Epilepsy in Chidren the Lancet

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    Epilepsy is suspected when there is repetition of seizures.The cause and clinical spectrum of epilepsy are extremelywide-ranging in children. Although for practical purposes,epilepsy might still be a useful diagnostic category, itwould be inappropriate to regard it as a single entity. ThisSeminar aims to critically review the main concepts thatunderlie classification of seizures and epilepsies inchildren, the rationale for prognostic considerations andfor choosing complimentary investigations, andtreatment.

    Definitions and terminology

    Seizures are described with standard terminology,


    and,where possible, classified in specific epilepsy types orsyndromes3,5 (panel 1 and table 1). A syndrome is acomplex of signs and symptoms defining a uniqueepilepsy condition.3 Syndromes are classified on the basisof seizure types, clinical context, neurophysiology, andneuroroimaging.3,5 Epilepsy can be generalised, if allseizures and electroencephalogram (EEG) abnormalitiesare generalised, or focal (partial) if clinical and EEGmanifestations suggest focal onset, but this distinction isnot always clear cut.3 Idiopathic epilepsies are notassociated with any brain lesions; they are caused by acomplex genetic predisposition or, rarely, single-geneinheritance. Symptomatic epilepsies result from a brain

    lesion, which is not necessarily detected by neuroimaging.The term cryptogenic is synonymous with presumedsymptomatic.3 Syndrome diagnosis is helpful in guidinginvestigations, and management, and is an earlyprognostic indicator.

    EpidemiologyWorldwide, it is estimated that 10·5 million childrenunder 15 years have active epilepsy, representing about25% of the global epilepsy population.6 Of the 3·5 millionpeople who develop epilepsy annually, 40% are youngerthan 15 years, and more than 80% live in developingcountries.6

    Population-based studies on childhood-onset epilepsy


    indicate annual incidence rates of 61–124 per 100 000 in

    developing countries, and 41–50 per 100000 in developedcountries.6 Incidence falls progressively from around150 per 100 000 in the first year of life to 45–50 per 100000after the age of 9 years.6 Cumulative incidence studiesindicate that up to the age of 15 years, 1·0–1·7% of children will have at least one unprovoked seizure, and0·7–0·8% repeated seizures.7,8 Frequency rates in Europeand North America vary from 3·6–6·5 per 1000, whereasAfrican and Latin American studies report rates of 6·6–17 per 1000.6

    Natural history

    In children who experience a first unprovoked focal orgeneralised tonic-clonic seizure, the cumulative risk of recurrence is 42% at 8 years’ follow-up, with only 3% of allrecurrencies occurring after 5 years.9 Multivariableanalysis has shown that risk factors for recurrence includea remote symptomatic cause, an abnormal EEG, a seizureoccurring when asleep, a history of febrile seizures, and

    Lancet 2006; 367: 499–524

    Department of Child Neurology

    and Psychiatry, University of 

    Pisa and IRCCS Fondazione

    Stella Maris, 56018

    Calambrone, Pisa, Italy

    (Prof R Guerrini)

    [email protected]

    www.thelancet.com Vol 367 February 11, 2006 499

    Epilepsy in childrenRenzo Guerrini

    10·5 million children worldwide are estimated to have active epilepsy. Over the past 15 years, syndrome-oriented clinicaland EEG diagnosis, and better aetiological diagnosis, especially supported by neuroimaging, has helped to clarify thediversity of epilepsy in children, and has improved management. Perinatal and postinfective encephalopathy, corticaldysplasia, and hippocampal sclerosis account for the most severe symptomatic epilepsies. Ion channel defects canunderlie both benign age-related disorders and severe epileptic encephalopathies with a progressive disturbance incerebral function. However, the reasons for age-related expression in children are not understood. Neither are themechanisms whereby an epileptic encephalopathy originates. Several new drugs have been recently introduced but haveprovided 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 severecognitive 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.

    Search strategy and selection criteria

    The information in this report is primarily on the basis of peer-reviewed medical

    publications from 1980 to 2005. PubMed was used to search for appropriate articles.

    Selection criteria included a judgment about novelty and importance of studies, and their

    relevance to the well informed general medical doctor and paediatrician. In the case of 

    treatment studies, only those studies in which efficacy claims were supported by a clinicaltrial have been cited. The rate of evidence for drug efficacy was rated according to the

    criteria that have recently been adopted and published by the Therapeutics and

    Technology Assessment Subcommittee and Quality Standards Subcommittee of the

    American Academy of Neurology and the American Epilepsy Society. All published trials in

    children were reviewed and rated according to such criteria. Cochrane reviews for

    treatment strategies were also considered (Cochrane Library database 2000–05).

    Several earlier, commonly quoted, key publications have also been cited. Many review

    articles and book chapters were included because they provided comprehensive overviews

    beyond the scope of this Seminar. Only reports published in English were reviewed. The

    reference list was modified during the review process according to reviewer’s suggestions.

    Key words used included: “epilepsy prognosis”, “cognitive side-effects”, “epilepsy

    syndrome”, “epilepsy surgery outcome”, “genetics of epilepsy”, “treatment of epilepsy”,

    “antiepileptic drugs”, and “antipileptic drug trials”.

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    postictal paresis.9 Treatment does not change therecurrence rates.10,11 About 64% of individuals that havehad 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 epilepsysyndromes and causes are not considered.

    About 75% of patients of all ages reach remission on

    antiepileptic drugs, but attempts at drug withdrawalafter 3 years of seizure control are followed by a relapsein 25% of patients.13 However, relapsing rates are highlyvariable in different epilepsy syndromes: 0% for benignrolandic epilepsy, 12% for childhood absence epilepsy,29% for focal symptomatic epilepsies, and 80% forjuvenile myoclonic epilepsy.14

    General aspects of prognosisMost children with epilepsy can be divided into fourmain prognostic groups.15 The first group is the benignepilepsies—eg, benign rolandic epilepsy (20–30% of patients), in which remission occurs after a few yearsand treatment can often be avoided. The second group isthe pharmacosensitive epilepsies—eg, most children

    with absence epilepsy (30% of patients), in whichseizure control is easily achieved by medication andspontaneous remission occurs after a few years. Thethird one is the pharmacodependent epilepsies, in whichdrug treatment will control seizures, but no spontaneousremission occurs—eg, juvenile myoclonic epilepsy andmany cases of symptomatic focal epilepsy (20% of patients). Drug withdrawal is followed by relapse and

    treatment will be lifelong. The fourth group is thepharmacoresistant (or refractory) epilepsies, with poorprognosis (13–17% of patients). The definition of pharmacoresistance is arbitrary and refers to both thefrequency and severity of seizures for an individualchild. Resistance to drugs can usually be predicted earlyafter an inadequate response to initial appropriatetreatment.16

    Although benign epilepsies and most pharmacosensi-tive idiopathic generalised epilepsies can be identifiedearly after onset, for many children with focal sympto-matic or presumed symptomatic epilepsies, and forsome of those with idiopathic generalised epilepsies,pharmacosensitivity or pharmacodependence are oftendefined accurately only in retrospect.

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    Panel 1: Definitions of key terms (from references 3 and 4)

    Epilepsy: A disorder of the brain characterised by an enduring predisposition to generate epileptic seizures and by the neurobiologic,

    cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one

    epileptic seizure

    Epileptic seizure: A transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in

    the brain

    Epileptic seizure type: An ictal event believed to represent a unique pathophysiologic mechanism and anatomic substrate. This is a

    diagnostic entity with aetiological, therapeutic, and prognostic implications.

    Epilepsy syndrome: A complex of signs and symptoms that define a unique epilepsy condition. This must involve more than just the

    seizure type: thus frontal lobe seizures per se, for instance, do not constitute a syndrome.

    Epileptic disease: A pathologic condition with a single specific, well-defined aetiology. Thus progressive myoclonus epilepsy is a

    syndrome, but Unverricht–Lundborg is a disease.

    Epileptic encephalopathy: A condition in which the epileptiform abnormalities themselves are believed to contribute to the

    progressive disturbance in cerebral function.Benign epilepsy syndrome: A syndrome characterised by epileptic seizures that are easily treated, or require no treatment, and remit

    without sequelae.

    Reflex epilepsy syndrome: A syndrome in which all epileptic seizures are precipitated by sensory stimuli. Reflex seizures that occur in

    focal and generalised epilepsy syndromes that also are associated with spontaneous seizures are listed as seizure types. Isolated reflex

    seizures also can occur in situations that do not necessarily require a diagnosis of epilepsy. Seizures precipitated by other special

    circumstances, such as fever or alcohol withdrawal, are not reflex seizures.

    Focal seizures and syndromes: Replaces the terms partial seizures and localisation-related syndromes.

    Simple and complex partial epileptic seizures: These terms are no longer recommended, nor will they be replaced. Ictal impairment

    of consciousness will be described when appropriate for individual seizures, but will not be used to classify specific seizure types.

    Idiopathic epilepsy syndrome: A syndrome that is only epilepsy, with no underlying structural brain lesion or other neurologic signs

    or symptoms. These are presumed to be genetic and are usually age dependent.

