Post on 30-Mar-2023
Review article
The spectrum of neuropsychiatric abnormalities associated with electricalstatus epilepticus in sleep
Aristea S. Galanopouloua,*,1, Aviva Bojkoa,1, Fred Ladoa, Solomon L Moshe a, b
aDepartment of Neurology, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Bronx NY 10461, USAbDepartment of Neuroscience and Pediatrics, The Einstein/Monte®ore Epilepsy Management Center, Bronx NY, USA
Received 19 October 1999; received in revised form 17 April 2000; accepted 2 May 2000
Abstract
Electrical status epilepticus in sleep (ESES) is an electrographic pattern consisting of an almost continuous presence of spike-wave
discharges in slow wave sleep. ESES is frequently encountered in pediatric syndromes associated with epilepsy or cognitive and language
dysfunction. It can be present in various evolutionary stages of a spectrum of diseases, the prototypes of which are the `continuous spikes and
waves during slow wave sleep' syndrome (CSWS), the Landau±Kleffner syndrome (LKS), as well as in patients initially presenting as benign
childhood epilepsy with centrotemporal spikes (BECTS). The purpose of this article is to review the literature data on the semiology,
electrographic ®ndings, prognosis, therapeutic options, as well as the current theories on the pathophysiology of these disorders. The frequent
overlap of CSWS, LKS, and BECTS urges an increased level of awareness for the occasional transition from benign conditions such as
BECTS to more devastating syndromes such as LKS and CSWS. Identi®cation of atypical signs and symptoms, such as high discharge rates,
prolonged duration of ESES, neuropsychiatric and cognitive dysfunction, lack of responsiveness to medications, and pre-existing neurologic
conditions is of paramount importance in order to initiate the appropriate diagnostic measures. Prolonged and if needed repetitive sleep
electroencephalographs (EEGs) are warranted for proper diagnosis. q 2000 Elsevier Science B.V. All rights reserved.
Keywords: Aphasia; Antiepileptics; Electrocorticography; Electroencephalography; Magnetoencephalography; Multiple subpial transections; Seizure; Sleep
1. Introduction
Various childhood epileptic syndromes associated with
dramatic activation of the epileptiform activities during
slow wave sleep may manifest with progressive psychomo-
tor decline, which cannot be otherwise attributed to known
metabolic or organic causes. The main representatives are
the continuous spike and waves during slow wave sleep
syndrome (CSWS) and the Landau±Kleffner syndrome
(LKS). The association of progressive cognitive and
language de®cits in children with `bioelectrical status'
epilepticus was described in 1942 by Kennedy and Hill,
who proposed the term `dementia dysrhythmica infantum'
(cited in [1]). In 1957, Landau and Kleffner published their
classical description of the syndrome of acquired aphasia
associated with a convulsive disorder [2]. Verbal auditory
agnosia was linked to the acquired epileptic aphasia in 1977
by Rapin et al. [3]. The ®rst association of electrical status
epilepticus (ESES) with cognitive and language dysfunction
as well as with seizures was reported by Patry and Tassinari
in 1971 [4].
In the literature, CSWS has been used interchangeably
with the term `electrical status epilepticus in sleep' (ESES),
in order to characterize either the syndrome or the electro-
graphic correlate of nearly continuous spike and wave
discharges in slow wave sleep. In this review, we will
use the term ESES in Ref. to the electroencephalographic
(EEG) abnormalities, and the term CSWS for the
syndrome. Although the presence of ESES is obligatory
for the diagnosis of CSWS, it is often seen in various
evolutionary stages of other syndromes, such as LKS and
benign epilepsy of childhood with centrotemporal spikes
(BECTS). We will focus on the clinical and electrophysio-
logic characteristics of CSWS, LKS, and BECTS, and will
attempt to de®ne their diagnostic features. The current and
prospective therapeutic modalities will be discussed, and
correlated with the dominant theories on the pathophysiol-
ogy of these conditions.
Brain & Development 22 (2000) 279±295
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S0387-7604(00)00127-3
www.elsevier.com/locate/braindev
* Corresponding author. Tel.: 11-718-430-2447; fax: 11-718-430-8899.
E-mail address: aris3@aol.com (A.S. Galanopoulou).1 These authors have contributed equally to this work.
2. Syndrome of continuous spike and waves during slowwave sleep (CSWS)
The ®rst association of ESES with epilepsy or language
delay was made in 1971 by Tassinari [4]. Nowadays it is
appreciated that ESES often accompanies epileptic
syndromes associated with partial or generalized seizures,
occurring during sleep, as well as atypical absences when
awake. Patry and Tassinari de®ned ESES as diffuse, contin-
uous 1±3 Hz paroxysmal activities at the onset of sleep,
which persist during the entire slow-wave sleep period,
occupying at least 85% of the EEG tracing. A quantitative
measure of the electroencephalographic abnormalities is the
spike-wave index (SWI), which represents the sum of all
spike and slow wave minutes multiplied by 100 and divided
by the total NREM minutes. Subsequent studies however
established that the clinical symptomatology of ESES-
related syndromes may appear even if the SWI is smaller
than 85 [5,6]. It appears that the diagnosis of ESES-related
syndromes derives from a combination of clinical and elec-
trographic features, such as: (1) dramatic activation of
epileptiform activities in slow wave sleep compared to
wakefulness, i.e. increase in frequency and diffusion of
spike-waves, and (2) a constellation of clinical symptoms,
such as gradual cognitive and behavioral deterioration and
acquired language impairment.
CSWS occurs only in the ®rst decade of life. It encom-
passes 0.5% of all childhood epilepsies [7]. Eighty percent
of CSWS patients present with seizures [8], which are
typically nocturnal partial motor or generalized convulsive
[9]. Less frequently (25%) neuropsychological distur-
bances are evident at the time of ®rst presentation [8],
and in some cases, may precede the onset of epilepsy.
ESES is rarely the ®rst sign [8]. Absences appear the
same time as ESES, usually 1±2 years after the onset of
convulsions [8]. A single seizure type has been observed in
12% of the cases [10]. The epilepsy is severe in 93% of the
patients, with numerous seizures per day [10], but even-
tually subsides. The presence of seizures with falls is char-
acteristic of this syndrome, occurring in 44.5% of CSWS
patients [11], whereas they are absent in LKS patients [8].
It is also thought that pure tonic seizures are always absent
[7±9]. Other epileptic or paroxysmal behaviors include
facial contractions followed by loss of consciousness
[11], myoclonic absences [11], infantile spasms [12],
generalized nonconvulsive seizures (Gaggero et al. in
[13]). Despite the fact that epilepsy may remit, the prog-
nosis may be complicated by the persistence of residual
neuropsychological de®cits.
One third of the CSWS patients [8] have precedent neuro-
logic conditions, as listed in Table 1. Although CSWS is not
considered to have a genetic predisposition, Blennow and
Ors reported on a pair of monozygotic twins who presented
with CSWS [13]. Neuroradiologic abnormalities are also
frequent (33±50%) [8,11], as summarized in Table 2. The
most common ®nding is diffuse or unilateral atrophy.
