskinesias later in
life [20-25].
Benign focal epilepsies in infancy — A number of benign focal epilepsy syndromes, both
familial and sporadic, have been described in infancy.
Benign focal epilepsy in infancy is thought to occur in two distinct forms: one with focal
seizures with altered awareness (also called complex partial seizures) and another with
focal seizures evolving to bilateral convulsive seizures beginning between 3 and 10 months
of age [26,27]. Half of patients have a family history of infantile seizures.
The interictal EEG is normal. The ictal EEG shows rhythmic focal discharges that are
predominantly temporal in the complex partial seizure variant and central in those with the
secondary generalized seizure variant.
Seizures remit in more than 90 percent of patients within four months and in all patients
within two years. Neurologic development is normal.
●Benign infantile convulsions (familial and sporadic forms) (see "Neonatal epilepsy
syndromes", section on 'Benign familial neonatal epilepsy' and "Neonatal epilepsy
syndromes", section on 'Benign neonatal convulsions')
●Benign infantile convulsions associated with mild gastroenteritis
●Benign infantile focal epilepsy with midline spikes and waves during sleep
Genetic epilepsy with febrile seizures plus — A group of genetic epilepsy syndromes, in
which there is a family pedigree of seizures with heterogeneous semiology that often begin
during the first year of life, is referred to as "genetic epilepsy with febrile seizures plus"
(GEFS+) [28]. Such syndromes are characterized by multiple febrile seizures, generalized
tonic-clonic seizures, and other seizure types including absences, myoclonic seizures, and
even focal seizures. (See "Clinical features and evaluation of febrile seizures", section on
'Genetic epilepsies with febrile seizures'.)
Myoclonic epilepsy of infancy — Myoclonic seizures may begin in the first year of life
[29]. Myoclonus is a brief synchronous jerk of one or more limbs with and without
involvement of the bulbar musculature. Jerks may be focal, multifocal, or generalized and
are more likely to be flexor than extensor. There can also be negative myoclonus, in which
there is inhibition of muscular activity that can be detected reliably by means of surface
electromyography (EMG). Myoclonus is termed epileptic when it occurs in association with
a synchronous cortical epileptiform discharge, usually a generalized spike-and-wave
discharge, or isolated spikes or sharp waves over the motor cortex (the latter may have to
be identified by special computer averaging techniques). Epileptic myoclonus must be
distinguished from other epileptic and non-epileptic conditions, including infantile spasms,
tonic seizures, normal physiologic sleep myoclonus (hypnic jerks), and benign startle
responses, among others. (See "Nonepileptic paroxysmal disorders in infancy".)
Myoclonic seizures in infants can be accompanied by other seizure types, including partial
and generalized convulsive seizures. These epileptic syndromes have been divided into a
benign and severe form based upon the clinical course, with the latter manifesting
psychomotor retardation, severe speech delay, and often ataxia. Some discussion has
occurred in the neurologic literature questioning the justification of subdividing the
myoclonic epilepsies into individual syndromes rather than considering them as a spectrum
from benign to very severe [30]. This latter approach seems more rational because there
are problems inherent with classifying epilepsies on the basis of subsequent
neurodevelopmental outcomes, which are not known at the time of presentation and can be
the result of competing causes.
Patients typically present in the first year of life with a prolonged, often febrile, clonic seizure
in the setting of normal cognitive and motor development prior to seizure onset. In most
patients, febrile and afebrile seizures, including episodes of status epilepticus, recur
repeatedly in the weeks to months after the initial event, and psychomotor impairment
begins shortly thereafter. Myoclonus, both epileptic and non-epileptic, occurs frequently.
The majority of older children and young adults with DS have motor system dysfunction,
gait and postural abnormalities, and cognitive and behavioral impairment.
Seizures tend to be refractory to antiseizure drugs, and some patients derive benefit from
nonpharmacologic therapies such as the ketogenic diet and vagus nerve stimulation. The
most commonly used antiseizure drugs
include valproate, clobazam, topiramate, levetiracetam, and stiripentol. Sodium channel
blocking drugs such as phenytoin should generally be avoided due to their potential to
worsen seizures.
