Clinical Practice Guidelines
for Epilepsy 2018

Published on: March 15, 2018

first edition first printing

Editorial supervisor: Japanese Society of Neurology
Editor: “Clinical Practice Guidelines for Epilepsy” Development Committee
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ii

Clinical Practice Guidelines for Epilepsy 2018

List of Authors
Editorial supervisor
Japanese Society of Neurology
(Collaborating Societies: Japan Epilepsy Society, Japan Neurosurgical Society, Japanese Society of Child Neurology,
Japanese Society of Neurological Therapeutics)

EditorClinical Practice Guidelines for Epilepsy Development Committee

Chairman:
Yoshikazu Ugawa, Professor, Department of Neurology, Fukushima Medical University

Vice-chairman:
Naoki Akamatsu, Professor, Department of Neurology, International University of Health and Welfare

Committee Members:
Akio Ikeda, Professor, Department of Epilepsy, Movement Disorders & Physiology, Kyoto University School of Medicine
Hiroto Iwasa, Director, Kisarazu Hospital, Kisarazu Epilepsy Center
Hirokazu Oguni, Professor, Department of Pediatrics, Tokyo Women’s Medical University
Kensuke Kawai, Professor, Department of Neurosurgery, Jichi Medical University
Kazutaka Jin, Associate Professor, Department of Epileptology, Tohoku University
Kenji Sugai, Director, Epilepsy Center, National Center of Neurology and Psychiatry
Kiyohito Terada, Chief, Department of Neurology, Shizuoka Institute of Epilepsy and Neurological Disorders
Shozo Tobimatsu, Professor, Department of Clinical Neurophysiology, Graduate School of Medical Sciences, Kyushu
University
Masato Matsuura, Vice-Director, Tazaki Hospital
Masahiro Mizobuchi, Director, Epilepsy Center, Department of Neurology, Nakamura Memorial Hospital
Eishu Nango, Chief Physician, Department of General Medicine, Tokyo Kita Social Insurance Hospital

Research collaborators and administrative staff:
Yoshihiro Sugiura, Associate Professor, Department of Neurology, Fukushima Medical University
Masahiro Iguchi, Assistant Professor, Department of Neurology, Fukushima Medical University
Madoka Yamazaki, Project Lecturer, Faculty of Health Science, Daito Bunka University

Evaluation & coordination members:
Sadatoshi Tsuji, Dean and Professor, School of Health Sciences at Fukuoka, International University of Health and Welfare
Shinichi Niwa, Adjunct Professor, Department of Psychiatry, Aizu Medical Center, Fukushima Medical University
Genjiro Hirose, Director of Neurological Center and Director of Epilepsy Center, Asanogawa General Hospital
Tateki Fujiwara, Honorary Director, Shizuoka Institute of Epilepsy and Neurological. Disorders

Preface  

iii

Publication of Clinical Practice Guidelines for Neurological Diseases
In 2001, the Executive Board of the Japanese Society of Neurology decided to develop clinical practice guidelines for the
major neurological diseases, based on a proposal by the then President Nobuo Yanagisawa. In 2002, “Treatment Guidelines
2002” for six diseases comprising “chronic headache”, “Parkinson disease, “epilepsy”, “amyotrophic lateral sclerosis”,“dementia”, and “cerebrovascular disease” were published.
Following the publication of “Treatment Guidelines 2002”, new knowledge was accumulated at an accelerated rate. In
2008, the Executive Board of the Japanese Society of Neurology (Past President, Shigeki Kuzuhara) decided to revise theguidelines. Six guideline development committees were organized to develop “Treatment Guidelines 2010” for “chronicheadache” (published in 2013), “dementia” (published in 2010), “epilepsy” (published in 2010), “multiple sclerosis” (publishedin 2010), “Parkinson disease” (published in 2011), and cerebrovascular disease (published in 2009), as well as a guideline
development committee for “genetic diagnosis of neurological disorders” (published in 2009).
On the occasion of the development of “Treatment Guidelines 2010”, the Japanese Society of Neurology established aconsistent structure, the guideline development committee, and procedures for all the guidelines to be developed by theSociety. Regarding conflicts of interest, the committee members involved in the development of these guidelines submitted
to the President a “Japan Neurological Society Declaration of Conflict of Interest” and obtained an “Approval Regarding
Conflict of Interest” from the Japanese Society of Neurology. With the exception of Parkinson’s disease, the revised guidelines
for all other diseases were developed by joint committees with corroboration from other academic societies.
The guidelines published between 2009 and 2011 were those for representative neurological diseases. However, due to anincrease in demand of guidelines for other neurological diseases, a decision was made at the Executive Board in 2011 to
publish new clinical practice guidelines for six additional neurological disorders (Guillain-Barré syndrome/Fisher syndrome,chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy, amyotrophic lateral sclerosis, bacterial
meningitis, Duchenne muscular dystrophy, and myasthenia gravis). These guidelines were published in 2013‒2014, and havebeen widely used clinically as “Guidelines 2013”.
For the present series of guideline revision/development, revision of the guidelines for “genetic diagnosis” (published in2009), “epilepsy” (published in 2010), “dementia” (published in 2010), “multiple sclerosis” (published in 2010), and“Parkinson disease” (published in 2011) as well as development of guidelines for “herpes simplex encephalitis” and “dystonia”
were approved at the Executive Board in 2013, while the development of “Clinical practice guideline for spinocerebelladegeneration and multiple system atrophy” was approved at the Executive Board in 2014.
As with previous guidelines, revision or development of the above guidelines was based on the concept of evidence-based
medicine (EBM) and guided by Minds Manual for Guideline Development 2007 edition, or 2014 edition for those guidelinesthat were able to utilize the 2014 edition (guidelines for multiple sclerosis/neuromyelitis optica, Parkinson’s disease, andepilepsy were developed according to the 2014 edition). The 2014 edition recommends introduction of the GRADE system,with the participation of both patients and medical staff in formulating the clinical questions. The GRADE system approachis also adopted as a part of the new guidelines.
Clinical practice guidelines are developed based on current medical knowledge with the purpose to assist clinicians inmaking clinical decisions to provide appropriate medical care. Clinical care provided for each patient should be decided
individually by the attending doctor based on all the clinical data, and the clinical practice guidelines by no means restrict
the clinical discretion of doctors. Clinical practice guidelines are not supposed to be applicable to all the patients; they are
created as a reference for each treatment setting after the doctor has accurately grasped the patient’s condition.
Treatments for neurological diseases are advancing rapidly, and the clinical practice guidelines will need to be revised
regularly in the future. We sincerely hope that the new clinical practice guidelines will help members of our Society in theirroutine medical practice, and we look forward to your evaluations and opinions to improve the clinical practice guidelines
for the next revision.
May 2017
Hidehiro Mizusawa, Past President
Ryosuke Takahashi, Executive President
Gen Sobue, Past Chairman, Guideline Executive Committee
Satoshi Kamei, Chairman, Guideline Executive Committee
Japanese Society of Neurology

iv

Clinical Practice Guidelines for Epilepsy 2018

Revision of the Clinical Practice Guidelines for Epilepsy
Introduction
Epilepsy affects a large number of people, and many doctors other than epilepsy specialists are involved in providing
treatment for these patients. For this reason, the Epilepsy Treatment Guideline Development Committee developed the
Epilepsy Treatment Guideline 2010 as a guide for general practitioners who treat patients with epilepsy. Following publicationof the guideline, new antiepileptic drugs were launched, and the British epilepsy guideline (NICE) was revised, so was
epilepsy classification by the International League Against Epilepsy (ILAE). In this revision, descriptions of new antiepileptic
drugs have been added. As the first attempt of the Society, systematic review was performed using the GRADE (Grading ofRecommendations Assessment, Development and Evaluation) system for three clinical questions (CQ) to be described later.
Anti-NMDA receptor antibody encephalitis, the treatment method of which has drawn attention in recent years, is also
described in the revised guideline, together with a brief summary of the latest diagnosis, tests, treatments and prognosis ofadult and childhood epilepsies.
Adopting the same approach as the previous edition, this revised guideline uses the format consisting of CQ (purpose) and
its answer. The CQs that have been systematically reviewed are colored in green to distinguish them from other CQs, andthe strength of recommendation and quality of evidence are described, followed by comment on the evidence. For the other
CQs, “Summary” is used to describe the overall opinions of experts (colored in red), followed by comment.
This guideline was prepared by the Clinical Practice Guidelines for Epilepsy Development Committee (abbreviated as
Guideline Development Committee hereinafter) of the Japanese Society of Neurology, and was developed in collaboration
with the Japan Epilepsy Society, the Japan Neurosurgical Society, the Japan Society of Child Neurology, and the JapaneseSociety of Neurological Therapeutics. The Guideline Development Committee consists of neurologists, pediatricians,
psychiatrists, and neurosurgeons who are members of the above-mentioned academic societies.

1. F
 unding Sources for the development of Clinical Practice Guidelines for Epilepsy and conflictsof Interest (COI) of committee members
Preparation of this guideline was funded by the Japanese Society of Neurology. The proceeds from sales of this guideline
will be appropriated to cover the cost of preparation.
The chairman, vice-chairman, committee members, external members, collaborators, and evaluation/coordinationcommittee members who are involved in the preparation of this guideline have submitted the “Declaration Form of Conflictof Interest for Preparation of the Japanese Society of Neurology Clinical Practice Guidelines” to the Executive President of
the Japanese Society of Neurology, and obtained approval from the Japanese Society of Neurology for the disclosure ofconflicts of interest.
The companies that have declared COI are shown below.
• ASKA Pharmaceutical Co. Ltd.
• Eisai Co., Ltd.
• Otsuka Pharmaceutical Co. Ltd.
• GlacoSmithKline K.K.
• Southern TOHOKU Hospital Group• Daiichi Sankyo Co., Ltd.
• Sumitomo Dainippon Pharma Co., Ltd.
• Association of Radio Industries and Businesses• MSD K.K.
• Nihon Kohden Corp.
• Novartis Pharma K.K.
• Medical Review Co., Ltd• UCB Japan Co. Ltd.

Preface  v

2. On the use of this guideline
This clinical practice guideline provides recommendations to support the clinical decisions of healthcare professionals,
and the recommendations have no enforcing power. The actual clinical decision should be made upon comprehensively
considering not only this clinical practice guideline, but also the latest evidence, patient values, and environmental factors.
This clinical practice guideline does not promise to improve clinical outcomes. The Guideline Development Committee
is not responsible for the results of medical treatments conducted using this clinical practice guideline.
This clinical practice guideline is not supposed to be used as evidence in a medical lawsuit. Since decision-making in
actual clinical practice is based on comprehensive assessments including patients’ values ​​and environmental factors whilereferring to the recommendations in the clinical practice guidelines, providing medical treatment that deviates from therecommendations of the clinical practice guideline does not necessarily imply negligence. This Guideline Development
Committee does not approve the use of this clinical practice guideline as evidence in a legal trial.

