Chapter 4
Epilepsies in Children and Adolescents andTheir Treatment
CQ 4-1

Which epilepsy syndromes with childhood or adolescent onset
have high prevalence?
Summary
According to epidemiological studies, partial epilepsy syndrome constitutes 60–70% of all childhood epilepsies,
generalized epilepsy syndrome 20–30%, and undetermined epilepsy around 1‒10%. In childhood epilepsies, many
epilepsy syndromes have good prognosis, such as childhood absence epilepsy and benign childhood epilepsy withcentrotemporal spikes. Childhood epilepsy covers the onset age range of one month after birth to around 18 yearsof age.

Comment
In a prospective community-based study, Berg et al.1) attempted to classify 613 patients with childhood epilepsy into
epilepsies, epilepsy syndromes and related seizure disorders. They found partial epilepsy in 58.6% of the cases, generalized
epilepsy in 29.0%, and undetermined epilepsy in 12.4%. Regarding the proportions of epilepsy syndromes, they reported 74
cases (12.1%) of childhood absence epilepsy, 59 cases (9.6%) of benign childhood epilepsy with centrotemporal spikes, 15cases (2.4%) of juvenile absence epilepsy, 12 cases (2.0%) of juvenile myoclonic epilepsy, 24 cases (3.9%) of West syndrome,
10 cases (1.6%) of Doose syndrome, and 4 cases (0.7%) of Lennox-Gastaut syndrome. In an epidemiological study conductedin Japan, Oka et al.2) analyzed 1,337 patients younger than 13 years with strictly defined epilepsies (excluding those with afirst unprovoked convulsion or febrile seizure), and classified 907 (75.8%) patients as partial epilepsy, 268 (22.4%) patients
as generalized epilepsy, 21 (1.8%) patients as undetermined epilepsy, with the remaining 141 (10.5%) patients as unclassifiable.
In addition, Wirrell et al.3) studied all 359 patients diagnosed with new-onset childhood epilepsy (0–17 years of age) in
Olmsted County, Minnesota in 1980–2004, and classified the epilepsy of each patient based on the 2010 ILAE classification(see Chapter 1, CQ1-3 on page 6). As for the classification of seizure type, focal seizure accounted for 68%, generalized orbilateral seizures 23%, spasms 3%, and undetermined 5%. For the classification of epilepsy syndrome, 105 cases (29.2%)
could be classified, and they comprised benign childhood epilepsy with centrotemporal spikes in 26 cases (7.2%), childhood
absence epilepsy in 17 cases (4.7%), juvenile absence epilepsy in 11 cases (3.1%), juvenile myoclonic epilepsy in 11 cases (3%),
West syndrome in 9 cases (2.5%), Doose syndrome in 2 cases (0.6%), Lennox-Gastaut syndrome in 1 case (0.3%), and mesial
temporal lobe epilepsy with hippocampal sclerosis in 8 cases (2.2%).

▪ References
1) Berg AT, Levy SR, Testa FM, et al. Classification of childhood epilepsy syndromes in newly diagnosed epilepsy: interrater agreement and reasonsfor disagreement. Epilepsia. 1999; 40(4): 439-444.
2) Oka E, Ohtsuka Y, Yoshinaga H, et al. Prevalence of childhood epilepsy and distribution of epileptic syndromes: a population-based survey inOkayama, Japan. Epilepsia. 2006; 47(3): 626-630.
3) Wirrell EC, Grossardt BR, Wong-Kisiel LC, et al. Incidence and classification of new-onset epilepsy and epilepsy syndromes in children in Olmsted
County, Minnesota from 1980 to 2004: a population-based study. Epilepsy Res. 2011; 95(1-2): 110-118.