    Symptomatic epilepsy syndrome: A syndrome in which the epileptic seizures are the result of one or more identifiable structural

    lesions of the brain.

    Probably symptomatic epilepsy syndrome: Synonymous with, but preferred to, the term cryptogenic, used to define syndromes

    that are believed to be symptomatic, but no aetiology has been identified.

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    Specific syndromes Age at onset Age at remission/ Monotherapy Possible Surgery

    prognosis or add-on add-onIdiopathic focal epilepsies Benign infantile seizures (non-familial) Infant Infant/good PB .. No

    of infancy and childhood Benign childhood epilepsy with 3–13 years 16 years/good VPA, CBZ .. No

    centrotemporal spikes

    Early and late onset idiopathic 2–8 years; 6–17 years 12 years or earlier; 18 years/good VPA, CBZ .. No

    occipital epilepsy

    Familial (autosomal Benign familial neonatal convulsions Newborn–young infant Newborn–young infant/good PB .. No

    dominant) epilepsies Benign familial infantile convulsions Infant Infant/good CBZ, PB .. No

    Autosomal dominant nocturnal frontal Childhood Unclear/variable CBZ, OXC, TPM, PHT, GBP LEV, PHT, PB, CLB No

    lobe epilepsy

    Fa milia l la teral tempora l lob e epilepsy Childhood–adol escence Unclear /va riable CBZ, OXC, VPA, TPM, LEV, PHT, PB, CLB No

    PHT, GBP

    Generalised epilepsies with febrile Childhood–adolescence Unclear/variable VPA, ESM, TPM, LTG CLB, LEV No

    seizures plus

    Symptomatic Limbic epilepsy 

    (or probably symptomatic) Mesial temporal lobe epi lepsy with School age or earlier Longlasting/variable CBZ, VPA, OXC, TPM, LEV, PHT, PB, CLB Temporal resection

    focal epilepsies hippocampal sclerosis PHT, GBP

    Mesial temporal lobe epilepsy defined Variable Longlasting/variable CBZ, VPA, OXC, TPM, LEV, PHT, PB, CLB Temporal resectionby specific causes PHT, GBP

    Other types defined by location and causes Variable Longlasting/variable CBZ, VPA, OXC, TPM, LEV, PHT, PB, CLB Lesionectomy/

    PHT, GBP cortical resection

    Neocortical epilepsies

    Rasmussen syndrome 6–12 years Progressive/ominous prognosis Plasmapheresis, PHT, CBZ, PB, TPM, Functional

    immunoglobulins CLB hemispherectomy

    Hemiconvul sion- hemiplegia syndr ome 1–5 years Chr onic/sever e prognosis CBZ, VPA, OXC, TPM, LEV, P HT, PB, CLB Functiona l

    PHT, GBP hemispherectomy

    Other types defined by location and cause Variable Longlasting/variable CBZ, VPA, OXC, TPM, LEV, PHT, PB, CLB Lesionectomy/

    PHT, GBP cortical resection

    Migrating partial seizures of early infancy Infant No remission/ominous prognosis PB, PHT, CBZ, TPM, VPA, BDZ No

    Idiopathic Benign myoclonic epilepsy in infancy 3 months–3 years 3–5 years/variable VPA BDZ No

    generalised epilepsies Epilepsy with myoclonic astatic seizures 3–5 years Variable/variable VPA, ESM, TPM BDZ, LTG, LEV No

    Childhood absence epilepsy 5–6 years 10–12 years/good VPA, ESM, LTG .. No

    Epilepsy with myoclonic absences 1–12 years Variable/guarded VPA, ESM BDZ No

    Idiopathic generalised epilepsies with

    variable phenotypes Juvenile absence epilepsy 10–12 years Usually lifelong/good VPA, ESM, LTG BDZ No

     Juvenile myoclonic epilepsy 12–18 years Usually lifelong/good VPA, TPM BDZ, PRM, PB No

    Epilepsy with generalised tonic-clonic 12–18 years Usually lifelong/good VPA, LTG, TPM, CBZ BDZ, LVT No

    seizures only

    Reflex epilepsies Idiopathic photosensitive occipital lobe 10–12 years Unclear/variable VPA LEV, BDZ No


    Other visual sensitive epilepsies 2–5 years Unclear/variable VPA LEV, BDZ No

    Startle epilepsy Variable Longlasting/guarded CBZ, VPA, OXC, TPM, LEV, PHT, PB, CLB Lesionectomy/

    PHT, GBP cortical resection

    Epileptic Early myoclonic encephalopathy and Newborn–infant No remission/ominous prognosis Steroids, PB BDZ No

    encephalopathies Ohtahara s yndrome

    West syndrome Infant Variable/variable Steoids, GVG BDZ, TPM Lesionectomy/

    cortical resection

    Dravet's syndrome (severe myoclonic Infant No remission/severe prognosis Stiripentol–CLB, VPA, BDZ No

    epilepsy in infancy) TPM

    Lennox-Gastaut syndrome 3–10 years No remission/severe prognosis .. BDZ Callosotomy

    Landau-Kleffner syndrome 3–6 years 8–12 years/guarded VPA, ESM, steroids BDZ, LTG Multiple subpialtransections

    Epilepsy with continuous spike waves 4–7 years 8–12 years/guarded VPA, ESM, seroids BDZ, LTG No

    during slow-wave sleep

    Progressive Unverricht-Lundborg, lafora, ceroido- Late infant–adolescent Progressive/ominous prognosis VPA, TPM BDZ, PB No

    myoclonus epi lepsies l ipofuscinoses, etc

    Seizures Benign neonatal seizures Newborn Newborn/good PB .. No

    not necessarily needing Febrile seizures 3–5 years 3–6 years/good VPA if repeated and .. No

    a diagnosis of epilepsy prolonged

    Reflex seizures Variable n/a .. .. No

    Drug or other chemically-induced seizures Variable n/a .. .. No

    Immediate and early post-traumatic Variable n/a .. .. No


    Table 1: Classification for epilepsy syndromes with an indication of age of onset, duration of active epilepsy, prognosis, and therapeutic options

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    Early response to drugs (75–100% seizure reductionwithin the first 3 months of treatment) is a goodpredictor of long-term remission, irrespective of thecause.12 However, idiopathic and presumed sympto-matic epilepsies are three times as likely to achieveremission than symptomatic forms.12

    Cause and pathophysiologyKnowledge of the cause and pathophysiology of childhood epilepsy has considerably improved withmodern neuroimaging and molecular genetic studies.

    However, our understanding of the causes and thereasons why specific syndromes appear with preciseage-relatedness is still very limited.

    Genetic and molecular basisMutations of single genes are known to cause epilepsy,but they can result in different phenotypes (table 2).Conversely, identical phenotypes might be a resultof different genotypes. Phenotypical variability hasbeen putatively attributed to modifier genes orpolymorphisms determining the phenotypical expres-sion or, alternatively, to environmental factors.17 Mostof the idiopathic epilepsies do not follow single-geneinheritance and their occurrence in large families israre.

    Idiopathic generalised epilepsiesIdiopathic generalised epilepsies have complexinheritance associated with the interaction of two ormore genes.18 Sporadic cases are common and affectedfamilies are usually small.19 Close relatives of probandshave a 4–10% risk of developing epilepsy,20 which ishighest in siblings and offspring than in other relatives.There is higher concordance for idiopathic generalisedepilepsies in monozygotic than dizygotic twins (0·76 vs0·33).21 Single-gene inheritance has been shown in rarefamilies. Mutations in the voltage-gated chloride channel

    gene (CLCN2) were identified in some families withidiopathic generalised epilepsies.22 One family withdominant juvenile myoclonic epilepsy harboured amutation in the 1 subunit of the GABAA receptor gene(GABRA1),23 and three additional pedigrees harbouredmutations of the EFHC1 gene, which causes reversal of EFHC1-induced neuronal cell death, and EFHC1dependent increase of R-type Ca+ current. However, thefinding of 2 subunit GABAA receptor gene (GABRG2 )mutations in families with predominantly childhoodabsence epilepsy, febrile seizures, and febrile seizuresplus (when febrile seizures occur or continue past 6 yearsof age) is in line with the hypothesis that a major geneconferring non-specific seizure susceptibility might beassociated with minor specific genes to determine

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    Function Locus Epilepsy syndrome Seizure types

    GABRA1 Partial inhibition of GABA- 5q34 AD JME TCS, myoclonic, absenceGABAA 1 receptor subunit activated currents

    GABRG2 Rapid inhibition of GABAergic 5q31 FS, CAE, GEFS Febrile, absence, TCS, myoclonic,

    GABAA receptor2 subunit neurons clonic, partial

    GABRD Decreased GABAA receptor current 1p36 GEFS Febrile and afebrile

    GABAA receptor 2 subunit amplitudes seizures

    SCN2A Fast sodium influx initiation and 2q24 GEFS BFNIC Febrile, afebrile generalised

    Sodium channel2 s ub un it pr op agat io n o f act io n p oten ti al toni c and T CS