Among the developmental migration disorders, polymicro-
gyria has a relative predilection to manifest as CSWS,
whereas other cortical developmental disorders do not
[14]. Guerrini et al. hypothesized that the preservation of
horizontal neuronal connections seen in polymicrogyric
cortices may allow the propagation and spreading of the
spike and wave discharges [14]. In contrast, other cortical
malformations disrupt the horizontal cortical lamination and
result in focal epileptic discharges that may not propagate as
easily.
Regardless of the prior cognitive status and development,
the appearance of CSWS is associated with emergence of
new cognitive and behavioral abnormalities [11]. The exact
incidence of each abnormality is dif®cult to assess since the
majority of these reports describe isolated cases or small
groups of patients with variable emphasis in the neuropsy-
chiatric pro®le. A universal decrease in the intelligence
quotient (IQ) or developmental quotient (DQ) is however
noted by most authors [12,13,15±19]. Attention de®cits and
hyperactivity are described in approximately two thirds of
the reported cases [13±15,17,18]. Temporospatial orienta-
tion was impaired in all patients with abnormal premorbid
cognitive state. In contrast, only half of the children with
previous normal development showed similar de®cits.
Language disturbance has been reported in 40±60% of the
CSWS patients, according to different studies [13,15,17±
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295280
Table 1
Personal antecedents in CSWS (31% [8], 61% [13])a
Prenatal or perinatal
abnormalities
38% [11], 33% [13]
Neonatal convulsions 10% [11], 5.55% [13]
Congenital hemiparesis 18% [105], 27% [11], 39% [13]
Neonatal purulent meningitis Two cases [13,39]
Psychomotor retardation 16.7% [13]
Shunts for hydrocephalus 30% of shunted patients have
CSWS [12]
Consanguinity 10% [11,13]
Febrile convulsions 5% [8]
Family history of epilepsy 10% [8,11], 16.7% [13]
a The data on Table 1 are based on a literature review. The data from Ref.
[11] are derived from the cases reported by Wolff et al. (n � 18).
Table 2
Neuroradiologic abnormalities in CSWS (33±60% [8,11,13])a
Atrophy, unilateral or diffuse The most common ®nding [11±
14,16,39]
Porencephaly 7% [11], 10% [13]
Pachygyria 3.5% [11], 10% [13]
Cortical developmental
disorders (CDD)
8% of CDD patients with
epilepsy have CSWS [14]
Perisylvian polymicrogyria 18% of patients have CSWS [14]
Hydrocephalus One case [39]
a The data on Table 2 are based on a literature review. Data from Ref.
[11] are derived from the cases reported by Wolff et al. (n � 18).
19]. A tendency towards expressive aphasia occurs in
CSWS patients, in contrast with the LKS patients who
tend to present with verbal or auditory agnosia [20]. Aggres-
siveness, language disorder, de®cits in relatedness and inhi-
bition [15,17,18,20], encopresis, enuresis [15], bizarre
behavior [15,17,18,21], emotional lability [15,17], psycho-
tic behavior [13,20±22], anxiety and phobias (Gaggero et al.
in [13]) as well as autistic-like behavioral features [21,23]
have also been described. Stereotypies, coprophagia,
compulsive hyperorality, depression, strange corporal
perception, automutilation, insensitivity to pain, echolalia
and echopraxia are also part of the spectrum of behavioral
disturbances. Parietal lobe dysfunction has been reported by
few authors, such as apraxia [20,24], hemineglect [24], and
impaired spatial orientation. Badinand Hubert et al. reported
a girl with CSWS and left parieto-occipital focus who mani-
fested Gerstman syndrome, i.e. dyscalculia and dyslexia,
with global dyspraxia, temporospatial de®cit, attention de®-
cit and hyperkinesis [25]. Zaiwalla et al. reported two
patients who manifested right hemispheric dysfunction,
including hemineglect or impairments in visuospatial and
temporospatial orientation [26]. Other de®cits include learn-
ing dif®culties [15], short-term memory impairment
[13,15,17,20], and de®cits in reasoning [15].
Several investigators showed that clinically unnoticed
epileptic discharges could be linked with the presence of
cognitive impairments [27±33]. Studies by Aarts [28],
Binnie [29] and Kasteleijn-Nolst Trenite [30] using the
Transitory Cognitive Impairment test under continuous
EEG recording on epileptic patients correlated the type of
cognitive de®cits with the focus and extent of the epilepti-
form discharges. These authors demonstrated that half of the
patients exhibited cognitive impairment during simulta-
neous generalized or focal discharges. Right-sided
discharges were associated with impaired performance in
the spatial memory task, whereas left-sided ones were asso-
ciated with errors in the verbal tasks. Interestingly, the high-
est rate of errors occurred when the discharge was
synchronous with the stimulus, whereas the least amount
of errors was observed when the discharge coincided with
the response. This observation concurs with the clinically
prominent attention de®cits of the CSWS patients. Further-
more, a high discharge rate was associated with low scho-
lastic performance, particularly arithmetics [16,30].
Rare reports however exist of CSWS without concomi-
tant cognitive impairments [34±36]. Prospective studies are
needed in order to more accurately correlate the timing of
the electrographic onset of ESES, in relation to the cognitive
deterioration, clarify the temporospatial evolution of the
SWI, and elucidate the factors involved in the genesis of
the cognitive deterioration.
2.1. Electroencephalography and functional imaging of
CSWS
The EEG of CSWS typically consists of continuous
spatially diffuse spikewave discharges in slowwave sleep
(stages III and IV). During wakefulness, the EEG of patients
with CSWS may show focal paroxysmal discharges. To
satisfy the de®nition of ESES, according to the original
de®nition given by Patry and Tassinari [4], spikewave
discharges must be present in more than 85% of slowwave
sleep. More lenient criteria are currently in use, which
include patients with smaller SWI, as long as the clinical
symptomatology resembles that of the classical cases, and
dramatic activation of the epileptiform discharges occurs in
slow wave sleep, compared with wakefulness. Spikewave
discharges are usually most abundant in the ®rst sleep cycle,
where they may account for 95±100% of slowwave sleep.
Later cycles of slowwave sleep may contain a greater quan-
tity of physiological sleep patterns, but the total duration of
spikewave discharges in slowwave sleep over the course of
the night should exceed 85% (Fig. 1). During wakefulness,
the rate of spikewave discharge is usually markedly
reduced, and the distribution of paroxysmal activity may
appear more focal. Frequent foci of spikewave discharges
in wakefulness are the frontotemporal region and the centro-
temporal region [10,11]. Seventy-one per cent of cases with
predominant anterior foci have a SWI from 85 to 100%,
which drops to 63.3% when foci are more posteriorly
located [5]. There is a slight right prevalence for anterior
foci [5]. In some patients the spike-waves may have a less
diffuse distribution during sleep. For instance, Gaggero et
al. reported two patients with CSWS who had almost contin-
uous presence of focal spike-waves at the frontocentral or
parieto-occipital areas bilaterally, occupying 50±85% of the
slow wave sleep [37].
