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Table of contents1. Epilepsy in children....................................................................................................................................... 1

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Document 1 of 1

Epilepsy in childrenAuthor: Guerrini, RenzoPublication info: The Lancet 367.9509 (Feb 11-Feb 17, 2006): 499-524.ProQuest document link

Abstract (Abstract): Generalised epilepsy with febrile seizures plus designates a spectrum of epilepsyphenotypes including febrile seizures and febrile seizures plus. Less common phenotypes are febrile seizures

plus with absence or myoclonic seizures, focal epilepsies, myoclonic astatic epilepsy, and Dravet's

syndrome.27,28 Mutations of 1 and 1 voltage-gated sodium channel subunit genes (SCN1B, SCN1A)29

account for 17% of generalised epilepsy with febrile seizures plus.30 Genetic heterogeneity is confirmed by the

finding of mutations in the 2 subunit GABA^sub A^ receptor gene (GABRG2) in rare families.31,32 Complex

inheritance in also possible in generalised epilepsy with febrile seizures plus.29

Abstract: 10.5 million children worldwide are estimated to have active epilepsy. Over the past 15 years,syndrome-oriented clinical and EEG diagnosis, and better aetiological diagnosis, especially supported by

neuroimaging, has helped to clarify the diversity of epilepsy in children, and has improved management.

Perinatal and postinfective encephalopathy, cortical dysplasia, and hippocampal sclerosis account for the most

severe symptomatic epilepsies. Ion channel defects can underlie both benign age-related disorders and severe

epileptic encephalopathies with a progressive disturbance in cerebral function. However, the reasons for age-

related expression in children are not understood. Neither are the mechanisms whereby an epileptic

encephalopathy originates. Several new drugs have been recently introduced but have provided limited

therapeutic benefits. However, treatment and quality of life have improved because the syndrome-specific

efficacy profile of drugs is better known, and there is heightened awareness that compounds with severe

cognitive side-effects and heavy polytherapies should be avoided. Epilepsy surgery is an important option for a

few well-selected individuals, but should be considered with great caution when there is no apparent underlying

brain lesion. [PUBLICATION ABSTRACT]

Full text: Headnote10.5 million children worldwide are estimated to have active epilepsy. Over the past 15 years, syndrome-

oriented clinical and EEG diagnosis, and better aetiological diagnosis, especially supported by neuroimaging,

has helped to clarify the diversity of epilepsy in children, and has improved management. Perinatal and

postinfective encephalopathy, cortical dysplasia, and hippocampal sclerosis account for the most severe

symptomatic epilepsies. Ion channel defects can underlie both benign age-related disorders and severe

epileptic encephalopathies with a progressive disturbance in cerebral function. However, the reasons for age-

related expression in children are not understood. Neither are the mechanisms whereby an epileptic

encephalopathy originates. Several new drugs have been recently introduced but have provided limited

therapeutic benefits. However, treatment and quality of life have improved because the syndrome-specific

efficacy profile of drugs is better known, and there is heightened awareness that compounds with severe

cognitive side-effects and heavy polytherapies should be avoided. Epilepsy surgery is an important option for a

few well-selected individuals, but should be considered with great caution when there is no apparent underlying

brain lesion.

Epilepsy is suspected when there is repetition of seizures. The cause and clinical spectrum of epilepsy are

extremely wide-ranging in children. Although for practical purposes, epilepsy might still be a useful diagnostic

category, it would be inappropriate to regard it as a single entity. This Seminar aims to critically review the main

concepts that underlie classification of seizures and epilepsies in children, the rationale for prognostic

09 October 2013 Page 1 of 40 ProQuest
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considerations and for choosing complimentary investigations, and treatment.

Definitions and terminology

Seizures are described with standard terminology,1-4 and, where possible, classified in specific epilepsy types

or syndromes3,5 (panel 1 and table 1). A syndrome is a complex of signs and symptoms defining a unique

epilepsy condition.3 Syndromes are classified on the basis of seizure types, clinical context, neurophysiology,

and neuroroimaging.3,5 Epilepsy can be generalised, if all seizures and electroencephalogram (EEG)

abnormalities are generalised, or focal (partial) if clinical and EEG manifestations suggest focal onset, but this

distinction is not always clear cut.3 Idiopathic epilepsies are not associated with any brain lesions; they are

caused by a complex genetic predisposition or, rarely, single-gene inheritance. Symptomatic epilepsies result

from a brain lesion, which is not necessarily detected by neuroimaging. The term cryptogenic is synonymous

with presumed symptomatic.3 Syndrome diagnosis is helpful in guiding investigations, and management, and is

an early prognostic indicator.

Epidemiology

Worldwide, it is estimated that 10.5 million children under 15 years have active epilepsy, representing about

25% of the global epilepsy population.6 Of the 3.5 million people who develop epilepsy annually, 40% are

younger than 15 years, and more than 80% live in developing countries.6

Population-based studies on childhood-onset epilepsy6 indicate annual incidence rates of 61-124 per 100 000

in developing countries, and 41-50 per 100 000 in developed countries.6 Incidence falls progressively from

around 150 per 100 000 in the first year of life to 45-50 per 100 000 after the age of 9 years.6 Cumulative

incidence studies indicate that up to the age of 15 years, 1.0-1.7% of children will have at least one unprovoked

seizure, and 0.7-0.8% repeated seizures.7,8 Frequency rates in Europe and North America vary from 3.6-6.5

per 1000, whereas African and Latin American studies report rates of 6.6-17 per 1000.6

Natural history

In children who experience a first unprovoked focal or generalised tonic-clonic seizure, the cumulative risk of

recurrence is 42% at 8 years' follow-up, with only 3% of all recurrencies occurring after 5 years.9 Multivariable

analysis has shown that risk factors for recurrence include a remote symptomatic cause, an abnormal EEG, a

seizure occurring when asleep, a history of febrile seizures, and postictal paresis.9 Treatment does not change

the recurrence rates.10,11 About 64% of individuals that have had seizures in childhood will be in remission (5

years) in adulthood.12 Of these patients, only 16% will be still on medication. The practical implications of these

figures are limited, however, if specific epilepsy syndromes and causes are not considered.



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About 75% of patients of all ages reach remission on antiepileptic drugs, but attempts at drug withdrawal after 3

years of seizure control are followed by a relapse in 25% of patients.13 However, relapsing rates are highly

variable in different epilepsy syndromes: 0% for benign rolandic epilepsy, 12% for childhood absence epilepsy,

29% for focal symptomatic epilepsies, and 80% for juvenile myoclonic epilepsy.14

General aspects of prognosis

Most children with epilepsy can be divided into four main prognostic groups.15 The first group is the benign

epilepsies-eg, benign rolandic epilepsy (20-30% of patients), in which remission occurs after a few years and

treatment can often be avoided. The second group is the pharmacosensitive epilepsies-eg, most children with

absence epilepsy (30% of patients), in which seizure control is easily achieved by medication and spontaneous

remission occurs after a few years. The third one is the pharmacodependent epilepsies, in which drug treatment

will control seizures, but no spontaneous remission occurs-eg, juvenile myoclonic epilepsy and many cases of

symptomatic focal epilepsy (20% of patients). Drug withdrawal is followed by relapse and treatment will be

lifelong. The fourth group is the pharmacoresistant (or refractory) epilepsies, with poor prognosis (13-17% of

patients). The definition of pharmacoresistance is arbitrary and refers to both the frequency and severity of

seizures for an individual child. Resistance to drugs can usually be predicted early after an inadequate response

to initial appropriate treatment.16

Although benign epilepsies and most pharmacosensitive idiopathic generalised epilepsies can be identified

early after onset, for many children with focal symptomatic or presumed symptomatic epilepsies, and for some

of those with idiopathic generalised epilepsies, pharmacosensitivity or pharmacodependence are often defined

accurately only in retrospect.



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Early response to drugs (75-100% seizure reduction within the first 3 months of treatment) is a good predictor of

long-term remission, irrespective of the cause.12 However, idiopathic and presumed symptomatic epilepsies

are three times as likely to achieve remission than symptomatic forms.12

Cause and pathophysiologyKnowledge of the cause and pathophysiology of childhood epilepsy has considerably improved with modern

neuroimaging and molecular genetic studies. However, our understanding of the causes and the reasons why



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specific syndromes appear with precise age-relatedness is still very limited.

Genetic and molecular basis

Mutations of single genes are known to cause epilepsy, but they can result in different phenotypes (table 2).

Conversely, identical phenotypes might be a result of different genotypes. Phenotypical variability has been

putatively attributed to modifier genes or polymorphisms determining the phenotypical expression or,

alternatively, to environmental factors.17 Most of the idiopathic epilepsies do not follow single-gene inheritance

and their occurrence in large families is rare.

Idiopathic generalised epilepsies

Idiopathic generalised epilepsies have complex inheritance associated with the interaction of two or more

genes.18 Sporadic cases are common and affected families are usually small.19 Close relatives of probands

have a 4-10% risk of developing epilepsy,20 which is highest in siblings and offspring than in other relatives.

