COLIN D. FERRIE
Leeds General Infirmary, Leeds
Most children who develop epileptic seizure disorders do well. As many as 60
expect to eventually become seizure free either through medication or spontaneous remission.
This chapter concerns those who do not. It deals with those epilepsies which can reasonably
be predicted to follow a severe course, rather than with those which are usually relatively
mild but which can, on occasions, prove more difficult.
The term ‘severe paediatric epilepsy syndrome’ does not have a precise meaning. Other terms
In the ILAE’s 2001 Diagnostic Scheme, the term ‘epileptic encephalopathy’ was introduced
‘A condition in which the epileptiform abnormalities themselves are believed to
In the 2010 reorganisation
severe paediatric epilepsy syndrome was recognised as a concept
that could be applied to any form of epilepsy, but there was recognition that children with
some epilepsy syndromes were more at risk than others, and it is these epilepsies that may be
referred to as epileptic encephalopathies. Most of the conditions discussed in this chapter are
epileptic encephalopathies, hence they are characterised not only by parmacoresistant
epileptic seizures, but also with an expectation that children will develop other problems,
including learning difficulties, behavioural problems (including autistic behaviours) and
sometimes physical problems such as ataxia. The concept implies that if epileptic activity can
be controlled, these other problems will be minimised. Some of the disorders discussed, such
as Ohtahara and Dravet syndromes, always behave as epileptic encephalopathies. Others,
such as West and Lennox Gastaut syndromes usually do, while others, such as Doose
syndrome, often do but quite frequently do not.
The epileptic encephalopathies are not neurodegenerative disorders in the usual meaning of
What makes an epilepsy severe?
We do not know the answer to this question. Almost certainly it has something to do with
‘symptomatic’ with ‘severe’. Also, it was felt likely that epilepsies caused by ion channel
disorders would be relatively mild. It is now clear that these are huge oversimplifications.
encephalopathy. Children with congenital hemiplegia due to middle cerebral artery infarcts
may develop a severe epilepsy but more usually the epilepsy is mild. Dravet syndrome (one
of the most severe of all childhood severe epilepsies) is a chanellopathy.
Severe epilepsy syndromes of the neonatal period
There are two well described epileptic encephalopathies in this age group. They share some
Ohtahara syndrome (also known as early infantile epileptic encephalopathy)
This is a rare epilepsy syndrome usually presenting in the first few days or weeks of life, but
sometimes as late as three months of age. Clinically it is characterised by the occurrence of
tonic seizures which can be generalised and symmetrical or lateralised. These tend to be very
frequent (often hundreds a day), occur both during awake and sleep and can be single or occur
in clusters (similar to infantile spasms). Other seizure types include focal motor seizures and
hemi- or generalised tonic-clonic seizures. Myoclonic seizures are not characteristic. The
EEG shows a burst-suppression pattern both during awake and sleep (Figure 1). Bursts,
usually lasting 2
6 seconds, consist of high amplitude slow waves intermixed with spikes.
These alternate with periods of suppression, usually lasting for 3
5 seconds, during which
the EEG is flat or nearly flat. Tonic seizures can occur during the bursts or can be associated
with periods of desynchronisation or ‘accentuation’ of the burst-suppression pattern.
Ohtahara syndrome is commonly caused by severe cerebral malformations, such as
The prognosis is very poor. Half of infants affected are said to die within weeks or months of
its onset. The remainder are left with severe learning difficulties and often with motor
impairments (cerebral palsy). Survivors often show an evolution to West syndrome and this
may subsequently evolve to Lennox-Gastaut syndrome. This observation lead to the concept
of the age-related encephalopathies.
Treatment with antiepileptic drugs (AEDs) is usually ineffective. ACTH has been used,
Early myoclonic encephalopathy
This is a also a rare neonatal epilepsy syndrome often presenting very shortly after birth and
nearly always within the first few weeks of life. It is characterised by erratic or fragmentary
myoclonus consisting of myoclonias affecting the face and limbs which shift from one part
of the body in a random and asynchronous manner. They may be single or repetitive and are
usually very frequent, if not near continuous. Massive axial myoclonic jerks may also occur.