Analysis of the digitized EEG of three patients with
CSWS showed that in slowwave sleep the diffuse-appearing
spikewave discharges frequently originated in focal regions
of brain and subsequently rapidly propagated within and
between hemispheres [38]. The rapidly propagated spike-
wave discharges arose from the same regions of brain that
generated more restricted, focal spike-wave discharges
during wakefulness. However, in each of the three patients
studied, there were additional foci of spikewave discharges
that were not seen during wakefulness. Estimation of inter-
hemispheric time differences in spikewave activity by
coherence and phase analysis in a separate series of three
patients with CSWS also veri®ed the rapid propagation of
spike activity from one hemisphere to another, suggesting a
focal origin to the spikewave discharge with rapid second-
ary bilateral synchrony [39].
In a series of ten patients with CSWS, single photon
emission computed tomography (SPECT) performed during
drowsiness revealed focal areas of hypoperfusion in six
patients, whereas four patients had normal scans. In four
of the six patients with abnormal SPECT studies, the region
of hypoperfusion correlated with the prevalent spike focus
detected by EEG [40]. Photon emission tomography (PET)
evaluation of six patients experiencing ongoing cognitive
and language decline as a result of CSWS found increased
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295 281
glucose utilization during sleep in focal regions of the brain
of ®ve of the six patients. Again, the hypermetabolic regions
identi®ed by PET correlated with the region of greatest
abnormality identi®ed by EEG [24].
2.2. CSWS: treatment
The treatment options for CSWS and LKS are often simi-
lar [41]. Seizures may respond to various antiepileptic medi-
cations. The resolution, however, of ESES and
neuropsychological de®cits often requires high dose corti-
costeroid or ACTH therapy [11,41]. The clinical and elec-
trographic improvement is often transient [11,14].
Ethosuximide alone or in combination with prednisone or
antiepileptics has resulted in clinical and electrographic
improvement [13,15,42]. Valproate in monotherapy or poly-
therapy, and lamotrigine in polytherapy trials have also been
effective [13,14]. Clobazam has been reported to have either
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295282
Fig. 1. The patient is a 7-year-old girl who presented with cognitive impairment and was diagnosed with CSWS. (A) EEG segment taken during wakefulness
shows a normal awake background. The EEG is displayed using a bipolar montage. The distance between vertical lines is one second. Eyeblink and muscle
artifacts are visible in the anterior leads bilaterally. (B) EEG segment taken from slow wave sleep. A generalized spike and slow wave discharge is present with
right sided predominance.
transient [11,13] or long-lasting effect [43] on CSWS. Lora-
zepam [16], clonazepam [18] in association with antiepilep-
tics, nitrazepam [16] and clomipramine [44] have also been
used.
In contrast to these successful trials, electrographic dete-
rioration has been associated with carbamazepine [45],
valproate [16], lorazepam [16]. Carbamazepine in particular
was shown to be more likely to lead to activation of diffuse
spikes during stage II sleep, compared with valproate or
untreated patients [45]. Clobazam has been associated
with exacerbation of hyperactive behavior, despite a partial
improvement of the SWI, and had to be discontinued [16].
The lack of prospective studies designed to compare the
various therapeutic agents in CSWS indicates that the ®nal
treatment choice in most cases is empiric. The current prac-
tice recommendations propose that ACTH, (e.g. 80 interna-
tional units daily with a 3 month taper) or high dose
prednisone (2±5 mg/kg/d po) be used as ®rst line treatment
when CSWS is diagnosed, followed by either ethosuximide
or valproate or benzodiazepines, as second line or adjunc-
tive medications [41]. Amphetamines have been used for
the symptomatic management of attention de®cit, hyperac-
tivity disorder in CSWS patients, with behavioral improve-
ment [13,46]. The EEG however remained unaffected
(Blennow et al. [13]).
2.3. CSWS: long-term prognosis
The epilepsy in CSWS shows a benign course, with
disappearance of clinical seizures during the teenage
years, in all cases [11]. Wolff et al. [13] report that they
never observed a seizure in CSWS patients after the age
of 15 years. The resolution of clinical seizures may precede
(30%), coincide with (30%) or follow (40%) the resolution
of ESES. Delayed resolution of seizures occurs in patients
with more severe epilepsy, such as those manifesting gener-
alized motor, tonic-atonic seizures or absences [11]. CSWS
resolves at the average age of 11 years and the EEG gradu-
ally normalizes within 3 years. In one study, the total dura-
tion of epilepsy was estimated to be 12 years [11].
In all cases, a signi®cant but often partial improvement
occurs in the cognitive and behavioral abnormalities after
resolution of the CSWS [11]. Almost half (47%) of the
patients with long-term follow up in Tassinari's study
were eventually leading a normal life, i.e. attending regular
school or working. The remaining were either institutiona-
lized or were not able to adapt properly in their working
environment.
3. Landau±Kleffner syndrome (LKS)
3.1. LKS: de®nition and epidemiology
The Landau±Kleffner syndrome (LKS), also known as
acquired epileptic aphasia, was initially described in 1957
[2]. It is an acquired childhood disorder consisting of audi-
tory agnosia [3], associated with focal or multifocal spikes
or spike and wave discharges. These are continuous or
nearly continuous during sleep. The onset is usually
between the ages of 3 to 7 years in a previously normal
child. Although LKS patients often appear to be deaf,
their normal audiograms and auditory evoked potentials
support the concept that there is an underlying disorder of
cortical processing of auditory information, a `verbal ± audi-
tory agnosia' [3]. Epileptic seizures and behavioral and
psychomotor disturbances are also observed, each in
approximately 72% of cases [47]. Seizures occur infre-
quently in children affected by this disorder. The EEG ®nd-
ings are usually more severe than would be anticipated by
the clinical epileptiform manifestations. Dulac et al.
reported that seizures in LKS patients are often nocturnal
simple partial motor as in `benign partial epilepsy of child-
hood with rolandic spikes' (BECTS) [48]. The same authors
have also described generalized tonic-clonic seizures, atypi-
cal absences, and more rarely myoclonic-astatic as manifes-
tations of LKS. Only rare cases of tonic seizures have been
described [42,47]. The seizures are usually self-limited, well
controlled by therapy, and decrease in frequency with age.
Seizures rarely occur after age 15 years [47]. LKS is a rare
disorder, with about 200 cases described in the literature,
from 1968 until 1992. It is possible that several other cases
have not been reported. LKS affects boys more frequently
than girls with a 2:1 ratio, without an apparent familial
pattern of transmission [47].
Patients with LKS, in contrast to those affected by CSWS,
rarely have premorbid conditions associated with central
nervous system dysfunction. Few of the reported antecedent
medical conditions are summarized in Table 3. There are
discrepant reports regarding the role of genetic factors in the
pathogenesis of LKS. Echenne described two homozygotic
twins, one with developmental dysphasia, and the other with
LKS (cited in [49]). Feekery et al. however observed normal
development in the identical twin of one of their LKS
patients [50].
3.2. LKS: neuropsychological and psychomotor dysfunction
The most frequently reported form of language disorder
in LKS is verbal auditory agnosia [3,47]. The aphasia
usually presents as language regression, and in the majority
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295 283
Table 3
Personal antecedents in LKS (3% [8])a
Encephalopathy 3% [8]
Congenital hemiparesis Single case (Battaglia in [13])
Focal lesions
(astrocytomas,
neurocysticercosis, focal
encephalitis)
Rare reports [77]
Family history of epilepsy 12% [47], 3% [8]
a The data on Table 3 are based on a literature review.
of cases (70%) it is diagnosed before the age of 6 years [47].