There is higher concordance for idiopathic generalised epilepsies in monozygotic than dizygotic twins (0.76 vs

0.33).21 Single-gene inheritance has been shown in rare families. Mutations in the voltage-gated chloride

channel gene (CLCN2) were identified in some families with idiopathic generalised epilepsies.22 One family

with dominant juvenile myoclonic epilepsy harboured a mutation in the al subunit of the GABA^sub A^ receptor

gene (GABRA1),23 and three additional pedigrees harboured mutations of the EFHC1 gene, which causes

reversal of EFHC1-induced neuronal cell death, and EFHC1 dependent increase of R-type Ca^sup +^ current.

However, the finding of 2 subunit GABA^sub A^ receptor gene (GABRG2) mutations in families with

predominantly childhood absence epilepsy, febrile seizures, and febrile seizures plus (when febrile seizures

occur or continue past 6 years of age) is in line with the hypothesis that a major gene conferring non-specific

seizure susceptibility might be associated with minor specific genes to determine specific subsyndromes.24,25

GABA is a ligand-gated Cl- ion channel, conferring fast inhibitory synaptic transmission; dysfunctional GABA,

and Cl- conductance can lead to impaired inhibitory mechanisms.26

Familial autosomal dominant epilepsies

Generalised epilepsy with febrile seizures plus designates a spectrum of epilepsy phenotypes including febrile

seizures and febrile seizures plus. Less common phenotypes are febrile seizures plus with absence or

myoclonic seizures, focal epilepsies, myoclonic astatic epilepsy, and Dravet's syndrome.27,28 Mutations of 1

and 1 voltage-gated sodium channel subunit genes (SCN1B, SCN1A)29 account for 17% of generalised

epilepsy with febrile seizures plus.30 Genetic heterogeneity is confirmed by the finding of mutations in the 2

subunit GABA^sub A^ receptor gene (GABRG2) in rare families.31,32 Complex inheritance in also possible in

generalised epilepsy with febrile seizures plus.29

Benign familial convulsions of the neonatal and infantile period encompass distinct age-related disorders.

Benign familial neonatal convulsions are highly penetrant, with short lasting seizures beginning between a few

days of life and 3 months. A few patients will manifest isolated seizures later in life. This disorder is associatedwith mutations of K+ channel genes KCNQ3 and KCNQ2.33,34 Benign infantile convulsions are characterised

by seizures between 4 and 8 months of age, often occurring in families. There is no known gene defect.35

Benign familial neonatal-infantile seizures begin between day 2 and 7 months of age, and are associated with

SCN2A gene mutations.36

Autosomal dominant nocturnal frontal lobe epilepsy is characterised by childhood-onset clusters of sleep-related

and hypermotor seizures. Mutations in the 4 and 2 subunits of the neuronal nicotinic acetylcholine receptor

genes (CHRNA4 and CHRNB2) have been identified37,38 in some families.

Autosomal dominant partial epilepsy with auditory features begins in childhood to adolescence with auditory

hallucinations, often with associated (olfactory, vertiginous, visual) symptoms.39 Mutations of LGI1-epitempin,

the leucine-rich glioma-inactivated 1 gene, were identified in many families.40

Chromosomal abnormalities

Chromosomal abnormalities are an important cause of epilepsy in children,41 and careful chromosomal studies



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should be done systematically in non-idiopathic epilepsies without a clear cause. Epilepsy might be the

presenting symptom or have suggestive clinical and EEG features. Angelman syndrome as a result of 15q11-

q13 deletion and the 4p-syndrome are associated with myoclonic and absence status,42 which might respond

to combinations of valproate, ethosuximide, and benzodiazepines. Patients with ring chromosome 20 are often

diagnosed on the basis of repetitive prolonged seizures with unresponsiveness that are drug-resistant.43

Abnormalities of cortical development and neurocutaneous disorders

The malformations of cerebral cortex account for at least 40% of drug-resistant childhood epilepsies.44 Some

malformations reviewed in this section have been associated with mutations of specific genes and genetic

counselling is now possible in a considerable number of patients.45

In hemimegalencephaly, one cerebral hemisphere is enlarged with a thick cortex and wide convolutions.46

Early continuous seizures are associated with major developmental impairment. Hemispherectomy might

control seizures47 and should be done early.

Focal cortical dysplasia includes a spectrum of abnormalities of the laminar structure of the cortex, variably

associated with aberrant neurons and balloon cells.48 MRI shows focal cortical thickening and high signal

intensity, but can also be normal. Focal cortical dysplasia causes infantile spasms or focal epilepsy48,49 with

frequent status epilepticus. Early surgical treatment is advocated in drug-resistant cases.50

Bilateral periventricular nodular heterotopia consists of subependymal nodules of grey matter. X-linked bilateral

periventricular nodular heterotopia is caused by mutations of the FIN1 gene.51,52 Mutations of the ARFGEF2

gene,53 and of other unknown genes are less frequent causes.

The agyria-pachygyria-band spectrum includes absent (agyria) or decreased (pachygyria) convolutions,54 and

subcortical band heterotopia. Mutations of the DCX gene, and mutations and deletions, or both, of the LIS1

gene account for most cases.55,56 Mutations of the Reelin gene57 or ARX gene58 are rare. Genetic testing

must be guided by neuroimaging and family ascertainment.59 Infantile spasms occur frequently.59

Schizencephaly consists of a unilateral or bilateral cleft of the cerebral hemispheres. Familial occurrence is very

rare. Mutations in the EMX2 gene were observed in rare cases,60 but need confirmation.

Polymicrogyria consists of cortical infoldings and thickening.61 Small areas might escape recognition by

imaging. 65% of children have intractable seizures.62 Bilateral perisylvian, parietal-occipital, or frontoparietal

polymicrogyria61 can be familial. Frontoparietal polymicrogyria is caused by mutations of the recessive gene

GPR56.63

Tuberous sclerosis is a dominant disorder associated primarily with abnormalities of the CNS, the skin, and the

kidney. The cortical tubers are visualised on MRI with T2 and fluid attenuated inversion recovery, but might

escape recognition in infants with incomplete myelination.64 The TSC1 and TSC2 genes account for most

cases.65 Epilepsy occurs in about 60% of patients.66 Infantile spasms are common and are often responsive to

vigabatrin.67 Epilepsy surgery can yield good seizure control in selected individuals.68Sturge-Weber syndrome is a non-familial phakomatosis, in which a venous angioma of the leptomeninges (all

cases) is accompanied by a homolateral naevus flammeus of the skin supplied by the trigeminal nerve (port-

wine stain; 90%).69 Unilateral convulsive status occurs in about 50% of patients, leaving half of them with

permanent hemiplegia.70 Surgical treatment is needed in up to 40% of children.69 Dysembryoplastic

neuroepithelial tumours have a developmental origin and supratentorial location.71 Grey and white matter are

both involved. MRI scan shows a hyperintense T1 lesion with multilocular appearance and peripheral

enhancement after gadolinium administration. These tumours cause childhood-onset drug-resistant focal

epilepsy. Complete surgical removal is associated with remission of epilepsy.72

Cerebral palsy

Cerebral palsy is often associated with epilepsy: about 50% in quadriplegia and hemiplegia, about 26% in both

spastic diplegia and in dyskinetic forms.73 Infantile spasms are observed in more than 15% of patients.73

Onset of epilepsy is usually early and the course tends to be severe. Only 12.9% achieve a remission of 2 years



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or more.74 Children with cerebral palsy and epilepsy function at lower levels than children with the same form of

cerebral palsy without epilepsy with respect to both intelligence and memory. Those with small lesions and

epilepsy do less well as a group than those with larger lesions but without epilepsy.75 Selected cases might

benefit from surgical treatment of epilepsy.