Other seizure types seen include: focal seizures, often subtle and manifested with, for
example, eye deviations or autonomic symptoms; tonic seizures; and epileptic spasms
(usually later in the evolution of the disorder). The EEG shows a burst-suppression pattern
(Figure 1), often more apparent in sleep than when awake. The myoclonias do not usually
have an EEG correlate.
Early myoclonic encephalopathy is often caused by inborn errors of metabolism, such as
Detailed metabolic studies are mandatory. These should include CSF studies for glycine to
exclude non-ketotic hyperglycinaemia. Not surprisingly, autosomal recessive inheritance is
often apparent. Structural brain defects, except for the development of diffuse atrophy, are
not expected. Unless a treatable metabolic disorder is found no effective treatment exists.
There is a very high mortality in the early weeks and months of life and survivors are left
with severe physical and mental impairments.
early myoclonic encephalopathy.
In infancy (i.e. the period from one month to two years of age), the first epilepsy syndrome
West syndrome occurs along with one of the most recently recognised epileptic
Dravet syndrome. Even more recently a third syndrome migrating focal
epilepsy of infancy
has been described.
West syndrome comprises a triad of epileptic spasms, mental retardation and hypsarrhythmia.
It usually starts between three and 12 months of age, with a peak at five months. Its incidence
The defining seizure type is epileptic spasms. This term is now preferred to infantile spasms,
brief contractions of axial and limb muscles lasting longer than myoclonic seizures (i.e.
longer than 100 milliseconds) and shorter than tonic seizures (i.e. shorter than a second
although many would say shorter than two seconds). Characteristically they occur in clusters
extensor or mixed flexor-extensor. The type does not appear to be important in terms of
aetiology or prognosis. They are usually symmetrical. However, asymmetrical spasms do
occur and often indicate focal structural brain pathology. Indeed a cluster of spasms may be
preceded by or be followed by a focal seizure. Spasms usually occur on arousal or when alert.
Exceptionally they occur during sleep. Loud noises, tactile stimuli and feeding may all
precipitate spasms. Early on in the course of the condition spasms may be very subtle and
infrequent (sometimes manifested with head nods), but tend to build up both in intensity and
frequency such that they eventually become obvious.
Prior to the onset of spasms, development may have been normal or delayed, reflecting the
of social disengagement, particularly for visual stimuli. Developmental deterioration during
the period of active spasms is usual, but not universal. Most children who have had spasms
will eventually have severe learning difficulties, but up to 15% will show normal or near
(Figure 2). However, up to one-third have other patterns. It comprises a chaotic mix of
asynchronous high amplitude slow waves with intermixed sharp waves and spikes. So-called
atypical or modified hypsarrhythmia includes cases with asymmetries, persistent foci, some
preservation of background rhythms and a degree of synchrony. Some of these, particularly
the first two, are associated with structural brain problems. During non-REM sleep a degree
of synchronisation is common and there may be preserved sleep elements. The EEG is usually
normal in REM sleep. Particularly early on in the disorder, the awake EEG may be normal
while the sleep EEG is abnormal. The ictal EEG, that is the EEG associated with spasms, is
very variable, with at least 11 patterns being described. However, most commonly it shows
a brief period consisting of a generalised high voltage slow wave, episodic, low amplitude
fast activity and then attenuation or flattening of the EEG (electrodecremental response).
For many years West syndrome was recognised to occur in symptomatic and cryptogenic
idiopathic form exists. At least 85% of cases are symptomatic (Table 1). The single
commonest cause is tuberous sclerosis. An increasing number where an aetiology was not
previously apparent have now been found to be genetic in origin, e.g. CDKL5 in girls,
shows symmetrical hypsarrhythmia. The spasm coincides with a large amplitude slow wave
followed by an electrodecremental response.
Chromosomal and genetic disorders Down syndrome
Fragile X syndrome
X-linked infantile spasms
Malformations of cortical
Amino and organic
Postnatal disorders Severe infections
Early onset polio and
and non-epileptic disorders, including: benign (non-epileptic) myoclonus of infancy; benign
neonatal sleep myoclonus; Sandifer’s syndrome; and colic.