The aphasia in children with LKS stems from receptive
dysfunction, unlike in other more typical forms of acquired
childhood aphasia. For that reason, these patients are some-
times mistakenly considered to have acquired deafness
[49]. Reading, writing and use of sign language are rela-
tively conserved, pointing more towards verbal auditory
agnosia with varying degree of mutism [51]. The aphasia
in children with LKS may be only one component of a
more complex neuropsychological disorder associated
with other cognitive and behavioral de®cits [47]. In cases
where the epileptic process associated with the aphasia
originates in areas of the brain responsible for behavior
control, an acquired psychosis or an autistic syndrome
can be the prevalent manifestations [49]. Loss of language
also creates an obvious barrier to effective communication
and may be the culprit for severe secondary behavioral
problems [47]. Psychomotor disturbances, in particular
hyperkinesis, are present in approximately 72% of cases
[47]. The relative severity of the cognitive, behavioral,
linguistic and psychomotor disturbances can vary over
time in the same patient. This clinical picture is different
from that seen in other forms of acquired childhood apha-
sias associated with organic brain lesions, which are
usually acute in onset and frequently associated with
other neurological symptoms, such as motor, sensory, cere-
bellar or cranial nerve de®cits.
A number of investigators described the salient neurop-
sychological and psychomotor abnormalities that affect
children with LKS. Beaumanoir [47] summarized 113
published cases of LKS patients. Verbal auditory agnosia
developed in 82% whereas 13% had a pre-existing distur-
bance of language acquisition. Hyperkinetic syndrome
developed in 80%. The most common presenting symptoms
were aphasia (in 54% of cases) and epilepsy (in 30%), or a
combination of both (15%). Guerreiro et al. [52] described
®ve children affected by LKS with disease onset between 3
and 9 years of age. All ®ve presented with verbal auditory
agnosia, and 4 (80%) had hyperactivity. Only one had autis-
tic behavior. Hirsch et al. [53] described ®ve patients with
LKS who had onset of symptoms between 3 and 7 years of
age. Verbal auditory agnosia with hyperkinesis and seizures
were the prominent symptoms in three of those patients.
One child had auditory agnosia with global regression of
higher cortical functions and one had transient aphasia with
massive intellectual deterioration and psychotic behavior.
Rossi et al. [54] described 11 patients with LKS, with a
mean age of 5 years and 7 months who were observed for
a mean period of 9 years and 8 months. Three patients had a
mild speech delay noted before the onset of aphasia. At the
last observation, language was normal in two (18%), and
moderately compromised in ®ve (46%). The remaining four
patients remained severely compromised in their language
development. The IQ before the onset of LKS was normal in
all cases. At the last observation, IQ remained normal in
two, borderline in two, mildly retarded in four, moderately
retarded in two, and severely retarded in one. There was a
signi®cant discrepancy in scores between verbal and perfor-
mance items on the IQ tests, with performance scores
consistently higher. Hyperkinesis was noted at onset of
LKS in eight patients (73%), irritability in six (55%), autis-
tic-like behavior in four (36%) and attention de®cit disorder
in four (36%). At the last observation, unspeci®ed beha-
vioral disturbances were present in ®ve children, attention
de®cit disorder in three, hyperkinesis in two, autistic-like
traits in two, and introversion, irritability and phobic mani-
festations each in one patient.
Bishop [55], in a study comparing sentence structure and
comprehension in children with LKS to a group of
profoundly deaf children, as well as to a group with devel-
opmental expressive disorder, concludes that children with
LKS fail to abstract the hierarchical structure of sentences.
Their language comprehension is deviant rather than
delayed. This is not restricted to the auditory modality,
but persists when written or signed language is used.
Profoundly deaf children show a strikingly similar pattern
of performance. Children with developmental expressive
disorder do not show the abnormal patterns of performance
found in the LKS group. He suggests that the deviant
comprehension of LKS and deaf children is a consequence
of their reliance on the visual modality to learn grammar.
3.3. Electroencephalography, electrocorticography and
functional imaging of LKS
The EEG ®ndings in LKS are variable. Often, the awake
EEG identi®es one or more spike foci in the posterior
temporal or parietooccipital regions of either or both hemi-
spheres. Sleep typically activates the EEG, and causes an
increase in discharge rate, as well as wider spread of the
epileptic spike discharge [47]. In many LKS cases, the
spikewave activity during sleep meets the criteria for
ESES, described earlier. To some, the EEG similarities
between LKS and CSWS have suggested that the two
syndromes represent different expressions of the same
pathological process [54,56,57], although others have
presented evidence to the contrary [58]. The exact percen-
tage of patients with an epileptic focus at the nondominant
hemisphere is dif®cult to evaluate, but there are reports
documenting that this is a possibility. For instance, Bulteau
et al. reported a right handed boy who had a right centro-
temporal interictal focus, and an increase of his spike-wave
activities over the right temporal area, in sleep [23]. Clini-
cally this boy had verbal agnosia, apraxia, attention and
memory problems. Metz-Lutz et al. reported that a right
handed boy with seizures, auditory agnosia, reduced
language and paraphasias had ESES consisting of bilateral
spike-wave, predominating on the right temporal area [59].
ESES may also present with a unilateral distribution, as in
the case of an LKS patient presented by Hirsch et al. [22].
In 37 patients with LKS, who also manifested ESES,
apparently synchronous bihemispheric discharges were in
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295284
fact unilateral and propagated rapidly, to the opposite
hemisphere. In these patients, who were evaluated for
surgical treatment of their illness, the presence of focal
origin of bihemispheric discharges was assessed using
intracarotid infusions of methohexital and amobarbitol.
Infusion of methohexital, a drug that blocks excitatory
synaptic transmission and enhances inhibitory synaptic
transmission, was used to distinguish autonomously active
epileptogenic lesions from those that were present as a
result of synaptically propagated epileptic activity. During
recovery from methohexital suppression of background
activity, it was possible to detect a propagation delay in
the onset of spikes in one hemisphere, suggesting that
spikes originated in the opposite hemisphere. Intracarotid
infusion of amobarbitol to anesthetize the hemisphere
containing the autonomously active epileptogenic lesion
abolished the paroxysmal activity in both hemispheres.
Injecting amobarbitol into the opposite hemisphere, on
the other hand, abolished paroxysmal activity ipsilaterally
and not contralaterally, indicating that the epileptogenic
zone was restricted to one hemisphere even though
synchronous bihemispheric discharges were usually seen
under physiological conditions [60,61].