Hippocampal sclerosis

The terms hippocampal sclerosis, Ammon's horn sclerosis, and mesial temporal sclerosis designate subtly

different entities featuring gliosis and neuronal loss in such structures. Primary nerve cell loss in the

hippocampus, especially the CA1 and CA4 sections,76 is accompanied by sprouting of mossy fibres.77 The

resulting altered circuitry can facilitate local epileptogenesis.77 Hippocampal sclerosis is unilateral in 80% of

cases.78 An extrahippocampal lesion might co-occur (dual pathology).79 Hippocampal sclerosis is closely

related to mesial temporal lobe epilepsy.80 MRI studies in children with temporal lobe epilepsy detected

hippocampal sclerosis in 21% of children with new onset seizures,81 and in 57% of those with refractory

seizures.54 A causative relation has been suggested between prolonged febrile seizures and subsequent

temporal lobe epilepsy with hippocampal sclerosis.82,83 However, the sequence of febrile status followed by

temporal lobe epilepsy is rare from a population perspective.84 Although developmental lesions85 or specific

genetic factors86 might predispose to febrile status followed by hippocampal sclerosis, and temporal lobe

epilepsy, prospective studies are needed to clarify whether a specific age window exists during which the brain

would be more vulnerable. Hippocampal sclerosis might also result from repeated seizures that arise from

distantly located epileptogenic lesions.87

Complete seizure remission after surgery is observed in about 78% of children with temporal lobe epilepsy as a

result of hippocampal sclerosis.80

Postinfective epilepsy

Epileptic seizures might occur during an acute infection of the CNS or as a remote complication. About 5% of

patients with CNS infections develop epilepsy;88 however, the types of infections and their frequency vary in

different geographical areas.89 A distinction between acute symptomatic seizures and chronic epilepsy is only

feasible with bacterial meningitis and herpes virus encephalitis, but not with neurocysticercosis or HIV

encephalopathy.90 About 35% of children with bacterial meningitis have acute seizures and 5.4% develop

subsequent epilepsy.91 In general, acute seizures amplify the risk of late epilepsy, but no specific data are

available.90 Neurocysticercosis in children often manifests with seizures,90 which are more severe during the

active disease than in the chronic inactive stage of calcification.92

Seizures and epilepsy following acute brain injury

About 3-10% of children with head injury present with an early post-traumatic seizure, usually within 24 h.93

Early seizures after trivial head injury have an excellent prognosis and are not correlated with late seizures;94

they should not be treated at all. Focal neurological signs, depressed skull fracture, brain oedema, and acutesubdural haematoma are associated with the greatest risk.93 Children under the age of 5 years are at higher

risk of status epilepticus.93 After severe injury, generalised tonic-clonic seizures within the first week and a low

initial Glasgow Coma Scale are associated with a substantial risk of late epilepsy.95 Phenytoin or

carbamazepine treatment reduces the risk of early seizures, but does not change late post-traumatic epilepsy or

mortality.96 Therefore, treatment should not be maintained after acute neurological manifestations have

resolved.93 Incidence of epilepsy after mild head injury is similar to that of the general population,97 but rises to

9% after severe injury.95 Late post-traumatic epilepsy occurs within the first year in 42% of cases and within the

fourth year in 71%.94 A first late post-traumatic seizure is likely to recur and should therefore be treated.93

Post-traumatic psychogenic non-epileptic seizures have been described in children.98

Diagnosis

Two-thirds of cases can be assigned to specific syndromes early, after undertaking EEG in all children and

neuroimaging where appropriate.99,100 Of the remaining percentage, about 30% will be assigned to more



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specific categories within 2 years.101

History taking is the main diagnostic instrument. It should assemble a coherent sequence of manifestations that

is made likely by the functional characteristics of the brain, according to age and neurological status. It should

include developmental milestones, drug history, and the effect that seizures have on the child and the family. In

older children, direct questioning can clarify subjective symptoms. Description of seizures should be focused on

the very initial ictal manifestations and include the whole sequence and postictal occurrence, circumstances of

occurrence, and precipitating factors. Parents can be asked to emulate attacks and use home videotape

recordings. Clinical examination should include neurological, skin, and ocular assessment, and measurement of

head circumference.

EEG might reveal paroxysmal abnormalities. However, with few exceptions, diagnosis does not depend

primarily on EEG, as interictal EEG abnormalities are observed in 5-8% of healthy children.102 Sleep EEG

enhances the positivity rate of routine EEG from 60% to 90%.103 Intermittent photic stimulation and

hyperventilation are essential in children. Video-EEG recordings, with simultaneous sampling of EEG,

electromyogram, electrocardiogram, respirogram, and electro-oculogram are invaluable for characterising

complex clinical manifestations.104 Long-term cable telemetry is essential to capture and quantify seizures. A

normal interictal EEG does not exclude epilepsy when there is a convincing clinical history. Surface EEG can

sample electrical activity only originating from the scalp convexity, leaving the mesiobasal brain surface and the

inner cortex virtually unexplored.

The International League Against Epilepsy has proposed a diagnostic scheme3 that is divided in five parts, or

axes. Definitions of key terms are shown in panel 1.3,4 The diagnostic axes include descriptive terminology for

ictal semiology (axis 1), detailed descriptions of epileptic seizure types (axis 2), epileptic syndromes (axis 3),

diseases frequently associated with epileptic seizures or syndromes (axis 4), and the impairment classification

derived from WHO International Classification of Functioning, Disability and Health (axis 5). Their most recent

versions can be found at the International League Against Epilepsy website.

Differential diagnosis

In children, several non-epileptic paroxysmal events need to be differentiated from epilepsy. Misdiagnosis is

frequent and is an important cause of pseudo-refractory epilepsy.105 Furthermore, cognitive or behavioural

symptoms of epilepsy are often interpreted as psychogenical manifestations and sleep-related epileptic seizures

as parasomnias.106

Reflex anoxic seizures and breath-holding spells occur in about 4% of children, and onset is in infancy. Reflex

anoxic seizures results from temporary asystole of reflex origin, whereas breath-holding spells originate during

expiratory apnoea with intrapulmonary blood shunting and inconsistency between ventilation and perfusion.107

Typically, a powerfully crying child loses muscle tone and consciousness, and might present with body

stiffening, limb jerking, and upward or downward eye deviation. After 30-60 s, hypertonus resolves andconsciousness resumes.107

Cardiogenic syncopes are rare in children and are usually caused by structural heart defects, especially aortic

stenosis, or by rhythm disturbances, especially the long QT syndromes.108 Syncopal attacks resemble

convulsive seizures. Long QT syndromes can cause sudden death, which can be prevented by pacemaker

placement.

Gastro-oesophageal reflux is manifested in small children as episodes of change in colour, respiratory rate

disturbances, or bradycardia. Dystonic posturing and opisthotonous might occur.109

Psychogenic pseudo-epileptic seizures is the common term for grouping non-epileptic behavioural

manifestations, also called non-epileptic seizures. They are observed in children as young as 5 years who often

have concomitant epilepsy,110 and can cause pseudo intractability. Attacks usually resemble generalised tonic-

clonic seizures, but movements are coordinated, with a crescendo of intensity and do not occur when the

patient is alone. Recovery is rapid. Precipitation by observation is frequent, especially during EEG



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recording.110

The paroxysmal dyskinesias include dystonic or choreoathetotic attacks that can be precipitated by sudden

movement (kinesigenic), by prolonged exercise (exercise-induced), or be spontaneous (non-kinesigenic).

Consciousness is preserved. Duration and frequency of attacks are variable. Ictal EEG is normal and familial

occurrence is frequent. Antiepileptic drugs are often effective. Co-occurrence of epileptic seizures in the same

patient or in relatives is not uncommon.111

Benign infantile myoclonus can occur in healthy infants as clusters of repetitive axial jerks that might simulate

infantile spasms.112 EEG is normal and the course is spontaneously favourable.

Self-gratification behaviour is observed more frequently in girls, in late infancy or early childhood, as episodes of

rhythmic contractions of the lower limbs and trunk, with eye staring and withdrawal, which simulate

unresponsiveness. 102

Migraine can be accompanied by phosphenes or amaurosis, often followed by headache and vomiting, which

are not rarely misdiagnosed as manifestations of focal epileptic seizures.113 However, migraine symptoms

have a slower course, and visual phenomena are not coloured and present as broken lines (fortification spectra)

or undulating patterns. In occipital epilepsy, they are usually described as coloured, rotating circles.114

Clouding of consciousness can occur in both conditions. Migraine and epileptic seizures might co-occur, either

in different attacks or as parts of the same episode.

Night terrors or pavor nocturnus typically appear after sleeping for a few hours. The child screams while sitting

terrified in bed for several minutes. Attempts of establishing a reassuring contact are unsuccessful until the child

falls asleep again: the child has no recollection of this event. Such episodes can occur regularly for a period of

time but disappear within age 5.115 Differential diagnosis from nocturnal frontal lobe epilepsy might need ictal

recordings.

Somnambulism or sleepwalking results from an incomplete arousal during which the child can walk or make

simple activities. It must be differentiated from nocturnal epileptic wandering,116 an expression of frontal lobe

seizures.

Neuroimaging

Structural neuroimaging

CT can detect small calcified lesions or bone scalloping and remodelling. It is indicated in emergency settings,

such as status epilepticus or to assess the consequences of head injury prompted by seizures.

MRI is the procedure of choice, although children with uncomplicated febrile convulsions and typical idiopathic

epilepsy do not need imaging. Conversely, children with non-idiopathic focal epilepsy should always have an

MRI. Seizure semiology and the EEG should guide the imaging study.

Abnormalities of cortical development are the most common cause of symptomatic childhood epilepsy.117 In

the first 6 months of life, T2-weighted images are needed to identify cortical abnormalities, whereas T1 imagesbetter appreciate maturational changes, especially in myelination.117 Subsequently, such sequence modalities

have a reverse role and are better complemented by inversion recovery sequences, offering a higher T1-

weighted contrast and fluid-attenuated inversion recovery sequences, which eliminate cerebrospinal fluid

distortion.