There are many treatment strategies for West syndrome. Conventional AEDs may have a role
particularly in Japan. However, in most countries the choice of initial treatment is usually
between vigabatrin and steroid treatment. With regard to steroids, preparations used most
often are natural and synthetic ACTH given intramuscularly and oral prednisolone.
Vigabatrin is particularly effective for spasms due to tuberous sclerosis. A recent UK
sclerosis found evidence in favour of the former, although this must be balanced against the
potentially severe, even fatal adverse effects of steroids. Surgery has a role in cases due to
focal brain pathology.
The prognosis is generally, but not universally, poor: 15
develop normally or near normally. However, around 60% are left with intractable seizures
(often Lennox-Gastaut syndrome) and two-thirds have severe learning difficulties and/or
This epilepsy syndrome is increasingly recognised. It is more common in boys. It begins in
the first year of life and affected children are previously normal. The first seizure is usually
febrile. There may be nothing remarkable about the seizure but characteristically it is
complex, being prolonged and/or focal. Febrile status is common. In addition, the provoking
fever is often relatively mild. Indeed in some cases the child may simply be unwell without
clear evidence of a fever. The child recovers as expected but further similar seizures usually
occur, often becoming more and more frequent with time. Some are provoked by non-febrile
illnesses, immunisations, hot baths and even hot weather. During this stage of the condition,
development continues normally. A second stage then ensues, usually in the second or third
year of life, with a polymorphous epilepsy. Seizure types often include myoclonic seizures,
febrile and non-febrile convulsive seizures (tonic-clonic, clonic or hemiconvulsions), atypical
absences and focal seizures. Episodes of convulsive and non-convulsive status epilepticus
may occur. As well as temperature provoking seizures, some patients are photosensitive.
During this stage of the disease development stagnates and there is often a true regression.
Neurological signs, such as ataxia and pyramidal signs, commonly develop. Eventually all
children are left with severe, often profound, learning difficulties. In late childhood a final
stage ensues during which seizures tend to continue but are less frequent and development
At presentation the EEG in Dravet syndrome is initially normal, except that about one-fifth
phase the EEG begins to slow and becomes dominated by diffuse theta and delta. Paroxysmal
abnormalities of polyspike and/or spikes and slow waves usually become frequent occurring
in brief bursts, which are often asymmetrical.
Genetic factors are very important in Dravet syndrome, but the condition rarely recurs in
inheritance. A family history of epilepsy (of various types) is very common. Probably more
than 80% of subjects with typical Dravet syndrome and a smaller, but still significant, number
of atypical cases have mutations on the SCN1A gene which codes for a sodium channel.
Given that the same mutations may be associated with much milder epilepsy phenotypes, it
is clear that other genetic or environmental factors must be involved in producing the Dravet
phenotype but these remain to be elucidated. Other investigations are expected to be normal,
though diffuse atrophy may develop on brain imaging.
Response to AEDs is poor, although temporarily good results can be obtained from a number
avoided. Stiripentol in conjunction with sodium valproate and/or clobazam has been shown
to be beneficial in a double-blind, placebo-controlled trial. The ketogenic diet may be useful.
This rare syndrome starts any time between birth and about seven months in previously
normal children. It is characterised by focal seizures with motor and prominent autonomic
symptoms and with secondary generalised seizures. Seizures vary in their intensity and
duration; episodes of status are common. The seizures tend to increase in frequency,
becoming virtually continuous. EEG background is slow with varying side emphasis and
multifocal spikes develop. Ictal discharges involve multiple independent sites, moving from
one cortical area to another. Investigations, except EEG are normal. It is likely to be genetic
in origin; a recent study suggested up to 50% may be due to a mutation in the KCNT1 gene.
Response to treatment is poor and there is a high mortality.