Noninvasive localization of the origin of spikes in cases
of LKS using magnetoencephalography has been
performed in a small number of patients, and has
produced consistent results across patients and from differ-
ent laboratories. In a series of seven patients with LKS,
the earliest spike origin was consistently localized to the
cortex lining the Sylvian ®ssure [62±64], and similar
results have been reported, but not quanti®ed, by others
[60,61]. In ®ve most affected patients evaluated by Pateau
(1994), the auditory evoked ®eld produced by pure tones
was consistently abnormal. In two patients, the presenta-
tion of an auditory stimulus often triggered an epileptic
spike [63]. In a separate series of six patients, it was found
that auditory stimuli presented immediately following a
spontaneous spikewave discharge produced a delayed
and attenuated auditory evoked potential response
compared to the response obtained in the absence of
spikewave discharges [65]. These results indicate that
the neuronal populations serving auditory processing
may overlap with the population of neurons responsible
for spike generation. The presence of continuous parox-
ysmal activity in a region of cortex may be suf®cient to
disrupt normal synaptic function, and consequently,
language processing and acquisition. This disruption,
however, is not complete. Intraoperative electrocorticogra-
phy in a surgically treated anesthetized patient with LKS
demonstrated that the ability to distinguish the phonemes
`ba' and `ga' was preserved in this patient despite the
presence of frequent spikewave activity [66].
Neuroimaging with single photon emission computed
tomography (SPECT) has also been used to characterize
and localize the pathological lesion in patients with LKS.
In a series of ®ve patients with LKS studied by SPECT, all
of the patients were found to have a focal region of
increased perfusion in the left temporal lobe [52].
3.4. LKS: treatment
Several antiepileptic agents have been effective in the
treatment of LKS. Corticosteroids, however, are most effec-
tive for treating both clinical and electrophysiological
abnormalities. Relapses can be observed on withdrawal of
treatment [41,47,49,53,67]. Sulthiame, a carbonic anhy-
drase inhibitor, has also been shown bene®cial for the treat-
ment of LKS patients [68] in Japan, but it is not FDA
approved in USA. Valproate, ethosuximide and various
benzodiazepines are partially and transiently effective.
Phenytoin, carbamazepine and phenobarbital are either inef-
fective or appear to worsen the condition [49,53]. The ef®-
cacy of the agents listed above has not been tested in a
randomized controlled double-blinded study. Bergvist et
al. reported bene®cial effects of the ketogenic diet in
patients with acquired epileptic aphasia [69]. Anecdotal
reports of bene®cial effects of repeated IVIG or vigabatrin
administration in patients with Landau±Kleffner syndrome
have been reported [70±73].
In 1995, F. Morrell and his colleagues published their
®rst promising data from multiple subpial transections
(MST) performed in 14 LKS patients. Multiple subpial
transections of a region of cortex disrupt the tangential
intracortical connections that permit propagation of parox-
ysmal activity, while preserving radial connections that are
important to language. Selection criteria included: (i) a
severe epileptic encephalopathy with bilateral diffuse
spike and slow wave complexes in slow wave sleep, (ii)
evidence of a unilateral focus of the diffuse epileptic
abnormalities (secondary bilateral synchrony), (iii) relative
preservation of non-verbal skills, and (iv) acquired
language disorder including verbal agnosia, in a context
of a normal for age premorbid language ability [61]. Elec-
troclinical improvement was noted in 79% of them. More
recently, a follow-up study (0.5±6.6 years) from the same
group compared pre- and postsurgical performance of 14
LKS patients in two tests: the Peabody picture vocabulary
test-revised (PPVT-R) which evaluates receptive language,
as well as the expressive one word picture vocabulary test-
revised (EOWPVT-R), which assesses expressive language
[74]. Signi®cantly improved post-surgical mean and stan-
dard scores were found in both tests. The results did not
seem to be affected by the time period between diagnosis
and surgery. Right-sided MST (n � 5) was associated with
higher rate of improvement in the expressive (80%) rather
than the receptive functions (20%), while left-sided MST
(n � 9) was associated with slightly higher rate of
improvement in the receptive functions (66.6%) rather
than the expressive (44%). A total of 71.5% of the cases
improved in one (42.9%) or two (28.6%) test scores. Two
patients deteriorated. None of the children who improved
in both tests required any assistance at school, whereas ®ve
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295 285
of the six children with improvement in one test required
special aids [74]. There is no similar study testing the
effect of MST in CSWS with prominent neuropsycho-
logical abnormalities. These promising results were
reiterated by Sawhney et al. [75], who reported postopera-
tive speech recovery in three LKS patients, following
MST.
3.5. LKS: long-term prognosis
Long-term prognosis in LKS is dif®cult to predict, since
there is limited number of studies reporting adequate long-
term follow-up. Mantovani and Landau reported on nine
patients with LKS who were followed for 10±28 years.
The overall clinical status and language were normal in
less than half (cited in [41]). Other studies (reviewed in
[41]) con®rm that aphasia persists in the majority of
patients. Only half of patients with LKS are able to live a
relatively normal life [24,41,47,54]. Other authors (Bishop
[76] and Dulac [48]) have suggested that long-term prog-
nosis is affected by the age at onset, with those affected early
having a worse outcome. In these cases of LKS, the
dysfunction may be bilateral from the start. Another possi-
bility is that the nonstructural abnormalities seen in LKS do
not have the same ability to shift language to the contral-
ateral hemisphere as structural lesions do. In cases of struc-
tural brain disease, it has been shown that before age 5±6
years, there is considerable plasticity of language represen-
tation, and signi®cant injury to the dominant hemisphere is
capable of forcing language function into the contralateral
hemisphere [51]. Of note, a few cases of children with LKS
and a focal brain lesion were reported recently [77]. In those
patients, aphasia resolved after resection of the lesion. In
addition, the long-term prognosis is probably determined by
factors such as the frequency of epileptic discharges in the
language zone, the duration of the epileptic disorder, the
extension of the epileptic dysfunction to the contralateral
cortex, the ef®cacy of the antiepileptic agents, and the ef®-
cacy of psychological and speci®c educational therapy
[49,67].
4. Benign childhood epilepsy with centrotemporal spikes(BECTS)
4.1. BECTS: de®nition and epidemiology
BECTS is a primary convulsive disorder characterized
by simple partial seizures that tend to become generalized
when occurring nocturnally [78]. The age of onset is from
3 to 13 years. The pattern of the partial seizures in BECTS
is very characteristic and consists of brief hemifacial
twitches followed by arrest of speech, drooling with preser-
vation of consciousness [78,79]. BECTS is considered a
benign disorder as seizure frequency is typically low and
remission occurs usually during puberty [78]. BECTS is
one of the most common epileptic syndromes in childhood,
occurring in 15±24% of young patients with epilepsy [78].
It is considered to be a genetically determined disorder,
with a probable autosomal dominant pattern of transmis-
sion [79], and a slight (3:2) male to female prevalence.
Febrile convulsions are the presenting symptom in 9±
20% of children with BECTS [80]. In rare patients with
BECTS neuroimaging may reveal abnormalities such as
arachnoid cysts, congenital toxoplasmosis, cortical dyspla-
sias, opercular macrogyrias, ventricular enlargement,
lipoma of the corpus callosum, and enlarged sylvian
®ssure. These studies are reviewed by Gelisse et al. [81].
Tumors may also present with clinical manifestations
resembling BECTS, an association that led to the use of
the term `pseudo-BECTS' [82]. Gelisse et al. recently
reported a patient with BECTS who manifested hippocam-
pal atrophy on the MRI [81]. Lundberg et al. studied 18
children with BECTS and described hippocampal abnorm-
alities in six of them, ipsilaterally to the EEG abnormalities
[83]. These included hippocampal asymmetries or high
signal intensities on T2-weighted images.