3. Outline of the method of systematic review (Part II)
In the present guideline, systematic review was conducted in three CQs described below, and the digest is summarized inPart II. Details are published on the website of Japanese Society of Neurology.
CQ9-2 	Should temporal lobe resection be added to drug therapy in drug-resistant temporal lobe epilepsy?
CQ10-1	Should vagus nerve stimulation therapy be added to drug therapies for drug-resistant temporal lobe epilepsy?
CQ10-2	When conducting vagus nerve stimulation for drug resistant epilepsy, which intensity of stimulation (high orlow) should we use?
The recommendations were made according to the GRADE system, which is an international standard approach for
guideline development. In the GRADE system, a systematic review is conducted for each outcome; then based on the results,a panel meeting is convened to formulate the recommendations.
Formulating clinical question (CQ)
The CQ was decided by the Guideline Development Committee, as the clinical issue for which a recommendations canbe expected to improve the quality of diagnosis and treatment for drug-resistant epilepsy.
CQ was formulated by the PICO format. PICO is the acronym for patient (P), intervention (I), comparison (C) andoutcome (C). For each CQ, outcome was decided at the Guideline Development Committee meeting. The outcome wasgraded on a scale of 9 to 1 in descending order of importance. Eventually, outcomes graded as critical (scores 9 to 7) or
important (scores 6 to 4) were selected for systematic review.
Literature search
We requested a librarian who had a contract with Japanese Society of Neurology to construct literature search formulaeand conduct literature search. MEDLINE and Cochrane CENTRAL were used in the search. From the articles yielded fromthe search, duplicates were excluded, the remaining papers were screened by title and abstract, then the full texts were
evaluated, and sorted by outcome. Only literature of randomized controlled trials (RCTs) was adopted for systematic review.
The outline of literature search is shown in the flow diagram.
Integrating evidence data
For each CQ, meta-analysis was conducted for each outcome, where possible. Meta-analysis was performed using the
Cochrane standard application, Review Manager (RevMan) [Computer program] version 5.3 (Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2014).
Fixed-effect models were used for integration of outcomes: Mantel-Haenszel method was used when the outcomes werebinary variables, and inverse variance method was used when the outcomes were continuous variables.
Risk ratio and 95% confidence interval were calculated for outcomes that were binary variables, and mean difference andstandard deviation were calculated for outcomes that were continuous variables, and presented as forest plots.
When the data was not adequate for performing meta-analysis, requests were made to the researchers to obtain more data.
Evaluating quality of evidence
The quality of evidence was evaluated by the method proposed by the GRADE working group, and was graded as “high”,“moderate”, “low”, and “very low”. Since only RCTs were evaluated in this clinical practice guideline, the quality of evidence
started from a score of “high”. From there, the score might be downgraded depending on the result of evaluation of theviClinical Practice Guidelines for Epilepsy 2018

following: “risk of bias”, “inconsistency: variation of treatment estimates between studies”, “indirectness: dissociation
between PICO of primary study and PICO of CQ”, “imprecision: low precision of the effect estimate due to small numberof samples or events”, and “publication bias: influence by studies that are not published due to negative results”, according to
the method defined by the GARDE working group.
After determining the final quality of evidence, the results of systematic review were tabulated in the Summary of Findings(SoF) table and GRADE Evidence Profile. GRADEproGDT (https://gradepro.org/) was used for tabulation.
Determination of overall quality of evidence for all outcomes
For each CQ, we adopted the highest quality of evidence if the effects of all the important outcomes were in the same
direction of either benefit or harm to the patient. On the other hand, we adopted the lowest quality of evidence if the effects
of some outcomes were in the direction of benefit while others were in the direction of harm . This quality of evidence issynonymous with the “certainty of evidence” in the recommendation statement.
In the alphabetical notation of GRADE, “high” certainty of evidence is represented by “A”, “moderate” by “B”, “low” by“C”, and “very low” by “D”.
Formulating recommendation from evidence
Recommendation was formulated using the SoF table and GRADE Evidence Profile.
Four factors determine recommendation: “overall quality of evidence for all outcomes”, “balance of benefit and harm”,“variation in values and preferences” and “resources (cost)”.
To determine recommendation at the panel meeting, the following were discussed: “priority of the issue”, “desirable
effects”, “undesirable effects”, “certainty of evidence”, “uncertainty and diversity of values towards major outcomes”, “balance
between desirable and undesired effects”, “costs and resources required”, “acceptability to stakeholders”, and “feasibility”.
The results are described in in the former half of the Evidence-to-Decision (EtD) table; “Evaluation table of recommendation
judgment criteria”.
Then, based on the “Evaluation table of criteria for determining recommendation”, consensus was formed regarding thestrength and direction of recommendation. The grade of recommendation was presented by a combination of the strength
determined as “strong or weak” and the direction determined as “recommended or not recommended”. In GRADE numericalnotation, strong recommendation is represented by “1” and weak recommendation by “2”. The rationale for therecommendation is shown in the latter part of the EtD table; “Recommendation decision table”.
Panel meeting
Panelists participated in the panel meeting include epilepsy specialists (neurologists, pediatricians, psychiatrists andneurosurgeons) who are members of the Clinical Practice Guideline Developing Committee, as well as primary care
physicians, representatives of patients’ families, lawyers, and all other stakeholders.
A panel meeting was held on October 23, 2016, in which CQ9-2, CQ10-1 and CQ10-2 were discussed from noon toevening. The panel meeting was moderated by Eishu Nango, an expert in clinical practice guideline development methods.
After commenting on the GRADE system, participants discussed based on the SoF table, GRADE Evidence Profile, anddraft recommendation statements.
For CQ10-1 and CQ10-2, the recommendations were unanimously agreed. Regarding CQ9-2, almost all the panelists
expressed the opinion that the strength of recommendation was “strong”, but the certainty of evidence was “very low”.
Therefore, “weak recommendation” was decided according to the GRADE rules.
Writing the clinical practice guidelines
Based on the recommendations decided at the panel meeting, the draft of the guidelines was written, was externallyevaluated, and then finalized.

Preface  vii

4. About the notation of antiepileptic drug
For all the drugs that are approved in Japan, the names are written in katakana in the text (Table 1). On the other hand,† is added to denote drugs that are not covered by insurance in Japan.
February 2018
“Clinical Practice Guidelines for Epilepsy” Development Committee
Chairman Yoshikazu Ugawa
Secretariat Yoshihiro Sugiura

Table 1. Antiepileptic drugs approved in Japan.
Generic nameacetazolamide
ethosuximide
oxcarbazepine1)
gabapentin2)
carbamazepine
clonazepam3)
clobazamdiazepam
potassium bromide
stiripentol4)
sultiame
zonisamide
topiramate5)
nitrazepam
valproate
vigabatrin6)
phenytoin
phenobarbital
primidone
perampanel7)
lacosamide8)
lamotrigine9)
ruﬁnamide10)
levetiracetam11)

Abbreviation
AZM
ESM
OXC
GBP
CBZ
CZP
CLB
DZP
KBr
STP
ST
ZNS
TPM
NZP
VPA
VGB
PHT
PB
PRM
PER
LCM
LTG
RFN
LEV

Major brand name
DiamoxEpileo pepti mal, Zarontin
OcnobelGabapenTegretolLandsen, Rivotril,
MystanCercine, Horizon, Diapp
Potassium bromide
Diacomit
Ospolot
ExcegranTopinaBenzalin
Depakene, Selenica
SabrilAleviatin, Hydantol
PhenobalPrimidone
Fycompa
VimpatLamictal
Inovelon
E Keppra1) Oxcarbazepine is approved as combination therapy for partial seizures in children aged 4 years or older, who do not respondadequately to other antiepileptic drugs.
2) Gabapentin is approved as combination therapy for partial seizures in patients aged 3 years or older, who do not respond adequately
to other antiepileptic drugs.
3) Clobazam is approved as combination therapy for partial or generalized seizures not responding adequately to other antiepileptic
drugs.
4) Stiripentol is approved as adjunctive therapy to valproic acid and clobazam for Dravet syndrome.
5) Topiramate is approved as combination therapy for partial seizures in patients aged 2 years or older, who do not respond adequately
to other antiepileptic drugs.
6) Vigabatrin is approved for West syndrome.
7) Perampanel is approved as combination therapy for partial seizures and tonic-clonic seizures in patients aged 12 years or older, who
do not respond adequately to other antiepileptic drugs.
8) Lacosamide is approved as combination therapy for partial seizures not responding adequately to other antiepileptic drugs.
9) Lamotrigine is approved as monotherapy for partial seizures, tonic-clonic seizures and typical absence seizures (aged 15 or older), andas combination therapy for partial seizures, tonic-clonic seizures and generalized seizures in Lennox-Gastaut syndrome notresponding adequately to other antiepileptic drugs.
10) Rufinamide is approved as combination therapy for tonic seizures and atonic seizures in Lennox-Gastaut syndrome in patients aged
4 years or older, who do not respond adequately to other antiepileptic drugs.
11) Levetiracetam is approved as monotherapy for partial seizures in patients aged 4 years or older, and as combination therapy for tonicclonic seizures.

viii

Clinical Practice Guidelines for Epilepsy 2018

CONTENTS
Publication of Clinical Practice Guidelines for Neurological Diseases
Revision of the Clinical Practice Guidelines for Epilepsy

Part I Clinical Practice Guidelines for Epilepsy 2018
Chapter 1 Diagnosis, Classification and Differential Diagnosis of Epilepsies (Including REM Sleep
Behavior Disorder)
CQ1-1
CQ1-2
CQ1-3
CQ1-4
CQ1-5
CQ1-6

What is epilepsy?...........................................................................................................................................2
What are the key clinical features to be included in history taking for epilepsy diagnosis?............................4
How are epileptic seizure types, epilepsies, epilepsy syndromes, and related seizure disorders
classified?.......................................................................................................................................................6
Which diseases should be differentiated from epilepsy in adults?.................................................................10
Which diseases should be differentiated from epilepsy in children?.............................................................11
What are the practical procedures for the diagnosis of epilepsy?..................................................................13

Chapter 2 Examinations for Clinical Practice of Epilepsy
CQ2-1
CQ2-2
CQ2-3
CQ2-4
CQ2-5

How useful is EEG for the diagnosis of epilepsy?.........................................................................................14
What is the significance of EEG examination in the treatment of epilepsy?................................................16
What is the significance of long-term video-EEG monitoring in clinical practice of epilepsy?.....................17
What are the essential neuroimaging studies for clinical practice of epilepsy?.............................................18
What are the useful functional neuroimaging studies for presurgical evaluation of epilepsy?......................19

Chapter 3 Drug Therapy for Adult Epilepsy
CQ3-1
CQ3-2
CQ3-3
CQ3-4
CQ3-5
CQ3-6
CQ3-7
CQ3-8
CQ3-9

Should drug therapy be started after the first epileptic seizure?....................................................................21
What are the recommended drugs for new-onset partial epilepsy?...............................................................22
What are the recommended drugs for new-onset generalized epilepsy?.......................................................24
Which antiepileptic drugs should be avoided for generalized epilepsies?......................................................25
What are the recommended drugs for patients with a risk of psychiatric symptoms?...................................26
What are the recommended drugs when complicated with medical diseases?..............................................28
What are the recommended drugs for elderly-onset epilepsy? .....................................................................29
What are the combined drugs that require special caution for epilepsy patients?.........................................30
What are the precautions when switching from the original antiepileptic drugs to generic drugs?..............32

Chapter 4 Epilepsies in Children and Adolescents and Their Treatment
CQ4-1
CQ4-2
CQ4-3
CQ4-4
CQ4-5
CQ4-6

Which epilepsy syndromes with childhood or adolescent onset have high prevalence?................................33
What examinations are recommended for the first unprovoked seizure in children and adolescents?..........35
For unprovoked seizures in children and adolescents, is the long-term prognosis worse if treatment
would start after the second seizure.............................................................................................................37
How to make a diagnosis of juvenile myoclonic epilepsy?............................................................................38
What are the first-line drugs for childhood- or adolescence-onset epilepsy with undetermined
seizure type (partial or generalized)?............................................................................................................39
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 arein the therapeutic ranges, which drugs should be the next candidates?....................................................... 40

