when and how should we treat epilepsy in children?

SYMPOSIUM: NEUROLOGY

When and how should wetreat epilepsy in children?Stephen Nirmal

Rachel Hutchinson

AbstractThis article draws on recent guidelines and evidence to briefly look at the

diagnosis (and misdiagnosis) of epilepsy in children and aims to address

the issue of when to treat, when not to treat and how to treat epilepsy by

seizure and syndrome type with the use of illustrative cases.

Key to the management of epilepsy is individualizing treatment, taking

into consideration not only seizure type or epilepsy syndrome but also co-

medication, co-morbidity, lifestyle factors, and the preferences of the

child and family.

Anti-epileptic drugs frequently have adverse effects and it is imperative

to consider the risk versus benefit balance for each child.

Keywords anti-convulsants; epilepsy; seizures; treatment

Introduction

Epilepsy is defined by the International League Against Epilepsy

(ILAE) as “a chronic neurological disorder characterized by

recurrent epileptic seizures”. The World Health Organisation

(WHO) states that epilepsy “may vary from a brief lapse of

attention or muscle jerks, to severe and prolonged convulsions.

The seizures are caused by sudden, usually brief, excessive

electrical discharges in a group of neurones in the brain.”

Epilepsy refers to a large and diverse group of disorders,

which share the tendency to have recurrent epileptic seizures.

Approximately one in 200 children in the UK have a form of

epilepsy and between 40 and 80 children die as a result of their

epilepsy every year.

In this article we will discuss the salient points of when and

how to initially treat epilepsy in children. It is beyond the scope

of this review to discuss refractory epilepsies. If seizures

continue despite trials with two anti-epileptic drugs (AED) then

referral to a Paediatric Neurologist should be considered. Non-

drug treatment such as ketogenic diet, vagal nerve stimulation

and neuro-surgery will not be discussed.

Diagnosis

Epilepsy is a clinical diagnosis aided by investigations such as

EEG and MR imaging. It is important to establish the seizure

type or types, where possible the epilepsy syndrome, and also to

Stephen Nirmal MBBS DCH MD(Paeds) FRCPCH is Consultant Paediatrician at

the James Paget University Hospital, Great Yarmouth, UK.

Rachel Hutchinson MBBS BSc is Foundation Yr 2 at the James Paget

University Hospital, Great Yarmouth, UK.

PAEDIATRICS AND CHILD HEALTH 23:6 257

look for an underlying cause. Although accurately diagnosing

the seizure type can help with the correct choice of medication,

syndromic and aetiologic diagnosis is useful for prognostication

and determining duration of treatment. Classification of

epilepsy continues to evolve with advances in imaging and

genetics.

Unfortunately, misdiagnosis is common. One study showed

that in 30% of children referred to a tertiary centre in Denmark

with a diagnosis of epilepsy, the diagnosis was subsequently

disproved. Staring episodes were the most commonly mis-

diagnosed clinical feature. Accurate diagnosis of epilepsy is, after

all, the foundation on which all treatment is based. Inadequate or

wrong diagnosis is likely to lead to inapt and sometimes harmful

treatment.

The reasons for misdiagnosis are many and varied; some

reasons are given below.

� The epilepsies are exclusive among the more common

medical disorders in that their diagnosis is usually made

entirely on the basis of the history, which needs to be

diligently considered.

� The EEG, which some clinicians unfortunately think is the

confirmatory test for epilepsy, lacks both sensitivity and

specificity required to make it useful in the initial

diagnosis.

� Lack of knowledge of the myriad presentations of epileptic

and non-epileptic conditions, especially the non-epileptic

conditions which can mimic epilepsy, among clinicians

involved with the initial diagnosis.

� Failure to recognize diagnostic uncertainty between the

epilepsies and non-epileptic events and a tendency to err

towards epilepsy, due to fear of repercussions of delayed

diagnosis and treatment.

Case vignettes

� How would you manage a 7-month-old boy who over the

past few weeks has not been interested in his surroundings

and has developed clusters of head nods, especially on

awakening? Would his management be different if his

development is normal?

� Should an 18-month-old boy who has had a single gener-

alized convulsive seizure lasting 2 minutes associated with

a temperature of 39.0 �C be started on a regular anti-

convulsant drug? What if he had three further similar

seizures associated with fever over the next 6 months?

What if the seizure had lasted 10 minutes?

� Should AED treatment be recommended for a 6-year-old

girl with typical absence seizures which started 4 months

earlier? She has on average around 10 absences noticed in

a day and continues to do well in school. She has no other

seizure types.