Chapter 433▪ Search formula and secondary reference sources
PubMed search: December 31, 2015(((epilepsy/TH or epilepsy syndrome/AL) and ((epidemiology/TH or epidemiology/AL) or (prevalence/TH or prevalence/AL) or (incidence/TH or
incidence /AL) or (classification/TH or classification/AL)))) and (DT = 2008:2015 and (PT = excluding case report) and (PT= excluding proceedings)
and CK= neonatal, infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18)) = 271
Ichushi search: December 31, 2015
#1 epilepsy/TH or epilepsy syndrome/AL 46,973#2 epidemiology/TH or epidemiology/AL 249,524#3 prevalence/TH or prevalence/AL 13,162#4 incidence/TH or incidence/AL 37,381#5 classification/TH or classification/AL 126,662#6 #2 or #3 or #4 or #5 399,286#7 #1 and #6 2,059#8 (#7) and (DT = 2008:2015 (PT= excluding case report) AND (PT = excluding proceedings) CK ­= neonatal, infancy (1‒23 months), earlychildhood (2‒5), childhood (6‒12), adolescence (13‒18)) = 271((((epilepsy/TH or epilepsy syndrome/AL) and ((epidemiology/TH or epidemiology/AL) or (prevalence/TH or prevalence/AL) or (incidence/THor incidence/AL) or (classification/TH or classification/AL)))) and (DT = 2008:2015 and (PT = excluding case report) and (PT = excluding
proceedings) and CK = neonatal, infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18))) and (Japan Epilepsy
Society/AL) = 13

34

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 4-2

What examinations are recommended for the first unprovokedseizure in children and adolescents?
Summary
The examinations are basically the same as those in adults (see also Chapter 2 “Examinations for Clinical Practiceof Epilepsy”). They include electroencephalogram (EEG), neuroimaging studies, and routine blood tests. Of these,
EEG can detect epileptiform activities at a higher rate than in adults, and it is the most useful examination. MRI is
recommended among the neuroimaging modalities.

Comment
1. EEG

Previous studies reported that epileptiform EEG abnormalities are detected in 18‒56% of children after new-onset
seizures (compared with 13–35% in adults)1). In addition, an epidemiological study including children and adults shows that
we rarely detect an epileptiform abnormality after the third negative EEG examination2). The patients with epileptiformdischarges have epilepsy approximately two times more frequently than those with normal EEGs1). In a prospective study inchildren with a first unprovoked seizure conducted by Shinnar et al.3), EEG abnormalities were found in 135 (42%) of 321
children studied. The EEG abnormalities comprised focal spikes in 77 cases, generalized spike-and-wave complexes in 28
cases, slowing in 43 cases, and nonspecific abnormalities in 7 cases. The detection rate was higher in partial seizures than ingeneralized seizures, higher in children aged 3 years or older than in younger children, and higher in symptomatic epilepsies
than in idiopathic epilepsies. In the symptomatic epilepsy group, seizure recurrence was observed in 54% of 103 cases with
EEG abnormalities, but in only 25% of 165 cases without any EEG abnormalities. EEG abnormalities, especially epileptiformdischarges and localized slow waves, are useful for predicting seizure recurrence. When used in combination with otherclinical findings, EEG may play an important role in the diagnosis of epilepsy syndrome even in patients with only a single
seizure. For example, when a child with a convulsion attack during sleep for the first time shows spikes in the centrotemporal
region, a diagnosis of childhood benign epilepsy with centrotemporal spike is strongly suggested, and the prognosis can bepredicted.

2. Neuroimaging examinations
There is no sufficient evidence on whether neuroimaging examination should be performed routinely after the first
unprovoked seizure in children. If symptomatic epilepsy is suggested, neuroimaging studies are recommended, especially
MRI. Shinnar et al.4) performed imaging examinations in 411 children with a first unprovoked seizure, and found brain
tumor and neurocysticercosis in two children each. They enrolled the remaining 407 children in a prospective study. Amongthem, 58 children underwent MRI examination, and abnormalities were found in 19 children (33%), including corticaldysplasia in six children with normal imaging findings at the initial examination. In a prospective study conducted by
Tanabe et al.5) in Japan, MRI examination was performed in children having a first seizure, and abnormal findings weredetected in 10 of 41 children (24.4%), including cortical dysplasia in 4 children. Even with these results, the clinicalsignificance of the lesions shown by imaging studies should be evaluated carefully, especially for their epileptogenicity.