Hippocampal structures and areas of cortical dysplasia are well defined using 3-D sequences producing 1.5 mm

images.117 The use of gadolinium contrast is indicated in selected lesions.

Functional neuroimaging

Functional imaging can be used in candidates for epilepsy surgery with the purpose of reducing the need for

invasive explorations, particularly intracranial EEC monitoring118 and the sodium amobarbital (Wada) test.119

^sup 1^H proton magnetic resonance spectroscopy can show abnormal N-acetylaspartate and creatine ratios,

or both, probably indicating neuronal dysfunction and gliosis.120

Functional MRI has been used to map functional cortical areas and study their relation with the epileptogenic



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cortex.121 The need for training and cooperation limits this technique to children older than 7-8 years and with

adequate cognitive skills.122 PET with 2-deoxy-2[^sup 18^F]fluoro-D-glucose measures regional glucose and

oxygen use in the brain. Focal hypometabolism might correspond to structural epileptogenic changes that are

not visible by MRI.123 The PET tracer flumazenyl, which binds to the GABA^sub A^ subunit receptor, has a

higher sensitivity than 2-deoxy-2[^sup 18^F]fluoro-D-glucose in demarcating the epileptogenic cortex.124

Single photon emission CT with technetium -99m is used to assess local cerebral blood flow, showing interictal

reduction and ictal amplification in the epileptogenic area.125

Classification and response to treatment of the different epilepsy types

An example of a classification of epilepsy syndromes, with a schematic indication of their main clinical

characteristics is shown in table 2. The most important syndromes are reported in the following sections.

Focal epilepsies and epileptic syndromes

Idiopathic focal epilepsies

Idiopathic focal epilepsies are the most frequent epilepsy syndromes in children. They have an age-dependent

course and might occur in more than one family member. Response to antiepileptic drags is usually satisfactory

but it is unclear whether treatment changes the outcome. Parents usually accept withholding treatment if it is

explained that the disorder is self-limiting and does not induce brain damage. If treatment is necessary,

carbamazepine or valproate are preferred.126

Benign childhood epilepsy with centrotemporal spikes represents 8-23% of childhood epilepsies.127 Seizure

onset is between 3 and 13 years. Prognosis is excellent with remission within adolescence.128 Typical seizures

cause sleep arousal with lateralised facial contraction, anarthria, dribbling, and a grunting sound, without loss of

consciousness. Sometimes the homolateral upper limb is involved. Secondary generalisation can supervene.

Interictal EEG shows typical biphasic centro-temporal spikes, with a tangential dipolar distribution, which often

become bilateral during sleep. The total number of seizures a child will have is variable but antiepileptic drugs

treatment can often be avoided.129 Atypical EEG characteristics are not rare and are often associated with

atonic seizures and a complicated evolution, including paradoxical aggravation with carbamazepine

treatment.130

Benign epilepsy of childhood with occipital paroxysms was originally described as an idiopathic focal epilepsy

with age at onset between 6 and 17 years, with visual ictal symptoms, frequent postictal migraine, and interictal

unilateral or bilateral occipital spike-and-wave EEG discharges that are facilitated by eye closure.131 This form

accounts for no more than about 1% of epilepsies.

A more frequent form of this syndrome, observed in about 3% of all children with epilepsy, appears between 2

and 8 years with prolonged but rare sleep-related seizures with tonic eye and head deviation, vomiting, and

hemiclonic jerks.132 Differential diagnosis includes acute symptomatic seizures, or abdominal emergencies and

symptomatic occipital epilepsy.102 Treatment is rarely necessary.132Symptomatic focal epilepsies

Symptomatic focal epilepsies account for about 40% of all epilepsies in children,133 and are defined according

to seizure semiology pointing to a lobar location. However, the epileptogenic area itself can be associated with

multilobar networks. Seizures might include a single symptom or have complex symptomatology. The temporal

sequence of events is related to the origin and propagation of the discharge.134 The very first manifestation of

a seizure localises its onset. Alteration of consciousness has classically been considered the hallmark of

complex partial seizures, with respect to simple partial seizures in which awareness is preserved. However,

alteration of consciousness indicates extensive seizure spread but no origin or distribution.135 Postictal

sleepiness is frequent in children and has a major relevance for differential diagnosis. Scalp EEG can be

misleading.

Attributing seizure origin to a specific area is difficult when neuroimaging is normal, unless a highly

characteristic clustering of symptoms occurs.



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Mesial temporal lobe epilepsy is the best defined focal symptomatic epilepsy syndrome. Most children with this

syndrome have hippocampal sclerosis, which is visible on MRI,81 and about 40% of these have a history of

prolonged febrile seizures.136 Typical seizures start at around 5 to 10 years or earlier,81 and include an initial

rising epigastric sensation with fear, oro-alimentary automatisms (chewing, swallowing, lip smacking), alteration

of consciousness with staring, and postictal confusion.80 Aphasia is often observed when the dominant

hemisphere is involved. In infants and small children, reduction of motor activity might be the prominent feature,

without automatisms (hypomotor seizures).137 Interictal EEG can be normal or show unilateral or bilateral

temporal abnormalities. Memory disturbances are common. Drug resistance is frequent. Anterior temporal

lobectomy or more selective resections give excellent results in about 80% of children.80

Frontal lobe epilepsy is relatively frequent in children. Seizures are usually brief (seconds to tens of seconds)

and sleep-related. They are highly stereotyped in the same patient. Arousal from sleep, with opening of the

eyes and a frightened expression is often the first ictal manifestation.138 Consciousness disruption is variable

but recovery of awareness is fast. Subjective symptoms are ill defined. Onset of motor phenomena is with tonic

asymmetric posturing or repetitive hyperkinetic automatisms. Most children exhibit organised movements of the

proximal limbs (hypermotor seizures).139 Epileptic nocturnal wanderings are longer attacks (2-3 min) with

arousal from sleep and an ambulatory behaviour during which a frightened child might scream and attempt to

escape.116 Frontal lobe seizures in the awake child can cause violent drop attacks.140 Interictal and even ictal

EEG is often normal, or shows abnormalities that enable neither lateralisation nor localisation.139

Occipital lobe epilepsy of symptomatic origin can be difficult to diagnose in children because seizure spread

masks initial symptoms.141 Ictal elementary visual hallucinations (coloured blobs, flashes of light), associated

to peripheral visual field deficit (hemianopia) are typical.142 Lateral movements of the eyes are frequent.

Perinatal ischaemic insults and cortical malformations are frequent causes.141 Sturge-Weber syndrome,

coeliac disease, Lafora disease, and mitochondrial disorders also cause occipital seizures.141 Interictal EEG

abnormalities are usually increased during eye-closure.

Pharmacological treatment of focal epilepsies

Monotherapies with valproate or carbamazepine have shown similar effectiveness and good tolerability in

children with newly diagnosed focal epilepsy with or without secondary generalisation.143 Phenytoin,

phenobarbital, carbamazepine, and valproate had a comparable efficacy, with 20% of children being seizure-

free and 73% achieving a 1-year remission by 3 years of follow up.144 However, phenobarbital caused severe

sedative side-effects and phenytoin had low tolerability. Newer drugs might provide alternative monotherapies,

but very few comparative controlled trials are available in children.145 Two class I studies used topiramate in

children older than 3 years,146 or than 6 years,147 with new or recently diagnosed focal epilepsy. Higher doses

of topiramate were more effective than lower doses,146 and 100 or 200 mg/day were equivalent in safety to 600

mg carbamazepine and 1250 mg valproate.147 Use of fixed doses, however, is flawed with respect tooptimisation dose studies. Oxcarbazepine and phenytoin had a comparable efficacy, but discontinuation rate

was higher for phenytoin.148

Studies that have been done on newly diagnosed focal epilepsy might have masked specific drug effects on

aetiologically homogeneous syndromes. Despite this limitation, it is now recommended that children with newly

diagnosed focal epilepsy are initiated on either carbamazepine or valproate, and that topiramate is considered

as an alternative monotherapy.145 Lamotrigine and gabapentin are potentially interesting initial monotherapies,

although the only available two class I studies145 did not include children. Evidence about the effectiveness of

monotherapy with tiagabine, levetiracetam, and zonisamide is insufficient.145

Controlled trials in pharmacoresistant focal epilepsies have shown the efficacy of add-on topiramate,149

lamotrigine,150 oxcarbazepine,151 gabapentin,152 and clobazam.153,154 However, development of tolerance

hampers the long term use of clobazam. Evidence about add-on efficacy of levetiracetam, tiagabine, and

zonisamide is insufficient.155



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When assessing the patient's response to the different drugs, it is wise to explore whether a surgical option is

possible. However, since trying the many drugs now available would require a long time, surgery should be

considered soon after resistance to two appropriate drugs has been shown.16,133

Idiopathic generalised epilepsies

Idiopathic generalised epilepsies are frequent and onset is in infancy to adolescence. Idiopathic generalised

epilepsies are genetically determined (see section on genetic and molecular basis). Neuroimaging is normal

and suggestions that morphological cortical abnormalities might underlie idiopathic generalised epilepsies156

have not been confirmed.157 As a result of the overlapping features between different idiopathic generalised

epilepsies, the term idiopathic generalised epilepsies with variable phenotypes has been suggested as all-

inclusive.3 Social adjustment is usually good but some patients have behavioural or learning difficulties.