    SCN1A Somatodendritic sodium influx 2q24 GEFS SMEI Febrile, absence, myoclonic,

    Sodium channel1 subunit TCS, partial

    SCN1B Coadjuvate and modulate subunit 19q13 GEFS Febrile, absence, tonic

    Sodium channel1 subunit clonic, myoclonic

    KCNQ2 M current interacts with KCNQ3 20q13 BFNC Neonatal convulsions

    Potassium channel

    KCNQ3 M current interacts with KCNQ2 8q24 BFNC Neonatal convulsions

    Potassium channel

     ATP1A2 Dysfunction of ion transportation 1q23 BFNIC and familial Infantile convulsions


    , K

    -ATPase pump hemiplegic migraineCHRNA4 Nicotinic current modulation; 20q13 ADNFLE Sleep-related focal seizures

    Acetylcholine receptor 4 subunit interacts w ith2 subunit

    CHRNB2 Nicotinic current modulation; 1p21 ADNFLE Sleep-related focal seizures

    Acetylcholine receptor 2 subunit interacts w ith4 subunit

    LGI1 D is re gu lates h om eo stas is, in te ract io ns 1 0q24 A DP EA F P ar tia l s ei zu res with audi to ry

    Leucine-rich,glioma activated between neurons and glia? or visual hallucinations

    CLCN2 Neuronal chloride efflux 3q26 IGE TCS, myoclonic, absence

    Voltage-gated chloride channel

    EFHC1 Reduced mouse hippocampal 6p12-p11 JME TCS, myoclonic

    P ro te in wi th an EF -h an d mo tif in du ce d apo ptosi s

    BRD2 (RING3) ? 6p21 JME TCS, myoclonic

    Nuclear transcriptional regulator

    AD=autosomal dominant. ADNFLE=autosomal dominant nocturnal frontal lobe epilepsy. ADPEAF=autosomal dominant partial epilepsy with auditory features. BFNC=benign familial

    neonatal convulsions. GEFS=generalised epilepsy with febrile seizures plus. TCS=tonic-clonic seizures. MAE=myoclonic astatic epilepsy. SMEI=severe myoclonic epilepsy of infancy.

    BFNIC=benign familial neonatal-infantile convulsion. XL=X-linked. JME=juvenile myoclonic epilepsy.

    Table 2: Identified genes for epilepsy

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    specific subsyndromes.24,25 GABA is a ligand-gated


    ion channel, conferring fast inhibitory synaptictransmission; dysfunctional GABA, and Cl— conductancecan lead to impaired inhibitory mechanisms.26

    Familial autosomal dominant epilepsiesGeneralised epilepsy with febrile seizures plus designatesa spectrum of epilepsy phenotypes including febrileseizures and febrile seizures plus. Less commonphenotypes are febrile seizures plus with absence ormyoclonic seizures, focal epilepsies, myoclonic astaticepilepsy, and Dravet’s syndrome.27,28 Mutations of 1 and1 voltage-gated sodium channel subunit genes (SCN1B,SCN1A)29 account for 17% of generalised epilepsy withfebrile seizures plus.30 Genetic heterogeneity is confirmed

    by the finding of mutations in the 2 subunit GABAAreceptor gene (GABRG2 ) in rare families.31,32 Complexinheritance in also possible in generalised epilepsy withfebrile seizures plus.29

    Benign familial convulsions of the neonatal andinfantile period encompass distinct age-related disorders.Benign familial neonatal convulsions are highlypenetrant, with short lasting seizures beginning betweena few days of life and 3 months. A few patients willmanifest isolated seizures later in life. This disorder isassociated with mutations of K+ channel genes KCNQ3and KCNQ2 .33,34 Benign infantile convulsions arecharacterised by seizures between 4 and 8 months of age,

    often occurring in families. There is no known genedefect.35 Benign familial neonatal-infantile seizures beginbetween day 2 and 7 months of age, and are associatedwith SCN2A gene mutations.36

    Autosomal dominant nocturnal frontal lobe epilepsy ischaracterised by childhood-onset clusters of sleep-relatedand hypermotor seizures. Mutations in the 4 and 2subunits of the neuronal nicotinic acetylcholine receptorgenes (CHRNA4 and CHRNB2 ) have been identified37,38 insome families.

    Autosomal dominant partial epilepsy with auditoryfeatures begins in childhood to adolescence withauditory 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 abnormalitiesChromosomal abnormalities are an important cause of epilepsy in children,41 and careful chromosomal studiesshould be done systematically in non-idiopathicepilepsies without a clear cause. Epilepsy might be thepresenting symptom or have suggestive clinical andEEG features. Angelman syndrome as a result of 15q11–q13 deletion and the 4p-syndrome are associatedwith myoclonic and absence status,42 which mightrespond to combinations of valproate, ethosuximide,and benzodiazepines. Patients with ring chromosome20 are often diagnosed on the basis of repetitive

    prolonged seizures with unresponsiveness that are



    Abnormalities of cortical development andneurocutaneous disordersThe malformations of cerebral cortex account for at least40% of drug-resistant childhood epilepsies.44 Some mal-formations reviewed in this section have been associatedwith mutations of specific genes and genetic counsellingis now possible in a considerable number of patients.45

    In hemimegalencephaly, one cerebral hemisphere isenlarged with a thick cortex and wide convolutions.46 Earlycontinuous seizures are associated with major develop-mental impairment. Hemispherectomy might controlseizures47 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 ballooncells.48 MRI shows focal cortical thickening and highsignal intensity, but can also be normal. Focal corticaldysplasia causes infantile spasms or focal epilepsy48,49 withfrequent status epilepticus. Early surgical treatment isadvocated in drug-resistant cases.50

    Bilateral periventricular nodular heterotopia consists of subependymal nodules of grey matter. X-linked bilateralperiventricular nodular heterotopia is caused by muta-tions of the FLN1 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 andsubcortical band heterotopia. Mutations of the DCX gene,and mutations and deletions, or both, of the LIS1 geneaccount for most cases.55,56 Mutations of the Reelin gene57

    or ARX gene58 are rare. Genetic testing must be guided byneuroimaging and family ascertainment.59 Infantilespasms occur frequently.59

    Schizencephaly consists of a unilateral or bilateral cleftof the cerebral hemispheres. Familial occurrence is veryrare. Mutations in the EMX2 gene were observed in rarecases,60 but need confirmation.

    Polymicrogyria consists of cortical infoldings and

    thickening.61 Small areas might escape recognition byimaging. 65% of children have intractable seizures.62 Bilat-eral perisylvian, parietal-occipital, or frontoparietal poly-microgyria61 can be familial. Frontoparietalpolymicrogyriais caused by mutations of the recessive gene GPR56 .63

    Tuberous sclerosis is a dominant disorder associatedprimarily with abnormalities of the CNS, the skin, and thekidney. The cortical tubers are visualised on MRI with T2and fluid attenuated inversion recovery, but might escaperecognition in infants with incomplete myelination.64 TheTSC1 and TSC2 genes account for most cases.65 Epilepsyoccurs in about 60% of patients.66 Infantile spasms arecommon and are often responsive to vigabatrin.67 Epilepsysurgery can yield good seizure control in selectedindividuals.68

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    Sturge-Weber syndrome is a non-familial phako-

    matosis, in which a venous angioma of the leptomeninges(all cases) is accompanied by a homolateral naevusflammeus of the skin supplied by the trigeminal nerve(port-wine stain; 90%).69 Unilateral convulsive statusoccurs in about 50% of patients, leaving half of them withpermanent hemiplegia.70 Surgical treatment is needed inup to 40% of children.69 Dysembryoplastic neuroepithelialtumours have a developmental origin and supratentoriallocation.71 Grey and white matter are both involved. MRIscan shows a hyperintense T1 lesion with multilocularappearance and peripheral enhancement after gadoliniumadministration. These tumours cause childhood-onsetdrug-resistant focal epilepsy. Complete surgical removal isassociated with remission of epilepsy.72

    Cerebral palsyCerebral palsy is often associated with epilepsy: about 50%in quadriplegia and hemiplegia, about 26% in both spasticdiplegia and in dyskinetic forms.73 Infantile spasms areobserved in more than 15% of patients.73 Onset of epilepsyis usually early and the course tends to be severe. Only12·9% achieve a remission of 2 years or more. 74 Childrenwith cerebral palsy and epilepsy function at lower levelsthan children with the same form of cerebral palsywithout epilepsy with respect to both intelligence andmemory. Those with small lesions and epilepsy do lesswell as a group than those with larger lesions but without



    Selected cases might benefit from surgicaltreatment of epilepsy.