Chapter 5 Drug-Resistant Epilepsy
CQ5-1
CQ5-2
CQ5-3

What is the definition of drug-resistant epilepsy?........................................................................................ 44
What are the true drug-resistant epilepsies in adults?.................................................................................. 46
What are the drug-resistant epilepsies in children?......................................................................................47

Preface  ix

CQ5-4
CQ5-5
CQ5-6

What is pseudo-resistant epilepsy?...............................................................................................................49
How to manage drug-resistant epilepsies?....................................................................................................50
What are the intellectual prognosis and social prognosis of drug-resistant epilepsy?....................................52

Chapter 6 Treatment Guide by Epilepsy Syndrome
CQ6-1
CQ6-2
CQ6-3
CQ6-4
CQ6-5

What are the drug options for idiopathic partial epilepsy?...........................................................................55
What are the drug options for childhood absence epilepsy?.........................................................................56
What are the drug options for Lennox-Gastaut syndrome?..........................................................................57
What are the drug options for juvenile myoclonic epilepsy?.........................................................................59
What are the drug options for epilepsy with generalized tonic-clonic seizures alone (epilepsy with
grand mal on awakening)?...........................................................................................................................61

Chapter 7 Adverse Effects of Antiepileptic Drugs
CQ7-1

What are the adverse effects of antiepileptic drugs?.....................................................................................63

Chapter 8 Status Epilepticus
CQ8-1
CQ8-2
CQ8-2-(1)CQ8-2-(2)CQ8-2-(3)CQ8-2-(4)CQ8-2-(5)CQ8-2-(6)
CQ8-3
CQ8-4

What is the definition of status epilepticus?.................................................................................................65
Which drugs are used for convulsive status epilepticus?.............................................................................. 66
What treatment should be given when intravenous line has not yet been established?.................................68
What are the drugs for stage 1 status epilepticus?........................................................................................69
How effective is intravenous fosphenytoin for status epilepticus?.................................................................70
How effective is intravenous phenobarbital for status epilepticus?...............................................................71
How effective is midazolam for status epilepticus?.......................................................................................72
How effective is intravenous levetiracetam for status epilepticus?................................................................73
How effective is general anesthesia for refractory status epilepticus?............................................................74
Does EEG monitoring during status epilepticus have clinical significance?.................................................75

Chapter 9 Surgical Treatment for Epilepsy
CQ9-1
CQ9-2
CQ9-3
CQ9-4
CQ9-5
CQ9-6
CQ9-2

Which kinds of epilepsies (syndromes) are indications for surgical treatment?............................................76
Is temporal lobe resection effective for drug-resistant temporal lobe epilepsy?............................................ 77
What are the indications for chronic intracranial EEG (long-term intracranial EEG) in presurgicalevaluation?...................................................................................................................................................79
How to determine the timing of considering surgical treatment?................................................................ 80
Is surgical treatment effective even for drug-resistant epilepsies in children?................................................81
What is the risk of psychiatric symptoms after epilepsy surgery?.................................................................82
Should temporal lobe resection be added to drug therapy in drug-resistant temporal lobe epilepsy?............83

Chapter 10 Stimulation Therapy for Epilepsy
CQ10-1
CQ10-3
CQ10-1
CQ10-2Is vagus nerve stimulation therapy effective for drug resistant epilepsy?.......................................................86
Is intracranial electrical stimulation therapy with implanted electrodes effective for epilepsy?.....................88
Should vagus nerve stimulation therapy be added to drug therapies for drug-resistant temporal lobe
epilepsy?.......................................................................................................................................................89
When conducting vagus nerve stimulation for drug-resistant epilepsy, which intensity of stimulation(high or low) should we use?........................................................................................................................92

Chapter 11 Termination of Epilepsy Treatment
CQ11-1
CQ11-2
CQ11-3
CQ11-4
CQ11-5x

How many years after seizure remission should treatment termination be considered?................................95
Does the risk of seizure recurrence differ depending on seizure type, epilepsy type, or epilepsy
syndrome?....................................................................................................................................................97
Is there an optimal dose reduction speed of antiepileptic drugs?..................................................................98
What are the poor prognostic factors in treatment termination?..................................................................99
Should driving be avoided during dose reduction of antiepileptic drug?....................................................100

Clinical Practice Guidelines for Epilepsy 2018

Chapter 12 Drug Concentration Monitoring
CQ12-1
CQ12-2
CQ12-3
CQ12-4

When should serum concentrations of antiepileptic drugs be monitored?..................................................101
Serum concentration monitoring is useful for which drugs?......................................................................103
Is serum concentration monitoring a requisite in the treatment of patients with hepatic or renal
dysfunction?...............................................................................................................................................106
What are the drugs that interact with antiepileptic drugs?.........................................................................108

Chapter 13 Epilepsy and Women
CQ13-1
CQ13-2
CQ13-3
CQ13-4
CQ13-5
CQ13-6
CQ13-7

What kind of advice and information should be provided regarding pregnancy and childbirth
for women with epilepsy?...........................................................................................................................113
What is to be noted for antiepileptic medication in women at childbearing age?....................................... 116
Is folic acid supplementation needed?......................................................................................................... 118
Is it useful to monitor serum concentrations of antiepileptic drugs during pregnancy?.............................. 119
Are women with epilepsy more likely to have complications during pregnancy?........................................120
Can women with epilepsy have a natural delivery? How are seizures treated during delivery?...................121
Can women taking antiepileptic drugs breastfeed a baby?.........................................................................122

Chapter 14 Diagnosis of psychogenic nonepileptic seizures
CQ14-1
CQ14-2

How are psychogenic nonepileptic seizures differentiated from epileptic seizures?.....................................123
How are psychogenic nonepileptic seizures treated?...................................................................................125

Chapter 15 Psychotic Symptoms of Epilepsy
CQ15-1
CQ15-2

What kinds of psychoses accompany epilepsy and what are their treatments?...........................................127
How to manage depression and suicide-related behaviors associated with epilepsy?...................................129

Chapter 16 Acute Symptomatic Seizures
CQ16-1
CQ16-2
CQ16-3
CQ16-4
CQ16-5
CQ16-6

What is the definition of acute symptomatic seizure?.................................................................................131
What are the causes of acute symptomatic seizures?...................................................................................132
How to manage patients with acute symptomatic seizures?........................................................................133
What kinds of examination are needed for acute symptomatic seizures?....................................................135
How to treat acute symptomatic seizures?..................................................................................................136
How to diagnose and treat anti-NMDA receptor encephalitis?..................................................................137

Chapter 17 Epilepsy and Genetics
CQ17-1
CQ17-2

Relation between epilepsy and genetics......................................................................................................138
Current situation of genetic research and genetic testing for epilepsy........................................................139

Chapter 18 Advice and Information for Patients
CQ18-1
CQ18-2

What kinds of advice should be given to patients?.....................................................................................142
How to give advice on driver’s license?.......................................................................................................143

Part II Systematic Review Digest
CQ9-2
CQ10-1
CQ10-2

Should temporal lobe resection be added to drug therapy in drug-resistant temporal lobe epilepsy?..........148
Should vagus nerve stimulation therapy be added to drug therapies for drug-resistant temporal lobe
epilepsy?.....................................................................................................................................................162
When conducting vagus nerve stimulation for drug resistant epilepsy, which intensity of stimulation(high or low) should we use?......................................................................................................................178

Preface  xiPart I
The Clinical Practice Guidelines
for Epilepsy 2018

Chapter 1
Diagnosis, Classification and Differential
Diagnosis of Epilepsies (Including REM Sleep
Behavior Disorder)
CQ 1-1

What is epilepsy?
Summary
Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures. In other words,
epilepsy is a chronic brain disease, in which abnormal hyperexcitable neurons in the brain cause recurrence of seizure
symptoms. Seizures occur suddenly, manifesting physical symptoms different from the normal state, alteredconsciousness, and motor and sensory changes. The possibility of epilepsy is adequately high if accompanied by
seizures.

Comment
Cerebral neurons generate regular rhythm electrically, while maintaining synchronous neuronal activity in the brain.
Epilepsy is caused by a sudden disturbance of this activity accompanied by abnormal, disorderly discharges of the electricalactivities of neurons in the brain (excessive excitation or synchronization). This may occur in an afebrile state, and the seizure
symptoms are diverse depending on the region of the brain that is involved in the abnormal electrical activity1). These
symptoms include not only “convulsions and spasms” but also various symptoms such as “feeling black out”, “jerking of thebody”, “moving around with loss of consciousness” (see CQ1-4 on page 10, and CQ1-5 on page 11). In addition, epilepsy ischaracterized by recurrence. Electroencephalography (EEG) has a central role in various examinations and is necessary toestablish the diagnosis (see CQ1-6 on page 13).
Traditionally, epilepsy was defined as “two unprovoked seizures occurring at intervals of longer than 24 hours”. In 2014,a task force of the International League Against Epilepsy Organization (ILAE) recognized that epilepsy may be present inspecial circumstances that do not meet the criteria of “two unprovoked seizures”. In order to address this issue, the task force
proposed to consider epilepsy as a disease of the brain defined by any of the following criteria 2): (1) at least two unprovoked(or reflex) seizures occurring at intervals of longer than 24 hours; (2) one unprovoked (or reflex) seizure and a probability offurther seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next
10 years (see Note below); and (3) diagnosis of an epilepsy syndrome.
The term “unprovoked seizure” is a term that describes spontaneous seizure as a chronic disease without a definitive
trigger. In contrast, “provoked seizure” is also known as acute symptomatic seizure or situation-related seizure, which occurs
secondary to acute brain disorders such as encephalitis, trauma, cerebrovascular disorders, and metabolic disorders 3).
Note: Number (2) in the second paragraph signifies that if there is one unprovoked seizure and the risk of recurrence canbe proven to be over 60%, then patient care should be initiated assuming a diagnosis of epilepsy. Some specific examples
include patients with a single seizure occurring at least one month after onset of stroke, and children with a single seizure
simultaneous with a structural or indirect symptomatic etiology for the symptom and an epileptiform EEG. Another example
is patients in whom a specific epilepsy syndrome associated with persistent threshold change can be detected after a single
seizure. Even when the first seizure manifests as status epilepticus, this by itself does not imply epilepsy 2).

2

Part IThe Clinical Practice Guidelines for Epilepsy 2018

▪ References
1) Iinuma K, Fujiwara T, Ikeda A, et al. Japan Epilepsy Society, Task Force on Guideline Committee. Guideline for Diagnosis of Epilepsy. Tenkan
Kenkyu. 2008; 26(1): 110-113 (in Japanese).
2) Fisher RS, Accvedo C, Arzimanoglou A, et al. ILAE Official Report. A practical clinical definition of epilepsy. Epilepsia. 2014; 55(4): 475-482.
3) Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010; 51(4): 671-675.