Clinical features — The criteria defining LGS are relatively nonspecific, leading to the
inclusion of children whose seizures have a wide variety of etiologies. The syndrome is
characterized by:
●Multiple seizure types, particularly tonic and atypical absence seizures, but also
atonic and myoclonic seizures. Periods of nonconvulsive status epilepticus occur in
most cases at some stage.
●A slow (less than 2.5 Hertz) spike-wave pattern on the interictal EEG that is
generalized and usually has highest amplitude in the frontal region (also called an
"atypical spike and wave" pattern).
●Mental retardation (occasionally progressive) with or without other neurologic
abnormalities. Psychotic symptoms are common. Often neurodevelopment is normal
before the first seizure.
This syndrome has many causes, including genetic disorders, neurocutaneous syndromes
(eg, tuberous sclerosis), encephalopathies following hypoxic-ischemic insults, meningitis,
and head injuries. Approximately 40 percent of patients have an unknown etiology, although
these children are increasingly found to have genetic disorders, particularly chromosomal
syndromes or de novo mutations [33].
Up to 25 percent of children with LGS have a history of infantile spasms. Children with this
syndrome are often difficult to manage medically and have a poor seizure and neurologic
prognosis. Mortality is also high (standardized mortality ratio [SMR] = 14) [34]. Patients
without an identifiable cause usually have a somewhat milder phenotype and less profound
functional and neurologic impairment in adulthood [35].
Treatment — The optimal therapy for LGS is uncertain and may depend in part upon the
underlying etiology. Systematic reviews of randomized controlled trials have concluded that
no drug has been shown to be highly effective, although valproic
acid, lamotrigine, topiramate, rufinamide, felbamate, and clobazam may be helpful [36-38].
In contrast, carbamazepine can precipitate drop attacks in some of these children.
Two randomized studies have demonstrated that clobazam may be an effective treatment in
children with LGS. In one trial, 217 patients with LGS were randomized to one of four
treatment arms: placebo or clobazam 0.25, 0.5, or 1 mg/kg per day [39]. After 12 weeks, a
>50 percent reduction in drop seizures was observed in 32, 43, 59, and 78 percent of
patients in each respective treatment group, demonstrating a dose-response effect; the
differences were statistically significant for the two higher clobazam dose groups versus
placebo. In another trial, high-dose clobazam (1 mg/kg per day) was associated with a
greater number of patients achieving a >50 percent reduction in drop seizures compared to
low-dose clobazam (0.25 mg/kg per day) (83 versus 38 percent) [40]. Clobazam is now
available in the US.
Because seizures are often medically refractory, other treatment options are often
considered. The ketogenic diet has been helpful in some children with LGS [41]. (See "The
ketogenic diet and other dietary therapies for the treatment of epilepsy".) Vagus nerve
stimulation also appears to be effective in some patients with LGS, leading to a greater than
50 percent reduction in seizure frequency (particularly for atonic and tonic seizures), as well
as shortened seizure duration and reduced number of antiseizure drugs prescribed [42,43].
(See "Vagus nerve stimulation therapy for the treatment of epilepsy", section on
'Generalized epilepsies'.) Other surgical options, including corpus callosotomy or lesional
epilepsy surgery in patients with hypothalamic hamartoma, may be considered in some
refractory cases [44,45]. (See "Seizures and epilepsy in children: Refractory seizures and
prognosis", section on 'Epilepsy surgery'.)
Although terminology is not applied consistently, most use LKS to refer to the epileptic
encephalopathy associated with predominant language regression, CSWS to refer to the
more severe epilepsy syndrome associated with global developmental regression, and
ESES to refer to the EEG pattern of continuous or near-continuous spike-and-wave during
sleep that can be associated with a variety of clinical presentations. Benign childhood
epilepsy with centrotemporal spikes (BECTS), also known as benign rolandic epilepsy of
childhood, is considered by many to lie on the most benign end of this spectrum and is
discussed separately. (See "Benign focal epilepsies of childhood", section on 'Benign
epilepsy with centrotemporal spikes'.)