3. Routine blood tests
In children, routine blood tests have clinical significance because the first seizure may also occur under conditions of
hypoglycemia or electrolyte abnormalities.

Chapter 435

▪ References
1) Wirrell EC. Prognostic significance of interictal epileptiform discharges in newly diagnosed seizure disorders. J Clin Neurophysiol. 2010; 27(4):239-248.
2) Baldin E, Hauser WA, Buchhalter JR, et al. Yield of epileptiform electroencephalogram abnormalities in incident unprovoked seizures: a populationbased study. Epilepsia. 2014; 55(9): 1389-1398.
3) Shinnar S, Kang H, Berg AT, et al. EEG abnormalities in children with a first unprovoked seizure. Epilepsia. 1994; 35(3): 471-476.
4) Shinnar S, O’Dell C, Mitnick R, et al. Neuroimaging abnormalities in children with an apparent first unprovoked seizure. Epilepsy Res. 2001;
43(3): 261-269.
5) Tanabe T, Hara K, Kashiwaki M, et al. Prospective study of first unprovoked seizure. No To Hattatsu. 2005; 37(6): 461-466 (in Japanese withEnglish abstract).

▪ Search formula and secondary reference sources
PubMed search: December 31, 2015((unprovoked) AND ((first AND diagnosis [sh]))) AND ((seizures [mesh] OR seizure)) Filters: Publication date from 2008/01/01 to 2015/12/31;
English; Japanese#1 seizures [mesh] OR seizure 111,023#2 first AND diagnosis [sh] 403,484#3 unprovoked 1,332#4 #1 AND #2 AND #3 149#5 #4 AND Filters: Publication date from 2008/01/01 to 2015/12/31; English; Japanese = 51
Ichushi search: December 31, 2015(((((epilepsy/TH or epilepsy/AL)) and (SH = diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, nucleotide diagnosis, ultrasounddiagnosis)) and (onset/AL))) and (DT = 2008:2015 and PT = excluding proceedings and CK = infancy (1‒23 months), early childhood(2‒5),childhood (6‒12), adolescence (13‒18) and SH = diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, nucleotide diagnosis, ultrasounddiagnosis) = 15(((epilepsy/TH or epilepsy/AL)) and (SH = diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, nucleotide diagnosis, ultrasounddiagnosis)) and (onset/AL))) and (DT = 2008:2015 and PT = excluding proceedings and CK = infancy (1‒23 months), early childhood (2‒5),childhood (6‒12), adolescence (13‒18) and SH = diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, nucleotide diagnosis, ultrasounddiagnosis)) and (Japan Epilepsy Society/AL) = 1

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 4-3

For unprovoked seizures in children and adolescents, is the longterm prognosis worse if treatment would start after the second
seizure?
Summary
For unprovoked seizures in children and adolescents, the long-term seizure outcome is not affected even if treatment
is started after the second seizure, as in the case of adults (see CQ3-1 on page 21).

Comment
There have been debates on whether there is any difference in the long-term outcome between patients who startantiepileptic drug therapy promptly after the first epileptic seizure and those who start later. According to a large-scale,prospective, randomized, controlled trial reported from the UK, immediate treatment after onset was superior to delayed
treatment in terms of prompt seizure control, but there was no significant difference in the long-term outcome (remission)1).
There was also no significant difference in QOL such as employment status. The natural courses of the epilepsies were notaffected by the number of epileptic seizures. Apart from controlling seizures, it is an unsolved issue in clinical epileptologyof whether antiepileptic drug treatment also changes the natural course of epilepsy. To date, there is no clear evidence thatantiepileptic drugs affect the natural course of epilepsy.
On the other hand, there is evidence that even when patients with unprovoked seizures are followed without any treatment,
seizures do not recur in one-half of them. Therefore, if treatment is started after the first seizure, one-half of the patientswould be treated unnecessarily. Most clinicians start treatment with antiepileptic drugs when seizures are repeated three orfour times, but there are only a few studies on the short-term and long-term outcome of this policy.