The following epilepsy syndromes in childhood are often severe, constituting epileptic
and the related disorder of epilepsy with continuous spike and waves during slow-wave sleep;
and myoclonic absence epilepsy. Note that the propensity of these syndromes to act as
epileptic encephalopathies varies: Landau-Kleffner syndrome always does so whilst Doose
syndrome, which is classified as an idiopathic generalised epilepsy, sometimes does but often
Probably no syndrome diagnosis is more abused and misunderstood than Lennox-Gastaut
syndrome (LGS). Some authorities, particularly in the United States, classify virtually all
drug-resistant epilepsies characterised by multiple seizure types as LGS. Used in this way,
the diagnosis is of little use in helping management. The alternative, much favoured in Europe
and increasingly in the UK, is to use a narrower definition of the syndrome. This approach
will be used here. LGS usually begins between three and five years of age, but can start as
early as one year or as late as adolescence. Its incidence is said to be 2.8 per 10,000 live births
but because of its intractable nature its prevalence in children with seizures may be up to 5%.
It is characterised by seizures of multiple, mainly generalised, type and learning difficulties.
The three most characteristic seizure types are tonic (particularly axial tonic seizures), atonic
focal seizures. Myoclonic seizures are not usually prominent, although they can occur. A so-
called myoclonic variant of LGS is described in which myoclonic seizures are prominent.
However, children with this may be better classified as Doose syndrome. Tonic seizures can
occur both when awake and in sleep, but the latter are a particular feature of LGS. Tonic,
atonic and to a lesser extent, myoclonic seizures frequently cause astatic seizures (i.e. drop
attacks) in LGS. Finally, episodes of non-convulsive status epilepticus are common.
The background EEG in LGS is usually diffusely slow. Two main paroxysmal EEG features
Slow (<2.5 Hz) spike and wave discharges which are usually generalised and
ictal or ictal. If the latter they can be associated with atypical absences or atonic
Fast rhythms or rhythmic rapid spikes at frequencies of 10–20 Hz which are usually
seen in slow wave sleep. These may accompany tonic seizures.
Figure 3. Upper EEG
Slow spike and wave discharge; lower EEG – fast rhythms.
from which LGS sometimes evolves. Two-thirds to three-quarters of children with LGS have
developmental problems prior to onset of seizures. This reflects the diverse aetiologies
associated with LGS. With the onset of seizures development stagnates and, at times of
particularly frequent seizures, may regress. Nearly but not all children with LGS eventually
have learning difficulties, usually severe, and behavioural problems are also very frequent.
With increasing age some children become seizure free but many continue to have the
phenotype of LGS into adult life or else develop a rather non-specific epilepsy with less
frequent convulsive and non-convulsive seizures. Features which suggest a better prognosis
include cryptogenic or idiopathic in type, more frequent myoclonic seizures, EEGs which
feature some fast spike and/or polyspike and wave discharges, older age of onset and rapid
control of seizures.
LGS is notoriously drug resistant, although some children will respond to AEDs, albeit often
are usually used first. Benzodiazepines and lamotrigine can also be helpful, although the latter
may exacerbate myoclonic seizures. Ethosuximide may help atypical absences in particular.
Drugs such as carbamazepine and phenyotin should be used with particular caution as they
may exacerbate some seizure types. Felbamate, topiramate, lamotrigine and rufinamide have
all been shown in randomised controlled studies to be superior to placebo in LGS and both
levetriracetam and zonisamide are also probably appropriate drugs to try. Non drug
treatments which can be helpful include the ketogenic diet and vagal nerve stimulation. Very
occasionally children develop LGS as a consequence of surgically remediable focal
pathology. Callosotomy has an occasional role to play for the treatment of astatic seizures.
Doose syndrome (also called epilepsy with myoclonic-atonic seizures or epilepsy with myo-
This syndrome usually starts between two and four years of age, but can begin as early as the
first year of life or up to mid-childhood. Boys are affected more than girls and development
is normal prior to the onset of seizures. It is now considered to be an idiopathic generalised
are then followed by the characteristic seizure, the so-called myo-atonic seizure which
combines a symmetrical myoclonic jerk immediately followed by an atonic seizure, usually
causing a drop attack. Children with Doose syndrome may also have independent atonic and
myoclonic seizures and brief typical absence seizures. Episodes of non-convulsive status
epilepticus lasting hours or days occur in some children. Being an IGE, investigations other
than EEG are expected to be normal. Inter-ictal EEG may show rhythmic theta in the
parasagittal regions, with frequent clusters of generalised spike-wave discharges at 2
and/or polyspike or polyspike and wave discharges (Figure 4). These patterns may also be
The prognosis is variable. Many children (perhaps up to half) with the syndrome become free
of the drop attacks, although they may continue to have GTCS, and develop normally or near
normally. In others drop attacks may continue for years and learning difficulties become
apparent. It is these children with Doose syndrome who appear to have an epileptic
The response to AEDs varies from complete responses to marked drug resistance. Drugs
topiramate, levetiracetam and benzodiazepines. Lamotrigine may also be helpful but there is
concern that it can exacerbate myoclonic seizures. Drugs mainly active against focal seizures,
such as carbamazepine may exacerbate seizures and should be avoided. Doose syndrome
often responds very well to the ketogenic diet.