� Should a 7-year-old girl with severe learning difficulties

who has started having 1 or 2 atypical absence seizures

a day be started on AED? What if she were having atonic

seizures as well? Would your advice differ if she was

functioning at Gross Motor Function Classification System

level 1 or 5?

� Should a 9-year-old boy who has had four brief nocturnal

focal sensory motor seizures affecting the oro-pharyngo-

� 2012 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.paed.2012.11.012


laryngeal area in the past 4 months be treated with AED?

What if a couple of the focal seizures had generalized, each

lasting 2 or 3 minutes.

� Should a 15-year-old girl with occasional early morning

jerks for a few months presenting with one generalized

tonic-clonic seizure be started on AED? Would your advice

be different if she had not had the generalized tonic-clonic

seizures (GTCS)?

� Should a 16-year-old boy who has had two unprovoked

generalized tonic-clonic seizures, each lasting 2e3

minutes, 18 months apart, be started on AED?

When to treat?

Treatment should be considered only after the diagnosis of

epilepsy is secure. The child and/or carer should be involved in

decision making. It is abundantly clear that the clinician and

a well-informed patient/carer reach the best treatment choice

jointly. Treatment decisions reached otherwise are also likely to

lead to poor compliance.

Recent NICE guidance states that “the AED treatment strategy

should be individualised according to the seizure type, epilepsy

syndrome, co-medication and co-morbidity, the child, young

person or adult’s lifestyle, and the preferences of the person and

their family and/or carers as appropriate.”

Three considerations might lead to the decision to start early

and aggressive treatment: the dangers of the seizures, the chance

of intractability and the possibility of intellectual decline caused

by recurrent seizures or epileptic activity.

Whilst AEDs cannot “cure” epilepsy they are important in

reducing seizure frequency for two reasons:

� To reduce the risk of seizure associated accidents, anoxia

and sudden death.

� It is hypothesized that they may prevent damage to the

functioning of the brain in terms of memory, cognition and

behaviour of children.

The advantages of using AED should be carefully weighed

against the adverse effects of AED.

Key principles of treatment

C It is widely accepted that treatment should be initiated

following two or more unprovoked convulsive seizures

C The diagnosis of epilepsy needs to be re-evaluated if events

continue despite an optimal dose of first line AED

C Treat epilepsy with monotherapy wherever possible

C Start with low dose AED and increase slowly, carefully moni-

toring for side effects

C Where an epilepsy syndrome has been identified, treatment

should be of the syndrome rather than individual seizure

types.

When not to treat?

Where diagnosis is uncertain (i.e. unclassified paroxysmal

events) a period of ‘watchful waiting’, regular reassessment and

close follow up should be offered rather than initiating AED


treatment. Starting AED treatment and using the response as

a diagnostic test is not advocated.

There is no role for long-term AED treatment where a revers-

ible cause for a seizure can be found. This would include febrile

seizures or seizures secondary to electrolyte imbalances.

It is generally accepted that AED treatment should not be

commenced after a first unprovoked seizure. Recurrence after

a single unprovoked seizure in childhood is about 50%. Those

with recurrence have a similar outcome of their epilepsy

compared to children presenting with multiple seizures, regard-

less whether they were treated after the first seizure or not. This

argues in favour of postponing AED treatment until at least

a second seizure has occurred.

The decision to start treatment after the first seizure is

controversial, but initiation of AED treatment could be consid-

ered after a first unprovoked seizure if:

� The child has a neurological deficit or

� There is clear epileptiform abnormalities on EEG or

� Brain imaging shows a structural abnormality

Benign focal epilepsies such as Panayiotopoulos syndrome

and benign childhood epilepsy with centro-temporal spikes need

not be treated with regular AED.

A recent study from Holland shows long-term AED treatment

may not be necessary in children who present with a cluster of

epileptic seizures within a short period of time or children who

present with a solitary unprovoked status epileptic seizure.

Treatment by seizure type

Focal

Focal seizures are the most common seizure type in children.

They are defined by ILAE as seizures that originate within

networks limited to one hemisphere.

Evidence for treatment of focal seizures in children is limited.

Frew et al. showed that there is no significant difference between

lamotrigine monotherapy and carbamazepine monotherapy for

the proportion of seizure-free children. Carbamazepine and

lamotrigine have similar adverse events profiles. Carbamazepine

was shown to be the most cost effective monotherapy.

NICE recommends that carbamazepine or lamotrigine be used

as first line monotherapy in children with newly diagnosed focal

seizures. Levetiracetam, oxcarbazepine or sodium valporate

should be used as second line therapy if carbamazepine or

lamotrigine are not tolerated. Adjunctive therapy should only be

considered if none of these five AED therapies are effective or

tolerated.

