Chapter 6
Treatment Guide by Epilepsy Syndrome
Table 1. Drug options for various epilepsy syndromes.
Epilepsy syndrome

First-line drugs

Second-line drugs

Idiopathic partial
epilepsy

carbamazepine valproate
levetiracetam

lamotrigine
oxcarbazepine*
topiramate*gabapentin*
clobazam*lamotrigine

Childhood absence
epilepsy

valproate ethosuximide

Lennox-Gastautsyndrome

valproate (for women ofchild-bearing potential,
see Chapter 13)

lamotrigine*
zonisamide
topiramate*ruﬁnamide*

Juvenile myoclonic
epilepsy

valproate (for women ofchild-bearing potential,
see Chapter 13)

Epilepsy withgeneralized tonic-clonicseizures alone

valproate (for women ofchild-bearing potential,
see Chapter 13

levetiracetam*lamotrigine
zonisamide
topiramate*zonisamide
lamotrigine
levetiracetam*
topiramate*

Combination
therapy, othersultiame(BECTS)

clobazam(drop seizure)*
ethosuximide(atypical absence
seizure)levetiracetam
clonazepam(myoclonic seizure)

Drugs to avoid if
possible

gabapentin
carbamazepine
phenytoin
gabapentin
carbamazepine

gabapentin
carbamazepine
phenytoinclobazam**: covered by medical insurance in Japan.
• topiramate and gabapentin are covered by medical insurance as adjunctive therapy for partial seizures.
• clobazam is covered by medical insurance as adjunctive therapy for partial seizure and generalized seizures.
• lamotrigine is covered by medical insurance as monotherapy for partial seizures, tonic-clonic seizures and absence seizures,
and also as adjunctive therapy for Lennox-Gastaut syndrome.
• ruﬁnamide is covered by medical insurance as adjunctive therapy for tonic seizures and atonic seizures in Lennox-Gastautsyndrome.
• levetiracetam is covered by medical insurance as monotherapy for partial seizures, and also as adjunctive therapy for tonicclonic seizures.

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 6-1

What are the drug options for idiopathic partial epilepsy?
Summary(1) Because some patients with idiopathic partial epilepsy may not require therapeutic intervention, the expected
beneficial effect and the adverse effect from treatment should be considered carefully.
(2) First-line drugs for idiopathic partial epilepsy are carbamazepine, valproate, and levetiracetam.
(3) Second-line drugs are lamotrigine, oxcarbazepine, topiramate, gabapentin, and clobazam.
(4) Sultiame is also used as a second-line drug for benign childhood epilepsy with centrotemporal spikes (BECTS).

Comment
Basically, idiopathic partial epilepsy has good prognosis, and in some patients, seizure may occur only once in a life-time.
Therefore, therapeutic intervention is sometimes unnecessary. For this reason, it is necessary to explain to the family (and thepatient him/herself) about the therapeutic effects and the adverse effects of treatment with antiepileptic drugs, and to
consider the whole treatment policy1).
No randomized controlled trial (RCT) of drug therapy for idiopathic partial epilepsy has been conducted, and generalantiepileptic drugs (carbamazepine, valproate, levetiracetam, lamotrigine, oxcarbazepine, topiramate, gabapentin, andclobazam) are used 2, 3). Among them, carbamazepine, valproate, levetiracetam are considered to be first-line drugs inconsideration of their seizure control effect and adverse effects2, 4).
In an RCT of sultiame for benign childhood epilepsy with centrotemporal spikes (BECTS), which is the main idiopathic
partial epilepsy, the seizure control rate was 40% in the control group compared with 87.1% in the sultiame group, indicating
the effectiveness of sultiame5). For BECTS, RCTs were conducted for sultiame and levetiracetam6) as well as for oxcarbazepine
and levetiracetam7). In these two trials, the seizure control rates were 90.9% for sultiame versus 81.0% for levetiracetam, and72.2% for oxcarbazepine versus 90.5% for levetiracetam, both reported high seizure control effect.