▪ Search formula and secondary reference sources
PubMed search: September 12, 2008
epilepsy [Mesh] and (define* OR definition*) = 2,382
No references that could serve as evidence were found in Ichushi Web.
PubMed search: June 28, 2015((((((((epilepsy/classification [majr] OR epilepsy/diagnosis [majr])) AND ((define* OR definite*)))) AND (Humans [Mesh] AND (English [LA] OR
Japanese [LA]))) AND (“2008” [Date-Publication]: “2015” [Date-Publication]))) AND ((“ILAE”) OR (“NICE” OR “National Institute for Healthand Care Excellence”)) = 17
Ichushi search: June 25, 2015(((Differential diagnosis/TH) and (((REM sleep behavior disorder/TH or REM sleep behavior abnormality/AL) or (epilepsy/MTH)) and (Japan
Epilepsy Society/AL)))) and (DT = 2008:2015 and PT = excluding proceedings and CK = human) = 6

Chapter 1  

3

CQ 1-2

What are the key clinical features to be included in history
taking for epilepsy diagnosis?
Summary
Accumulation of detailed information (medical history) and a witness of the actual seizure are most useful for the
diagnosis of epilepsy. The chief complaint in most cases is a convulsive seizure (non-convulsive seizure in some cases).
However, usually it is necessary to confirm the history of the seizure at least twice in order to diagnose epilepsy.

Comment
Detailed history taking of clinical features 1 to 3 described below is important for making a diagnosis1, 2).

1. It is important to obtain seizure information from the patient and a witness of the seizure.
a.	 Frequency of seizureb.	 Situation and trigger of the seizure (such as photosensitivity)c.	 Symptoms before and during seizure (physical symptoms, psychological symptoms, and consciousness impairment)d.	 Duration of symptomse.	 Symptoms after the seizuref.	 Presence or absence of injury, tongue bite and urinary incontinenceg.	 Headache and muscle pain after seizureh.	 A ge of the first seizure for a patient with multiple seizuresi.	 Change and evolution of seizure and type of seizurej.	 The last seizurek.	 Relation between seizure and wake-sleep states

2. It is important to include the following clinical features in history taking from a witness of seizure.
a.	 Frequency of seizureb.	 Detailed situations observed before and during seizure (patient’s response, arm and leg movements, open or closed
eyes, eyeball displacement, making sound, facial pallor, respiration and pulse)c.	 Details of movements and behaviors after seizured.	 Video recorded by family members

3. When recording the medical history in the clinical record, it is important to include the following
demographic characteristics.
a.	 A ge (many epilepsies are age-dependent)b.	 Sexc.	 Past history (including perinatal abnormalities, febrile convulsions, head trauma, and mental illness)d.	 Comorbid conditions (see Table 1)e.	 History of alcohol consumption, regular medications, and history of narcotic usef.	 Family historyg.	 Social history

4

Part IThe Clinical Practice Guidelines for Epilepsy 2018

▪ References
1) Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. A national clinical guideline, 2003, p.3-7.
2) Stokes T, Shaw EL, Juarez-Garcia A, et al. Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults andchildren in primary and secondary care. London: Royal College of General Practitioners, 2004, p. 49-50, 85-95.

▪ Search formula and secondary reference sources
PubMed search: October 30, 2008((epileptic seizures or epilepsy) and diagnosis and (interview or (history taking)) and (“sensitivity and specificity” [mh] OR sensitivity [tiab] OR
specificity [tiab] OR likelihood ratio* OR practice guideline [pt] OR likelihood functions [mh] or meta-analysis [mh] OR meta-analysis [pt] ORmetaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation studies [pt] OR validation studies [pt] OR systematic review* OR
systematic [sb] = 58
No references that could serve as evidence were found in Ichushi Web.
PubMed search: June 28, 2015((((((((epilepsy [majr]) AND medical history taking [mesh])) AND (“2008” [Date-Publication]: “2015” [Date-Publication])) AND (English[Language] OR Japanese [Language]))) AND Humans [Filter])) AND (“ILAE” OR “NICE”) = 0
Ichushi search: June 25, 2015(((((epilepsy/MTH)) and (SH = diagnosis)) and (history taking/MTH))) and (DT = 2008:2015 and PT = excluding proceedings) = 0

Table 1. Main comorbid conditions of epilepsy.
1. Birth asphyxia
2. Brain malformation
3. Genetic abnormality
4. Chromosomal abnormality
5. Developmental disorder
6. Metabolic abnormality
7. Hypoxia

8. Central nervous system infection
9. Autoimmune encephalitis
10. Cerebral hemorrhage
11. Cerebral infarction
12. Brain tumor
13. Brain trauma
14. Dementia

Chapter 1  

5

CQ 1-3

How are epileptic seizure types, epilepsies, epilepsy syndromes,
and related seizure disorders classified?
Summary
Classification of epileptic seizures is indispensable for subsequent patient care, examinations, and choice ofantiepileptic drugs. The ILAE classifications are widely used. Diagnosis of epilepsy for patients has importantsignificance on physical, mental, social and economic status. Therefore, it is recommended that specialists conduct
definitive clinical diagnosis of epilepsy.

Comment
Currently, the following ILAE classifications are widely used in Japan: the classification of epileptic seizures of 1981 1) andthe classification of epilepsies, epileptic syndromes and related seizure disorders of 1989 2). However, the ILAE task force
proposed a new disease classification in 2010 3). Tables 1 and 2 show the corresponding classification categories in the new
and old classifications of 1981, 1989 and 2010 4). This guideline follows the classification of seizure types of 1981, in which
epileptic seizures are divided into partial and generalized seizures. “Partial” is used to indicate “focal” or “localizationrelated”.
The feature of the 1981 classification of seizure types is based on an accurate correspondence between seizure symptoms
and EEG findings (left column of Table 1), and the scheme is based on “epileptic discharge” on EEG, which is the information
with the highest sensitivity and specificity. On the other hand, the feature of the 1989 classification of epilepsies and epilepsy
syndromes is based on a 2 × 2 classification table (left column of Table 2). With this classification, idiopathic epilepsies andsyndromes are not necessary only generalized epilepsies but also include some partial epilepsies. Conversely, within
symptomatic epilepsies and syndromes, partial epilepsies and generalized epilepsies are both clearly classified. Furthermore,among these four categories, apart from symptomatic partial epilepsies, all the others have in principle age-dependent onset
and reflect the element of onset age at the same time.
1. Idiopathic partial epilepsies are benign, (1) with childhood onset, (2) manifest localization-related seizure symptoms andlocalized EEG findings, (3) show no abnormal neuroimaging findings, and (4) remit by adolescence. This category
includes benign epilepsy with centrotemporal sharp waves and Panayiotopoulos type with focus in the occipital region.
2. Symptoms suggestive of symptomatic partial epilepsies include: (1) a history of disease that may constitute the etiology,(2) aura, (3) local motor or sensory signs at onset or during seizure, and (4) automatism. However, even with absence
seizures, automatism may sometimes occur.
3. Idiopathic generalized epilepsies rarely have onset older than at 25 years of age and show no other neurological symptoms.
The symptoms suggesting this category include: (1) childhood onset (before adolescence), (2) induced by sleep deprivation
and alcohol, (3) tonic-clonic seizure or myoclonic seizure immediately after waking, (4) seizure type is absence, with noother neurologic symptoms (5) spontaneous photoreaction on EEG, including generalized 3-Hz spike-and-slow-wave
complexes or multiple spike-and-slow-wave complexes.
4. Symptoms suggestive of symptomatic generalized epilepsies include: (1) very early onset (neonatal period, infancy: under
1 year of age), (2) frequent seizures, (3) mental retardation and neurological symptoms from before onset, (4) progression
and regression of neurological symptoms, (5) diffuse EEG abnormalities, and (6) organic morphological abnormalities inthe brain.

6

Part IThe Clinical Practice Guidelines for Epilepsy 2018

The basic concepts for the 2010 classifications are as follows.
1. Modes of seizure manifestation and classification of seizures
The term partial seizure is eliminated, and is replaced by “focal seizures” (with or without impairment of consciousness)(right column of Table 1). “Generalized” and “focal” are redefined. Generalized seizures are seizures that occur within the
network of bilateral cerebral hemispheres, and this network is rapidly involved in seizure. Focal seizures are seizures that
occur within the network limited to unilateral cerebral hemisphere and is either discretely localized or more widelydistributed within unilateral hemisphere.
2. Classification of underlying causes
Instead of the traditional terms “idiopathic”, “symptomatic” and “cryptogenic”, the 2010 classification recommends
modified concepts using the new terms “genetic”, “structural-metabolic” and “unknown”.
This chapter is based on the classifications reported up to the time of this writing (2016), and the classifications publishedthereafter are not addressed.

▪ References
1) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminologyof the International League Against Epilepsy. Epilepsia. 1981; 22(4): 489-501.
2) Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League
Against Epilepsy. Epilepsia.1989; 30(4): 389-399.
3) Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts of organization of seizures and epilepsies: Report of the ILAE Commission
on Classification and Terminology, 2005-2009. Epilepsia. 2010; 51(4): 676-685.
4) Tobimatsu S. Chapter 1. Epidemiology of Epilepsy. 2. Classification (comparison of 1981, 1989 and 2010). In: Guidebook for Epileptologists, Japan
Epilepsy Society (Ed.) Shindan To Chiryousha, Tokyo. 2014, p. 5-10 (in Japanese).

▪ Search formula and secondary reference sources
PubMed search: October 17, 2008((epileptic seizures) or epilepsy) and diagnosis and (classification or categorization) and (“sensitivity and specificity” [mh] OR sensitivity [tiab] OR
specificity [tiab] OR likelihood ratio* OR practice guideline [pt] OR likelihood functions [mh] or meta-analysis [mh] OR meta-analysis [pt] ORmetaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation studies [pt] OR validation studies [pt] OR systematic review* OR
systematic [sb] = 273
No references that could serve as evidence were found in Ichushi Web.
PubMed search: June 28, 2015(((((((epilepsy/classification [majr]) AND classification [ti])) AND(“2008” [Date-Publication]: “2015” [Date-Publication])) AND (English[Language] OR Japanese [Language])) AND Humans [Filter])) AND (“ILAE” OR “NICE”) = 22
Ichushi search: June 25, 2015(((epilepsy/MTH) and (classification/TI))) and (DT = 2008:2015 and PT = excluding proceedings) = 0

Chapter 1  

7

Table 1. International classifications of epileptic seizure types: corresponding categories for the 1981classification and the 2010 revised classification.
1981 classification of seizure type a2010 revised classification of seizure type b

Partial (focal, local) seizures

Focal seizures

A. Simple partial seizures (consciousness not impaired)
1. With motor signs
2. With somatosensory or special sensory symptoms
3. With autonomic symptoms or signs
4. With psychiatric symptoms (most experienced as “complex
partial seizures”

A. Without impairment of consciousness With observable motor or autonomic components. Thisroughly corresponds to the concept of “simple partial seizure.
“Focal motor” and “autonomic” are terms that may adequately
convey this concept depending on the seizure manifestations).
 Involving subjective sensory or psychic phenomena only. This
corresponds to the concept of an aura, a term endorsed in the2001 Glossary.

B. Complex partial seizures
1. Simple partial onset followed by impairment of consciousness   a. With simple partial at onset   b. With automatism at onset   c. With impairment of consciousness at onset

B. With impairment of consciousness This roughly corresponds to the concept of complex partial
seizure. “Dyscognitive” is a term that has been proposed forthis concept.

C. Partial seizures evolving to secondarily generalized seizures
1. Simple partial seizures (A) evolving to generalized seizures
2. Complex partial seizures (B) evolving to generalized seizures
3. Simple partial seizures evolving to complex partial seizures
evolving to generalized seizures

Evolving to a bilateral, convulsive seizure (involving tonic, clonic,
or tonic-clonic components). This expression replaces the term“secondarily generalized seizure.