4.2. BECTS: neuropsychological, intellectual and
behavioral ®ndings
Normal neurologic and cognitive ®ndings have been
considered a prerequisite for the diagnosis of BECTS.
Some recent studies, however, have found impaired visuo-
motor coordination, learning disabilities, hyperkinesis,
attention de®cit, clumsiness and developmental dysphasia
in many children affected by this disorder [80,84,85].
Staden et al. [85] reported on 20 children with BECTS,
13 of whom had language dysfunction. Reading, spelling,
auditory verbal learning, auditory discrimination with
background noise, and expressive grammar were most
frequently affected. The only parameter which positively
correlated with the presence of language dysfunction was
the high frequency of epileptiform discharges (.10 spikes/
min). Weglage et al. [84] described children with BECTS
who showed signi®cantly poorer results with respect to IQ
(full scale and performance IQ), visual perception, spatial
orientation, short term memory and ®ne motor perfor-
mance. De®cits in performance IQ were signi®cantly corre-
lated with frequency of spikes in the EEG, but not with
frequency of seizures, lateralization of the EEG focus, or
time since diagnosis [84]. For instance, the 12 children
with more than six spikes/min of the awake EEG demon-
strated a mean (^SD) performance IQ (PIQ) of 93 ^ 14,
compared with a mean (^SD) PIQ of 110 ^ 12.5 of the
control group, comprised of normal children (P , 0:05).
Croona et al. [86] studied 17 children with BECTS using
an extensive battery of neuropsychological tests appropri-
ate for the evaluation of immediate and delayed recall of
auditory-verbal and visual material, verbal ¯uency,
problem-solving ability, and visuospatial constructional
ability. They also administered Raven's colored matrices
and questionnaires to assess school functioning and beha-
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295286
vior. The results were correlated with those of normal
classmates. Children with BECTS had signi®cantly lower
scores than their control subject partners. Intellectual abil-
ities did not differ and neither did school functioning or
behavior according to teachers. Parents however recog-
nized greater dif®culties with concentration, temperament,
and impulsiveness in children with BECTS.
4.3. Electroencephalography of BECTS
The epileptic spikes of BECTS typically appear stereo-
typed and repetitive, and they usually occur most frequently
in light sleep (Fig. 2). In light sleep, spikes appear more
diffuse and generalized [87]. In routine EEG records, the
spikes of BECTS appear to arise from a horizontal current
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295 287
Fig. 2. This is a 9-year-old boy with BECTS. (A). EEG during wakefulness consists of a normal background. (B) EEG during sleep demonstrates repetitive
stereotyped left centrotemporal spikes (shown by asterisks). The distance between vertical lines is one second.
dipole with a frontal positivity and a centrotemporal nega-
tivity. Dipole source localization by magnetoencephalogra-
phy has shown that the spikes of BECTS originate in the
region of rolandic ®ssure [88].
The realization that frequent spike activity may disrupt
normal brain function and development receives support
from the growing evidence that children with BECTS
experience subtle impairments in language function [85]
and in IQ [84]. IQ loss was signi®cantly correlated with
spike frequency, but not with duration of the condition or
with seizure frequency. In these patients with spikes that
arise in the rolandic area [88], there is evidence suggesting
that the presence of neurological de®cits is associated with
greater variability and size of the brain region giving rise to
epileptic activity [89±91].
4.4. BECTS: treatment
BECTS typically presents with brief seizures, usually
responsive to antiepileptics. Because of the benign nature
of this disorder, the current recommendations suggest treat-
ment only when seizures are recurrent and frequent, or
when the epileptic events are disruptive to the patient or
the family [78]. For nocturnal seizures, a single bedtime
dose of controlled release carbamazepine, phenytoin or
phenobarbital is suf®cient. Valproate and sulthiame have
been used as alternative therapy. Gabapentin administered
as monotherapy is effective in controlling seizures in chil-
dren with BECTS and is well tolerated in this population
[92]. Anticonvulsants are tapered off 1±2 years after
seizure control, even in cases when the EEG has not
normalized completely [78].
4.5. BECTS: long-term prognosis
BECTS is generally a benign condition. In 20% of the
cases however the epileptic events may be frequent and
persist despite antiepileptics [78,79]. Status epilepticus has
been reported occasionally [78,79]. Recurrence of seizures
has been reported in 1±2% of the cases, and denotes the
occurrence of new epilepsy. These are mostly nocturnal,
generalized or provoked by alcohol or sleep deprivation
[78,79]. In a follow-up study of children with BECTS,
D'Alessandro et al. demonstrated normalization of
previously impaired cognitive functions [93].
5. Comparison of CSWS, LKS, and BECTS
In an attempt to correlate clinical, electrographic and
neuropsychiatric ®ndings, Rousselle and Revol [20]
reviewed the existing literature on ESES and categorized
the patients in 4 groups. These data are summarized in
Table 4. This comprehensive review tends to suggest that
the duration and origin of the epileptiform activity may be
responsible for the variable symptomatology between
groups 1 through 4. Speci®cally, longer duration of ESES
(more than 2 years) tended to be associated with greater
impact on the cognitive and neuropsychiatric sphere. In
addition, CSWS patients with prominent cognitive and
behavioral dysfunction tended to have a frontal focus,
whereas those with prominent language dysfunction had a
temporal focus. There is, however, a considerable overlap
between groups, which makes it dif®cult to draw clear
borders between them.
Mira et al. reviewed the cases submitted to the Venice
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295288
Table 4
Categorization of patients with prominent nocturnal epileptiform activitiesa
Group 1 Group 2 Group 3 Group 4
Prototype BECTS LKS CSWS CSWS
Number of patients 35 33 99 42
Prominent feature Seizures Language disorder Global deterioration Global deterioration
Initial neuro-psychiatric
examination
Normal Normal Normal Abnormal (focal or diffuse)
Duration of ESES 6 months (4±14 months) 17 months (2±48 months) 26 months (3±60 months) 27 months (18±48 months)
SWI in slow wave sleep 71% (44±97%) 76% (37±90%) 80% (55±100%) 80% (53±100%)
Focus of spike wave discharges Rolandic Temporal 86% Frontal in 75%; right
hemisphere in 70%
Frontal
Language impairment None reported in this review 100%, verbal-auditory
agnosia; minority:
expressive aphasia
40%, predominantly
expressive aphasia
Present
Global deterioration None reported in this review Minor Major Major
a Table 4 is based on data reported by Rousselle and Revol [20]. Group 1 included patients with a normal neurological examination who were thought to
represent atypical idiopathic epilepsy, manifesting as a combination of atypical absences and partial motor seizures with signi®cant nocturnal electroence-
phalographic abnormalities. Group 2 was comprised of patients with language impairment as prominent feature, the majority having been diagnosed with
Landau±Kleffner syndrome. Groups 3 and 4 consisted of patients with prominent neuropsychological rather than language deterioration (CSWS patients). The
patients included in group 3 had normal prior neurological examination and development, whereas patients in group 4 had initial focal or diffuse brain
dysfunction.