▪ References
1) Oguni H. Treatment of benign focal epilepsies in children: when and how should be treated? Brain Dev. 2011; 33(3): 207-212.
2) Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or
topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007; 369(9566): 1000-1015.
3) Wheless JW, Neto W, Wang S. Topiramate, carbamazepine, and valproate monotherapy: double-blind comparison in children with newly diagnosed
epilepsy. J Child Neurol. 2004; 19(2): 135-141.
4) Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord. 2007; 9(4):353-412.
5) Rating D, Wolf C, Bast T. Sulthiame as monotherapy in children with benign childhood epilepsy with centrotemporal spikes: a 6-month randomized,
double-blind, placebo-controlled study. Sulthiame Study Group. Epilepsia. 2000; 41(10): 1284-1288.
6) Borggraefe I, Bonfert M, Bast T, et al. Levetiracetam vs. sulthiame in benign epilepsy with centrotemporal spikes in childhood: a double-blinded,
randomized, controlled trial (German HEAD study). Eur J Paediatr Neurol. 2013; 17(5): 507-514.
7) Coppola G, Franzoni E, Verrotti A, et al. Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy of childhood withcentrotemporal spikes (BECTS): an open-label, parallel group trial. Brain Dev. 2007; 29(5): 281-284.

▪ Search formula and secondary reference sources
PubMed search: June 25, 2015((((“Epilepsies, Partial” [Mesh]) AND ((idiopathy) OR idiopathic)) AND Anticonvulsants/therapeutic use [Mesh])) OR “Epilepsy, Rolandic/drug
therapy” [Mesh] Filters: Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 55件
Ichushi search: June 15, 2015(((((anti-epileptic drug/TH or antiepileptic drug/AL)) and ((idiopathic partial epilepsy/AL) or (((epilepsy-focus/TH or partial epilepsy/AL)) and(idiopathic/AL))))) and (PT = excluding proceedings)) = 41
Secondary reference source
The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. National Institute for Healthand Care Excellence.
http://www.nice.org.uk/guidance/cg137

Chapter 6

55

CQ 6-2

What are the drug options for childhood absence epilepsy?
Summary(1) The first-line drugs are valproate and ethosuximide.
(2) The second-line drug is lamotrigine.
(3) Do not use gabapentin, carbamazepine or phenytoin.

Comment
Traditionally, valproate, ethosuximide, and lamotrigine have been used for the treatment of childhood absence epilepsy1).
In a randomized control trial (RCT), valproate and ethosuximide showed equivalent seizure control effect (16-week seizure
control rates of 58% and 53%, respectively), and both were more effective than lamotrigine (29%)2). Although ethosuximide
is superior to valproate from the viewpoint of adverse effects, valproate is superior in being easy to take. On the other hand,valproate is used rather than ethosuximide when complicated by generalized tonic-clonic seizures.
Gabapentin3), carbamazepine4, 5), and phenytoin5) have been reported to exacerbate absence seizures.

▪ References
1) Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion, 2005. J Child Neurol. 2005; 20: (Suppl 1): S1-56.
2) 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.
3) Trudeau V, Myers S, LaMoreaux L, et al. Gabapentin in naive childhood absence epilepsy: results from two double-blind, placebo-controlled,
multicenter studies. J Child Neurol. 1996; 11(6): 470-475.
4) Horn CS, Ater SB, Hurst DL. Carbamazepine-exacerbated epilepsy in children and adolescents. Pediatr Neurol. 1986; 2(6): 340-345.
5) Osorio I, Reed RC, Peltzer JN. Refractory idiopathic absence status epilepticus: A probable paradoxical effect of phenytoin and carbamazepine.
Epilepsia. 2000; 41(7): 887-894.