Seizures are primarily generalised absence, myoclonic, and tonic-clonic. Interictal EEG abnormalities are 3 Hz

generalised spike/polyspike and wave discharges.

Most patients respond to antiepileptic drugs but response is drug-specific. Valproate is effective in about 80% of

patients,145 whereas other drugs, such as ethosuximide, lamotrigine, and topiramate have a more selective

action. There is no evidence that any other drug is effective,145,155 and some drugs might precipitate seizure

worsening.158

Childhood absence epilepsy and juvenile absence epilepsy

Childhood absence epilepsy represents about 12% of childhood epilepsy.101 Onset is between age 5 and 7

years. A genetic background is often noted. Very frequent, typical absence seizures (up to hundreds per day)

are observed, lasting about 10 s, accompanied by rhythmic 3 Hz generalised spike and wave complexes.

Absences disappear before adulthood in up to 90% of cases in which no other seizure types are associated.159

If absences persist, generalised tonic-clonic seizures usually appear. Early and late onset (9 years),

initial drug resistance, and photosensitivity have a less favourable prognosis.

Juvenile absence epilepsy starts at around 10-12 years and partly overlaps with juvenile myoclonic epilepsy.

Absence seizures cluster upon awakening.160 Generalised tonic-clonic seizures, often precipitated by sleep

deprivation, occur in up to 80% and photosensitivity in 20%.161 Long-term prognosis is unclear.

In two comparative trials, valproate and ethosuximide showed similar efficacy in controlling absence

seizures.162,163 Lamotrigine was effective as monotherapy in a double-blind trial on new onset absence

seizures,164 and in add-on in resistant absence seizures.165 However, in a recent Cochrane review,166

evidence arising from such trials was not considered sufficient to inform clinical practice. Valproate is regarded

as the drug of choice because of its effectiveness on possibly associated seizures and lower cost.102

Ethosuximide and lamotrigine are an alternative in children with only absence seizures.162 Some children might

need a combination of drugs.

Myoclonic astatic epilepsyMyoclonic astatic epilepsy epitomises a spectrum of idiopathic generalised epilepsies with prominent myoclonic

seizures, appearing in previously healthy children.167 Myoclonic astatic epilepsy represents about 2% of all

childhood epilepsies.168 Onset is between 2 and 6 years of age.168 Myoclonic seizures and atonic falls might

be repeated many times daily and are often associated with episodes of non-convulsive status epilepticus and

generalised tonic-clonk seizures.169 Interictal EEG, often normal at onset, can become very disorganised.167

Outcome is unpredictable. Remission within a few months or years with normal cognition is possible even after

a severe course.168,170 About 30% of children experience an epileptic encephalopathy with longlasting

intractability and cognitive impairment.

A few children with myoclonic astatic epilepsy inherited SCN1A and GABRG2 gene mutations from parents with

generalised epilepsy with febrile seizures plus.171 However, the genetics of myoclonic astatic epilepsy are

complex.

No controlled trials are available. Treatment is primarily with valproate and ethosuximide, often together.170



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Lamotrigine,172 topiramate,173 and benzodiazepines might be useful.

Epilepsy with seizures precipitated by light stimulation

In visual sensitive (or photosensitive) epilepsies, seizures are precipitated by environmental photic stimuli.174

The age of onset peaks at 11 years. The term photosensitivity only designates the abnormal EEG response to

flickering light,174 a finding also observed in 4% of healthy children or adolescents.175 Photic-induced

absences, myoclonic seizures, and generalised tonic-clonic seizures are observed in idiopathic generalised

epilepsies and in Dravet's syndrome.176 Single or repeated seizures when playing video games or in front of

the television (especially with a 50 Hz screen) might appear without a history of spontaneous seizures. The

seizures manifest as either general tonic-clonic seizures or prolonged attacks with visual symptoms and

vomiting.112 An outbreak was reported in Japan, where several hundreds of children and adolescents

experienced a seizure when watching a popular cartoon.177 Self-induction is sometimes observed, especially in

children with absences or myoclonic jerks who indulge in compulsively staring or blinking in front of light sources

or contrasted patterns.178

Sensitivity to visual stimuli is associated with the inability of the visual cortex to process afferent inputs of high

luminance and contrast through the normal mechanisms of cortical gain control.179

If attacks are infrequent, preventive measures might be sufficient. The triggering power of 50 Hz television

screens is lowered by strengthing the ambient light and by watching at a distance >2 . 5 m. 100 Hz television

screens are much less provocative.180 Video games should be avoided. If treatment is necessary, valproate is

the drug of choice.181 Polarised glasses or optical filters for screens have proved helpful in severe

cases.182,183

The epileptic encephalopathies

Epileptic encephalopathies are conditions in which seizures, the epileptiform abnormalities, or both, contribute

to the progressive disturbance in cerebral function.3 About 40% of all epilepsies occurring in the first 3 years of

life fit this definition.184 However, epileptic encephalopathies represents more a concept and an operational

category than a syndrome spectrum. Some syndromes such as infantile spasms, severe myoclonic epilepsy,

epilepsy with continuous spike and waves during sleep, or Lennox-Gastaut syndrome are always manifested as

epileptic encephalopathies, irrespective of the underlying cause and severity of EEG abnormalities. Some

syndromes with usually good outcome, such as benign rolandic epilepsy, might have a complicated evolution,

including learning and language impairment, when severe spike-and-wave discharges appear.130,185

Persistent spike- and wave-related anatomy-specific cortical dysfunction has been blamed for such an ominous

evolution.186,187 Myoclonic-astatic epilepsy might unpredictably evolve as epileptic encephalopathy or rapidly

remit without consequences on cognitive outcome, irrespective from its initial clinical and EEG

characteristics.167 In such cases it is entirely unclear which factors, clinical or EEG, can be blamed for either

outcome. Finally, a particular situation is represented by epileptic encephalopathies that appear in children witha highly epileptogenic, usually developmental, brain lesion from which epileptic activity spreads to intact, remote

areas, interferes with their function, and amplifies the clinical consequences of the malformation.

Although vigorous early treatment is often advocated in epileptic encephalopathies, for most conditions there

are no established endpoints and drug choices are empirically established. Surgical treatment can be

successful in selected cases. However, only in some syndromes early treatment has a definite effect on long-

term prognosis.188 In many individuals the underlying cause, which often remains unrecognised, probably

plays a greater part than is acknowledged in determining cognitive outcome.

Infantile spasms and West syndrome

Infantile spasms are typical of the first year of life, are usually resistant to conventional antiepileptic drugs and

are associated with developmental delay, or deterioration, and a hypsarrhythmic EEG pattern, which expresses

a chaotic disorganisation of electrogenesis. In West syndrome, all these elements occur together. However,

infantile spasms might occur without the typical EEG or developmental features. A cumulative incidence of 2.9



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per 10 000 live births and an age-specific prevalence of 2.0 per 10 000 in 10-year-old children were observed in

the USA.189 Epileptic spasms can rarely appear in older children.190

Infantile spasms are manifested as clusters of increasing-plateau-decreasing intensity brisk (0.5-2.0 s) flexions

or extensions of the neck, with abduction or adduction of the upper limbs. Clusters include a few units to several

dozens of spasms and are repeated many times per day. After a series, the child is usually exhausted.

Asymmetric spasms are often associated with a lateralised brain lesion,191 although unilateral lesions might

cause symmetric spasms. Other seizure types can coexist.

Developmental delay pre-dates the onset of spasms in about 70% of children.102 Disappearance of social

smile, loss of visual attention,191 or autistic withdrawal are often observed with the onset of spasms.