The underlying etiology of disorders in this spectrum is unknown in most cases, although
genetic causes may be increasingly recognized in both sporadic and familial cases. As an
example, mutations in GRIN2A, a gene that encodes the alpha-2 subunit of the N-methyl-D-
aspartate (NMDA)-selective glutamate receptor, were identified in 10 families with a
spectrum of clinical phenotypes ranging from atypical rolandic epilepsy to LKS and CSWS,
and in an additional eight subjects without a family history [47]. In other
series, GRIN2A mutations were identified in 12 of 245 individuals (5 percent) with BECTS, 9
of 51 individuals (18 percent) with CSWS, and 4 of 44 cases (9 percent) of epilepsy-aphasia
syndromes ranging from BECTS to CSWS [48,49]. Affected patients have a distinct speech
phenotype, with prominent dysarthria and dyspraxia, which may have a lifelong impact on
speech intelligibility [50].
In addition, early developmental lesions such as cortical malformations (eg, polymicrogyria)
or vascular insults have been described in 40 to 60 percent of patients with CSWS but are
rare in LKS [51-54].
Children with LKS develop normally until approximately three to six years of age, when they
begin to lose language function. This later age of onset is in contrast with that of children
with autism. The disorder begins with an auditory verbal agnosia; the children behave as if
they are deaf. They ultimately have difficulties with expressive language and many have
personality disorders and hyperkinetic behavior. They do not develop the striking behaviors
associated with autism spectrum disorders, and usually they do not manifest a decline of
overall cognitive function. (See 'Relationship with autism' below.)
Approximately 75 percent of children with LKS have clinical seizures, but these are rarely
severe. The electroencephalogram (EEG) abnormalities are quite dramatic and are required
to make the diagnosis. The typical findings are bilateral centrotemporal spikes and sharp
waves with fields that spread widely throughout both hemispheres. The diffuse spread of
this bihemispheric focal activity often leads to the appearance of "generalized spike and
wave" discharges. When the child falls asleep, the epileptiform activity becomes virtually
continuous and is classified as electrical status epilepticus during sleep (ESES). To be
considered ESES, more than 85 percent of non-REM sleep should be occupied by
continuous epileptiform activity, although an exact cutoff is not specified in the International
League Against Epilepsy (ILAE) criteria, and some authors use lower thresholds (eg, more
than 50 percent) [46].
With sophisticated imaging and nuclear medicine techniques, the epileptiform process can
be shown to originate in the language cortex of the dominant temporal lobe and secondarily
to spread to homologous cortex in the other hemisphere and beyond [55]. No structural
abnormalities are typically seen on routine neuroimaging with CT or MRI. However,
volumetric analysis of MRI in four children with typical LKS has shown volume reductions of
26 to 51 percent in the bilateral superior temporal areas [56], regions that correspond to the
auditory association cortex. It is unclear if this focal cortical atrophy is the cause of LKS or
the result of intractable epileptiform activity [57].
Epileptic encephalopathy with continuous spikes and waves during sleep (CSWS) —
CSWS is an epileptic encephalopathy characterized by seizures, developmental regression
in at least two domains, and an EEG pattern of ESES. It is a rare condition that makes up
less than 1 percent of patients seen in pediatric epilepsy centers [60]. The etiology of
CSWS is unknown in many cases, but up to half of patients may have a structural cause
identified and some may carry causative genetic mutations in GRIN2A. (See 'Syndromes
with electrical status epilepticus during sleep' above.)
As with LKS, children with CSWS exhibit normal or only mildly abnormal development until
about two to four years of age, when they begin having seizures. Seizures during the initial
stage often occur out of sleep and are typically unilateral clonic or tonic-clonic [61].
Additional seizure types may include atonic and atypical absence seizures, occasionally
progressing to nonconvulsive status epilepticus. There is typically a marked increase in the
frequency and types of seizures within the first few years after seizure onset. This is
accompanied by a severe neurocognitive regression that occurs around five to six years of
age in most patients [61]. Unlike LKS, regression is seen across a wide spectrum of
domains, including language, behavior, learning, memory, attention, social interactions,
motor skills, and global intelligence.
During wakefulness, the EEG typically shows focal or multifocal spikes. As in LKS, the
hallmark EEG feature of CSWS is ESES, characterized by continuous or near-continuous
bilateral or occasionally lateralized slow spikes and waves occupying at least 85 percent of
non-REM sleep.