▪ Search formula and secondary reference sources
PubMed search: June 25, 2015
“Epilepsy, Absence/drug therapy” [Mesh] Filters: Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 91
Ichushi search: June 15, 2015(((((epilepsy-absence/TH or absence epilepsy/AL)) or ((epilepsy-absence /TH or absence seizures/AL)))) and (PT = excluding proceedings and SH =drug therapy)) = 88
Secondary reference source
The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. National Institute for Healthand Care Excellence.
http://www.nice.org.uk/guidance/cg137

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CQ 6-3What are the drug options for Lennox-Gastaut syndrome?
Summary(1) L ennox-Gastaut syndrome (LGS) is often drug resistant, and correct clinical evaluation and consideration oftreatment goal are needed when planning treatment.
(2) The first-line drug is valproate, but for child-bearing aged women, priority is given to drugs other thanvalproate.
(3) In the case that valproate cannot be used, or valproate is not adequately effective, lamotrigine, zonisamide,
topiramate, rufinamide or levetiracetam is used.
(4) Clobazam is used for drop seizures, while ethosuximide is used for atypical absence seizures.
(5) Do not use gabapentin or carbamazepine.
(6) When treatment is difficult, refer to epilepsy specialists.

Comment
Lennox-Gastaut syndrome (LGS) manifests many types of seizures such as tonic seizures, atypical absences, atonic
seizures, and myoclonic seizures. These seizures are drug resistant and may further be complicated by mental retardation orother features. Too high doses of antiepileptic drugs for controlling resistant seizures may impair quality of life (QOL), anddrugs used to control some seizures may exacerbate other types of seizures. Therefore, it is necessary to set appropriate
treatment goals while reevaluating the QOL and the QOL-impairing factors1).
Expert opinion recommends valproate as the first-line drug, followed by topiramate and lamotrigine as other first-line
drugs2).
The efficacy of lamotrigine3), topiramate4), and rufinamide5) for LGS has been studied in randomized control trials (RCTs).
The effective rates (50% seizure reduction rates) of these drugs when used as adjunctive therapy were 33% for lamotrigine(placebo 16%)3), 33% for topiramate (placebo 8%)4), and 32.7% for rufinamide (placebo 11.7%)5). A cohort study ofzonisamide was conducted, and the effective rate (50% seizure reduction rate) when used as adjunctive therapy was 51.6%6).
The effectiveness of clobazam for drop attacks in LGS was studied in a RCT. The effective rate (50% seizure reductionrate) when used at doses of 0.2‒1 mg/kg/day was 77.6%7). Ethosuximide has been reported to be effective for atypical absence
seizures and myoclonic seizures with few adverse effects, and is therefore recommended as a drug for these seizures8).
A report has shown that gabapentin and carbamazepine increase seizure frequency in LGS9).

▪ References
1) Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial
methodology. Lancet Neurol. 2009; 8(1): 82-93.
2) Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord. 2007; 9(4):353-412.
3) Motte J, Trevathan E, Arvidsson JF, et al. Lamotrigine for generalised seizures associated with the Lennox-Gastaut syndrome. Lamictal LennoxGastaut Study Group. New Engl J Med. 1997; 337(25): 1807-1812.
4) Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group.
Neurology. 1999; 52(9): 1882-1887.
5) Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008; 70(21):1950-1958.
6) You SJ, Kang H, Kim HD, et al. Clinical efficacy of zonisamide in Lennox-Gastaut syndrome: Korean multicentric experience. Brain Dev. 2008;
30(4): 287-290.
7) Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011; 77(15):1473-1481.
8) Farrell K. Symptomatic generalized epilepsy and Lennox-Gastaut syndrome. In: Wyllie E ed. Wyllie’s Treatment of Epilepsy: Principles and Practice,
2nd edition. ed. Baltimore; Williams & Wilkins, 1996, p.530-539.
9) Schmidt D, Bourgeois B. A risk-benefit assessment of therapies for Lennox-Gastaut syndrome. Drug Safety. 2012; 22(6): 467-477.