    Hippocampal sclerosisThe terms hippocampal sclerosis, Ammon’s hornsclerosis, and mesial temporal sclerosis designate subtlydifferent entities featuring gliosis and neuronal loss insuch structures. Primary nerve cell loss in thehippocampus, especially the CA1 and CA4 sections,76 isaccompanied by sprouting of mossy fibres.77 Theresulting altered circuitry can facilitate localepileptogenesis.77 Hippocampal sclerosis is unilateral in80% 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 inchildren with temporal lobe epilepsy detectedhippocampal sclerosis in 21% of children with new onsetseizures,81 and in 57% of those with refractory seizures.54

    A causative relation has been suggested betweenprolonged febrile seizures and subsequent temporal lobeepilepsy with hippocampal sclerosis.82,83 However, thesequence of febrile status followed by temporal lobeepilepsy is rare from a population perspective.84 Althoughdevelopmental lesions85 or specific genetic factors86 mightpredispose to febrile status followed by hippocampalsclerosis, and temporal lobe epilepsy, prospective studiesare needed to clarify whether a specific age window existsduring which the brain would be more vulnerable.Hippocampal sclerosis might also result from repeated

    seizures that arise from distantly located epileptogenic



    Complete seizure remission after surgery is observed inabout 78% of children with temporal lobe epilepsy as aresult of hippocampal sclerosis.80

    Postinfective epilepsyEpileptic seizures might occur during an acute infectionof 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 differentgeographical areas.89 A distinction between acute sympto-matic seizures and chronic epilepsy is only feasible withbacterial meningitis and herpes virus encephalitis, but notwith neurocysticercosis or HIV encephalopathy.90 About

    35% of children with bacterial meningitis have acuteseizures and 5·4% develop subsequent epilepsy.91 Ingeneral, acute seizures amplify the risk of late epilepsy,but no specific data are available.90 Neurocysticercosis inchildren often manifests with seizures,90 which are moresevere during the active disease than in the chronicinactive stage of calcification.92

    Seizures and epilepsy following acute brain injuryAbout 3–10% of children with head injury present with anearly post-traumatic seizure, usually within 24 h.93 Earlyseizures after trivial head injury have an excellentprognosis 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 greatestrisk.93 Children under the age of 5 years are at higher riskof status epilepticus.93 After severe injury, generalisedtonic-clonic seizures within the first week and a low initialGlasgow Coma Scale are associated with a substantial riskof late epilepsy.95 Phenytoin or carbamazepine treatmentreduces the risk of early seizures, but does not change latepost-traumatic epilepsy or mortality.96 Therefore, treat-ment should not be maintained after acute neurologicalmanifestations have resolved.93 Incidence of epilepsy aftermild head injury is similar to that of the generalpopulation,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 betreated.93 Post-traumatic psychogenic non-epilepticseizures have been described in children.98

    DiagnosisTwo-thirds of cases can be assigned to specific syndromesearly, after undertaking EEG in all children andneuroimaging where appropriate.99,100 Of the remainingpercentage, about 30% will be assigned to more specificcategories within 2 years.101

    History taking is the main diagnostic instrument. Itshould assemble a coherent sequence of manifestationsthat is made likely by the functional characteristics of the

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    brain, according to age and neurological status. It should

    include developmental milestones, drug history, and theeffect that seizures have on the child and the family. Inolder children, direct questioning can clarify subjectivesymptoms. Description of seizures should be focused onthe very initial ictal manifestations and include the wholesequence and postictal occurrence, circumstances of occur-rence, and precipitating factors. Parents can be asked toemulate attacks and use home videotape recordings.Clinical examination should include neurological, skin,and ocular assessment, and measurement of headcircumference.

    EEG might reveal paroxysmal abnormalities. However,with few exceptions, diagnosis does not depend primarilyon EEG, as interictal EEG abnormalities are observed in

    5–8% of healthy children.102 Sleep EEG enhances thepositivity rate of routine EEG from 60% to 90%.103

    Intermittent photic stimulation and hyperventilation areessential in children. Video-EEG recordings, withsimultaneous sampling of EEG, electromyogram, electro-cardiogram, respirogram, and electro-oculogram areinvaluable for characterising complex clinical manifes-tations.104 Long-term cable telemetry is essential to captureand quantify seizures. A normal interictal EEG does notexclude epilepsy when there is a convincing clinicalhistory. Surface EEG can sample electrical activity onlyoriginating from the scalp convexity, leaving the mesiobasalbrain surface and the inner cortex virtually unexplored.

    The International League Against Epilepsy has proposeda diagnostic scheme3 that is divided in five parts, or axes.Definitions of key terms are shown in panel 1.3,4 Thediagnostic axes include descriptive terminology for ictalsemiology (axis 1), detailed descriptions of epileptic seizuretypes (axis 2), epileptic syndromes (axis 3), diseases fre-quently associated with epileptic seizures or syndromes(axis 4), and the impairment classification derived fromWHO International Classification of Functioning, Dis-ability and Health (axis 5). Their most recent versions canbe found at the International League Against Epilepsywebsite.

    Differential diagnosis

    In children, several non-epileptic paroxysmal events needto be differentiated from epilepsy. Misdiagnosis isfrequent and is an important cause of pseudo-refractoryepilepsy.105 Furthermore, cognitive or behavioural symp-toms of epilepsy are often interpreted as psychogenicalmanifestations and sleep-related epileptic seizures asparasomnias.106

    Reflex anoxic seizures and breath-holding spells occurin about 4% of children, and onset is in infancy. Reflexanoxic seizures results from temporary asystole of reflexorigin, whereas breath-holding spells originate duringexpiratory apnoea with intrapulmonary blood shuntingand inconsistency between ventilation and perfusion.107

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

    limb jerking, and upward or downward eye deviation.

    After 30–60 s, hypertonus resolves and consciousnessresumes.107

    Cardiogenic syncopes are rare in children and areusually caused by structural heart defects, especially aorticstenosis, or by rhythm disturbances, especially the longQT syndromes.108 Syncopal attacks resemble convulsiveseizures. Long QT syndromes can cause sudden death,which can be prevented by pacemaker placement.

    Gastro-oesophageal reflux is manifested in smallchildren as episodes of change in colour, respiratoryrate disturbances, or bradycardia. Dystonic posturing andopisthotonous might occur.109

    Psychogenic pseudo-epileptic seizures is the commonterm for grouping non-epileptic behavioural manifesta-

    tions, also called non-epileptic seizures. They are observedin children as young as 5 years who often have concomi-tant epilepsy,110 and can cause pseudo intractability. Attacksusually resemble generalised tonic-clonic seizures, butmovements are coordinated, with a crescendo of intensityand do not occur when the patient is alone. Recovery israpid. Precipitation by observation is frequent, especiallyduring EEG recording.110

    The paroxysmal dyskinesias include dystonic orchoreoathetotic attacks that can be precipitated by suddenmovement (kinesigenic), by prolonged exercise (exercise-induced), or be spontaneous (non-kinesigenic). Conscious-ness is preserved. Duration and frequency of attacks are

    variable. Ictal EEG is normal and familial occurrence isfrequent. Antiepileptic drugs are often effective. Co-occurrence of epileptic seizures in the same patient or inrelatives is not uncommon.111

    Benign infantile myoclonus can occur in healthy infantsas clusters of repetitive axial jerks that might simulateinfantile spasms.112 EEG is normal and the course isspontaneously favourable.

    Self-gratification behaviour is observed morefrequently in girls, in late infancy or early childhood, asepisodes of rhythmic contractions of the lower limbs andtrunk, with eye staring and withdrawal, which simulateunresponsiveness.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 symptomshave a slower course, and visual phenomena are notcoloured and present as broken lines (fortification spectra)or undulating patterns. In occipital epilepsy, they areusually described as coloured, rotating circles.114 Cloudingof consciousness can occur in both conditions. Migraineand epileptic seizures might co-occur, either in differentattacks or as parts of the same episode.

    Night terrors or pavor nocturnus typically appear aftersleeping for a few hours. The child screams while sittingterrified in bed for several minutes. Attempts of estab-lishing a reassuring contact are unsuccessful until thechild falls asleep again: the child has no recollection of this

    For the International League

    Against Epilepsy see


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    event. Such episodes can occur regularly for a period of 

    time but disappear within age 5.


    Differential diagnosisfrom nocturnal frontal lobe epilepsy might need ictalrecordings.

    Somnambulism or sleepwalking results from anincomplete arousal during which the child can walk ormake simple activities. It must be differentiated fromnocturnal epileptic wandering,116 an expression of frontallobe seizures.

    NeuroimagingStructural neuroimagingCT can detect small calcified lesions or bone scallopingand 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 idiopathicepilepsy do not need imaging. Conversely, children withnon-idiopathic focal epilepsy should always have an MRI.Seizure semiology and the EEG should guide the imagingstudy.

    Abnormalities of cortical development are the mostcommon cause of symptomatic childhood epilepsy.117 Inthe first 6 months of life, T2-weighted images are neededto identify cortical abnormalities, whereas T1 imagesbetter appreciate maturational changes, especially inmyelination.117 Subsequently, such sequence modalities have

    a reverse role and are better complemented by inversionrecovery sequences, offering a higher T1-weighted contrastand fluid-attenuated inversion recovery sequences, whicheliminate cerebrospinal fluid distortion.

    Hippocampal structures and areas of cortical dysplasiaare well defined using 3-D sequences producing 1·5 mmimages.117 The use of gadolinium contrast is indicated inselected lesions.