Generalized seizures

Generalized seizures

A. 1. Absence seizures   a. Impairment of consciousness only   b. With mild clonic components   c. With atonic components   d. With tonic components   e. With automatisms   f. With autonomic component (b-f may be alone or in
combination)
2. Atypical absence seizure   a. Changes in tone more pronounced than A1   b. Onset/offset not abrupt

A. Absence seizures
1. Typical absence seizure
3. Absence with special features   Myoclonic absence   Eyelid myoclonia

2. Atypical absence seizure

B. Myoclonic seizures

B. 1. Myoclonic seizures
2. Myoclonic atonic seizure
3. Myoclonic tonic seizure

C. Clonic seizures

C. Clonic seizure

D. Tonic seizures

D. Tonic seizure

E. Tonic-clonic seizures

E. Tonic-clonic seizure (in any combination)(no clearly corresponding entity)
F. Atonic seizures

F. Atonic seizure

Unclassified epileptic seizures
Neonatal seizures

Unclassified epileptic seizures
Epileptic spasms

Rhythmic eye movements
Chewing
Swimming movement
Seizures that cannot be clearly diagnosed into one of the above
categories should be considered “unclassified” until additional
information allows their accurate diagnosis. However,“unclassified” is not considered a classification category.
Modified from: Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on
Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1981; 22(4): 489-501.
b
Modified from: Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts of organization of seizures and epilepsies:
Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010; 51(4): 676-685.
a8Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 2. International classification of epilepsy syndromes: 1989 classification and 2010 revisedclassification.
1989 classification of epilepsy syndromes a
1. Localization-related (focal, local, partial) epilepsies andsyndromes
1.1 Idiopathic (age-related onset)· Benign childhood epilepsy with centrotemporal spikes· Childhood epilepsy with occipital paroxysms· Primary reading epilepsy
1.2 Symptomatic· Chronic progressive epilepsia partialis continua of childhood(Kojewnikow’s syndrome )· Syndromes characterized by seizures with specific modes ofprecipitation· Temporal lobe epilepsies· Frontal lobe epilepsies· Parietal lobe epilepsies· Occipital lobe epilepsies
1.3 Cryptogenic
2. Generalized epilepsies and syndromes
2.1 Idiopathic (with age-related onset - arranged by age)· Benign neonatal familial convulsions· Benign neonatal convulsions· Benign myoclonic epilepsy in infancy· Childhood absence epilepsy (pyknolepsy)· Juvenile absence epilepsy· Juvenile myoclonic epilepsy (impulsive petit mal)
· Epilepsy with grand mal (GTCS) seizures on awakening· Other generalized idiopathic epilepsies not defined above· Epilepsies with seizures precipitated by specific modes ofactivation
2.2 Cryptogenic or symptomatic (arranged by age)· West syndrome (infantile spasm, nodding spasm)· L ennox-Gastaut syndrome· Epilepsy with myoclonic-astatic seizures· Epilepsy with myoclonic absences
2.3 Symptomatic
2.3.1 Non-specific etiology· Early myoclonic encephalopathy· Early infantile epileptic encephalopathy with suppression burst· Other symptomatic generalized epilepsies not defined above
2.3.2 Specific syndromes
3. Epilepsies and syndromes undetermined whether focal or
generalized
3.1 With both generalized and focal seizures· Neonatal seizures· Severe myoclonic epilepsy in infancy· Epilepsy with continuous spike-waves during slow-wave sleep· Acquired epileptic aphasia (Landau-Kleffner syndrome)· Other undetermined epilepsies not defined above
3.2 Without unequivocal generalized or focal features
4. Special syndromes
4.1 Situation-related seizures· Febrile convulsions· Isolated seizures or isolated status epilepticus· Seizures occurring only when there is an acute metabolic or
toxic event such as alcohol, drugs, eclampsia, nonketotic
hyperglycemia, etc.

2010 revised classification of epileptic syndromes b
Electroclinical syndromes (arranged by age at onset) c
Neonatal period   Benign familial neonatal epilepsy   Early myoclonic encephalopathy  Ohtahara syndrome
Infancy
Epilepsy of infancy with migrating focal seizures
West syndrome
Myoclonic epilepsy in infancy
Benign infantile epilepsy
Benign familial infantile epilepsy
Dravet syndrome
Myoclonic encephalopathy in nonprogressive disordersChildhood
Febrile seizures plus (have infancy onset)
Early onset benign childhood occipital epilepsy syndrome(Panayiotopoulos syndrome) Epilepsy with myoclonic atonic (previously astatic) seizures Benign epilepsy with centrotemporal spikes
Autosomal-dominant nocturnal frontal lobe epilepsy Late
onset childhood occipital epilepsy (Gastaut type) Epilepsy with myoclonic absences Lennox-Gastaut syndrome
Epileptic encephalopathy with continuous spike-and-wave
during sleep (CSWS)d Landau-Kleffner syndrome Childhood absence epilepsy
Adolescence-Adult Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with generalized tonic-clonic seizures alone Progressive myoclonus epilepsies Autosomal dominant epilepsy with auditory features Other familial temporal lobe epilepsies
Less specific age relationship Familial focal epilepsy with variable foci (childhood to adult) Reflex epilepsies
Distinctive constellations Mesial temporal lobe epilepsy with hippocampal sclerosis Rasmussen syndrome Gelastic seizures with hypothalamic hamartoma Hemiconvulsion-hemiplegia-epilepsy
Epilepsy not belonging to these diagnostic categories are
distinguished based on first, presence or absence ofstructural-metabolic disease (presumed cause), and second,mode of seizure onset (generalized vs. focal)
Epilepsies attributed to and organized by structural-metabolic
causes (arranged by etiology)
Malformations of cortical development (hemimegalencephaly,
heterotopias, etc.)
Neurocutaneous syndromes (tuberous sclerosis complex,
Sturge-Weber, etc.) Tumor Infection Trauma
Angioma Perinatal insults Stroke Others
Epilepsies of unknown cause
Conditions with epileptic seizures that are traditionally not
diagnosed as a form of epilepsy per se.
 Benign neonatal seizures Febrile seizures

Modified from: Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminologyof the International League Against Epilepsy. Epilepsia.1989; 30(4): 389-399.
bModified from: Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts of organization of seizures and epilepsies:
Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010; 51(4): 676-685.
cClassification of electroclinical syndromes does not reflect the etiology.
dSometimes also called “electrical status epilepticus during slow sleep (ESES).
a

Chapter 1  

9

CQ 1-4

Which diseases should be differentiated from epilepsy in adults?
Summary
The conditions that may be misdiagnosed as epilepsy are as follows.
(1) Syncope (vasovagal, cardiac, etc.)(2) Psychogenic nonepileptic seizures(3) Hyperventilation or panic disorder(4) Stroke (cerebral infarction, cerebral hemorrhage), transient ischemic attack(5) Parasomnia (REM sleep behavior disorders, non-REM parasomnia)(6) Acute intoxication (drugs, alcohol), drug withdrawal, alcohol withdrawal(7) Acute metabolic disorders (hypoglycemia, tetany, etc.)(8) Acute renal failure(9) Head injury (within one week)(10) Involuntary movements (tic, tremor, myoclonus, paroxysmal dyskinesia, etc.)(11) Episodic ataxia

Comment
Among patients visiting the emergency room with acute onset of loss of consciousness, the most common causes arevasovagal syncope or psychogenic nonepileptic seizure (40%), followed by epilepsy (29%) and cardiac syncope (8%) 1). In the
diagnosis of epilepsy, we should exclude or consider an associated cardiovascular factor 2). A syncope attack is characterized
by no change in consciousness level, fatigue, and malaise after an attack 3, 4). Patients who develop acute convulsion within 1
week after head injury have an overall risk of approximately 25% for developing epilepsy in the future 3). Alcohol withdrawal
may also cause a convulsive attack 3, 4).

▪ References
1) Day SC, Cook EF, Funkenstein H, et al. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med. 1982;
73(1): 15-23.
2) Zaidi A, Clough P, Cooper P, et al. Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol. 2000; 36(1):181-184.
3) Japanese Society of Neurology Ad Hoc Committee of Treatment Guidelines. Guideline for Treatment of Epilepsy 2002. Rinsho Shinkeigaku. 2002;
42(6): 549-597 (in Japanese).
4) Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. A national clinical guideline, 2003. p.3-5.

▪ Search formula and secondary reference sources
PubMed search: October 30, 2008((epileptic seizures) or epilepsy) and diagnosis and (distinguish or differentiate or “Diagnosis, Differential” [Mesh]) and (“sensitivity and specificity”[mh] OR sensitivity [tiab] OR specificity [tiab] OR likelihood ratio* OR practice guideline [pt] OR likelihood functions [mh]) and (meta-analysis[mh] OR meta analysis [pt]OR metaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation studies [pt] OR validation studies[pt] OR systematic review* OR systematic [sb]) = 32
No references that could serve as evidence were found in Ichushi Web.
PubMed search: June 28, 2015((((((“Epilepsy” [Major Mesh]) AND “diagnosis, differential” [MeSH Terms]) AND (English [Language] OR Japanese [Language])) AND(“2008”[Date-Publication]: “2015” [Date-Publication])) AND adult [MeSH])) AND (“ILAE” OR “NICE”) = 4
Ichushi search: June 25, 2015(((((epilepsy/MTH)) and (SH = diagnosis)) and (differential diagnosis/TH))) and (DT = 2008:2015 and PT = excluding proceedings and CK = adult(19‒44), middle-aged (45‒64), elderly (65‒), elderly (80‒)) = 3

10Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 1-5

Which diseases should be differentiated from epilepsy
in children?
Summary
Confirm that there are no features suggestive of the following pathological conditions. Especially, take history
carefully about the situation before and after the attack. In the case of children, check for fever, crying, diarrhea,
sleep-wake rhythm, and whether the child is hungry.
(1) Febrile convulsion(2) Breath-holding spells(3) Benign convulsions with mild gastroenteritis(4) Convulsion during sleep/sleep myoclonus(5) Non-REM parasomnia (night terror/sleepwalking)(6) Tic(7) Syncope (vasovagal, cardiac, etc.)(8) Psychogenic nonepileptic seizures(9) Masturbation(10) Acute metabolic disorders (hypoglycemia, tetany, etc.)

Comment
In children, some diseases or conditions with paroxysmal symptoms are often misdiagnosed as epileptic seizures. The
symptoms and the diseases/conditions that may show these symptoms are as follows: (1) generalized tonic convulsions andtonic-clonic convulsion: febrile convulsions, benign convulsions with mild gastroenteritis, some psychogenic seizures, acutemetabolic disorders, and prolonged cyanotic breath-holding attacks; (2) loss of consciousness and atonic attack: breathholding spells, vasovagal syncope, some psychogenic seizures, some acute metabolic disorders, and some febrile convulsions;(3) muscle jerks: sleep myoclonus and some psychogenic reactions; (4) strange behaviors such as fear and wandering: night
terror, sleepwalking, and psychogenic reactions. Medical history, symptoms, and onset age help differentiate these diseases
from epilepsy, and EEG examination is sometimes needed 1, 2). Note that some febrile convulsions (especially in children over
3 years of age) or some of the acute metabolic disorders may show epileptic discharges (epileptiform EEG) (Table 1).

▪ References
1) Iinuma K, Fujiwara T, Ikeda A, et al. Japan Epilepsy Society. Task Force on Guideline Committee. Guideline for Diagnosis of Epilepsy. Tenkan
Kenkyu 2008; 26(1): 110-113 (in Japanese).
2) Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. A national clinical guideline, 2003.