The hypsarrhythmic EEG is often absent in severe brain lesions, such as tuberous sclerosis or

lissencephaly.192 Misdiagnosis of colic, startles, Moro response, or shoulder shrugs is still frequent. Duration of

spasms is variable, depending both on treatment and on their tendency to remit or evolve into other seizure

types. Rapid spontaneous remission is rare. In about 50% of children, spasms disappear before the age of 3

years and in 90% before the age of 5 years.193

Presumed symptomatic (or cryptogenic) spasms appear in seemingly healthy children; symptomatic spasms

appear in children with developmental delay or a brain lesion, especially anoxic ischaemic encephalopathy and

brain malformations.59,194 Familial occurrence is rare.194,195

Prognosis depends more on the cause than on treatment. Unfavourable prognostic factors include

symptomaticity, early onset (younger than 3 months), pre-existing seizures other than spasms, asymmetric

EEG,196 and relapse after initial response to treatment. Good prognostic indicators include cryptogenicity,

normal brain MRI,196 typical hypsarrhythmia, rapid response to treatment, and no regression after onset of

spasms or its short duration.197 About 80% of patients have residual cognitive or behavioural impairment, but

only one-third of cryptogenic cases do.197 About 50% of children will have other epilepsy types. Mortality rates

of 5-31% have been reported, with higher rates arising from cumulative data and long-term follow-up.198

Infantile spasms must be differentiated from rarer, earlier onset conditions with ominous prognosis, such as the

early infantile epileptic encephalopathy and the early myoclonic encephalopathy.100

Vigabatrin and adrenocorticotropic hormone have proven effective in a few controlled trials, but uncertainties

remain regarding the best treatment.199 In two comparative studies, vigabatrin was slightly less effective than,

or as effective as, adrenocorticotropic hormone but better tolerated.200,201 Two randomised trials reported a

78% responder rate,202 and a higher effectiveness of high doses (100-148 mg/kg per day).203 Particular

efficacy has been shown in children with tuberous sclerosis.204 Response to 100 mg/kg per day occurs within a

few days. Many researchers regard vigabatrin as the first-line drug, despite the risk of visual field

constriction.205 This side-effect appears in 30-50% of patients having received a substantial drug load, but is

not ascertainable in small children. Responders should receive vigabatrin for no more than 6 months;206 non-responders should be switched to adrenocorticotropic hormone within 3 weeks. Adrenocorticotropic hormone

proved superior to prednisone in a controlled trial.207 It is used in daily doses from 20 to 40 IU.102 Non-depot

adrenocorticotropic hormone has a lower risk of causing persistent hypertension. An individualised regimen

starting with 3 IU/kg per day progressively increased, by doubling the doses (12 IU/kg per day, daily) every 2

weeks until a response is obtained, permits to keep dose-related side-effects such as hypertension, brain

shrinking, adrenal hypo-responsiveness, and cardiac hypertrophy to a minimum.208 Infections are a serious

complication of adrenocorticotropic hormone treatment and are responsible for most deaths.209 A 4-6 week

duration of adrenocorticotropic hormone course is advisable. Control of spasms is usually obtained within days

but behavioural improvement needs several weeks. Relapse rate is 30%.102 A second cycle of

adrenocorticotropic hormone is recommended after an initial good response. Valproate, topiramate, and

benzodiazepines, especially nitrazepam, might represent alternatives to vigabatrin or adrenocorticotropic

hormone.102 Video-EEG monitoring is necessary to show that the spasms have truly disappeared.210



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Surgical treatment should be considered early when drug resistance is faced and focal epileptogenesis is

shown.49 About 60% of operated children become seizure-free; the best results are obtained when operating

on small lesions.49 However, most children have large multilobar cortical dysplasias needing extensive

resections, with limited cognitive improvement.188

There is some evidence for use of the ketogenic diet in resistant spasms.211,212

Lennox-Gastaut syndrome

Lennox-Gastaut syndrome is characterised by brief tonic and atonic seizures, atypical absences, and a

generalised interictal EEG pattern of spike and slow wave discharges. It accounts for 2.9% of all childhood

epilepsy.101 Incidence peaks between 3 and 5 years of age. Cognitive and psychiatric impairment are frequent.

About 30% of cases occur in previously healthy children; most result from neuronal migration disorders and

hypoxic brain damage. About 40% of children have previous infantile spasms.102

Tonic seizures are particularly frequent during sleep. Epilepsy patients who have tonic and atonic seizures

when they are awake can violently collapse. Atypical absences might translate in non-convulsive status, which

can worsen cognitive deterioration.213

About 80% of patients continue to have seizures later in life, with symptomatic origin and early onset having the

poorest outcome. Long-term follow-up reports mortality rates of up to 17%.102

The optimum treatment for Lennox-Gastaut syndrome remains uncertain and no study has shown any one drug

to be highly effective.214 Broad spectrum drugs should be preferred,155 and many researchers combine

valproate and benzodiazepines.102 However, since double-blind trials indicate that add-on lamotrigine215,216

and topiramate217 might reduce drop attacks, and patients with Lennox-Gastaut syndrome are prone to

antiepileptic drug-induced seizure worsening if sedated,158 an association of valproate with lamotrigine or

topiramate should be preferred. Felbamate was also effective in a controlled trial,218 but its use is restricted by

toxicity.

It has been suggested that vagus nerve stimulation and the ketogenic diet can be useful in some cases.219

Anterior callosotomy might reduce seizures with drop attacks.220

Dravet's syndrome

Dravet's syndrome (or severe myoclonic epilepsy of infancy) represents about 1% of childhood epilepsies.221 It

begins with repeated and prolonged unilateral or generalised clonic seizures related to fever in seemingly

normal children.221 Subsequently, attacks also appear without fever and are variably associated with atypical

absences, myoclonic, and focal seizures. About 25% of children are photosensitive and indulge in self-

stimulation. Cognitive progress slows down around the second and third year to rapidly come to a standstill.222

Most children do not achieve language skills, and show attention deficit and hyperactivity. Neuroimaging is

normal. EEG, normal at onset, shows generalised and multifocal abnormalities. Mortality rates are at around

16%,221 mainly as a result from sudden death or accidents. Seizures persist into adulthood, with reducedseverity. About 60% of patients harbour mutations of the SCNlA gene, which are de novo in most (see section

on genetic and molecular basis).223

Phenobarbitone, valproate, benzodiazepines, and topiramate might have some efficacy.173,221 Stiripentol, an

inhibitor of p450 cytochromes, was effective in combination with clobazam in a class I trial.224 Stiripentol acts

by increasing the concentration of norclobazam, an active metabolite of clobazam. Phenytoin, carbamazepine,

and lamotrigine can worsen seizures.221,225

Landau-Kleffner syndrome (acquired epileptic aphasia) and epilepsy with continuous spike and waves during

slow wave sleep

In Landau-Kleffner syndrome and continuous spike and waves during slow wave sleep syndromes, frequent or

persistent discharges, with or without accompanying seizures, cause impairment of cortical functions.

Landau-Kleffner syndrome is a rare, severely disabling disorder, with an insidious, or sudden, loss of language

understanding (auditory agnosia), followed by progressive or fluctuating loss of verbal expression.226 Age at



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onset is between 3 and 7 years. Focal seizures represent the initial symptom in 60% of children, but are absent

altogether in 25%. They have variable severity but remit before adulthood. EEG abnormalities predominate in

the temporoparietal regions, bilaterally, or on either side.227 Interference by EEG discharges with auditory-

evoked responses228 suggests epileptic-induced dysfunction of auditory processing. The prognosis of aphasia

is unpredictable. However, onset before age 5 years and persistent EEG anomalies over the language areas

forecast a severe course.226 Patients might be left with normal language or mild-to-severe persistent defects.

No cause has been identified, although rare lesional cases have been reported.102

Treatment efficacy is empirically investigated. Large doses of adrenocorticotropic hormone or steroids for

prolonged periods (>3 months) have a definite effect on EEG and language.229,230 Repeated injections

several days apart might prevent major side-effects. Benzodiazepines, valproate, ethosuximide, and

immunoglobulins have obtained some success.230,231 Surgical treatment with multiple subpial transections

has produced longlasting improvement in selected cases,232 but the merit of this approach is difficult to assess

and further studies are needed. Language therapy is indicated.

In epilepsy with continuous spike and waves during slow wave sleep (or electrical status epilepticus during slow

sleep), continuous sleep-related EEG discharges, persisting for months to years, are associated with cognitive

decline. The syndrome appears in previously healthy or in developmentally-delayed children.233 Brain lesions,

especially polymicrogyria234 and porencephaly,233 are found in 30-50% of patients. Onset is insidious.

Seizures start at 3-5 years as nocturnal and focal attacks similar to rolandic epilepsy. After a few months,

continuous spike and waves during slow wave sleep and atypical or atonic absences appear. There is marked

decrease in intelligence quotient scores with attention deficit and hyperactivity, sometimes with language

disturbances and autistic features.226 Long-term course of epilepsy is favourable, but cognitive impairment,

persists in most children. A long duration of continuous spike and waves during slow wave sleep is the major

factor of a poor prognosis.235 The benign atypical partial epilepsy syndrome236 bears a close relation to

continuous spike and waves during slow wave sleep. Drug treatment is the same as in Landau- Kleffner

syndrome.

Febrile seizures

Febrile seizures occur during an acute febrile illness for which no cause can be found. This type of seizure

affects 2-4% of children aged 3 months to 5 years.237

Genetic factors are involved with both autosomal dominant and polygenic inheritance. During febrile seizures,

most children have respiratory tract infections.237 There is a substantial risk of occurrence in the 24 h after

receiving the diphtheria-pertussis-tetanus vaccine and in the 8-14 days after the measles, mumps, and rubella

vaccine.238

Febrile seizures are classed as simple when they are generalised, do not recur within the same illness, and last

less than 15 min. Febrile seizures are termed complex when they have focal features, are repeated within thesame illness, and are prolonged (>15 min). Neurological abnormalities predispose to complex febrile

seizures,239 which, in turn, have a higher risk of subsequent epilepsy.