    Functional neuroimagingFunctional imaging can be used in candidates for epilepsysurgery with the purpose of reducing the need for invasiveexplorations, particularly intracranial EEG monitoring118

    and the sodium amobarbital (Wada) test.119

    1H proton magnetic resonance spectroscopy can showabnormal N-acetylaspartate and creatine ratios, or both,probably indicating neuronal dysfunction and gliosis.120

    Functional MRI has been used to map functionalcortical areas and study their relation with the epilep-togenic cortex.121 The need for training and cooperationlimits this technique to children older than 7–8 yearsand with adequate cognitive skills.122 PET with 2-deoxy-2[18F]fluoro-D-glucose measures regional glucose andoxygen use in the brain. Focal hypometabolism mightcorrespond to structural epileptogenic changes that arenot visible by MRI.123 The PET tracer flumazenyl, whichbinds to the GABAA subunit receptor, has a highersensitivity than 2-deoxy-2[18F]fluoro-D-glucose in demar-cating the epileptogenic cortex.124

    Single photon emission CT with technetium –99m is

    used to assess local cerebral blood flow, showing interictalreduction and ictal amplification in the epileptogenicarea.125

    Classification and response to treatment of thedifferent epilepsy typesAn example of a classification of epilepsy syndromes, witha schematic indication of their main clinical character-istics is shown in table 2. The most important syndromesare reported in the following sections.

    Focal epilepsies and epileptic syndromesIdiopathic focal epilepsiesIdiopathic focal epilepsies are the most frequent epilepsy

    syndromes in children. They have an age-dependentcourse and might occur in more than one family member.Response to antiepileptic drugs is usually satisfactory butit is unclear whether treatment changes the outcome.Parents usually accept withholding treatment if it isexplained that the disorder is self-limiting and does notinduce brain damage. If treatment is necessary, carba-mazepine or valproate are preferred.126

    Benign childhood epilepsy with centrotemporal spikesrepresents 8–23% of childhood epilepsies.127 Seizure onsetis between 3 and 13 years. Prognosis is excellent withremission within adolescence.128 Typical seizures causesleep arousal with lateralised facial contraction, anarthria,

    dribbling, and a grunting sound, without loss of consciousness. Sometimes the homolateral upper limb isinvolved. Secondary generalisation can supervene.Interictal EEG shows typical biphasic centro-temporalspikes, with a tangential dipolar distribution, which oftenbecome bilateral during sleep. The total number of seizures a child will have is variable but antiepileptic drugstreatment can often be avoided.129 Atypical EEGcharacteristics are not rare and are often associated withatonic seizures and a complicated evolution, includingparadoxical aggravation with carbamazepine treatment.130

    Benign epilepsy of childhood with occipital paroxysmswas originally described as an idiopathic focal epilepsywith age at onset between 6 and 17 years, with visual ictal

    symptoms, frequent postictal migraine, and interictalunilateral or bilateral occipital spike–and-wave EEGdischarges that are facilitated by eye closure.131 This formaccounts for no more than about 1% of epilepsies.

    A more frequent form of this syndrome, observed inabout 3% of all children with epilepsy, appears between2 and 8 years with prolonged but rare sleep-related seizureswith tonic eye and head deviation, vomiting, and hemiclonicjerks.132 Differential diagnosis includes acute symptomaticseizures, or abdominal emergencies and symptomaticoccipital epilepsy.102 Treatment is rarely necessary.132

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

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    seizure semiology pointing to a lobar location. However,

    the epileptogenic area itself can be associated withmultilobar networks. Seizures might include a singlesymptom or have complex symptomatology. The temporalsequence of events is related to the origin and propagationof the discharge.134 The very first manifestation of a seizurelocalises its onset. Alteration of consciousness hasclassically been considered the hallmark of complexpartial seizures, with respect to simple partial seizures inwhich awareness is preserved. However, alteration of consciousness indicates extensive seizure spread but noorigin or distribution.135 Postictal sleepiness is frequent inchildren and has a major relevance for differentialdiagnosis. Scalp EEG can be misleading.

    Attributing seizure origin to a specific area is difficult

    when neuroimaging is normal, unless a highly character-istic clustering of symptoms occurs.

    Mesial temporal lobe epilepsy is the best defined focalsymptomatic epilepsy syndrome. Most children with thissyndrome have hippocampal sclerosis, which is visible onMRI,81 and about 40% of these have a history of prolongedfebrile seizures.136 Typical seizures start at around 5 to10 years or earlier,81 and include an initial rising epigastricsensation with fear, oro-alimentary automatisms (chewing,swallowing, lip smacking), alteration of consciousness withstaring, and postictal confusion.80 Aphasia is oftenobserved when the dominant hemisphere is involved. Ininfants and small children, reduction of motor activity

    might be the prominent feature, without automatisms(hypomotor seizures).137 Interictal EEG can be normal orshow unilateral or bilateral temporal abnormalities.Memory disturbances are common. Drug resistance isfrequent. Anterior temporal lobectomy or more selectiveresections 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) andsleep-related. They are highly stereotyped in the samepatient. Arousal from sleep, with opening of the eyes and afrightened expression is often the first ictal manifes-tation.138 Consciousness disruption is variable but recoveryof awareness is fast. Subjective symptoms are ill defined.Onset of motor phenomena is with tonic asymmetric

    posturing or repetitive hyperkinetic automatisms. Mostchildren exhibit organised movements of the proximallimbs (hypermotor seizures).139 Epileptic nocturnal wander-ings are longer attacks (2–3 min) with arousal from sleepand an ambulatory behaviour during which a frightenedchild might scream and attempt to escape.116 Frontal lobeseizures in the awake child can cause violent dropattacks.140 Interictal and even ictal EEG is often normal, orshows abnormalities that enable neither lateralisation norlocalisation.139

    Occipital lobe epilepsy of symptomatic origin can bedifficult to diagnose in children because seizure spreadmasks initial symptoms.141 Ictal elementary visual hallu-cinations (coloured blobs, flashes of light), associated toperipheral visual field deficit (hemianopia) are typical.142

    Lateral movements of the eyes are frequent. Perinatal

    ischaemic insults and cortical malformations are frequentcauses.141 Sturge-Weber syndrome, coeliac disease, Laforadisease, and mitochondrial disorders also cause occipitalseizures.141 Interictal EEG abnormalities are usuallyincreased during eye-closure.

    Pharmacological treatment of focal epilepsiesMonotherapies with valproate or carbamazepine haveshown similar effectiveness and good tolerability inchildren with newly diagnosed focal epilepsy with orwithout secondary generalisation.143 Phenytoin, pheno-barbital, carbamazepine, and valproate had a comparableefficacy, 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 drugsmight provide alternative monotherapies, but very fewcomparative controlled trials are available in children.145

    Two class I studies used topiramate in children older than3 years,146 or than 6 years,147 with new or recently diagnosedfocal epilepsy. Higher doses of topiramate were moreeffective than lower doses,146 and 100 or 200 mg/day wereequivalent in safety to 600 mg carbamazepine and 1250mg valproate.147 Use of fixed doses, however, is flawed withrespect to optimisation dose studies. Oxcarbazepine andphenytoin had a comparable efficacy, but discontinuationrate was higher for phenytoin.148

    Studies that have been done on newly diagnosed focalepilepsy might have masked specific drug effects onaetiologically homogeneous syndromes. Despite this lim-itation, it is now recommended that children with newlydiagnosed focal epilepsy are initiated on either carba-mazepine or valproate, and that topiramate is consideredas an alternative monotherapy.145 Lamotrigine andgabapentin are potentially interesting initial monothera-pies, although the only available two class I studies145 didnot include children. Evidence about the effectiveness of monotherapy with tiagabine, levetiracetam, and zon-isamide is insufficient.145

    Controlled trials in pharmacoresistant focal epilepsieshave shown the efficacy of add-on topiramate,149 lam-

    otrigine,150 oxcarbazepine,151 gabapentin,152 and clobazam.153,154However, development of tolerance hampers the longterm use of clobazam. Evidence about add-on efficacy of levetiracetam, tiagabine, and zonisamide is insufficient.155

    When assessing the patient’s response to the differentdrugs, it is wise to explore whether a surgical option ispossible. However, since trying the many drugs nowavailable would require a long time, surgery should beconsidered soon after resistance to two appropriate drugshas been shown.16,133

    Idiopathic generalised epilepsiesIdiopathic generalised epilepsies are frequent and onset isin infancy to adolescence. Idiopathic generalised epilep-sies are genetically determined (see section on genetic and

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    molecular basis). Neuroimaging is normal and sugges-

    tions that morphological cortical abnormalities mightunderlie idiopathic generalised epilepsies156 have not beenconfirmed.157 As a result of the overlapping featuresbetween different idiopathic generalised epilepsies, theterm idiopathic generalised epilepsies with variablephenotypes has been suggested as all-inclusive.3 Socialadjustment is usually good but some patients havebehavioural or learning difficulties.

    Seizures are primarily generalised absence, myoclonic,and tonic-clonic. Interictal EEG abnormalities are 3 Hzgeneralised spike/polyspike and wave discharges.

    Most patients respond to antiepileptic drugs butresponse is drug-specific. Valproate is effective in about80% of patients,145 whereas other drugs, such as ethosux-

    imide, lamotrigine, and topiramate have a more selectiveaction. There is no evidence that any other drug iseffective,145,155 and some drugs might precipitate seizureworsening.158

    Childhood absence epilepsy and juvenile absence epilepsyChildhood 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) areobserved, lasting about 10 s, accompanied by rhythmic3 Hz generalised spike and wave complexes. Absencesdisappear before adulthood in up to 90% of cases in which

    no other seizure types are associated.