Generalized tonic-clonic seizures

In GTCS there is sudden onset stiffening followed by rhythmic

jerking of the limbs and often associated with autonomic

phenomena. The ILAE define a generalized seizure as one where

“initial semiology indicates, or is consistent with, more than

minimal involvement of both cerebral hemispheres”.

As illustrated in the recent NICE guideline there is little or no

evidence pertaining to choice of AED therapies for GTCS in

children. In 2007, a meta-analysis of RCTs compared eight

monotherapies used to treat GTCS in adults. The meta-analysis

looked at several outcomes including; time to treatment failure,

time to 12 month remission, and time to first seizure. It was




shown that sodium valproate was significantly better than car-

bamazepine, topiramate and phenobarbital for time to treatment

failure and sodium valproate was significantly better than

lamotrigine for time to 12 months remission and time to first

seizure.

NICE recommends that sodium valproate be offered as a first

line therapy in GTCS. Lamotrigine should be considered as

second line. Carbamazepine and oxcarbazepine may be consid-

ered but may exacerbate myoclonic or absence seizures. It is

important to consider that these two seizure types may be seen in

conjunction with GTCS.

Absence seizures

Absence seizures are brief (5e20 seconds) epileptic seizures

characterized by sudden loss of awareness, cessation of volun-

tary activity with associated automatisms. Unlike most other

seizure types, absence seizures have a typical EEG appearance of

synchronous spike wave activity at around 3 Hz. Absence

seizures may be seen in several epilepsy syndromes (Figure. 1).

An RCT of just over 450 children with childhood absence

epilepsy syndrome published in 2010 showed that sodium val-

proate and ethosuximide were more effective than lamotrigine.

The side effect profiles of sodium valproate and ethosuximide

have been shown to be not significantly different. However more

patients on sodium valproate had problems with attention.

NICE recommends that first line treatment should be with

ethosuximide or sodium valproate. Sodium valproate is preferred

if there is a risk of GTCS also. NICE recommend that second line

treatment is lamotrigine. If monotherapy has not been effective

Figure 1 EEG demonstrating typical absence epilepsy e regular th


then consider using two of the three first and second line drugs

adjunctively.

Some AED therapies should not be used in children with

absence epilepsy as they may aggravate seizures. These are:

carbamazepine, gabapentin, oxcarbazepine, phenytoin and

vigabatrin.

Myoclonic seizures

Myoclonic seizures are defined by ILAE as “sudden, brief,

involuntary single or multiple contraction(s) of muscles(s) or

muscle groups of variable topography”.

NICE guidelines recommend that sodium valproate is offered

as first line monotherapy based on two low quality studies.

Evidence for treatment of juvenile myoclonic epilepsy syndrome

had been considered in making this recommendation.

Second line monotherapy should be with levetiracetam or

topiramate. Levetiracetam has been shown to be effective as an

adjunct and has a favourable side effect profile. For this reason

NICE have recommended consideration of its use as a second line

monotherapy should sodium valproate be deemed inappropriate.

Once again, there is limited evidence for the use of either of these

two drugs for treatment of myoclonic jerks.

A combination of sodium valproate with levetiracetam is

likely to be the most effective adjunctive treatment in myoclonic

seizures if monotherapy is providing ineffective control of

seizures.

Some potential options for treatment of myoclonic seizures

should the above treatments fail include clobazam and

clonazepam.

ree cycles per second spike and slow wave activity.




Myoclonic seizures may be aggravated by lamotrigine and

carbamazepine.

Case vignettes

Consideration of possible management strategies.

� This seven-month-old boy should have an urgent EEG to

look for hypsarrhythmia/modified hypsarrhythmia. If

episodes are not directly witnessed, then video recordings

of the episodes should be viewed. It is irrelevant whether

there are associated developmental concerns or not, as

initiation of treatment should not depend on this criterion.

In the absence of compatible EEG and diagnostic uncer-

tainty, obtain a sleep EEG. Infantile spasms (i.e. West

syndrome) is one of the epilepsy syndromes which should

be treated as an emergency. Detailed workup is necessary,

as in other epileptic encephalopathies, to seek an under-

lying cause. Tuberous sclerosis should be actively sought.

Treatment options are vigabatrin in tuberous sclerosis and

prednisolone in idiopathic and symptomatic, non-tuberous

sclerosis infantile spasms. Early detection and initiation of

treatment is likely to improve prognosis and referral to

a Paediatric Neurologist for advice on ongoing manage-

ment is necessary. There is an ongoing trial, International

Collaborative Infantile Spasms Study, which compares

hormonal treatment (either ACTH or prednisolone) and

vigabatrin given together (combined treatment) to

hormonal treatment alone.