Lumbar puncture is advised if there are signs of meningism or the child is younger than 18 months.

Neuroimaging should be reserved to children with prolonged postictal unresponsiveness or focal deficits.237

Most febrile seizures are short but those lasting longer than several minutes should be treated with rectal

diazepam. Recurrence risk is 30-40%.240 Prophylactic treatment is only justified in children who have had a

prolonged febrile seizures. Rectal diazepam at the onset of a new febrile seizure should be preferred to

continuous oral valproate or phenobarbital.237,241 Intermittent prophylaxis at times of fever is discouraged.

About 3-6% of children with febrile seizures will have epilepsy later in life,242 especially idiopathic generalised

epilepsies.

Progressive myoclonus epilepsies

Progressive myoclonus epilepsies are a group of syndromes including Lafora disease, Unverricht-Lundborg



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disease, myoclonus epilepsy with red ragged fibres, early infantile, late infantile, juvenile, and adult

ceroidlipofuscinosis, and sialidosis.243 The clinical picture includes multifocal and generalised myoclonus,

generalised tonic-clonic seizures, or clonic-tonic-clonic seizures, photosensitivity, cognitive deterioration,

cerebellar, and extrapyramidal signs. The different syndromes are identified by age at onset and rate of

progression. Specific genetic abnormalities are now identified for most disorders.243

Status epilepticus and seizure-induced brain damage

Status epilepticus is a neurological emergency defined as recurrent seizures, lasting for more than 30 min,

without interictal resumption of baseline CNS function.1 About 70% of episodes of status epilepticus are the

initial seizure and up to 27% of children with epilepsy will present with one or more episodes,244 although

specific syndromes have a different risk.

A pragmatic classification of status epilepticus is made according to the presence or absence of motor

manifestations, as a result of their impact on management and morbidity rates (panel 2).245 Convulsive

generalised or unilateral status, even if manifested as localised twitching or simple eyeball jerking, has

considerably more serious consequences than focal status.

The origins of the disorder, which are the main prognostic indicator of status epilepticus,244 are unevenly

distributed through age. Febrile status (20-30% of cases) occurs in infants or small children with no history of

seizures or acute CNS infection. Idiopathic status epilepticus (16-40%) occurs in the absence of any insult or in

idiopathic epilepsies. Remote symptomatic status epilepticus (14-23%) occurs especially in children with cortical

dysplasia or epileptic encephalopathy. Acute symptomatic convulsive status epilepticus (23-50%) complicates

an acute illness affecting the CNS, and represents 75% of status epilepticus in children younger than 1 year and

28% in those older than 3 years. Acute symptomatic status epilepticus has the highest mortality rates with

values reaching up to 20%.245,246 CNS infections are an overlooked cause of status epilepticus in infants in

developed countries,247 and the main cause in geographical areas with limited resources.248 Trauma, hypoxic

ischaemic damage, and metabolic/electrolytic disturbances are less frequent causes. Withdrawal of antiepileptic

drugs is a known precipitant of status epilepticus. However, antiepileptic drugs can also precipitate status

epilepticus if inappropriately chosen or because of paradoxical reaction.158,249



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Epilepsia partialis continua is characterised by focal motor seizures and semicontinuous distal jerks that resist

antiepileptic drugs. This form of epilepsy is caused by a lesion, most often cortical dysplasia. Rasmussen's

syndrome, a chronic hemispheric encephalitis, causes progressive epilepsia partialis continua and hemiparesis,

with dystonia, cognitive deterioration, and atrophy of one hemisphere.250,251

A chain of metabolic and excitotoxic events accompanying convulsive status epilepticus has been causally

related to neuronal damage, especially in the CAl and CA3 zones of the hippocampus, amygdala, cerebellar

cortex, thalamus, and cerebral neocortex.252 MRI during or shortly after status epilepticus can show swelling

and abnormal T2 or fluid-attenuated inversion recovery signal, possibly indicating cytotoxic and vasogenic

oedema, and alteration of the blood-brain barrier.253 Convulsive status epilepticus has been consistently

associated with neuronal necrosis in vulnerable regions of the brain, especially in the hippocampus, amygdala,

cerebellar cortex, thalamus, and cerebral neocortex.252

Seizure clusters might evolve into status epilepticus. Benzodiazepines administered by paramedics out of

hospital are effective in terminating prolonged seizures and seizure clusters.254 In a randomised trial,

midazolam was as effective and safe as rectal diazepam in the treatment of prolonged seizures in children.255

Pre-hospital treatment with rectal diazepam, buccal-nasal midazolam, or sublingual lorazepam has been

advised.245,256 However, acute parenteral treatment should be carefully supervised as it causes drowsiness

or sleep and, occasionally, cardiorespiratory collapse.257 Convulsive status epilepticus that is resistant to initial

benzodiazepine administration should always be approached according to a management protocol.257 Indeed,

although there is little evidence to show that of the numerous protocols that have been recommended one is

better than the other, the simple fact of adopting a protocol has itself been shown to reduce mortality and

morbidity.257 A suggested protocol for the managements of status epilepticus in children is presented in figure1.245 However, there is little evidence to show that of the various protocols that have been recommended one

is better than another.



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In the premonitory period of status epilepticus there is a gradual increase in the frequency of seizures. Early

prehospital treatment with parenteral benzodiazepines at this stage is often sufficient to prevent development of

full-blown status. In the early stage of status epilepticus, intravenous lorazepam is considered by many

researchers as a drug of choice as it is longer acting than other benzodiazepines, safer to administer

intravenously, and has a lower risk of cardiorespiratory depression. Most protocols recommend that even when

seizures cease following benzodiazepine administration, a maintenance antiepileptic drugs, such as

fosphenytoin intravenous, should be administered as seizure activity often starts again when the

benzodiazepine is eliminated. Established status epilepticus is usually entered once seizures have lasted >30

min. For practical purposes, it is suggested to consider established status epilepticus if early treatment has

failed or when no accurate estimate of the duration of status epilepticus can be made.257 At this stage,

fosphenytoin is considered the drug of choice by many researchers. Because 1.5 mg of fosphenytoin is

equivalent to 1 mg of phenytoin, the dosage, concentration, and infusion rates of intravenous fosphenytoin are

expressed as phenytoin equivalents (PE). If seizures persist >30-50 min, general anesthesia in the intensive

care unit is required. However, after a first intravenous administration of 20 mg PE/kg, additional 10 mg PE/kg

can be administered before starting phenobarbital, as many patients who fail to respond to the first

administration of phosphenytoin do so because of inadequate levels of phenytoin after the initial load. The risk

of mortality and morbidity at this stage is high. EEG monitoring is essential. In this scheme, midazolam is

preferred for the treatment of refractory status epilepticus as mortality appears to be lower in children with

convulsive status epilepticus who are treated with this drug.246

If status epilepticus is unexplained by clinical history, or focal neurological signs occur, a CT scan should be

done.245 If fever occurs, acute bacterial meningitis should be suspected even in the absence of classicalsigns.247 Early parenteral antibiotics at antimeningitic doses and, if not contraindicated, lumbar puncture, are

recommended.245,247



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Intravenous pyridoxine 100 mg should be administered to all infants with idiopathic drug-resistant status

epilepticus.258 Refractory status epilepticus as a result from unilateral cortical malformations, can be surgically

treated.259

Generalised non-convulsive status epilepticus, manifested as complete unconsciousness or reduced

interaction, drooling, and impaired gait balance (atypical absence status) is frequent in epileptic

encephalopathies. Non-convulsive status epilepticus is an under-recognised cause of coma. It was observed in

8% of comatose patients of all ages, with no clinical signs of seizure activity.260 Subtle forms often escape

recognition, especially in children with developmental delay. EEG shows continuous, diffuse spike-and-wave

discharges. Focal non-convulsive status epilepticus is rare in children. It might manifest as alteration of

consciousness with psychotic state or be indistinguishable from generalised non-convulsive status epilepticus.

EEG recording is essential for diagnosis. Peculiar forms of non-convulsive status epilepticus occur in children

with Angelman syndrome" or ring chromosome 20.261 Non-convulsive status epilepticus is not immediately life-

threatening; it should nonetheless be treated promptly, with the help of EEG monitoring, and a potential life-

threatening cause should be ruled out. Intravenous or rectal benzodiazepines are often effective, but non-

convulsive status epilepticus in patients with Lennox-Gastaut syndrome is very drug-resistant.245 Focal non-

convulsive status is usually treated with intravenous benzodiazepines or phenytoin.245

Overall mortality is 6%, but it is around 16% in convulsive status epilepticus alone.246 Acute symptomatic

status epilepticus, and status epilepticus in progressive encephalopathies account for most of the deaths.