Landau-Kleffner syndrome and ECSWS (or ESES)
Landau-Kleffner syndrome (also called acquired epileptic aphasia) and epilepsy with
continuous spike and waves during slow-wave sleep (ECSWS) or epileptic encephalopathy
with electrical status epilepticus during slow-wave sleep (ESES) overlap and therefore will
be considered together. The Landau-Kleffner syndrome (LKS) usually starts in otherwise
normal children between five and seven years of age but can start much earlier or later. It is
seizures; and behavioural problems. The language problem is initially auditory verbal agnosia
such that the children find difficulty in attributing semantic value to speech. This is often very
severe, causing the children to stop responding initially to the spoken word and sometimes to
environmental noises as well. They are often suspected of being deaf. A secondary motor
aphasia commonly develops. Epileptic seizures occur in three-quarters of patients with LKS.
The seizures can be of different types including GTCS and focal seizures. They are often, but
not always, infrequent. The behavioural problems, often severe, include hyperactivity and
attention deficits and autistic behaviours. The language problems, behavioural problems and
seizures often fluctuate in their severity and this may correlate with the EEG findings.
The EEG is characterised by mainly posterior temporal lobe foci of sharp slow-wave
non-REM sleep nearly always markedly increases the epileptiform abnormalities, such that
they often occupy at least 85% of non-REM sleep. This constitutes electrical status
epilepticus during slow wave sleep (ESES). Although ESES is very common in LKS it is not
a prerequisite and its presence may vary between EEGs.
Structural imaging in LKS is usually normal. Functional imaging often implicates the
The LKS nearly always eventually remits. Occasionally this can be after only a few weeks or
language and cognitive problems, although these are often milder than would be anticipated
during the active stage of the condition.
Seizures in LKS often respond well to conventional AEDs but often without improvement in
ethosuximide and benzodiazepines can be helpful. Some children respond very well to
treatment with steroids. If medical treatment fails the neurosurgical technique of multiple
subpial transections over Wernicke’s area has been reported to be helpful. It requires the area
of cortex ‘driving’ the problem to be identified. Multiple cortical cuts are made tangentially
to the surface disrupting horizontal fibres responsible for seizure propagation whilst leaving
vertical fibres responsible for normal functioning intact. Evaluation is detailed, and evidence
for true benefit limited.
Epilepsy with continuous spike and waves during slow-wave sleep (CSWS) is a related and
are neurodevelopmentally normal prior to the onset of seizure but others have a variety of
developmental problems, including cerebral palsy and learning difficulties. The condition
usually starts with seizures which are often nocturnal and hemi-convulsive in type. They may
be prolonged constituting status epilepticus. Usually after months or years the seizures
increase in frequency and become polymorphous. Indeed all types of seizures may occur
during this stage, except probably tonic seizures. With the increase in seizures
neuropsychological regression occurs and may be severe. There may be, in addition, acquired
motor deficits such as ataxia, hemiparesis and dyspraxia. An opercular syndrome with
drooling, feeding problems and dysarthria can occur.
The EEG hallmark of ECSWS is continuous (i.e. >85%), bilateral and diffuse spike and
Figure 5. The EEG from a boy with rolandic epilepsy who developed continuous spike and
wave during slow-wave sleep.
Many children with CSWS have structural brain abnormalities. In others the condition
develops in previously normal children. It is a rare complication of benign childhood epilepsy
with centro-temporal spikes (rolandic epilepsy) and other idiopathic focal epilepsies of
childhood. Carbamazepine has been implicated as precipitating it in some cases. Treatment
is similar to LKS and, as for LKS, the condition appears to eventually remit, but usually
leaving significant neurodevelopmental problems.