▪ Search formula and secondary reference sources
PubMed search: October 30, 2008((epileptic seizures) or epilepsy) and diagnosis and (distinguish or differentiate or “Diagnosis, Differential” [Mesh]) and (“sensitivity and specificity”[mh] OR sensitivity [tiab] OR specificity [tiab] OR likelihood ratio* OR practice guideline [pt] OR likelihood functions [mh]) and (meta-analysis[mh] OR meta analysis [pt] OR metaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation studies [pt] OR validation studies[pt] OR systematic review* OR systematic [sb]) = 32
No references that could serve as evidence were found in Ichushi Web.
PubMed search: June 28, 2015(((((((“Epilepsy” [Major Mesh]) AND diagnosis, differential [MeSH Terms])) AND (English [Language] OR Japanese [Language])) AND (“2008”[Date-Publication]: “2015” [Date-Publication])) AND “child” [Filter])) AND (“ILAE” OR “NICE”) = 1
Ichushi search: June 25, 2015((((((epilepsy/MTH)) and (SH = diagnosis)) and (differential diagnosis/TH))) and (DT = 2008:2015 and PT = excluding proceedings and CK=
infancy (2‒5), children (6‒12), young adult (13‒18))) and (Japan Epilepsy Society/AL) = 1

Chapter 1  

11

Table 1. Diseases that have to be differentiated from epilepsy in children – benign convulsions andrelated disorders.
Benign convulsion

Seizure symptoms

EEG
abnormality

Diagnosis

Febrile convulsion

Generalized tonic convulsion accompanied by fever of over 38°C;
tonic-clonic convulsions. From medical history and clinicalexaminations, convulsion seems not attributed to central nervous
system infection, metabolic abnormalities, or other obvious
causes. Atonic febrile convulsions such as atonia, staring, andupward rolling of eyeballs 5%; familial onset 20-30%. EEG may
show epileptiform waves.

+/-

Convulsions
occurring only
during fever. No
symptoms
suggestive of otherdisorders.

Breath-holding cyanotic
spellsChild cries uncontrollably due to pain, anger, or bad mood.
Suddenly stops breathing resulting in cyanosis. Loses
consciousness, becomes limp. If prolonged, whole body becomes
tonic.

-

Medical history.
If anxious,
perform EEG

pallidSuddenly loses consciousness without crying, due to sudden pain,
surprise, or fear. Becomes limp, face turns pale.

-

Benign convulsions withmild gastroenteritis

Generalized afebrile tonic-clonic convulsions caused by diarrhea
or vomiting for 2 to 5 days with mild or no dehydration.
Convulsions may be caused by vomiting alone before diarrhea
occurs. If no abnormalities found in EEG and electrolyte tests, thepossibility is high. Commonly seen in rotavirus infection. 80% of
patients show cluster of 2 or more spasms, lasting 2-3 days in20%.

-

Convulsion during sleep /sleep myoclonus

Convulsion during sleep: brief and minor convulsions occurring at
the beginning of sleep; single or repetitive. Although commonly
left-right asymmetric affecting lower limbs, may be seen in upper
limbs and head muscle. Sleep myoclonus: can occur in all sleep
stages, not only asynchronously but also left-right symmetrically;
not only in distal muscles but also in proximal muscles and trunk.

Medical history,
rotavirus antigen
in feces (otherviruses too),(EEG)

Symptoms, timeof occurrence.
If anxious,
perform EEG

Non-REM parasomnia
Night terror: strong fear that happens suddenly during sleep;(night terror/sleepwalking) showing screams, crying, excitement, tachycardia, etc.; lasting 1 to
10 minutes. One-half of patients also show sleepwalking.
Sleepwalking: suddenly rising during sleep, walking or runningaround, etc., lasting 1 to 40 minutes. Both occur during the first
one-third of sleep at night, and are common among 4-12 year-old
children. Do not wake up even when someone tries to wake them.
Patient does not remember the episode. There may be a family
history.

-

Symptoms, timeof occurrence.
If anxious, perform
EEG and poly­somnography

Tic

Abrupt movements noticeable in the face, neck, shoulders, upper
limbs, etc., which repeat regularly and constantly. Also occurs ineyeballs. Increase with mental tension. Does not disturb othermovements while the tic occurs. Does not bother the patient.
Does not occur during sleep.

-

Symptoms

Vasovagal syncope

Suddenly loses consciousness and collapses; becomes atonic. May
be postural dysregulation occurring during postural change or
standing; vagal reflex due to fear and pain; or reflex due to cough,urination, or swallowing. The duration of consciousness loss isshort.

-

Medical history
and symptoms

Psychogenic nonepileptic
seizures

Diverse seizure symptoms, difficult to diagnose from symptoms
alone. Tends to occur under the same situation. Usually does notoccur where nobody is watching. In the case of only psychogenic
reaction, the reaction may be concomitant with epilepsy. Ictal
EEG is necessary for a reliable diagnosis. See the section of“Psychogenic nonepileptic seizure” (CQ14-1 on page 123).

-

Symptoms
Ictal EEG

Masturbation

Repeated motion of extending lower limbs with force over a longtime. Conscious. When looking closely, the thighs and pelvis arerubbing against the bed or something. Symptoms are interrupted
when the thighs are separated. Sometimes red face can be seen.

-

Observe motions
carefully

Acute metabolic disorders(hypoglycemia, tetany,
etc.)

Hypoglycemia may cause loss of consciousness and tonic-clonic
convulsion. Hypocalcemia may cause tonic convulsion or tonicclonic convulsion. Hyponatremia may cause tonic-clonic
convulsion. Hyperammonemia may cause loss of consciousness
and tonic-clonic convulsion.

-/+

Blood glucose,serum calcium,
serum sodium,blood ammonia,
etc.

12

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 1-6

What are the practical procedures for the diagnosis of epilepsy?
Summary
The main procedures of diagnosis of epilepsy are summarized in Figure 1 1). It is recommended that a neurology
specialist should make a definitive clinical diagnosis of epilepsy.

Comment
In patients presenting with the first unprovoked seizures, EEG recording (including photic stimulation, hyperventilation,and sleep) is recommended 1, 2). Sleep-deprived EEG increases the detection rate of epileptic discharges 2). Neuroimaging
study 1) and video-EEG monitoring are necessary.

▪ References
1) Krumholz A, Wiebe S, Gronseth G, et al. Practice Parameter: Evaluating an apparent unprovoked first seizure in adults: Report of the Quality
Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007; 69(21): 1996-2007.
2) van Donselaar CA, Schimsheimer R-J, Geerts A, et al. Value of the electroencephalogram in adult patients with untreated idiopathic first seizures.
Arch Neurol. 1992; 49(3): 231-237.

▪ Search formula and secondary reference sources
PubMed search: October 30, 2008((epileptic seizures) or epilepsy) and diagnosis and (distinguish or differentiate or “Diagnosis, Differential” [Mesh]) and (“sensitivity and specificity”[mh] OR sensitivity [tiab] OR specificity [tiab] OR likelihood ratio* OR practice guideline [pt] OR likelihood functions [mh]) and (meta-analysis[mh] OR meta analysis [pt] OR metaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation studies [pt] OR validation studies[pt] OR systematic review* OR systematic [sb]) = 32
No references that could serve as evidence were found in Ichushi Web.
PubMed search: June 28, 2015((((epilepsy/diagnosis [majr]) AND diagnosis/methods [majr]) AND ((procedure* OR protocol*)))) AND (“2008” [Date-Publication]: “2015” [DatePublication])) AND (English [Language] OR Japanese [Language]) = 116
Ichushi search: June 25, 2015(((((epilepsy/MTH)) and (SH = diagnosis))) and (DT = 2008:2015 and PT = review)) and (Japan Epilepsy Society/AL) = 2

Figure 1. Procedures for the diagnosis of epilepsy.

Chapter 1  

13

Chapter 2
Examinations for Clinical Practiceof Epilepsy
CQ 2-1

How useful is EEG for the diagnosis of epilepsy?
Summary
Electroencephalography (EEG) is the most useful clinical examination for the diagnosis of epilepsy. In a
considerable number of patients, however, epileptic discharges cannot be detected by only a single routine EEG
examination, and multiple EEG recordings including sleep or sleep-deprived EEG are required.

Comment
Diagnosis of epilepsy is conducted in accordance with the International League Against Epilepsy (ILAE) classification of
epileptic seizure types (1981) as well as classification of epilepsies, epileptic syndromes and related seizure disorders (1989).
Thus, EEG findings are essential in addition to clinical seizure types and neurological symptoms. Regarding the EEG
recording methods, it is desirable to follow the guidelines of the Japanese Society of Clinical Neurophysiology 1).
However, in a considerable number of patients, seizure discharges cannot be detected by a single routine EEG examination.
In a systematic review of 12 articles with evidence levels of classes I and II [as defined by the American Academy of Neurology(AAN)] comprising 1,766 adult patients, approximately 50% of the patients with epilepsy had normal EEG 2). Regarding thequestion of how many EEG examinations are needed to exclude a diagnosis of epilepsy, there is no solid evidence-based
answer. However, some reports indicate that the more EEG examinations are repeated, the higher is the epileptic discharges
detection rate on EEG 3).
In addition, the diagnostic value of sleep EEG is high. In patients in whom no epileptic discharges are detected in awake
recordings, epileptic discharges are often detected by sleep EEG 3). Especially, it has been reported that during sleep, theepileptic discharges detection rate is higher in children than in adults, and higher for partial epilepsy than for generalized
epilepsy.
However, even if epileptic discharges are recorded in EEG, unless the discharges can explain the seizure symptom, thisfinding alone does not necessarily lead to a diagnosis of epilepsy. Abnormal EEG activity is also seen in some normal persons,and one paper reported that epileptiform discharges were recorded in 0.5% (69/13,658) of normal persons 3).
A recent systematic review of 15 articles with a total of 1,799 patients presenting with a first unprovoked seizure analyzed
the (1) sensitivity (percentage of patients with epileptiform discharges on routine EEG among those who had repeatedseizures during one-year follow-up and hence were diagnosed with epilepsy) and (2) specificity (percentage of patients finallydiagnosed with epilepsy among those who were found to have epileptiform discharges on routine EEG) separately in children
and adults 4). In adults, (1) sensitivity was 17.3% and (2) specificity was 94.7%. In children, (1) sensitivity was 58.7% and (2)specificity was 69.6%.

▪ References
1) Japanese Society of Clinical Neurophysiology, Clinical Electroencephalography Examination Standards Revision Committee. Revised clinicalelectroencephalography examination standards, 2002. Japanese Journal of Clinical Neurophysiology. 2003; 31(2): 221-242 (in Japanese). http://
jscn.umin.ac.jp/files/guideline/ClinicalEEGtest.pdf (in Japanese).
2) Krumholz A, Wiebe S, Gronseth G, et al. Practice Parameter: Evaluating an apparent unprovoked first seizure in adults: Report of the Quality
Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007; 69(21): 1996-2007.
3) National Collaborating Centre for Primary Care. The diagnosis and management of the epilepsies in adults and children in primary and secondarycare. 2004, p.1-397.
4) Bouma HK, Labos C, Gore GC, et al. The diagnostic accuracy of routine electroencephalography after a first unprovoked seizure. Eur J Neurol.
2016; 23(3): 455-463.