Colloquium (1993) on ESES, and analyzed the neuropsy-
chiatric de®cits of 59 cases evaluated by WISC-R (Wechs-
ler Intelligence Scale for Children) [94]. The scores
following EEG normalization were available for 32 of
these children. Comparison of the verbal and performance
IQ (VIQ, PIQ respectively) demonstrated the existence of a
discordance, or `gradient', in the VIQ and PIQ scores, in
all cases but one. In two thirds of the cases, this difference
was at least ten points. ESES patients were divided into
two groups, those with higher verbal scores (VIQ . PIQ),
such as CSWS patients, and those with higher performance
scores (PIQ . VIQ), such as LKS patients. A comparison
between the two groups is presented at Table 5. In
summary, all cases with ESES showed impairments in
logical-structural thought, and performance in tasks requir-
ing prompt and prolonged mental effort. Additional de®cits
were noted in practical intelligence, and activation of logi-
cal structures. Recovery occurred in almost all cases, but
was usually partial. Patients characterized by preferential
impairment of language, such as LKS patients, seemed to
be less impaired, and manifested mainly auditory agnosia.
In contrast, globally impaired children, such as in CSWS
presented with prominent neuropsychiatric manifestations,
and expressive aphasia. A general comparison of CSWS
and LKS is presented in Table 6. The signi®cant overlap of
these syndromes is evident by the comparisons in Tables
4±6. Few authors have proposed that early onset and long
duration of ESES, as well as high discharge frequency and
frontal origin of the principal focus of the epileptic
discharges are prognosticators of a more global impair-
ment. Prospective studies however are needed to con®rm
these statements. Awareness of the potential neuropsychia-
tric abnormalities, which may be associated with its
presence, is of paramount importance in initiating early
treatment.
6. Other syndromes manifesting ESES
6.1. Atypical benign partial epilepsy
Atypical benign partial epilepsy or pseudo-Lennox±
Gastaut syndrome [35] or petit mal variant usually affects
normal children, between the ages of 2±7 years. The seizures
may include generalized tonic-clonic seizures, atonic-astatic
or nodding seizures, atypical absences and rolandic seizures
[1]. The atypical benign partial epilepsy bears signi®cant
similarities with BECTS and Lennox±Gastaut syndromes,
but the severity of its clinical course is intermediate to that
of the other two syndromes. In contrast to Lennox±Gastaut
syndrome, which may manifest tonic drop attacks, patients
with atypical benign partial epilepsy manifest atonic drop
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295 289
Table 5
Evolution of IQ scores in patients with higher performance (PIQ . VIQ) or verbal (VIQ . PIQ) scoresa
Test PIQ . VIQ VIQ . PIQ
During ESES After EEG normalization During ESES After EEG normalization
n 20 12 12 8
Verbal tests
Normal 1/20 1/12 2/12 4/8
Impaired 6/20 8/12 7/12 4/8
Pathological 13/20 3/12 3/12 0/8
Verbal tests
Worse 1/12 2/8
Better 9/12 5/8
Same 2/12 1/8
Performance tests
Normal 5/20 4/12 0/12 1/8
Impaired 11/20 6/12 3/12 3/8
Pathological 4/20 2/12 9/12 4/8
Performance tests
Worse 2/12 2/8
Better 9/12 6/8
Same 1/12 0/8
Normal IQ scores 91% 46%
Gradient
Extreme 66 points 32 points
Mean 15.38 13.61 13.22 8.77
Overall WISC-R score
Worse 2/12 2/8
Improved 9/12 5/8
Unchanged 1/12 1/8
a The data in Table 5 is derived from Mira et al. [94].
attacks [95]. Tonic or tonic-astatic seizures never occur [1].
The EEG shows focal, multifocal or generalized sharp and
slow wave complexes, which are activated during sleep,
often in the form of bioelectrical status [1,95,96]. The
epilepsy has a favorable outcome, and resolves during
puberty [1]. Neuropsychological deterioration however
may occur, which at times may resemble severe dementia,
associated with dysarthria or dysphasia [1].
6.2. Acquired epileptiform opercular syndrome
The acquired epileptiform opercular syndrome is a rare
epileptic syndrome, which manifests with oro-facio-lingual
de®cits, such as severe oral motor dysfunction, drooling,
dysarthria, speech arrest or weakness of the face and tongue.
Symptoms appear around the age of 4±8 years [97±99]. The
seizures are typically focal motor, involving the face, and
occasionally rolandic seizures, partial complex or atypical
absences [97]. The EEG consists of spikes originating from
the centrotemporal areas on either side, and less commonly
from the temporal areas [97]. Spike and wave complexes
with secondary bilateral synchrony may appear, often acti-
vated by sleep. Rare case reports of children with ESES
manifesting as opercular syndrome have been reported
[97,100]. In these cases, carbamazepine therapy either
exacerbated seizures or was ineffective. Improvement was
noted with various combinations of clobazam, ethosuxi-
mide, methosuximide, valproate, clonazepam or ketogenic
diet [97,100] and the patients appear to slowly improve over
several years [97].
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295290
Table 6
Comparison of CSWS and LKSa
CSWS LKS
Sex 63±72 M [8,13] 68% M [8]
Past medical history 31% personal antecedents [8],
18% of polymicrogyric patients
have CSWS [14]
3% personal antecedents [8]
Family history of epilepsy 10% [8,13] 3% n� 31 [8], 12% [47]
Age at onset 5±7 years [8,14] 5±7 years [8]
Duration of ESES 26 months [20], 1.6±3.4 years
[13,14]
17 months [20]
Correlation of duration of ESES
with cognitive impairment or
seizures
No correlation [14], positive
correlation ([20], Wolff in [13])
First symptom Seizures 80%,
neuropsychological 25% [8]
Seizures 60%,
neuropsychological 40%,
never as typical CSWS [8]
Seizure types
Generalized (GTC, GNC, GC) 57% (Gaggero, n� 14 in [13]) 35% [8]
Partial 18% [8], 86% (Gaggero, n� 14
in [13]
26% [8]
Absence 20% initially, 48% during
CSWS [8]
40% [8]
Atonic 23% [8], 4/5 [14] Never [8], Bataglia [13]: one
case
Tonic Never [8] Only four case reports [42,47]
Worsening of epilepsy during
ESES
50% [8] 17% [8]
Neuroimaging 33% abnormal [8] 13% abnormal [8]
SWI asleep 82% [20] 76% [20]
Correlation of SWI with
cognitive impairment or seizures
No correlation [14,106] Unclear
Secondary bilateral synchrony Yes [14,39] Yes [54,61]
ESES focality Frontal 75% [30] Temporal 86% [30]
Language impairment 40% [30], expressive
.receptive aphasia
100% [30], verbal/auditory
agnosia
Behavioral/psychiatric 95% [30] 36±42% at ®rst observation,
45% at last observation [54]
IQ/DQ decrement Almost all [20] 64% [54]
Effective treatment ACTH, steroids, valproate,
ethosuximide, lamotrigine
ACTH, corticosteroids,
valproate, ethosuximide,
benzodiazepines, multiple
subpial transections
a The data in Table 6 are compiled from a literature review.