Chapter 657▪ Search formula and secondary reference sources
PubMed search: June 25, 2015(((“Lennox Gastaut Syndrome” [Mesh]) OR “Lennox Gastaut Syndrome” [TIAB])) AND “drug therapy” [Subheading] Filters: Publication datefrom 2008/01/01 to 2015/12/31; Humans; English; Japanese = 122
Ichushi search: June 29, 2015((((((Lennox-Gastaut syndrome/TH or Lennox-Gastaut syndrome/AL))) and (SH = drug therapy))) and (PT = excluding proceedings)) = 89
Secondary reference source
The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. National Institute for Healthand Care Excellence.
http://www.nice.org.uk/guidance/cg137

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CQ 6-4

What are the drug options for juvenile myoclonic epilepsy?
Summary(1) The first-line drug is valproate, but for child-bearing aged women, priority is given to drugs other than valproate.
(2) In the case that valproate cannot be used, or valproate is not adequately effective, monotherapy withlevetiracetam, lamotrigine, zonisamide or topiramate is used.
(3) Clonazepam is used as adjunctive therapy for myoclonic seizure.
(4) Do not use gabapentin, carbamazepine or phenytoin.

Comment
Juvenile myoclonic epilepsy (JME) mainly manifests myoclonic seizure and generalized tonic-clonic seizure. Both seizure
types are treatment targets, but generalized tonic-clonic seizure is often the main treatment target because of its high impact
on QOL.
Expert opinion for JME recommends valproate as the first-line drug1). There is no randomized control trial (RCT) of
valproate for JME alone, but RCT have demonstrated the efficacy of valproate for generalized epilepsies (seizure control rate92%), and its effect is superior to those of topiramate and lamotrigine2). Since valproate has been reported to be teratogenic3)
and affect cognitive ability of babies4), treatment with drugs other than valproate should be given priority in child-bearing
women.
In studies on JME, levetiracetam (seizure control rate 80%)5), lamotrigine (seizure control rate 81.9%)6), zonisamide(seizure control rate 38.5‒69.5%)7), and topiramate (seizure control rate 67%)8) have been shown to be effective as monotherapy.
Among these drugs, lamotrigine should be used carefully because it often exacerbates myoclonic seizure9). Clonazepam canbe effective for myoclonic seizure10).
A report has shown that gabapentin and carbamazepine exacerbate absence seizures and myoclonic seizures, while
phenytoin exacerbates absence seizures11). On the other hand, in a certain number of patients, a combination of carbamazepine
and valproate is needed to control generalized tonic-clonic seizures12).

▪ References
1) Wheless JW, Clarke DF, Arzimanoglou A, et al. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord. 2007; 9(4):353-412.
2) Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalized andunclassifiable epilepsy: an unblended randomised controlled trial. Lancet. 2007; 369(9566): 1016-1026.
3) Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs; an analysis of data from the EURAP
epilepsy and pregnancy registry. Lancet Neurol. 2011; 10(7): 609-617.
4) Meador K, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective
observational study. Lancet Neurol. 2013; 12(3): 244-252.
5) Sharpe DV, Patel AD, Abou-Khalil B, et al. Levetiracetam monotherapy in juvenile myoclonic epilepsy. Seizure. 2008; 17(1): 64-68.
6) Machado RA, Garcia VF, Astencio AG, et al. Efficacy and tolerability of lamotrigine in juvenile myoclonic epilepsy in adults: a prospective,
unblended randomized controlled trial. Seizure. 2013; 22(10): 846-855.
7) Kothare SV, Valencia I, Khurana DS, et al. Efficacy and tolerability of zonisamide in juvenile myoclonic epilepsy. Epileptic Disord. 2004; 6(4):267-270.
8) Levisohn PM, Holland KD. Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison. Epilepsy
Behav. 2007; 10(4): 547-552.
9) Biraben A, Allain H, Scarabin JM, et al. Exacerbation of juvenile myoclonic epilepsy with lamotrigine. Neurology. 2000; 55(11): 1758.
10) Obeid T, Panayiotopoulos CP. Clonazepam in juvenile myoclonic epilepsy. Epilepsia. 1989; 30(5): 603-606.
11) Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia. 1998; 39(1): 5-17.
12) Knott C, Panayiotopoulos CP. Carbamazepine in the treatment of generalised tonic clonic seizures in juvenile myoclonic epilepsy. J Neurol
Neurosurg Psychiatry. 1994; 57(4): 503.