Treatment and prognosis — There are no controlled clinical trials that have investigated
treatment in LKS or CSWS, and there is significant regional variation in the approach. As
with most types of epilepsy, surgical intervention is considered early for lesional cases.
Anecdotal evidence suggests that early initiation of antiseizure drugs and control of epileptic
activity improves long term prognosis.
Antiseizure drugs with some reported benefit include valproate, clonazepam, levetiracetam,
and others; polytherapy is often needed [58,59,62]. A trial of corticosteroids is
recommended if there is not a rapid response to antiseizure drugs [58,63]. High-dose
nocturnal benzodiazepines have been reported to reduce epileptiform activity in more than
half of patients with CSWS, in some cases accompanied by sustained clinical improvement
[64]. The effectiveness of therapy is measured by the patient’s clinical response (ie, control
of seizures), improving developmental milestones, and the proportion of spike-wave activity
on overnight EEG recordings.
Some patients with LKS and CSWS may benefit from surgical treatment, but the approach
must be individualized [63]. Multiple subpial transection is one such approach [65]. Subpial
transection consists of closely spaced slicing of the temporal lobe gyri involved in the
epileptic process, with interruption of the short cortical-cortical fibers in the white matter
immediately under the cortical gray. This limited slice disrupts the epileptic interconnections
and stops the epileptiform activity while sparing the thalamocortical fibers that subserve
normal cortical function. The results can be quite dramatic, with complete disappearance of
the epileptiform activity on the EEG and rapid return of language function. Despite the
rather extensive transections undertaken in some patients, few postoperative deficits have
been noted. Other surgical approaches in selected patients include lesionectomy, corpus
callosotomy, and hemispherectomy [66].
Despite aggressive treatment, some patients with LKS have persistent, intractable epilepsy,
and most patients have residual language dysfunction that diminishes their quality of life
[67]. Patients with CSWS typically have more severe neurocognitive regression and worse
long-term neurocognitive outcomes, particularly those with underlying structural causes
[51].
These disorders are discussed in detail separately. (See "Benign focal epilepsies of
childhood".)
Several epilepsy syndromes with markedly different clinical courses and prognoses have
absence seizures as the only or most predominant seizure type. The age of onset and
clinical phenotypes of the absence epilepsy syndromes are quite variable and often help to
define the particular syndrome (figure 1). The clinical expression of absence seizures
themselves may differ from one syndrome to the other; as an example, in epilepsy with
myoclonic absences (EMA), EEG spikes are followed by prominent myoclonic jerks that
may cause the child to fall, whereas in children with the more common childhood absence
epilepsy (CAE) and juvenile absence epilepsy (JAE), the spikes are not associated with
myoclonus.
Although the age of onset, clinical manifestations of the seizures, neurologic status of the
children, and prognosis differ among the various syndromes, the EEG patterns are quite
similar and the approach to treatment is fundamentally the same, with ethosuximide,
valproic acid, lamotrigine, and clonazepam considered to be the most effective antiseizure
drugs. (See "Childhood absence epilepsy", section on 'Treatment'.)
The other seizure types that accompany the absences are more specific for the particular
syndrome. The Lennox-Gastaut syndrome (LGS) and myoclonic-astatic epilepsy (MAE; also
referred to as myoclonic-atonic epilepsy) are more serious epilepsy disorders in which
children always have other seizure types, including tonic and atonic seizures, as well as
developmental delay or regression in association with the epilepsy.
The neurologic and cognitive status of the child also varies from syndrome to syndrome.
Children with CAE, juvenile myoclonic epilepsy (JME), and JAE usually are neurologically
and cognitively intact. Relatively minor behavioral, psychiatric, and cognitive impairments
are reported in a minority [69-71]. (See "Childhood absence epilepsy", section on 'Clinical
features' and "Juvenile myoclonic epilepsy", section on 'Clinical features'.)