    If absences persist,generalised tonic-clonic seizures usually appear. Early andlate onset (4 and 9 years), initial drug resistance, andphotosensitivity have a less favourable prognosis.

    Juvenile absence epilepsy starts at around 10–12 yearsand partly overlaps with juvenile myoclonic epilepsy.Absence seizures cluster upon awakening.160 Generalisedtonic-clonic seizures, often precipitated by sleep depriva-tion, 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 recentCochrane review,166 evidence arising from such trials wasnot considered sufficient to inform clinical practice.Valproate is regarded as the drug of choice because of itseffectiveness on possibly associated seizures and lowercost.102 Ethosuximide and lamotrigine are an alternative inchildren with only absence seizures.162 Some childrenmight need a combination of drugs.

    Myoclonic astatic epilepsyMyoclonic astatic epilepsy epitomises a spectrum of idiopathic generalised epilepsies with prominent myo-clonic seizures, appearing in previously healthy children.167

    Myoclonic astatic epilepsy represents about 2% of allchildhood 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 withepisodes of non-convulsive status epilepticus and gener-alised tonic-clonic seizures.169 Interictal EEG, oftennormal at onset, can become very disorganised.167 Out-come is unpredictable. Remission within a few months oryears with normal cognition is possible even after a severecourse.168,170 About 30% of children experience an epilepticencephalopathy with longlasting intractability and cog-nitive impairment.

    A few children with myoclonic astatic epilepsy inheritedSCN1A and GABRG2 gene mutations from parents withgeneralised 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.170Lamotrigine,172 topiramate,173 and benzodiazepines mightbe useful.

    Epilepsy with seizures precipitated by lightstimulationIn visual sensitive (or photosensitive) epilepsies, seizuresare precipitated by environmental photic stimuli.174 Theage of onset peaks at 11 years. The term photosensitivityonly designates the abnormal EEG response to flickeringlight,174 a finding also observed in 4% of healthy childrenor adolescents.175 Photic-induced absences, myoclonicseizures, and generalised tonic-clonic seizures are

    observed in idiopathic generalised epilepsies and inDravet’s syndrome.176 Single or repeated seizures whenplaying video games or in front of the television (especiallywith a 50 Hz screen) might appear without a history of spontaneous seizures. The seizures manifest as eithergeneral tonic-clonic seizures or prolonged attacks withvisual symptoms and vomiting.112 An outbreak wasreported in Japan, where several hundreds of children andadolescents experienced a seizure when watching apopular cartoon.177 Self-induction is sometimes observed,especially in children with absences or myoclonic jerkswho indulge in compulsively staring or blinking in frontof 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 normalmechanisms of cortical gain control.179

    If attacks are infrequent, preventive measures might besufficient. The triggering power of 50 Hz televisionscreens is lowered by strengthing the ambient light and bywatching at a distance2·5 m. 100 Hz television screensare much less provocative.180 Video games should beavoided. If treatment is necessary, valproate is the drug of choice.181 Polarised glasses or optical filters for screenshave proved helpful in severe cases.182,183

    The epileptic encephalopathiesEpileptic encephalopathies are conditions in whichseizures, the epileptiform abnormalities, or both, con-

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    tribute 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 encephalo-pathies represents more a concept and an operationalcategory than a syndrome spectrum. Some syndromessuch as infantile spasms, severe myoclonic epilepsy,epilepsy with continuous spike and waves during sleep, orLennox-Gastaut syndrome are always manifested asepileptic encephalopathies, irrespective of the underlyingcause and severity of EEG abnormalities. Somesyndromes with usually good outcome, such as benignrolandic epilepsy, might have a complicated evolution,including learning and language impairment, whensevere spike-and-wave discharges appear.130,185 Persistentspike- and wave-related anatomy-specific cortical

    dysfunction has been blamed for such an ominousevolution.186,187 Myoclonic-astatic epilepsy might unpre-dictably evolve as epileptic encephalopathy or rapidlyremit without consequences on cognitive outcome,irrespective from its initial clinical and EEG charac-teristics.167 In such cases it is entirely unclear whichfactors, clinical or EEG, can be blamed for either outcome.Finally, a particular situation is represented by epilepticencephalopathies that appear in children with a highlyepileptogenic, usually developmental, brain lesion fromwhich epileptic activity spreads to intact, remote areas,interferes with their function, and amplifies the clinicalconsequences of the malformation.

    Although vigorous early treatment is often advocated inepileptic encephalopathies, for most conditions there areno established endpoints and drug choices are empiricallyestablished. Surgical treatment can be successful inselected cases. However, only in some syndromes earlytreatment has a definite effect on long-term prognosis.188

    In many individuals the underlying cause, which oftenremains unrecognised, probably plays a greater part thanis acknowledged in determining cognitive outcome.

    Infantile spasms and West syndromeInfantile spasms are typical of the first year of life, areusually resistant to conventional antiepileptic drugs andare associated with developmental delay, or deterioration,

    and a hypsarrhythmic EEG pattern, which expresses achaotic disorganisation of electrogenesis. In West syn-drome, all these elements occur together. However, infan-tile spasms might occur without the typical EEG or develop-mental features. A cumulative incidence of 2·9 per 10 000live births and an age-specific prevalence of 2·0 per 10 000in 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 oradduction of the upper limbs. Clusters include a few unitsto several dozens of spasms and are repeated many timesper 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 inabout 70% of children.102 Disappearance of social smile,loss of visual attention,191 or autistic withdrawal are oftenobserved with the onset of spasms.

    The hypsarrhythmic EEG is often absent in severe brainlesions, such as tuberous sclerosis or lissencephaly.192

    Misdiagnosis of colic, startles, Moro response, or shouldershrugs is still frequent. Duration of spasms is variable,depending both on treatment and on their tendency toremit or evolve into other seizure types. Rapidspontaneous 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 appearin seemingly healthy children; symptomatic spasmsappear in children with developmental delay or a brainlesion, especially anoxic ischaemic encephalopathy andbrain malformations.59,194 Familial occurrence is rare.194,195

    Prognosis depends more on the cause than on treat-ment. Unfavourable prognostic factors include sympto-maticity, early onset (younger than 3 months), pre-existingseizures other than spasms, asymmetric EEG,196 andrelapse after initial response to treatment. Good prog-nostic indicators include cryptogenicity, normal brainMRI,196 typical hypsarrhythmia, rapid response totreatment, and no regression after onset of spasms or its

    short duration.


    About 80% of patients have residualcognitive or behavioural impairment, but only one-third of cryptogenic cases do.197 About 50% of children will haveother epilepsy types. Mortality rates of 5–31% have beenreported, with higher rates arising from cumulative dataand long-term follow-up.198

    Infantile spasms must be differentiated from rarer,earlier onset conditions with ominous prognosis, such asthe early infantile epileptic encephalopathy and the earlymyoclonic encephalopathy.100

    Vigabatrin and adrenocorticotropic hormone haveproven effective in a few controlled trials, but uncertaintiesremain regarding the best treatment.199 In two compar-ative studies, vigabatrin was slightly less effective than, or

    as effective as, adrenocorticotropic hormone but bettertolerated.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 beenshown in children with tuberous sclerosis.204 Response to100 mg/kg per day occurs within a few days. Manyresearchers regard vigabatrin as the first-line drug, despitethe risk of visual field constriction.205 This side-effectappears in 30–50% of patients having received asubstantial drug load, but is not ascertainable in smallchildren. Responders should receive vigabatrin for nomore than 6 months;206 non-responders should be switchedto adrenocorticotropic hormone within 3 weeks. Adreno-corticotropic hormone proved superior to prednisone in acontrolled trial.207 It is used in daily doses from 20 to

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    40 IU.102 Non-depot adrenocorticotropic hormone has a

    lower risk of causing persistent hypertension. Anindividualised regimen starting with 3 IU/kg per dayprogressively increased, by doubling the doses (12 IU/kgper day, daily) every 2 weeks until a response is obtained,permits to keep dose-related side-effects such as hyper-tension, brain shrinking, adrenal hypo-responsiveness,and cardiac hypertrophy to a minimum.208 Infections are aserious complication of adrenocorticotropic hormonetreatment and are responsible for most deaths.209 A4–6 week duration of adrenocorticotropic hormone courseis advisable. Control of spasms is usually obtained withindays but behavioural improvement needs several weeks.Relapse rate is 30%.102 A second cycle of adrenocortico-tropic hormone is recommended after an initial good

    response. Valproate, topiramate, and benzodiazepines,especially nitrazepam, might represent alternatives tovigabatrin or adrenocorticotropic hormone.102 Video-EEGmonitoring is necessary to show that the spasms havetruly disappeared.210

    Surgical treatment should be considered early whendrug resistance is faced and focal epileptogenesis isshown.49 About 60% of operated children become seizure-free; the best results are obtained when operating on smalllesions.49 However, most children have large multilobarcortical dysplasias needing extensive resections, withlimited cognitive improvement.188

    There is some evidence for use of the ketogenic diet in

    resistant spasms.