Epilepsy with myoclonic absences
Epilepsy with myoclonic absences (EMA) is a rare epilepsy syndrome which can start at any
time in childhood. The hallmark is myoclonic absence seizures. These are similar to typical
absence seizures but with superimposed rhythmic myoclonic jerks mainly of the upper limbs.
The jerks can be mild or severe. GTCS and atonic seizures may also occur. The EEG shows
a normal background with 3 Hz generalised spike and wave discharges. Simultaneous EMG
demonstrates the myoclonic jerks. Marked asymmetries and focal abnormalities may be
apparent. Slowing of the background may occur later.
EMA is now classified as a genetic generalised epilepsy (GGE) by the ILAE but most
variety of underlying aetiologies, including structural brain defects and chromosomal
abnormalities. Impaired cognitive functioning commonly develops even in those children
who were normal prior to the onset of the seizures. There is some evidence that successful
treatment of the seizures prevents or minimises this. Drugs active against absence seizures in
general should be tried and drugs such as carbamazepine mainly active in focal epilepsies
should be avoided. Relative seizure resistance is the rule.
Some aetiologies associated with severe childhood epilepsies
Some pathological entities are associated with a high likelihood of intractability. These are
for completeness will be briefly described here.
This very rare epilepsy usually begins with focal motor seizures, often very localised at least
initially. Episodes of focal motor status (epilepsy partialis continuans) is common. Other
seizure types, including GTCS, may occur. Over a period which can be only a matter of weeks
or else years, a progressive hemiplegia develops along with cognitive decline. Untreated the
disease eventually remits but usually leaving a dense motor deficit and severe learning
difficulties. Pathologically there are focal perivascular infiltrates characteristic of a viral or
autoimmune process: the cause, however, remains unknown. Early structural scans may be
normal or may show focal signal abnormalities. Later hemiatrophy develops. Some reports
suggest that bihemispheric involvement may occur but this is controversial. Some response
to conventional AEDs may occur, but nearly always this is temporary. Immunological
treatments, such as steroids and intravenous immunoglobulin are usually used, sometimes
with apparent success. However, most patients eventually require hemispherectomy.
Children should be reviewed in a specialised epilepsy surgery unit as timing of surgery will
Abnormalities of cortical development
Cortical dysplasias vary greatly in their epileptogenicity. This is perhaps best illustrated by
tuberous sclerosis. Many subjects with this live normal lives, others have mild epilepsies and
are of normal or near normal intelligence. However, many children with tuberous sclerosis
present very early on in life with severe epilepsy, particularly West syndrome, and are
devastated by the disorder.
Hemimegalencephaly is a particularly severe and complex dysplasia affecting one
present). It often presents with refractory focal seizures in early life. Early hemispherectomy
maximises developmental potential.
Dysembryoplastic neuroepithelial tumours
These are indolent cortical brain tumours which include both neural and glial elements. Most
are temporal in origin but any cortical region can be involved. They may be congenital. They
commonly present in childhood or early adult life with focal epilepsy, which has a tendency
to be refractory to medical treatment. There is evidence that the early surgical resection not
only controls seizures but improves neurodevelopmental outcome in those children who
present at an early age with intractable seizures.
This neurocutaneous disorder features a facial port wine stain with an ipsilateral pial angioma.
The clinical consequences are highly variable. However, a minority of infants with it develop:
refractory focal seizures, including episodes of potentially devastating status epilepticus;
progressive hemiplegia; and progressive cognitive decline. The last two of these appear to be
caused by a vascular steal phenomenon related to the pial angioma causing atrophy of the
underlying cortex. Surgical treatment with lobar, multilobar or hemispheric resection may
halt this progression.
Figures used here have been modified with permission from: A Clinical Guide to Epileptic Syndromes
DUCHOWNY M, CROSS JH, ARZIMANOGLOU A. Paediatric Epilepsy. McGraw Hill, New York, 2012.
PANAYIOTOPOLOUS CP. A Clinical Guide to Epileptic Syndromes and their Treatment (2
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