Similarly, the risk of subsequent epilepsy is estimated at 41% after acute symptomatic status epilepticus, but

does not differ from that following an initial short unprovoked seizure in idiopathic cases.245 Status epilepticus

has a high risk of recurrance, especially if it was the initial seizure and in symptomatic patients. Maintainance of

abortive treatment at home is advised in such cases.

Management and principles of treatmentMolecular targets and clinical efficacy of antiepileptic drugs

A spectrum of clinical efficacy is established for most available compounds, although their mechanisms of

action are not distinct (table 3) and are poorly understood. The main excitatory neurotransmitter in the CNS is

glutamate, which acts on three receptor types (N-methyl-D-aspartate, kainate/AMPA, and metabotropic). The

main inhibitory neurotransmitter is -aminobutyric acid, which acts on two receptor types. Activation of the

GABA-A receptor activates a Cl-permeable ion channel, producing membrane hyperpolarisation and a rapid

inhibitory response. GABA-A is also sensitive to benzodiazepines and barbiturates, which respectively modulate

frequency and duration of the ion channel opening.262 GABA-B receptor activation stimulates a metabotropic

receptor that is permeable to K+ ions and produces a slower response. Animal models have confirmed the

anticonvulsant affect of GABAergic potentiation and epileptogenicity of glutamaergic potentiation,263 and have

prompted the development of GABAergic drugs. However, neuroanatomic organisation of epileptogenic neural

networks, which might explain the opposite action of the same agents on different epilepsy types,158 remains



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poorly understood.

Syndrome-oriented drug choice

Knowledge of the main mechanisms of action, spectrum of efficacy of antiepileptic drugs, and correct syndrome

diagnosis should guide treatment. Efficacy and safety of the different drugs can be inferred from clinical trials

providing diverse levels of evidence (panel 3 and table 4).264-183 However, information about the range of

efficacy emerging from such trials is difficult to interpret. Different epilepsy syndromes and causes are often

lumped together and trials design is not sensitive for detecting possible seizure worsening. Finding that two or

more drugs are equivalent, when compared to one another, does not rule out the possibility that all drugs are

ineffective, and that spontaneous remissions or improvements substantially change the results. Information on

safety of antiepileptic drugs in children is poor as approval for paediatric use is only granted with considerable

delay, after promising results have been obtained in adults.

For patients who cannot be classified early, drugs with a wide spectrum of efficacy and lower cost, such as

valproate and carbamazepine should be preferred as the initial treatment.145 Newer drugs might be better

tolerated with equivalent efficacy, but more studies are needed to clarify how they compare with older drugs in

safety, pharmacokinetics, and the requirements for laboratory monitoring.145

When seizures are resistant to the initial monotherapy, choosing an alternative monotherapy or adding a

second drug is a matter of personal preference.263 The transition from initial monotherapy (A) to an alternative

monotherapy (B) should always pass through a transition phase where both drugs (A+B) are administered at full

dosage. During this phase, the effect of the combination of the two drugs is tested and then compared with

previous and subsequent monotherapy regimens.

When to start treatment

The decision to start treatment should be tailored to the individual child. Old statements: "one seizure is not

epilepsy" or "EEG should never be treated", are hazardous if systematically applied. Treatment can be withheld

without major risk in many children with single unprovoked seizures, febrile convulsions, benign focal epilepsies,

and in adolescents with isolated seizures.284 Likewise, children with profound developmental impairment and

mild epilepsy that does not affect the overall picture, should not be treated if drug administration adds practical

difficulties and side-effects without any positive counterpart. Convulsive status epilepticus, or seizures that are

symptomatic of malformations, should be treated promptly if further episodes pose an immediate danger. The

risk of accidental death related to severe seizures should also be regarded, especially in the neurologically

impaired.285

Delaying treatment might have devastating effects when clinically subtle or subclinical epileptic activity sustainscognitive impairment.286

Setting the targets of treatment



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The targets of treatment differ considerably in the common drug-sensitive epilepsies and in the complex drug-

resistant forms. In the first group, seizure control without adverse events, with possibly one drug and in the most

convenient and least expensive manner, is a reasonable target. Drug choices for these purposes vary little. For

complex and severe epilepsies the main goal should not necessarily be complete seizure control at all costs.

Such an attitude would lead to drug escalation and to heavy polytherapies with severe cognitive side-effects,

the consequences of which might be even worse than those of seizures. There is an increased risk for seizure

worsening with heavy polytherapies.230,287 Therefore, reducing seizure frequency should be attempted as an

outcome measure ensuring the best possible quality of life, which results from the balance between cognitive

side-effects of drugs, and intrinsic severity and frequency of seizures. Parents usually know this point of balance

very well and should always be carefully listened to.

Monitoring of antiepileptic drugs treatment

The essential measure is regular clinical supervision with special attention to sedative side-effects. Monitoring of

the concentration in the blood is not routinely indicated.288 However, some experts recommend this practice

when using some drugs or in specific circumstances. In particular, useful information might be drawn from

identifying the levels of phenytoin, as a result from its non-linear kinetics, and carbamazepine, because of its

rather narrow therapeutic index.289 Monitoring is also needed to assess compliance, especially in cases of

breakthrough seizures, clinically suspected toxicity, and drug interactions. In children who are seizure-free on

monotherapy with blood concentrations that are below the therapeutic range, no dosage adjustment is needed.

Conversely, the dose should be raised to the limit of clinical tolerance in resistant cases, not considering blood

concentrations. Blood concentrations are useless with some drugs and difficult to interpret with others,

especially in cases of interactions, of variable protein binding, and with drugs having active metabolites.289

Cognitive and behavioural effects of antiepileptic drugs

Cognitive impairment, often occurring in children with epilepsy is in part attributed to antiepileptic drugs.

However, although a detrimental dose-dependent effect of some antiepileptic drugs on cognition is self-evident,

only a few controlled studies have addressed this point in children.290 Clear evidence has only been obtained



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about reduction of intelligence quotient scores and increased P300 wave latency, an electrophysiological

marker of reduced speed in cognitive processing, in children treated with phenobarbital.291,292 Although such

effects are reversible upon drug withdrawal, enduring consequences in academic achievement have been

shown, suggesting that prolonged drug-induced decrease in cognitive processing in early childhood might not

be compensated upon at a later age.292 Carbamazepine does not affect intelligence quotient,293 but might

slightly impair children's memory, without affecting academic achievement.294,295 Phenytoin might slightly

affect intelligence quotient, but its effects on academic achievement are unknown.290 Effects of valproate on

memory were less pronounced than those of phenytoin and carbamazepine,296 but might not have been

adequately studied.290 There are no studies that have properly addressed the neuropsychological effects of

new antiepileptic drugs in children.

In a controlled trial, valproate was effective in treating children with explosive temper and mood lability.297

Lamotrigine, gabapentin, and levetiracetam, might amplify the risk for aggressive behaviour, especially in

cognitively impaired children.290 Improved alertness and mood have been reported with lamotrigine and

levetiracetam.290 However, such observations should be validated by prospective controlled studies.

Discontinuation of drug treatment

The optimum time to discontinue antiepileptic drugs in children in remission is difficult to establish. Evidence

from randomised trials indicates that after seizure remission 2 years or longer should be waited.298 However,

specific syndromes have different relapsing rates.14 Children with focal epilepsy and those in whom EEG

abnormalities increase or reappear when the dose has been reduced are at greater risk.298,299 There is

insufficient evidence to establish when to withdraw antiepileptic drugs in children with generalised epilepsy.298

Treatment should be discontinued over 3-12 months102 using the longer periods with drugs that have a high

risk of withdrawal seizures, such as benzodiazepines and phenobarbitone.

The ketogenic diet

In two open-label prospective studies the ketogenic diet has shown some efficacy in the treatment of children

with drug-resistant epilepsies,300,301 but no comparative trials are available. No specific syndrome responds

better than others, and assessment of risk and benefits needs further study. The mechanisms of action are not

known, but the nutrition predominantly rich in fat maintains ketosis in the long term and high concentrations of

ketone bodies have been correlated with better seizure control.302 The diet might result in being too restrictive,

and cause diarrhoea, vitamin deficiency, renal stones, and potentially lethal cardiomyopathy.303

Surgical treatment

Some children who are refractory to antiepileptic drugs can benefit from surgical treatment. Although the

benefits of early intervention have been emphasised,304 the average delay from seizure onset to surgery is still

too long, ranging from 12 to 15 years.304

Resective surgery, implies removal of the neuronal aggregate that is responsible for seizure generation;palliative or functional surgery aims at preventing or limiting propagation of seizure activity, without targeting

seizure control.

Several steps are needed to identify a child who can benefit from surgery (figure 2). Medical intractability should

be ascertained, possibly limited to the more appropriate drugs. The level of seizure-related disability should be

established on the