The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in...

Review article

The spectrum of neuropsychiatric abnormalities associated with electricalstatus epilepticus in sleep

Aristea S. Galanopouloua,*,1, Aviva Bojkoa,1, Fred Ladoa, Solomon L MosheÂ 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

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* Corresponding author. Tel.: 11-718-430-2447; fax: 11-718-430-8899.

E-mail address: [email protected] (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 TreniteÂ [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


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


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


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


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-


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


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


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


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].


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


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 MosheÂ 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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