� AED treatment for this child’s febrile seizures, whether

single or multiple, brief or prolonged, is not recom-

mended. A Cochrane Database of Systematic Review on

prophylactic management for febrile seizures in children

published in 2012 concludes that no clinically important

benefits for children with febrile seizures were found for

intermittent oral diazepam or phenobarbitone, intermit-

tent rectal diazepam, and regular phenobarbitone, val-

proate, phenytoin or pyridoxine. Adverse effects with

medication were reported in up to 30% of children. The

authors conclude by stating that ‘given the benign nature

of recurrent febrile seizures, and the high prevalence of

adverse effects of these drugs, parents and families should

be supported with adequate contact details of medical

services and information on recurrence, first aid

management and, most importantly, the benign nature of

the phenomenon’. If the seizure had lasted for

10 minutes, buccal midazolam (rescue therapy) could be

prescribed for use if the child has a further seizure lasting

longer than 5 minutes. A care plan needs to be in place

and parents/carers have to be trained in administering

this medication.

� This 6-year-old girl most likely has childhood absence

epilepsy (CAE), which is an age-dependent, idiopathic

form of generalized epilepsy. An EEG should be performed

to confirm the diagnosis. Typically in CAE, children have

20e100 absences a day but their true frequency is often

difficult to estimate due to the short duration of the

episodes. Although CAE occurs usually in neurologically

and intellectually normal children, some degree of cogni-

tive dysfunction is observed in about 30%e50% of


children. This is most often the result of ongoing ictal and

interictal discharges. In CAE the risks of accidents and

learning problems prompt early AED treatment. First line

treatment should be ethosuximide or sodium valproate

and second line medication is lamotrigine. If monotherapy

is ineffective then consider using two of the three first and

second line drugs adjunctively. Absence seizures usually

respond to appropriate treatment and remit in 90% of

children. Childhood absence epilepsy has an excellent

prognosis.

� Epilepsy occurs in about one third of children with severe

learning difficulties. In children with learning difficulties

differentiating epileptic seizures from non-epileptic

seizures can be difficult and so can classifying seizure

type and epilepsy syndromes. Though this 7-year-old girl

has severe learning difficulties, she requires the same

meticulous cogitation as a child who is otherwise normal

but has seizures. The impact of seizures, however, may

be very different. The following questions can help to

formulate a management plan. “What is the effect of these

seizures on the child’s everyday activities? Do these

seizures affect the ability of carers to provide care? Would

it make a difference to the quality of life if these seizures

are fully/partially controlled?” The answers to these

questions depend to a large extent on the type and

frequency of seizures, functional abilities of the child,

carer’s perceptions and age. GTCS or atonic seizures are

more likely to cause injury than absence or myoclonic

seizures, especially in children who are ambulant.

Another important consideration should be the possible

detrimental effect of AED treatment on behaviour and

alertness. Personally, in the given scenario, if carers

agree, we would withhold AED treatment for an occa-

sional absence, provided her EEG is otherwise normal.

Atonic seizures are quite difficult to control but AED

treatment with realistic goals is important. Is a child with

various severe handicaps that include epilepsy at greater

risk from multiple AED than from having a few more

seizures?

� This 9-year-old boy most likely has benign childhood

epilepsy with centro-temporal spikes (BCECTS), which

should be confirmed by a routine EEG, failing which,

a sleep-deprived EEG might be helpful. BCECTS is an

idiopathic epilepsy characterized by well defined electro-

clinical features. These include brief hemi-facial motor

seizures, speech arrest and excessive salivation, occurring

more often in sleep. Some of the focal seizures can evolve

into generalized tonic-clonic seizures. The EEG shows

centro-temporal (rolandic) spikes interictally. It is the most

common epilepsy syndrome in children aged between

4 and 12 years. In view of the benign nature of the

condition, regular AED treatment is unnecessary for the

vast majority of children. Seizures almost always remit in

adolescence, whether treated or not. However in certain

circumstances AED treatment may be indicated: large

numbers of seizures, secondary generalizations and when

ictal events are disruptive to patient/family. If treatment is

planned, sodium valproate or carbamazepine can be used.