In contrast, children with the Lennox-Gastaut and MAE syndromes have epileptic
encephalopathies with motor and cognitive impairment as well as abnormalities on imaging
studies, including evidence of an earlier brain injury and developmental and maturational
disorders. Children with EMA fall somewhere in between, with approximately 44 percent
having mental retardation prior to the onset of the seizures at 1 to 12 years of age (mean 7
years) [72]. Children with LGS and MAE have life-long neurologic deficits and many
continue to have seizures into adulthood.
●Myoclonic jerks (most frequent in the morning, within the first hour after awakening)
●Absence seizures ("typical" petit mal seizures that often precede the other seizures
and begin toward the end of the first decade)
●Generalized tonic-clonic seizures, which also have a tendency to occur upon
awakening
The clinical presentation, diagnosis and treatment of JME are discussed separately.
(See "Juvenile myoclonic epilepsy".)
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Numerous epilepsy syndromes characteristically have their onset in the first year of
life (table 2). These include benign familial infantile epilepsy, myoclonic epilepsy of
infancy, and infantile spasms. (See 'Syndromes with onset in infancy' above.)
●A severe form of myoclonic epilepsy of infancy (Dravet syndrome [DS]) is associated
with refractory epilepsy beginning in the first year of life and poor psychomotor
developmental outcome. Patients typically present with prolonged, often febrile, clonic
seizure in the setting of normal cognitive and motor development prior to seizure onset.
Mutations in SCN1A, a gene that encodes the alpha subunit of the voltage-gated
sodium channel, have been identified in up to 80 percent of patients with this
syndrome. (See "Dravet syndrome: Genetics, clinical features, and
diagnosis" and "Dravet syndrome: Management and prognosis".)
●The Lennox-Gastaut syndrome is associated with severe seizures in childhood. There
are many causes, including genetic syndromes and hypoxic ischemic insults. Children
usually present in the first seven years of life with a syndrome characterized by multiple
seizure types, particularly tonic and atonic seizures, an atypical, slow spike and wave
pattern on EEG, and mental retardation, often with psychotic features. The optimal
therapy is uncertain; some children benefit with treatment from antiseizure drug
therapy. Other treatment options include the ketogenic diet, vagal nerve stimulation,
and epilepsy surgery. (See 'Lennox-Gastaut syndrome' above.)
●Epilepsy syndromes marked by electrical status epilepticus during sleep (ESES) and
developmental regression include Landau-Kleffner syndrome (LKS), which affects
primarily language function, and continuous spikes and waves during sleep (CSWS),
which is associated with more global neurocognitive regression. (See 'Syndromes with
electrical status epilepticus during sleep' above.)
•Children with the LKS develop normally until approximately three to six years of
age, when they begin to lose language function. Approximately 75 percent of
children with LKS have clinical seizures, but they are rarely severe. Children with
CSWS typically have a more severe seizure disorder and more global
developmental regression. Characteristic EEG abnormalities include bilateral
centrotemporal spikes and sharp waves that spread widely throughout both
hemispheres. During sleep, epileptiform activity becomes continuous.
(See 'Landau-Kleffner syndrome' above and 'Epileptic encephalopathy with
continuous spikes and waves during sleep (CSWS)' above.)
•Early initiation of antiseizure drugs and control of epileptic activity may improve
long term prognosis. Other treatment options include corticosteroids and epilepsy
surgery. (See 'Treatment and prognosis' above.)
●Benign partial epilepsies of childhood (benign childhood epilepsy with centrotemporal
spikes, benign occipital epilepsy of childhood, Panayiotopoulos syndrome) are
idiopathic syndromes that occur in developmentally and neurologically normal children
and have a benign course, remitting prior to adulthood. (See "Benign focal epilepsies of
childhood".)
●Absence seizures are the only or most predominant seizure type in several epileptic
syndromes, which have markedly different clinical courses and prognoses. The age of
onset and clinical phenotypes of the absence syndromes often help to define the
particular syndrome. (See 'Absence epilepsies' above.)
●Juvenile myoclonic epilepsy can include any one or more of the following seizure
types: myoclonic jerks, absence seizures, and generalized tonic-clonic seizures. The
typical patient is neurodevelopmentally normal and presents after 10 years of age.
Sleep deprivation may be required to elicit the typical 4 to 6 hertz polysp