▪ References
1) Marson A, Jacoby A, Johnson A, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised
controlled trial. Lancet. 2005; 365(9476): 2007-2013.

▪ Search formula and secondary reference sources
PubMed search: December 31, 2015
(seizures [mesh] OR seizure) AND (first AND prognosis [MeSH]) AND unprovoked Filters: Publication date from 2008/01/01 to 2015/12/31;
English; Japanese; Child: birth-18 years#1 seizures [mesh] OR seizure 111,023#2 first AND prognosis [MeSH] 151,190#3 unprovoked 1,332#4 #1 AND #2 AND #3 149#5 #4 AND Filters: Publication date from 2008/01/01 to 2015/12/31; English; Japanese = 51
Ichushi search: December 31, 2015((((epilepsy/TH or epilepsy/AL) and (seizure/AL)) and (outcome/TH))) and (DT = 2008:2015 and (PT = excluding case report) and (PT = excluding
proceedings) and CK = neonate, infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18) and SH = treatment) = 8(((epilepsy/TH or epilepsy/AL) and (seizure/AL)) and (outcome /TH))) and (DT = 2008:2015 and (PT = excluding case report) and (PT = excluding
proceedings) and CK = neonate, infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18) and SH = treatment)) and(Japan Epilepsy Society/AL) = 0

Chapter 4

37

CQ 4-4

How to make a diagnosis of juvenile myoclonic epilepsy?
Summary
Juvenile myoclonic epilepsy is a disease with major symptoms of myoclonic seizures and generalized tonic-clonicseizures. Medical history, onset age, triggers of seizures, and electroencephalographic findings are important for
diagnosis.

Comment
Myoclonic seizures are sudden, brief, shock-like muscle jerks affecting muscles of the face, trunk and extremities. The jerks
occur in a single muscle or several muscles together1). Usually, no loss of consciousness is associated with the seizures.
Although the seizures may occur alone, they may also develop into generalized tonic-clonic seizures. Myoclonic seizures arereadily induced by external stimuli, especially by photic stimuli.
Juvenile myoclonic epilepsy (JME) accounts for 26% of idiopathic generalized epilepsy and 5–10% of all epilepsies2).
Symptoms suggestive of this epilepsy are (1) childhood to adolescent onset, (2) induced by sleep deprivation and alcohol, (3)tonic-clonic seizure or myoclonic seizure in the early morning, (4) brief absence seizure, (5) photoparoxysmal EEG responsewith generalized 3-Hz spike-and-wave complexes or polyspike-and-wave complexes3).

▪ References
1) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission of Classification and Terminologyof the International League Against Epilepsy. Epilepsia. 1981; 22(4): 489-501.
2) Grünewald RA, Panayiotopoulos CP. Juvenile myoclonic epilepsy. A review. Arch Neurol. 1993; 50(6): 594-598.
3) Zifkin B, Andermann E, Andermann F. Mechanisms, genetics, and pathogenesis of juvenile myoclonic epilepsy. Curr Opin Neurol. 2005; 18(2):147-153.