One to two years after the last seizure, AED can be



Important side effects of common AEDs

AED Common side effects

Sodium valproate Weight gain, nausea, vomiting, tremors, hair

loss, polycystic ovarian syndrome, liver and

pancreatic problems, blood dyscrasias,

teratogenicity

Carbamazepine Sedation, dizziness, ataxia, skin rash

(occasionally Steven-Johnson syndrome),

hyponatremia, weight gain, seizure worsening

in some epilepsy syndromes

Lamotrigine Sedation, ataxia, dizziness, skin rash

(occasionally Steven-Johnson syndrome)

Topiramate Sedation, somnolence, cognitive problems,

weight loss, word-finding difficulty, renal

stones

Levetiracetam Somnolence, dizziness, cognitive slowing,

psychosis

Ethosuximide GI problems, drowsiness, insomnia, skin rash,

Blood dyscrasias, rarely hallucinations and

psychosis

Table 1


discontinued without waiting for normalization of EEG.

Rarely, spontaneously or following carbamazepine,

seizures can worsen e ‘atypical evolutions’.

� This 15-year-old girl most likely has juvenile myoclonic

epilepsy (JME). JME is an idiopathic generalized epilepsy

characterized by adolescent onset myoclonic jerks on

awakening, GTCS and in around a third of patients,

typical absences. Sleep deprivation, fatigue and alcohol

are the most powerful triggers for both jerks and GTCS.

Patients usually come to medical attention only after the

occurrence of GTCS and the history of myoclonic seizures

is often obtained retrospectively. The EEG is nearly

always abnormal and a normal EEG warrants a sleep-

deprived EEG. Focal EEG abnormalities are seen in up

to one third of patients and are often misinterpreted as

evidence for focal epilepsy. This syndrome persists

throughout life and the risk of further GTCS in this

teenager is high. We would encourage her to start medi-

cation, which is usually required lifelong. Choice of AED

is controversial; sodium valproate is the most effective

AED for controlling seizures, but due to concerns

regarding side effects (weight gain and teratogenicity),

lamotrigine or levetiracetam is advocated as first line for

girls of child-bearing age. To the question of whether AED

treatment is indicated if she has had only myoclonic

seizures: GTCS occur in most patients (more than 90%)

and they usually appear a few months after myoclonic

seizures. Hence she is at a high risk for subsequent GTCS

and our advice would be that she should consider starting

regular AED treatment.

� Epilepsy is defined as a tendency to have recurrent

unprovoked seizures. To establish that a patient has this

predilection, most accept that one should have had at

least two unprovoked seizures. However, several studies

demonstrate that after a second seizure only 70%e80%

progress to have a third. A recent study from Netherlands

has suggested that omitting or postponing treatment after

multiple infrequent GTCS usually does not worsen prog-

nosis. Principal thoughts in the mind of this 16-year-old

boy following two unprovoked GTCS would be the effect

another seizure would have on relationships, driving and

independence. In the given scenario, our inclination

would be to adopt a ‘wait and watch’ policy and not to

start regular AED treatment if there are no risk factors

such as neurological deficit or clear epileptiform abnor-

malities on EEG. The risk for further seizures after

a solitary unprovoked seizure have been shown to be

increased in the presence of risk factors which include

neurological deficits and clear epileptiform abnormalities

on EEG and it seems likely that this is also true after

a second seizure. However the final outcome of the

consultation should depend primarily on the wishes of

the teenager (Table 1).

Summary and conclusions

Advice on when and how to treat epilepsy must be individual-

ized. It should be based on evaluating how epileptic seizures

affect various issues, including the quality of life of the child


and family, cognitive functioning, behaviour and general

health. The decision should be based on a consideration of the

consequences, both good and bad, of the different courses of

action. The clinician’s responsibility is to ensure that children

and their families fully understand the condition and to help

them assess the risks and benefits of AED treatment versus non-

treatment, and advise on the choice of AED, if the decision is to

treat. A

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Practice points

C The diagnosis of epilepsy is primarily based on the clinical

history.

C The diagnosis may be aided or clarified by an EEG, video-EEG

and MR imaging.

C Treatment should be considered only after the diagnosis of

epilepsy is secure.

C It is widely accepted that treatment should be initiated

following two or more unprovoked convulsive seizures.

C Management should be individualized for each child.

C Treat with low dose monotherapy wherever possible and

increase doses slowly.

C Anti-epileptic drugs can have serious adverse effects, espe-

cially if multiple drugs are used.

C Referral to a tertiary centre is necessary in refractory epilepsies.


and unclassifiable epilepsy: an unblinded randomised controlled trial.

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12 Tomson T, Hiilesmaa V. Epilepsy in pregnancy. BMJ 2007; 335:

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PAEDIATRICS AND CHILD HEALTH 23:6 262 � 2012 Elsevier Ltd. All rights reserved.


when and how should we treat epilepsy in children?

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