14Part IThe Clinical Practice Guidelines for Epilepsy 2018

▪ Search formula and secondary reference sources
PubMed search: November 8, 2008
epilepsy [majr] AND (electroencephalography [majr] OR “brain wave” OR “brain waves”) AND classification AND (“sensitivity and specificity”[mh] OR diagnostic errors [mh] OR sensitivity [tiab] OR specificity [tiab] OR predictive value* OR likelihood ratio* OR false negative* OR false
positive* OR controlled clinical trial [pt] OR randomized controlled trial [pt] OR double blind method [mh] OR single blind method [mh] ORpractice guideline [pt] OR diagnosis, differential [mh] OR consensus development conference [pt] OR random* [tiab] OR random allocation [mh]OR single blind* [tiab] OR double blind* [tiab] OR triple blind* [tiab] OR likelihood functions [mh] OR area under curve [mh] OR reproducibilityof results [mh] OR meta-analysis [mh] OR meta-analysis [pt] OR metaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation
studies [pt] OR validation studies [pt] OR systematic review* OR systematic [sb]) = 150
No references that could serve as evidence were found in Ichushi Web.
Additional PubMed search: July 1, 2015
(epilepsy/diagnosis [MeSH Major Topic]) AND Electroencephalography [MeSH] Filters: Clinical Trial; Guideline; Meta-Analysis; Randomized
Controlled Trial; Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 85
No references that could serve as evidence were found in Ichushi Web.

Chapter 2

15

CQ 2-2

What is the significance of EEG examination in the treatmentof epilepsy?
Summary
Generally, EEG examination is useful for the evaluation of therapeutic effect and prognosis of epilepsy.

Comment
Many reports have shown that EEG examination is generally useful for the evaluation of the therapeutic effect and theprognosis of epilepsy. In the treatment of epilepsy patients, it is important to follow the pattern of appearance of epileptic
discharges and their frequency over time 1, 2). In particular, in patients with absence seizure, since the occurrence rate of 3-Hz
spike-and-wave complex on EEG reflects the disease severity, it is useful to do follow-up EEG in order to monitor thetherapeutic effect 3). Also, the type of epilepsy may change, and EEG examination is useful to capture this change 3). However,there is a lack of clear evidence on these issues, and epilepsy patients do not always show abnormal findings in EEG
examinations. On the other hand, even if epileptiform discharges are detected, if they are interictal abnormalities and thepatient is clinically seizure-free, we do not always need to increase the drug dose or add a new antiepileptic drug. Hence, weshould interpret EEG findings during the treatment process taking into account the clinical course and other findings.
Furthermore, regarding the question of how often EEG examination should be done during epilepsy treatment, there is no
solid evidence.

▪ References
1) Fowle AJ, Binnie CD. Uses and abuses of the EEG in epilepsy. Epilepsia. 2000; 41(Suppl 3): S10-18.
2) Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: evaluating an apparent unprovoked first seizure in adults: Report of the Quality
Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007; 69(21): 1996-2007.
3) Binnie CD, Stefan H. Modern electroencephalography: its role in epilepsy management. Clin Neurophysiol. 1999; 110(10): 1671-1697.

▪ Search formula and secondary reference sources
PubMed search: October 30, 2008
(epileptic seizures OR epilepsy) AND diagnosis AND “electroencephalography” [MeSH Terms] AND (“sensitivity and specificity” [mh] ORsensitivity [tiab] OR specificity [tiab] OR likelihood ratio* OR practice guideline [pt] OR likelihood functions [mh]) AND (meta-analysis [mh] OR
meta-analysis [pt] OR metaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation studies [pt] OR validation studies [pt] ORsystematic review* OR systematic [sb]) = 125
No references that could serve as evidence were found in Ichushi Web.
Additional PubMed search: July 2, 2015((epilepsy [MeSH Major Topic]) AND Electroencephalography [MeSH Major Topic] AND (Monitoring, Physiologic [Mesh] OR monitor*)) Filters:
Guideline; Meta-Analysis; Randomized Controlled Trial; Clinical Trial; Publication date from 2008/01/01 to 2015/12/31; Humans; Japanese;
English = 27
No references that could serve as evidence were found in Ichushi Web.

16

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 2-3What is the significance of long-term video-EEG monitoringin clinical practice of epilepsy?
SummaryLong-term video-electroencephalography (VEEG) monitoring is a useful examination for making a definitive
diagnosis of epilepsy, diagnosis of seizure type, and localization of epileptogenic zone.

Comment
Long-term video-electroencephalography (VEEG) monitoring examination simultaneously records video and EEG
throughout 24 hours of a day, usually for several days 1). The main purpose of this examination is to record “habitual
seizures”. While seizures are recorded at a rate of 2.5‒7% in routine EEG examinations, reports have shown that seizures arerecorded in 70‒85% of the patients when VEEG is performed for 3.5‒6 days 1, 2).
By analyzing the video (seizure symptoms) and EEG (ictal EEG findings), the following can be achieved: (1) differentiationof epileptic seizure from non-epileptic seizure; (2) in the case of epileptic seizure, differentiation of generalized seizure frompartial seizure; (3) in the case of focal seizure, localization of epileptogenic zone 3). Recordings for long duration sometimes
reveal seizures not accompanied by clinical symptoms and interictal abnormalities not usually captured by routine EEG. The
results of the VEEG study may greatly advance the diagnosis and treatment strategy or change them considerably. According
to previous reports, the diagnosis and therapeutic strategy were altered in 55‒60% of the patients who underwent VEEG 1-3).
Patients suspected of being refractory to drug therapy should undergo VEEG examination in a specialized facility 4). VEEG
is not only important in localization of the epileptogenic zone for epilepsy surgery, but is also useful for making a definitive
diagnosis of epilepsy and defining the disease type.

▪ References
1) Michel V, Mazzola L, Lemesle M, et al. Long-term EEG in adults: sleep-deprived EEG (SDE), ambulatory EEG (Amb-EEG) and long-term videoEEG recording (LTVER). Neurophysiol Clin. 2015; 45(1): 47-64.
2) Ghougassian DF, d’Souza W, Cook MJ, et al. Evaluating the utility of inpatient video-EEG monitoring. Epilepsia. 2004; 45(8): 928-932.
3) Yogarajah M, Powell HW, Heaney D, et al. Long term monitoring in refractory epilepsy: the Gowers Unit experience. J Neurol Neurosurg
Psychiatry. 2009; 80(3): 305-310.
4) Labiner DM, Bagic AI, Herman ST, et al. Essential services, personnel, and facilities in specialized epilepsy centers—revised 2010 guidelines.
Epilepsia. 2010; 51(11): 2322-2333.

▪ Search formula and secondary reference sources
PubMed search: July 2, 2015(“epilepsy/diagnosis” [MeSH Major Topic]) AND ((“video recording” [MeSH Terms]) OR ((Monitoring, Physiologic [Mesh] OR monitor*)))Filters: Clinical Trial; Guideline; Randomized Controlled Trial; Meta-Analysis; Publication date from 2000/01/01 to 2015/12/31; Humans; English;
Japanese = 77
No references that could serve as evidence were found in Ichushi Web.

Chapter 2

17

CQ 2-4

What are the essential neuroimaging studies for clinical practiceof epilepsy?
Summary
In the diagnosis of epilepsy, it is necessary to perform magnetic resonance imaging (MRI) or computed tomography(CT). MRI is especially useful in the diagnosis of partial epilepsy.

Comment

MRI or CT examination is essential for the diagnosis of epilepsy 1-3). However, this does not apply to idiopathic generalized
epilepsy or idiopathic partial epilepsy, because organic lesions are rarely found in these epilepsies. Although there is no class
I and II evidence based on direct comparison between MRI and CT, MRI is considered to have higher diagnostic utility
than CT, and is the first choice among several imaging studies 1). Especially when making a diagnosis of partial epilepsy,
MRI is a requisite. However, CT is preferable in the case of emergency, when the patient has a contraindication for MRI, or
when a calcified lesion is suspected 4).
Specifically, the “practical clinical definition of epilepsy” reported by ILAE in 2014 recommends making a diagnosis of
epilepsy in patients presenting with a first unprovoked seizure in whom MRI or CT examination shows organic lesions
suggesting stroke, central nervous system infection, and traumatic brain injury, even though they have experienced only one
seizure episode 2), because these patients have a high risk of seizure recurrence.
Regarding MRI imaging methods, fluid attenuated inversion recovery (FLAIR) images are useful in addition to theconventional T1-weighted and T2-weighted images. FLAIR images have been reported to enhance the diagnostic sensitivity
for epileptogenic lesions such as hippocampal sclerosis and cortical dysplasia. For detecting hippocampal sclerosis, crosssectional images perpendicular and parallel to the long axis of the hippocampus are needed 5). Also, 3 Tesla MRI is usefulwhen evaluating the indication for epilepsy surgery 6). It is reported that 3 Tesla MRI depicts some lesions, such as hippocampal
sclerosis, cortical dysplasia, and dysembryoplastic neuroepithelial tumor (DNT), which are not detected by 1.5 Tesla MRI 6).

▪ References

1) Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: Evaluating an apparent unprovoked first seizure in adults: Report of the Quality
Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007; 69(21): 1996-2007.
2) Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014; 55(4): 475-482.
3) Whiting P, Gupta R, Burch J, et al. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise theseizure focus in people with refractory epilepsy being considered for surgery. Health Technol Assess. 2006; 10(4): 1-250, iii-iv.
4) Harden CL, Huff JS, Schwartz TH, et al. Reassessment: Neuroimaging in the emergency patient presenting with seizure (an evidence-based review)
Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007; 69(18): 1772-1780.
5) Morioka T, Nishio T, Mihara F, et al. Efficacy of the fluid attenuated inversion recovery (FLAIR) sequence of MRI as a preoperative diagnosis ofhippocampal sclerosis. Neurol Surg. 1998; 26(2): 143-150. (in Japanese with English abstract)6) Winston GP, Micallef C, Kendell BE, et al. The value of repeat neuroimaging for epilepsy at a tertiary referral centre: 16 years of experience. Epilepsy
Res. 2013; 105(3): 349-355.

▪ Search formula and secondary reference sources

PubMed search: October 30, 2008((epileptic seizures OR epilepsy) AND (“Magnetic Resonance Imaging” [Mesh] OR “Tomography, X-Ray Computed” [Mesh])) AND (“sensitivity
and specificity” [mh] OR sensitivity [tiab] OR specificity [tiab] OR likelihood ratio* OR practice guideline [pt] OR likelihood functions [mh] AND
meta-analysis [mh] OR meta-analysis [pt] OR metaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR validation studies [pt] ORsystematic review* OR systematic [sb]) = 126
No references that could serve as evidence were found in Ichushi Web.
Additional PubMed search: July 2, 2015(“epilepsy/diagnosis” [MeSH Major Topic]) AND ((“magnetic resonance imaging” [MeSH Terms] OR “ultrasonography” [MeSH Terms])) Filters:
Clinical Trial; Guideline; Meta-Analysis; Randomized Controlled Trial; Publication date from 2008/01/01 to 2015/12/31; Humans; English;
Japanese = 48
No references that could serve as evidence were found in Ichushi Web.

18

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 2-5

What are the useful functional neuroimaging studies forpresurgical evaluation of epilepsy?
Summary
Nuclear medicine imaging techniques [interictal glucose metabolism fluorodeoxyglucose-positron emission
tomography (FDG-PET), cerebral blood flow single photon emission computed tomography (SPECT), and iomazenil
SPECT, as well as ictal cerebral blood flow SPECT] and magnetoencephalography (MEG) may be useful as presurgicalevaluation tools for partial epilepsy by providing localization of MRI-negative epileptogenic zones.