▪ Search formula and secondary reference sources
PubMed search: December 31, 2015
Myoclonic Epilepsy, Juvenile/diagnosis [majr] Filters: Publication date from 2000/01/01 to 2015/12/31; English; Japanese; Child: birth-18 years#1 Myoclonic Epilepsy, Juvenile/diagnosis [majr] 119#2 AND Filters: Publication date from 2000/01/01 to 2015/12/31; English; Japanese; Child: birth-18 years = 57
Ichushi search: December 31, 2015(((epilepsy-myoclonus-juvenile/TH) or (epilepsy-myoclonus-juvenile/AL))) and (PT = excluding proceedings and SH = diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, nucleotide diagnosis, ultrasound diagnosis) = 33((((epilepsy-myoclonus-juvenile/TH) or (epilepsy-myoclonus-juvenile/AL))) and (PT = excluding proceedings and SH = diagnostic use, diagnosis,
diagnostic imaging, X ray diagnosis, nucleotide diagnosis, ultrasound diagnosis)) and (Japan Epilepsy Society/AL) = 0

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 4-5

What are the first-line drugs for childhood- or adolescence-onset
epilepsy with undetermined seizure type (partial or generalized)?
Summary
Valproate, carbamazepine, zonisamide, levetiracetam, and lamotrigine are the candidate drugs, and physicians
should select one of them taking into consideration various factors including the antiepileptic spectrum, age, sex,
and adverse effect profile. Carbamazepine has been reported to exacerbate generalized seizures other than generalized
tonic-clonic seizure. For lamotrigine, physicians should strictly follow the package insert for the dosage andadministration, and it therefore takes a long time to up-titrate to the effective dosage. For child-bearing aged women,
see Chapter 13 (page 113).

Comment
When 260 children with newly diagnosed idiopathic generalized epilepsy and partial epilepsy were randomly allocated totreatment with valproate or carbamazepine, the efficacy did not differ significantly between the two drugs1). Valproate wasmore effective than carbamazepine for generalized seizures (all ages)2). Carbamazepine may exacerbate idiopathic andsymptomatic generalized epilepsies manifesting absence and myoclonic seizures3). Zonisamide is effective for partial seizuresand secondarily generalized seizures, but physicians should pay attention to some adverse effects including hypohidrosis andimpaired cognitive function in children4). Levetiracetam is also effective for partial seizures and secondarily generalized
seizures, with only few adverse effects including teratogenicity. Lamotrigine has broad spectrum antiepileptic activities forpartial seizures, generalized seizures, and absence seizures, with generally few adverse effects including teratogenicity; butnote that the prescribed dosage and administration processes have to be strictly followed.

▪ References
1) Verity CM, Hosking G, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric
EPITEG Collaborative Group. Dev Med Child Neurol. 1995; 37(2): 97-108.
2) Cowling BJ, Shaw JE, Hutton JL, et al. New statistical method for analyzing time to first seizure: example using data comparing carbamazepine andvalproate monotherapy. Epilepsia. 2007; 48(6): 1173-1178.
3) Guerrini R, Belmonte A, Genton P. Antiepileptic drug-induced worsening of seizures in children. Epilepsia. 1998; 39(Suppl 3): S2-10.
4) Ohtahara S. Zonisamide in the management of epilepsy. Japanese experience. Epilepsy Res. 2006; 68(Suppl 2): S25-33.

▪ Search formula and secondary reference sources
PubMed search: December 31, 2015
(epilepsy/drug therapy AND carbamazepine/therapeutic use) Filters: Publication date from 2008/01/01 to 2015/12/31; English; Japanese; Child:birth-18 years#1 epilepsy/drug therapy AND carbamazepine/therapeutic use 2,944#2 Filters: Publication date from 2008/01/01 to 2015/12/31; English; Japanese; Child: birth-18 years = 207
Ichushi search: December 31, 2015
(epilepsy/TH) or (epilepsy/AL)) and ((“Valproic Acid”/TH) or (Carbamazepine/TH) and (DT = 2008:2015 and PT = excluding proceedings and
CK = infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18)))) and (SH = therapeutic use, pharmacotherapy) = 296(epilepsy/TH) or (epilepsy/AL)) and ((“Valproic Acid”/TH) or (Carbamazepine/TH))) and (DT = 2008:2015 and PT = excluding proceedings and
CK = infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18)))) and (SH = therapeutic use, pharmacotherapy)) and(Japan Epilepsy Society/AL) = 17