Chapter 659▪ Search formula and secondary reference sources
PubMed search: June 25, 2015
“Myoclonic Epilepsy, Juvenile/drug therapy” [Mesh] Filters: Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 63
Ichushi search: June 29, 2015((((Juvenile myoclonic epilepsy/AL) or (epilepsy-myoclonus-juvenile/TH))) and (PT = excluding proceedings and SH = drug therapy)) = 35
Secondary reference source
The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. National Institute for Healthand Care Excellence.
http://www.nice.org.uk/guidance/cg137

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CQ 6-5

What are the drug options for epilepsy with generalized tonicclonic seizures alone (epilepsy with grand mal on awakening)?
Summary(1) The first-line drug is valproate, but for child-bearing aged women, priority is given to drugs other than valproate.
(2) In the case that valproate cannot be used, or valproate is not adequately effective, zonisamide, lamotrigine,
levetiracetam or topiramate is used.
(3) In the case that the above drugs cannot be used, or when these drugs are not completely effective, adjunctive
therapy with clobazam is used.

Comment
The epilepsy traditionally called “epilepsy with grand mal on awakening” was changed to “epilepsy with generalized tonicclonic seizures alone” in the 2010 International League Against Epilepsy (ILAE) classification of epilepsy syndromes1).
There is no randomized controlled trial (RCT) exclusively on epilepsy with generalized tonic-clonic seizures alone, but ameta-analysis on generalized tonic-clonic seizures has demonstrated the efficacy of valproate and phenytoin2). Since valproate
has been reported to be teratogenic3) and affect cognitive ability of babies4), treatment with drugs other than valproate should
be given priority in child-bearing aged women.
Zonisamide (seizure control rate 42.6%)5), lamotrigine (seizure control rates 30‒37% at one year or 40 weeks after starting
treatment)6-8), levetiracetam (seizure control rate 34.2%)9), and topiramate (seizure control rate 39‒49%)8, 10) have beenreported to be effective in controlling generalized tonic-clonic seizures. The efficacy of phenytoin and phenobarbital has also
been reported, but they are not used as first-line drugs because of the adverse effect profile. As adjunctive therapy, clobazam
also exhibits seizure control effect (seizure control rate 10‒30%)11).

▪ References
1) Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission
on Classification and Terminology, 2005-2009. Epilepsia. 2010; 51(4): 676-685.
2) Tudur Smith C, Marson AG, Chadwick DW, et al. Multiple treatment comparisons in epilepsy monotherapy trials. Trials. 2007; 8: 34.
3) Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs; an analysis of data from the EURAP
epilepsy and pregnancy registry. Lancet Neurol. 2011; 10(7): 609-617.
4) Meador K, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective
observational study. Lancet Neurol. 2013; 12(3): 244-252.
5) Yamauchi T, Aikawa H. Efficacy of zonisamide: our experience. Seizure. 2004; 13(Suppl 1): S41-48.
6) Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison withphenytoin. Epilepsia. 1999; 40(5): 601-607.
7) Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet. 1995; 345(8948):
476-479.
8) Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised andunclassifiable epilepsy: an unblended randomised controlled trial. Lancet. 2007; 369(9566): 1016-1026.
9) Berkovic SF, Knowlton RC, Leroy RF, et al. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007; 69(18):1751-1760.
10) Privitera MD, Brodie MJ, Mattson RH, et al. Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed
epilepsy. Acta Neurol Scand. 2003; 107(3): 165-175.
11) Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group. Epilepsia.
1991; 32(3): 407-416.

Chapter 661▪ Search formula and secondary reference sources
PubMed search: June 26, 2015(((“Epilepsy, Tonic-Clonic” [Mesh]) OR ((((“Epilepsy” [Mesh]) AND awaking [TIAB])) AND “Grand mal” [TIAB]))) AND ((“Drug Therapy”[Mesh]) OR “drug therapy” [Subheading]) Filters: Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 169件
Ichushi search: June 29, 2015((((epilepsy with GTCS on awakening/AL) or (awakening/AL and seizure/AL and (epilepsy/TH or epilepsy/AL)))) and (PT = excluding proceedings
and SH = drug therapy)) = 35
Secondary reference source
The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. National Institute for Healthand Care Excellence.
http://www.nice.org.uk/guidance/cg137

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