    Lennox-Gastaut syndromeLennox-Gastaut syndrome is characterised by brief tonicand atonic seizures, atypical absences, and a generalisedinterictal EEG pattern of spike and slow wave discharges.It accounts for 2·9% of all childhood epilepsy.101 Incidencepeaks between 3 and 5 years of age. Cognitive andpsychiatric impairment are frequent. About 30% of casesoccur in previously healthy children; most result fromneuronal 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 absencesmight translate in non-convulsive status, which canworsen cognitive deterioration.213

    About 80% of patients continue to have seizures later inlife, with symptomatic origin and early onset having thepoorest outcome. Long-term follow-up reports mortalityrates of up to 17%.102

    The optimum treatment for Lennox-Gastaut syndromeremains uncertain and no study has shown any one drugto be highly effective.214 Broad spectrum drugs should bepreferred,155 and many researchers combine valproate andbenzodiazepines.102 However, since double-blind trialsindicate 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 itsuse is restricted by toxicity.

    It has been suggested that vagus nerve stimulation andthe ketogenic diet can be useful in some cases.219 Anteriorcallosotomy might reduce seizures with drop attacks.220

    Dravet’s syndromeDravet’s syndrome (or severe myoclonic epilepsy of infancy) represents about 1% of childhood epilepsies.221 Itbegins with repeated and prolonged unilateral orgeneralised clonic seizures related to fever in seeminglynormal children.221 Subsequently, attacks also appearwithout 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 thesecond and third year to rapidly come to a standstill.222

    Most children do not achieve language skills, and showattention deficit and hyperactivity. Neuroimaging isnormal. EEG, normal at onset, shows generalised andmultifocal abnormalities. Mortality rates are at around16%,221 mainly as a result from sudden death or accidents.Seizures persist into adulthood, with reduced severity.About 60% of patients harbour mutations of the SCN1Agene, which are de novo in most (see section on geneticand molecular basis). 223

    Phenobarbitone, valproate, benzodiazepines, and topira-mate might have some efficacy.173,221 Stiripentol, aninhibitor of p450 cytochromes, was effective in combina-tion with clobazam in a class I trial.224 Stiripentol acts byincreasing the concentration of norclobazam, an activemetabolite of clobazam. Phenytoin, carbamazepine, andlamotrigine can worsen seizures.221,225

    Landau-Kleffner syndrome (acquired epileptic aphasia)and epilepsy with continuous spike and waves duringslow wave sleepIn Landau-Kleffner syndrome and continuous spike andwaves during slow wave sleep syndromes, frequent orpersistent 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 languageunderstanding (auditory agnosia), followed by progressiveor fluctuating loss of verbal expression.226 Age at onset isbetween 3 and 7 years. Focal seizures represent the initialsymptom in 60% of children, but are absent altogether in25%. They have variable severity but remit before adult-hood. EEG abnormalities predominate in the temporo-parietal regions, bilaterally, or on either side.227 Interferenceby EEG discharges with auditory-evoked responses228

    suggests epileptic-induced dysfunction of auditory pro-cessing. The prognosis of aphasia is unpredictable. How-ever, onset before age 5 years and persistent EEG anomaliesover the language areas forecast a severe course.226 Patients

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    might be left with normal language or mild-to-severe

    persistent defects. No cause has been identified, althoughrare lesional cases have been reported.102

    Treatment efficacy is empirically investigated. Largedoses of adrenocorticotropic hormone or steroids forprolonged periods (3 months) have a definite effect onEEG and language.229,230 Repeated injections several daysapart might prevent major side-effects. Benzodiazepines,valproate, ethosuximide, and immunoglobulins haveobtained some success.230,231 Surgical treatment withmultiple subpial transections has produced longlastingimprovement in selected cases,232 but the merit of thisapproach is difficult to assess and further studies areneeded. Language therapy is indicated.

    In epilepsy with continuous spike and waves during

    slow wave sleep (or electrical status epilepticus duringslow sleep), continuous sleep-related EEG discharges,persisting for months to years, are associated with cogni-tive decline. The syndrome appears in previously healthyor in developmentally-delayed children.233 Brain lesions,especially polymicrogyria234 and porencephaly,233 are foundin 30–50% of patients. Onset is insidious. Seizures start at3–5 years as nocturnal and focal attacks similar to rolandicepilepsy. After a few months, continuous spike and wavesduring slow wave sleep and atypical or atonic absencesappear. There is marked decrease in intelligence quotientscores with attention deficit and hyperactivity, sometimeswith language disturbances and autistic features.226

    Long-term course of epilepsy is favourable, but cognitiveimpairment, persists in most children. A long duration of continuous spike and waves during slow wave sleep is themajor factor of a poor prognosis.235 The benign atypicalpartial epilepsy syndrome236 bears a close relation tocontinuous spike and waves during slow wave sleep. Drugtreatment is the same as in Landau-Kleffner syndrome.

    Febrile seizuresFebrile seizures occur during an acute febrile illness forwhich no cause can be found. This type of seizure affects2–4% of children aged 3 months to 5 years. 237

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

    most children have respiratory tract infections.237 There is asubstantial risk of occurrence in the 24 h after receiving thediphtheria-pertussis-tetanus vaccine and in the 8–14 daysafter the measles, mumps, and rubella vaccine.238

    Febrile seizures are classed as simple when they aregeneralised, do not recur within the same illness, and lastless than 15 min. Febrile seizures are termed complexwhen they have focal features, are repeated within thesame illness, and are prolonged (15 min). Neurologicalabnormalities 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. Neuro-imaging should be reserved to children with prolongedpostictal unresponsiveness or focal deficits.237

    Most febrile seizures are short but those lasting longer

    than several minutes should be treated with rectaldiazepam. Recurrence risk is 30–40%.240 Prophylactictreatment is only justified in children who have had aprolonged febrile seizures. Rectal diazepam at the onset of a new febrile seizure should be preferred to continuousoral valproate or phenobarbital.237,241 Intermittent prophy-laxis at times of fever is discouraged. About 3–6% of children with febrile seizures will have epilepsy later inlife,242 especially idiopathic generalised epilepsies.

    Progressive myoclonus epilepsiesProgressive myoclonus epilepsies are a group of syn-dromes including Lafora disease, Unverricht-Lundborgdisease, myoclonus epilepsy with red ragged fibres, early

    infantile, late infantile, juvenile, and adult ceroid-lipofuscinosis, and sialidosis.243 The clinical pictureincludes multifocal and generalised myoclonus, gener-alised tonic-clonic seizures, or clonic-tonic-clonic seizures,photosensitivity, cognitive deterioration, cerebellar, andextrapyramidal signs. The different syndromes are iden-tified by age at onset and rate of progression. Specificgenetic abnormalities are now identified for mostdisorders.243

    Status epilepticus and seizure-induced braindamageStatus epilepticus is a neurological emergency defined as

    recurrent seizures, lasting for more than 30 min, withoutinterictal resumption of baseline CNS function.1 About70% of episodes of status epilepticus are the initial seizureand up to 27% of children with epilepsy will present withone or more episodes,244 although specific syndromes havea different risk.

    A pragmatic classification of status epilepticus is madeaccording to the presence or absence of motor manifes-tations, as a result of their impact on management andmorbidity rates (panel 2).245 Convulsive generalised orunilateral status, even if manifested as localised twitchingor simple eyeball jerking, has considerably more seriousconsequences than focal status.

    The origins of the disorder, which are the main

    prognostic indicator of status epilepticus,244 are unevenlydistributed through age. Febrile status (20–30% of cases)occurs in infants or small children with no history of seizures or acute CNS infection. Idiopathic statusepilepticus (16–40%) occurs in the absence of any insult orin idiopathic epilepsies. Remote symptomatic statusepilepticus (14–23%) occurs especially in children withcortical dysplasia or epileptic encephalopathy. Acutesymptomatic convulsive status epilepticus (23–50%)complicates an acute illness affecting the CNS, andrepresents 75% of status epilepticus in children youngerthan 1 year and 28% in those older than 3 years. Acutesymptomatic status epilepticus has the highest mortalityrates with values reaching up to 20%.245,246 CNS infectionsare an overlooked cause of status epilepticus in infants in

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    developed countries,


    and the main cause in geographicalareas with limited resources.248 Trauma, hypoxic ischaemicdamage, and metabolic/electrolytic disturbances are lessfrequent causes. Withdrawal of antiepileptic drugs is aknown precipitant of status epilepticus. However, anti-epileptic drugs can also precipitate status epilepticus if inappropriately chosen or because of paradoxical reac-tion.158,249