6.3. Benign occipital epilepsy of childhood
Benign occipital epilepsy of childhood or Panayotopou-
los syndrome [101] may also manifest psychomotor dete-
rioration, behavioral disturbances and seizures, and
occasionally ESES [102,103]. It has clinical and electro-
graphic similarities with BECTS. The diagnostic features,
which differentiate it from BECTS, are: (1) various visual
symptoms, (2) migrainous symptoms, and (3) unilateral or
bilateral spike-wave complexes in the posterior regions,
inhibited by eye-opening (scotosensitivity) [102]. Similar
to the other ESES related syndromes, the seizures in benign
occipital epilepsy of childhood also resolve during puberty
[102,103].
7. Differential diagnosis from other syndromes withprominent epileptiform discharges
7.1. Myoclonic-astatic epilepsy or Doose's syndrome
In contrast to the other syndromes described in this
review, myoclonic-astatic epilepsy of early childhood is a
primary generalized epilepsy [95]. There is a strong genetic
susceptibility since in 32% of the patients, there is a family
history of seizures. Furthermore, there is increased inci-
dence of photosensitivity or spike-wave complexes in the
relatives of patients with myoclonic-astatic syndrome [95].
Epilepsy starts during the ®rst 5 years of life in 94% of the
patients, and includes myoclonic or myoclonic-astatic
seizures (100%), generalized tonic-clonic seizures (75%),
absences (62%), status of myoclonic-astatic seizures or
absences (36%), nocturnal tonic seizures (30%), febrile
convulsions (28%) [95]. Focal seizures are not a character-
istic of myoclonic-astatic syndrome, but may occur in the
rare coexistence of a primary brain lesion [95]. The EEG
consists of slow spike-wave complexes, often irregular,
rarely in sequences, and often interrupted by high amplitude
delta waves [95]. In the case of myoclonic seizures, the
record shows short paroxysms of spike-wave complexes
or polyspike waves. In patients with myoclonic-astatic
seizures, the EEG shows slow spike-wave complexes or
spike-wave variants [95]. During nocturnal tonic seizures,
the EEG shows 10±15 Hz spike discharges [95]. Pseudofoci
of epileptiform activities may be present, but these charac-
teristically shift from side to side. In the very rare occasions
that these are constantly localized in one area, the existence
of a primary brain lesion should be sought [95]. According
to Doose, complete seizure control is achieved by the age of
7 years, in 54% of the patients [95]. The treatment of choice
is valproate. Ethosuximide is also effective, as well as primi-
done as combination therapy. ACTH and acetazolamide
may be ef®cacious in status. Clonazepam on the other
hand may activate tonic seizures and even provoke tonic
status [95]. Overall the prognosis is variable. Onset of
epilepsy at the ®rst year of life, nocturnal seizures ± parti-
cularly if tonic in nature -, long lasting status consisting of
myoclonic-astatic or absence seizures, frequent generalized
tonic-clonic seizures and persistence of rhythmic slowing
with absence of posterior alpha rhythm until adulthood and
adolescence are unfavorable features [95].
The presence of drop attacks in both myoclonic-astatic
epilepsy of early childhood as well as in CSWS syndrome
may create diagnostic dilemmas in some cases. In contrast
to CSWS, myoclonic-astatic epilepsy of early childhood is a
primary generalized epilepsy, with rare focal seizures, and
occasional tonic seizures. Nocturnal seizures are not as
common as CSWS, but once present they herald a bad prog-
nosis.
7.2. Lennox±Gastaut syndrome
The differentiation between Lennox±Gastaut and ESES-
related syndromes belies on several electrographic and clin-
ical features. The EEG in Lennox±Gastaut rarely manifests
SWI greater than 50% [6], and it typically consists of poly-
spike and wave complexes. In contrast, ESES consists of
spike-wave complexes [4]. The effect of sleep and wakeful-
ness is dramatic and appears suddenly in ESES, whereas it is
insidious in Lennox±Gastaut [104]. Finally, tonic seizures
are almost never present in ESES syndromes, but are typical
of Lennox±Gastaut patients [6].
8. Conclusions ± future directions
There is no doubt that early recognition of the spectrum
of the ESES associated disorders is of paramount impor-
tance, since it affects a sensitive stage in the language and
cognitive development of the children. Awareness of the
possibility that seemingly benign epileptic syndromes may
transform into devastating syndromes, such as CSWS, is
crucial for the prompt recognition of `atypical' symptoms
and signs, which may be premonitory of a more malignant
course. For instance, children with language regression,
behavioral abnormalities, deteriorating school performance,
abnormal EEG background, high discharge frequency, lack
of responsiveness to appropriate medications, or existence
of prior neurologic abnormalities may warrant further inves-
tigation with a sleep EEG record or an overnight EEG moni-
toring. Prospective studies are needed in order to better
de®ne the natural history of these syndromes, and test the
individual predictive role of the above factors.
Despite the investigation of patients with CSWS and with
the LKS syndrome using various methods, the origin of the
continuous spike and wave discharge in sleep remains
unknown. Nevertheless, the electrophysiological investiga-
tion of CSWS and LKS with EEG, magnetoencephalogra-
phy, PET, and SPECT, has provided some clues to the
mechanism of cognitive impairment. In particular, it
seems increasingly likely that the neuropsychological de®-
cits in CSWS arise from ongoing paroxysmal activity [57],
rather than from an undiscovered underlying process that
A.S. Galanopoulou et al. / Brain & Development 22 (2000) 279±295 291
gives rise to both the paroxysmal activity and the neurop-
sychological decline. There is increasing evidence that at
least part of the pathology originates in focal regions of
cortex. The conclusion that CSWS and LKS represent the
effects of a potentially focal `epileptic encephalopathy'
would be signi®cant, and would provide a rationale for
surgical treatment. While it is fortunate that these devastat-
ing illnesses remain relatively rare, the small numbers of
patients available for study poses an obstacle for clinical
investigation into the pathophysiology of the disorder and
the identi®cation of better treatments.
Activity dependent synaptic plasticity is thought to be
critical for the establishment of appropriate neuronal
connections, during development. Frank Morrell [61]
hypothesized that the effect of epileptogenic discharges on
neuronal networks destined to subserve language, was to
activate and perpetuate synaptic arrangements that are func-
tionally inappropriate. Hopefully, the rapidly advancing
developmental molecular biology may elucidate the mole-
cular mechanisms responsible for these disorders, and offer
new hopes for novel therapeutic modalities.
Acknowledgements
Dr Moshe is the recipient of a Martin A. and Emily L.
Fisher fellowship in neurology and pediatrics.
Appendix. Abbreviations
BECTS Benign childhood epilepsy with centro-temporal
spikes
CSWS Continuous spikes and waves during slow wave
sleep
EEG Electroencephalography
ESES Electrical status epilepticus in sleep
GC Generalized clonic seizure
GNC Generalized nonconvulsive seizure
GTC Generalized tonic clonic seizure
IQ Intelligence quotient
LKS Landau±Kleffner syndrome
MST Multiple subpial transections
PET Photon emission tomography
PIQ Performance intelligence quotient
SPECT Single photon emission computed tomography
SWI Spike wave index
VIQ Verbal intelligence quotient
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