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 with centrotemporal spikes. Childhood epilepsy covers the onset age range of one month after birth to around 18 years of 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, 15 cases (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 conducted in Japan, Oka et al.²⁾ analyzed 1,337 patients younger than 13 years with strictly defined epilepsies (excluding those with a first 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 or bilateral 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 reasons for 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 in Okayama, 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.

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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), early childhood (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/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))) and (Japan Epilepsy Society/AL) = 13

CQ 4-2

What examinations are recommended for the first unprovoked seizure in children and adolescents?

Summary

The examinations are basically the same as those in adults (see also Chapter 2 “Examinations for Clinical Practice of 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 epileptiform discharges have epilepsy approximately two times more frequently than those with normal EEGs¹⁾. In a prospective study in children 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 in generalized 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 epileptiform discharges and localized slow waves, are useful for predicting seizure recurrence. When used in combination with other clinical 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 be predicted.

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. Among them, 58 children underwent MRI examination, and abnormalities were found in 19 children (33%), including cortical dysplasia 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 were detected in 10 of 41 children (24.4%), including cortical dysplasia in 4 children. Even with these results, the clinical significance 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.

▪ 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 population-based 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 with English abstract).

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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, ultrasound diagnosis)) 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, ultrasound diagnosis) = 15

(((epilepsy/TH or epilepsy/AL)) and (SH = diagnostic use, diagnosis, diagnostic imaging, X ray diagnosis, nucleotide diagnosis, ultrasound diagnosis)) 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, ultrasound diagnosis)) and (Japan Epilepsy Society/AL) = 1

CQ 4-3

For unprovoked seizures in children and adolescents, is the long-term 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 start antiepileptic 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 not affected by the number of epileptic seizures. Apart from controlling seizures, it is an unsolved issue in clinical epileptology of whether antiepileptic drug treatment also changes the natural course of epilepsy. To date, there is no clear evidence that antiepileptic 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 patients would be treated unnecessarily. Most clinicians start treatment with antiepileptic drugs when seizures are repeated three or four 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.

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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

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-clonic seizures. 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 are readily 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 response with 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 Terminology of 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.

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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

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 and administration, 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 to treatment with valproate or carbamazepine, the efficacy did not differ significantly between the two drugs¹⁾. Valproate was more effective than carbamazepine for generalized seizures (all ages)²⁾. Carbamazepine may exacerbate idiopathic and symptomatic generalized epilepsies manifesting absence and myoclonic seizures³⁾. Zonisamide is effective for partial seizures and secondarily generalized seizures, but physicians should pay attention to some adverse effects including hypohidrosis and impaired 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 for partial seizures, generalized seizures, and absence seizures, with generally few adverse effects including teratogenicity; but note 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 and valproate 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.

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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

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 their adverse effect profiles. However, when absence seizures and myoclonic seizures coexist, we should consider the fact that 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 is considered less effective than ethosuximide.

c. Myoclonic seizure

For juvenile myoclonic epilepsy, levetiracetam^†, lamotrigine and topiramate^† are recommended. For myoclonic seizure 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 their adverse 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 and partial seizures, there were also no significant differences in efficacy among phenobarbital, phenytoin, carbamazepine, and valproate²⁾. In adults and children with generalized epilepsy or unclassified epilepsy randomly allocated to treatment with valproate, 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 then carbamazepine 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 drugs^{4, 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 with lamotrigine⁶⁾. 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 paper^{8, 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 of deteriorating myoclonic seizures in patients with Dravet syndrome (severe myoclonic epilepsy in infancy) and in some patients with juvenile myoclonic epilepsy.

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-clonic seizures¹¹⁾. When the effects and efficacy of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate were compared 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 from oxcarbazepine.

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 outcomes at 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 patients with 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

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(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