Chapter 4

39

CQ 4-6

If seizures recur in those treated with valproate for childhood/adolescent generalized seizure or carbamazepine for childhood/adolescent partial seizures, even when their drug concentrations
are in the therapeutic ranges, which drugs should be the next
candidates?
Summary

1. In the case of recurrence when valproate is used for generalized seizures
a. Generalized tonic-clonic seizure (GTCS)
Select lamotrigine, carbamazepine, oxcarbazepine†, clobazam, levetiracetam, or topiramate†, considering theiradverse effect profiles. However, when absence seizures and myoclonic seizures coexist, we should consider the factthat carbamazepine and oxcarbazepine† have a risk of aggravating these seizures.
b. Absence seizures
Ethosuximide is recommended. If ethosuximide cannot be used, lamotrigine is recommended, although it isconsidered less effective than ethosuximide.
c. Myoclonic seizure
For juvenile myoclonic epilepsy, levetiracetam†, lamotrigine and topiramate† are recommended. For myoclonicseizure complicating other epilepsies, clonazepam and clobazam are selected although the evidence is low.

2. In the case of recurrence when carbamazepine is used for partial seizures
Select zonisamide, lamotrigine, levetiracetam, clobazam, topiramate, valproate, or gabapentin, considering theiradverse effect profiles.

Comment
1) There was no significant difference in effectiveness between valproate and carbamazepine in children with new-onset
generalized tonic-clonic seizures or partial seizures1). In children with new-onset generalized tonic-clonic seizures andpartial seizures, there were also no significant differences in efficacy among phenobarbital, phenytoin, carbamazepine, andvalproate2). In adults and children with generalized epilepsy or unclassified epilepsy randomly allocated to treatment withvalproate, lamotrigine or topiramate, valproate was the best in both tolerability and efficacy. As the initial treatment for
generalized tonic-clonic seizures, NICE guideline 2012 recommends valproate followed by lamotrigine, and thencarbamazepine and oxcarbazepine†, or adjunctive therapy using clobazam, levetiracetam or topiramate† 3).
2) In randomized controlled trials comparing valproate, ethosuximide, and lamotrigine for childhood absence epilepsy,
valproate and ethosuximide were superior in efficacy to lamotrigine, but there was no difference between the two former
drugs4, 5). However, since ethosuximide has less adverse effects compared to valproate, ethosuximide is recommended as
the first-line drug for childhood absence epilepsy.
3) In a study comparing valproate and lamotrigine for juvenile myoclonic epilepsy, no significant difference in seizure control
rate was observed between the two drugs, while the rate of discontinuation due to adverse effects was lower withlamotrigine6). In an randomized controlled trial (RCT) for idiopathic generalized epilepsy with myoclonic seizures,
levetiracetam reduced myoclonic seizures at a significantly higher rate compared to placebo7). In addition, expert consensus
studies recommended the following drugs for myoclonic seizure, in the order of: valproate, clonazepam, and clobazam in
one paper, and valproate and lamotrigine in another paper8, 9). Based on all these studies, valproate followed by levetiracetam,lamotrigine, clonazepam, and clobazam are recommended. However, it should be noted that lamotrigine has a risk ofdeteriorating myoclonic seizures in patients with Dravet syndrome (severe myoclonic epilepsy in infancy) and in somepatients with juvenile myoclonic epilepsy.

40

Part IThe Clinical Practice Guidelines for Epilepsy 2018

4) In children aged 2‒16 years with partial epilepsy and in some children with generalized epilepsy, there was no significant
difference in efficacy among clobazam, carbamazepine and phenytoin when used as monotherapy10). However, in Japan,
clobazam is currently not approved for monotherapy.
5)Lamotrigine and carbamazepine were equivalent in efficacy for partial seizures with or without generalized tonic-clonicseizures11). When the effects and efficacy of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate werecompared in 1,721 adults and children with partial epilepsy, lamotrigine was more useful than carbamazepine, gabapentin
or topiramate in terms of lower discontinuation rate and fewer adverse effects, and was not significantly different fromoxcarbazepine.
6) NICE guideline 2012 recommends adjunctive use of clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine,
valproate or topiramate12).
*For the use of perampanel in patients aged 12 years and above, and lacosamide in patients aged 16 years and above, see
Chapter 3 “Drug Therapy for Adult Epilepsy”.