    Epilepsia partialis continua is characterised by focalmotor seizures and semicontinuous distal jerks that resistantiepileptic drugs. This form of epilepsy is caused by alesion, most often cortical dysplasia. Rasmussen’ssyndrome, a chronic hemispheric encephalitis, causesprogressive epilepsia partialis continua and hemiparesis,

    with dystonia, cognitive deterioration, and atrophy of onehemisphere.250,251

    A chain of metabolic and excitotoxic events accompa-nying convulsive status epilepticus has been causallyrelated to neuronal damage, especially in the CA1 andCA3 zones of the hippocampus, amygdala, cerebellarcortex, thalamus, and cerebral neocortex.252 MRI during orshortly after status epilepticus can show swelling andabnormal T2 or fluid-attenuated inversion recovery signal,possibly indicating cytotoxic and vasogenic oedema, andalteration of the blood-brain barrier.253 Convulsive statusepilepticus has been consistently associated with neuronalnecrosis in vulnerable regions of the brain, especially inthe 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 seizuresand seizure clusters.254 In a randomised trial, midazolamwas as effective and safe as rectal diazepam in thetreatment of prolonged seizures in children.255 Pre-hospitaltreatment with rectal diazepam, buccal-nasal midazolam,or sublingual lorazepam has been advised.245,256 However,acute parenteral treatment should be carefully supervisedas it causes drowsiness or sleep and, occasionally,cardiorespiratory collapse.257 Convulsive status epilepticusthat is resistant to initial benzodiazepine administrationshould always be approached according to a managementprotocol.257 Indeed, although there is little evidence toshow that of the numerous protocols that have been

    recommended one is better than the other, the simple factof adopting a protocol has itself been shown to reducemortality and morbidity.257 A suggested protocol for themanagements of status epilepticus in children ispresented in figure 1.245 However, there is little evidence toshow that of the various protocols that have beenrecommended one is better than another.

    In the premonitory period of status epilepticus there isa gradual increase in the frequency of seizures. Early pre-hospital treatment with parenteral benzodiazepines atthis 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 thanother benzodiazepines, safer to administer intravenously,and has a lower risk of cardiorespiratory depression.Most protocols recommend that even when seizurescease following benzodiazepine administration, amaintenance antiepileptic drugs, such as fosphenytoinintravenous, should be administered as seizure activityoften starts again when the benzodiazepine iseliminated. Established status epilepticus is usuallyentered once seizures have lasted 30 min. For practicalpurposes, it is suggested to consider established statusepilepticus if early treatment has failed or when noaccurate estimate of the duration of status epilepticus canbe 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, thedosage, concentration, and infusion rates of intravenousfosphenytoin are expressed as phenytoin equivalents(PE). If seizures persist 30–50 min, general anesthesiain the intensive care unit is required. However, after afirst intravenous administration of 20 mg PE/kg,additional 10 mg PE/kg can be administered beforestarting phenobarbital, as many patients who fail torespond to the first administration of phosphenytoin doso because of inadequate levels of phenytoin after theinitial load. The risk of mortality and morbidity at thisstage is high. EEG monitoring is essential. In thisscheme, midazolam is preferred for the treatment of refractory status epilepticus as mortality appears to be

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    Panel 2: Classification of status epilepticus

    Convulsive status epilepticus






    Focal (partial)

    Focal motor

    Focal motor with secondary generalisation

    Epilepsia partialis continua


    Non-convulsive status epilepticus



    Focal status epilepticus

    With sensory symptomatology

    With affective symptomatology

    Complex partial status epilepticus*

    Continuous spike and wave during slow sleep

    *No wholly satisfactory term for complex partial status epilepticus is proposed in

    the new International League Against Epilepsy classification.

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    lower in children with convulsive status epilepticus whoare treated with this drug.246

    If status epilepticus is unexplained by clinical history, orfocal neurological signs occur, a CT scan should bedone.245 If fever occurs, acute bacterial meningitis shouldbe suspected even in the absence of classical signs.247 Earlyparenteral antibiotics at antimeningitic doses and, if notcontraindicated, lumbar puncture, are recommended.245,247

    Intravenous pyridoxine 100 mg should be administered

    to all infants with idiopathic drug-resistant statusepilepticus.258 Refractory status epilepticus as a result fromunilateral cortical malformations, can be surgicallytreated.259

    Generalised non-convulsive status epilepticus,manifested as complete unconsciousness or reducedinteraction, drooling, and impaired gait balance (atypicalabsence status) is frequent in epileptic encephalopathies.Non-convulsive status epilepticus is an under-recognised

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    Initial stabilisation1 Confirm diagnosis

    2 Check airway, administer oxygen, give suction

    3 Monitor vital signs, ECG, oxygen saturation, blood pressure

    Time (min)

    No response

    No response

    No response

    No response

    1 Take blood for:

     • Glucose

      • UE, Ca2 Mg2

      • Sample to store for

      toxicology, metabolic test

    2 Start intravenous maintenance fluids

      0·45% NaCl/5% dextrose






    Consider IO needle until intravenous route established

    Intramuscular midazolam 0·1–0·2 mg/kg (or)

    Per rectum diazepam 0·5 mg/kg




    Intravenous lorazepam 0·05–0·1 mg/kg

    Repeat lorazepam

    Intravenous fosphenytoin 20 mg PE/kg infusion slowly

    No faster than 1 mg PE/kg per min

    Additional fosphenytoin 10 mg PE/kg

    Rapid sequence intubation and ventilation

    Transfer to paediatric intensive care unit

    Give intravenous phenobarbital 20 mg/kg

    infusion no faster than 100 mg/min

    Monitor blood pressure for depression

    Start EEG monitoring

    Give bolus midazolam 0·15–0·2 mg/kg,

    followed by infusion of 1–2 g/kg per min,

    increasing every 15 min by 1–2 mg/kg permin until response obtained

    Refractory SE

    Established SE

    Early SE

    Premonitory SE

    Intravenous access

    Figure 1: Algorithm for the treatment of status epilepticus in children

    PE=phenytoin equivalents, SE=status epilepticus.

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    cause of coma. It was observed in 8% of comatose patientsof all ages, with no clinical signs of seizure activity.260 Subtleforms often escape recognition, especially in children withdevelopmental delay. EEG shows continuous, diffusespike-and-wave discharges. Focal non-convulsive statusepilepticus is rare in children. It might manifest asalteration of consciousness with psychotic state or beindistinguishable from generalised non-convulsive statusepilepticus. EEG recording is essential for diagnosis.

    Peculiar forms of non-convulsive status epilepticus occurin children with Angelman syndrome42 or ringchromosome 20.261 Non-convulsive status epilepticus isnot immediately life-threatening; it should nonetheless betreated promptly, with the help of EEG monitoring, and apotential life-threatening cause should be ruled out.Intravenous or rectal benzodiazepines are often effective,but non-convulsive status epilepticus in patients withLennox-Gastaut syndrome is very drug-resistant.245 Focalnon-convulsive status is usually treated with intravenousbenzodiazepines or phenytoin.245

    Overall mortality is 6%, but it is around 16% inconvulsive status epilepticus alone.246 Acute symptomaticstatus epilepticus, and status epilepticus in progressive

    encephalopathies account for most of the deaths.Similarly, the risk of subsequent epilepsy is estimated at41% after acute symptomatic status epilepticus, but doesnot differ from that following an initial short unprovokedseizure in idiopathic cases.245 Status epilepticus has a highrisk of recurrance, especially if it was the initial seizureand in symptomatic patients. Maintainance of abortivetreatment at home is advised in such cases.

    Management and principles of treatmentMolecular targets and clinical efficacy of antiepilepticdrugsA spectrum of clinical efficacy is established for mostavailable compounds, although their mechanisms of actionare 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 inhibitoryneurotransmitter is -aminobutyric acid, which acts ontwo receptor types. Activation of the GABA-A receptoractivates a Cl-permeable ion channel, producing mem-brane hyperpolarisation and a rapid inhibitory response.GABA-A is also sensitive to benzodiazepines and barbi-turates, which respectively modulate frequency and

    duration of the ion channel opening.


    GABA-B receptoractivation stimulates a metabotropic receptor that ispermeable to K ions and produces a slower response.Animal models have confirmed the anticonvulsant affectof GABAergic potentiation and epileptogenicity of gluta-maergic potentiation,263 and have prompted the develop-ment of GABAergic drugs. However, neuroanatomicorganisation of epileptogenic neural networks, whichmight explain the opposite action of the same agents ondifferent epilepsy types,158 remains poorly understood.

    Syndrome-oriented drug choiceKnowledge of the main mechanisms of action, spectrumof efficacy of antiepileptic drugs, and correct syndrome

    diagnosis should guide treatment. Efficacy and safety of the different drugs can be inferred from clinical trialsproviding diverse levels of evidence (panel 3 andtable 4).264–283 However, information about the range of efficacy emerging from such trials is difficult to interpret.Different epilepsy syndromes and causes are oftenlumped together and trials design is not sensitive fordetecting possible seizure worsening. Finding that two ormore drugs are equivalent, when compared to oneanother, does not rule out the possibility that all drugs areineffective, and that spontaneous remissions or improve-ments substantially change the results. Information onsafety of antiepileptic drugs in children is poor as approvalfor paediatric use is only granted with considerable delay,after promising results have been obtained in adults.

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    channel channel receptor transaminase transporter receptor receptor efficacy

    Benzodiazepines .. .. Yes .. .. .. .. Broad spectrum

    Carbamazepine Yes .. .. .. .. .. .. Focal, GTC

    Ethosuximide Yes Yes .. .. .. .. .. Abse