▪ References
1) Verity CM, Hosking G, Easter DJ. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric
EPITEG Collaborative Group. Dev Med Child Neurol. 1995; 37(2): 97-108.
2) de Silva M, MacArdle B, McGowan M, et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium
valproate for newly diagnosed childhood epilepsy. Lancet. 1996; 347(9003): 709-713.
3) National Institute for Health and Care Excellence (NICE). Epilepsies: Diagnosis and Management. London, 11 January 2012. http://www.nice.org.
uk/guidance/cg137
4) Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010; 362(9):790-799.
5) Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomesat 12 months. Epilepsia. 2013; 54(1): 141-155.
6) Machado RA, García VF, Astencio AG, et al. Efficacy and tolerability of lamotrigine in juvenile myoclonic epilepsy in adults: a prospective,
unblinded randomized controlled trial. Seizure. 2013; 22(10): 846-855.
7) Noachtar S, Andermann E, Meyvisch P, et al. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology.
2008; 70(8): 607-616.
8) Inoue Y, Nishida T, Fujiwara T, et al. Expert consensus of epilepsy treatment. Tenkan Kenkyu. 2004; 22(2): 128-139 (in Japanese).
9) Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion, 2005. J Child Neurol. 2005; 20(Suppl 1): S1-56.
10) Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy. Canadian Study Group for Childhood
Epilepsy. Epilepsia. 1998; 39(9): 952-959.
11) Reunanen M, Dam M, Yuen AW. A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patientswith newly diagnosed or recurrent epilepsy. Epilepsy Res. 1996; 23(2): 149-155.
12) The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE clinical guideline
CG137. https://www.nice.org.uk/guidance/cg137▪ Search formula and secondary reference sources
PubMed search: December 31, 2015
(epilepsy/drug therapy AND carbamazepine/therapeutic use) Filters: Publication date from 2008/01/01 to 2015/12/31; English; Japanese; Child:birth-18 years#1 epilepsy/drug therapy AND carbamazepine/therapeutic use 2,944#2 Filters: Publication date from 2008/01/01 to 2015/12/31; English; Japanese; Child: birth-18 years = 207
Ichushi search: December 31, 2015((epilepsy/TH) or (epilepsy/AL)) and ((“Valproic Acid”/TH) or (Carbamazepine/TH)) and (DT = 2008:2015 and PT = excluding proceedings and
CK = infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18)))) and (SH = therapeutic use, pharmacotherapy) = 296(((epilepsy/TH) or (epilepsy/AL)) and ((“Valproic Acid”/TH) or (Carbamazepine/TH)))) and (DT = 2008:2015 and PT = excluding proceedings and
CK = infancy (1‒23 months), early childhood (2‒5), childhood (6‒12), adolescence (13‒18)))) and (SH = therapeutic use, pharmacotherapy)) and(Japan Epilepsy Society/AL) = 17

Chapter 4

41

Table 1. Drug options by seizure type in revised NICE guideline (2012).
Seizure typeFirst-line drugs

Adjunctive drugs

Generalized
tonic–clonicseizureoxcarbazepine†
carbamazepine
valproate lamotrigine

clobazam
topiramate†valproatelamotrigine
levetiracetam
lamotrigine

Tonic seizure oratonic seizure

valproate

Absence seizure

ethosuximide
valproate lamotrigine

ethosuximide
valproatelamotrigine

Myoclonic seizure

topiramate† valproate
levetiracetam†

topiramate†valproate
levetiracetam†

Partial seizure(including
secondarily
generalized)

oxcarbazepine†
carbamazepine
valproate lamotrigine
levetiracetam

oxcarbazepine
carbamazepine
gabapentin
clobazam
topiramate
valproatelamotrigine
levetiracetam

Other drugs that may
be considered

topiramate†rufinamide

clobazamclonazepam†
zonisamide
topiramate†levetiracetam†
clobazamclonazepam
zonisamide
piracetam

Do not offer drugs
oxcarbazepine†acarbamazepinea
gabapentin†avigabatrin†aphenytoina
oxcarbazepine†
carbamazepine
gabapentin†
vigabatrin†
oxcarbazepine†
carbamazepine
gabapentin†
phenytoin
vigabatrin†
oxcarbazepine†
carbamazepine
gabapentin†
phenytoin
vigabatrin†zonisamide
vigabatrin†
phenobarbital
phenytoinlacosamide: in the case of complication by absence seizure or myoclonic seizure, in the case of juvenile myoclonic epilepsy: not covered by medical insurance in Japan (as of December 6, 2017)(Modified from NICE guideline 2012)
a

†

42

Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 2. Drug options by epileptic syndrome in revised NICE guideline (2012).
Epilepsy syndrome
Childhood absence epilepsy
Juvenile absence epilepsy

Adjunctive
drugs
Idiopathic epilepsy
ethosuximide
ethosuximide
valproatevalproatelamotrigine
lamotrigine
First-line drugs

Juvenile myoclonic epilepsy

topiramate†valproatelamotrigine
levetiracetam

topiramate†valproatelamotrigine
levetiracetam

Epilepsy with generalized tonic–clonicseizures alone(grand mal epilepsy on awakening

oxcarbazepine†
carbamazepine
valproatelamotrigine

Idiopathic generalized epilepsy

topiramate†valproatelamotrigine

clobazam
topiramate†valproatelamotrigine
levetiracetam
topiramate†valproatelamotrigine
levetiracetam

Benign epilepsy with centrotemporal
spikesoxcarbazepine†
carbamazepine
valproatelamotrigine
levetiracetam

Panayiotopoulos syndrome
Late-onset childhood occipital epilepsy(Gastaut type)

Infantile spasm (West syndrome) not
due to tuberous sclerosis
Infantile spasm (West syndrome) due totuberous sclerosis
Dravet syndrome (severe myoclonic
epilepsy in infancy)

oxcarbazepine
carbamazepine
gabapentin
clobazam
topiramate
valproatelamotrigine
levetiracetam
Epileptic encephalopathy
Discuss with or refer tospecialist facility
ACTH
steroidvigabatrin
Discuss with or refer tospecialist facility

Other drugs that
may be consideredclonazepam
clobazam†zonisamide
topiramate†levetiracetam†clonazepam
clobazamzonisamide

oxcarbazepine†
carbamazepine
gabapentin†
vigabatrin†phenytoin
oxcarbazepine†
carbamazepine
gabapentin†
vigabatrin†phenytoinclonazepam
clobazamzonisamide

oxcarbazepine†
carbamazepine
gabapentin
vigabatrin
phenytoinzonisamide
vigabatrin†
phenobarbital
phenytoinlacosamide

clobazamstiripentol

oxcarbazepine†
gabapentin
carbamazepine
vigabatrin
phenytoinlamotrigine

topiramate
valproate
Epilepsy with continuous spike andwave during slow sleep
Lennox–Gastaut syndrome

Landau–Kleffner syndrome
Myoclonic-astatic epilepsy

Discuss with or refer tospecialist facility
Discuss with or refer tospecialist facility
valproate
Discuss with or refer tospecialist facility
Discuss with or refer tospecialist facility

lamotrigine

Do not offer
drugs

topiramate
rufinamide

oxcarbazepine†
gabapentin
carbamazepine
vigabatrin†

Only those drugs that are available for use in Japan†: not covered by medical insurance in Japan (as of December 6, 2017)(Modified from NICE guideline 2012)

Chapter 443