Comment
In the presurgical evaluation of surgical indication for patients with partial epilepsy, nuclear medicine neuroimaging
studies as well as magnetoencephalography (MEG) are used to localize the epileptogenic zones. Although the usefulness ofthese modalities in preoperative diagnosis is yet to be established 1), they may be useful in localizing MRI-negative
epileptogenic zones. Even for MRI-positive lesions (with MRI structural lesions), additional information may be obtained.
Nuclear medicine imaging techniques include positron emission tomography (PET) and single photon emission computed
tomography (SPECT). In general, epileptogenic zones exhibit reduced metabolism or blood flow during the interictal period,and increased metabolism or blood flow during the ictal period. The above examinations are conducted to image thesechanges in an attempt to identify the epileptogenic zone. PET methods include FDG-PET using [18F] fluorodeoxyglucose(FDG) to observe glucose metabolism, and SPECT methods include cerebral blood flow SPECT using N-isopropyl-123I-piodoamphetamine (IMP) or 99mTc-ethyl-cysteinate dimer (ECD) to measure cerebral blood flow.
The spatial resolution of FDG-PET is higher than that of SPECT, and the detection power of epileptogenic zone is also
higher. Hence, FDG-PET may be useful for the detection of MRI-negative epileptogenic zone 2). Especially, coregistering
FDG-PET image to MRI enables us to know the accurate distribution of the regions with reduced metabolism. On the other
hand, while many reports have indicated that ictal SPECT, which captures the high blood flow region at the time of seizure,is the most powerful method to detect the responsible focus, there is no clear evidence to support it 2). Another powerful
method is the subtraction ictal SPECT coregistered to MRI (SISCOM). In this method, the regions of statistically increased
blood flow obtained by subtracting the interictal SPECT image from the ictal SPECT image are superimposed on MRI. Thismethod is useful for detecting the epileptogenic zone in extra-temporal lobe epilepsy or MRI-negative partial epilepsy 3, 4).
Iomazenil SPECT using 123I-iomazenil depicts the distribution of central benzodiazepine receptors (BZR). Central BZR
couples with the GABA A receptor (the primary inhibitory neurotransmitters) to form the chloride channel. These inhibitory
neurotransmitters are presumably decreased in the epileptogenic zone. Thus, iomazenil SPECT was anticipated to be capableof directly depicting their distribution. However, there is no clear evidence for its usefulness 5).
MEG is a neuromagnetic technique that measures the magnetic field generated by electrical activity of neurons. Thismethod estimates the location of electrical source of interictal epileptic discharges. Magnetic source imaging is the techniqueof superimposing this electrical source on anatomical MRI. This method is a useful tool for noninvasive presurgical evaluationof epilepsy surgery 6). When all noninvasive presurgical examinations fail to pinpoint the location of the epileptogenic zone,
we should perform invasive EEG recording using subdural electrodes. In that case, magnetic source imaging provides useful
information for deciding the sites of electrode placement. Use of magnetic source imaging in presurgical epilepsy evaluation
has been found to correlate significantly with postoperative seizure-free outcome 7, 8).

Chapter 2

19▪ References
1) Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. Lancet Neurol. 2014; 13(11): 1114-1126.
2) Whiting P, Gupta R, Burch J, et al. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise theseizure focus in people with refractory epilepsy being considered for surgery. Health Technol Assess. 2006; 10(4): 1-250, iii-iv.
3) Matsuda H, Matsuda K, Nakamura F, et al. Contribution of subtraction ictal SPECT coregistered to MRI to epilepsy surgery: a multicenter study.
Ann Nucl Med. 2009; 23(3): 283-291.
4) Von Oertzen TJ, Mormann F, Urbach H, et al. Prospective use of subtraction ictal SPECT coregistered to MRI (SISCOM) in presurgical evaluationof epilepsy. Epilepsia. 2011; 52(12): 2239-2248.
5) Kaneko K, Sasaki M, Morioka T, et al. Pre-surgical identification of epileptogenic areas in temporal lobe epilepsy by 123I-iomazenil SPECT: A
comparison with IMP-SPECT and FDG-PET. Nucl Med Commun. 2006; 27(11): 893-899.
6) Lau M, Yam D, Burneo JG. A systemic review on MEG and its use in the presurgical evaluation of localization-related epilepsy. Epilepsy Res. 2008;
79(2-3): 97-104.
7) Knowlton RC, Razdan SN, Limdi N, et al. Effect of epilepsy magnetic source imaging on intracranial electrode placement. Ann Neurol. 2009;65(6): 716-723.
8) De Tiège X, Carrette E, Legros B, et al. Clinical added value of magnetic source imaging in the presurgical evaluation of refractory focal epilepsy. J
Neurol Neurosurg Psychiatry. 2012; 83(4): 417-423.

▪ Search formula and secondary reference sources
PubMed search: October 9, 2008#1 ((epilepsy [majr] AND electroencephalography [majr] OR “brain wave” OR “brain waves” AND Magnetoencephalography [majr])) AND (metaanalysis [mh] OR meta-analysis [pt] OR metaanaly* [tiab] OR “meta analysis” OR multicenter study [pt] OR evaluation studies [pt] ORvalidation studies [pt] OR systematic review* OR systematic [sb] OR “sensitivity and specificity” [mh] OR diagnostic errors [mh] OR sensitivity[tiab] OR specificity [tiab] OR predictive value* OR likelihood ratio* OR false negative* OR false positive* OR controlled clinical trial [pt] OR
randomized controlled trial [pt] OR double blind method [mh] OR single blind method [mh] OR practice guideline [pt] OR diagnosis,
differential [mh] OR consensus development conference [pt] OR random* [tiab] OR random allocation [mh] OR single blind* [tiab] OR double
blind* [tiab] OR triple blind* [tiab] OR likelihood functions [mh] OR area under curve [mh] OR reproducibility of results [mh]) = 25
#2 (epilepsy AND FDG-PET) AND (“sensitivity and specificity” [mh] OR sensitivity [tiab] OR specificity [tiab] OR likelihood ratio* OR practiceguideline [pt] OR likelihood functions [mh]) = 117#3 (epilepsy AND (“tomography, emission-computed, single-photon” [MeSH Terms] OR(“tomography” [All Fields] AND “emission-computed”[All Fields] AND “single-photon” [All Fields]) OR “single-photon emission-computed tomography” [All Fields] OR “spect” [All Fields] OR“SPECT” [All Fields])) AND (“sensitivity and specificity” [mh] OR sensitivity [tiab] OR specificity [tiab] OR likelihood ratio* OR practiceguideline [pt] OR likelihood functions [mh]) = 153
No references that could serve as evidence were found in Ichushi Web.
Additional PubMed search: July 2, 2015(“epilepsy/diagnosis” [MeSH Major Topic]) AND ((((Magnetoencephalography [MH]) OR “FDG-PET”) OR ((“SPECT” OR “Tomography,
Emission-Computed, Single-Photon” [MeSH]))) OR (“PET” OR “Positron-Emission Tomography”)) Filters: Clinical Trial; Meta-Analysis;
Randomized Controlled Trial; Guideline; Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 26
No references that could serve as evidence were found in Ichushi Web.

20

Part IThe Clinical Practice Guidelines for Epilepsy 2018

Chapter 3
Drug Therapy for Adult Epilepsy
CQ 3-1

Should drug therapy be started after the first epileptic seizure?
Summary
After a first unprovoked seizure, treatment with antiepileptic drugs should not be started, except under thefollowing circumstances. Even after a first seizure, treatment initiation is considered if there is a neurologicalabnormality, an abnormal electroencephalogram, a lesion shown by neuroimaging studies, or a family history of
epilepsy, because the recurrence rate is high under the above conditions. Treatment may be started after a first seizure
in some patients in consideration of the patient’s social situation or desire. In the elderly, treatment is consideredafter a first seizure since the risk of recurrence after the initial seizure is high. After a second seizure, starting
antiepileptic drug is recommended because the risk of seizure recurrence within one year is high.

Comment
Patients with a first unprovoked seizure have approximately 35% risk of recurrence in the subsequent 5 years, whereas
patients with a second attack have a risk of recurrence of 73% within one year 1, 2).
At the start of treatment, especially for a long-term treatment policy, patients should be given explanations of theirdisease condition, treatment period, adverse effects of drugs, etc., and given due respect of self-determination of their own
treatment 3-5).
The risk of recurrence after the first seizure is high (66–90%) in elderly people compared to young people. Therefore,
treatment is often started after the first seizure 6).
When comparing starting drug therapy immediately after the first seizure, after the first recurrence, and after the fifth
recurrence, there is a slight difference among the three timings of treatment initiation in the seizure control rate during thesubsequent 2 years, but no difference in more long-term seizure outcome. In a study of 525 epilepsy patients (mean age 29
years; mean onset age 26 years; idiopathic epilepsy in 27%, symptomatic epilepsy in 29%, and cryptogenic epilepsy in 45%)
followed for an average of 5 years, 37% of the patients with more than 20 seizures before starting treatment (n = 185) hadrecurrence within one year, compared with 29% among patients with 20 or less seizures before treatment initiation, and thedifference was significant 4). In addition, the prevalence of persistent seizures was higher in patients with symptomatic or
cryptogenic epilepsy than in those with idiopathic epilepsy (40% vs. 26%)

▪ References
1) Hauser WA, Rich SS, Lee JR, et al. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med. 1998; 338(7): 429-434.
2) Hauser WA, Anderson VE, Loewenson RB, et al. Seizure recurrence after a first unprovoked seizure. N Engl J Med. 1982; 307(9): 522-528.
3) Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: Evaluating an apparent unprovoked first seizure in adults (an evidence-based review):
report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007;
69(21): 1996-2007.
4) Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000; 342(5): 314-319.
5) 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.
6) Ramsay RE, Macias FM, Rowan AJ. Diagnosing of epilepsy in the elderly. Int Rev Neurobiol. 2007; 81: 129-151.

Chapter 3

21

CQ 3-2

What are the recommended drugs for new-onset partial epilepsy?
Summary 1-7)
The recommended first-line drugs are carbamazepine, lamotrigine and levetiracetam, followed by zonisamide andtopiramate. The recommended second-line drugs are phenytoin, valproate, clobazam, clonazepam, phenobarbital,
gabapentin, lacosamide and perampanel.

Comment
For new-onset epilepsy, treatment with antiepileptic drug usually starts with monotherapy. The drugs are selected taking
into consideration the conditions of individual patients based on the diagnosis of seizure type and epilepsy. Basically,
antiepileptic drugs are started at low doses, and the doses are increased gradually until seizures are controlled. If seizures are
not controlled by the first antiepileptic drug, review the diagnosis of epilepsy, check the status of compliance with drug
taking, and confirm whether the maximum tolerated dose has been reached. If the initial drug (first-line drug) is judged to
be ineffective, prescribe the next drug (another first-line drug or a second-line drug) (Table 1).
In February 2018, clobazam, gabapentin, topiramate, and perampanel were approved for adjunctive use with other agentsin Japan.

▪ References
1) 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.
2) Chadwick DW, Anhut H, Greiner MJ, et al. A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International
Gabapentin Monotherapy Study Group 945-77. Neurology. 1998; 51(5): 1282-1288.
3) Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/
Carbamazepine Monotherapy Trial Group. Lancet.1995; 345(8948): 476-479.
4) Nieto-Barrera M, Brozmanova M, Capovilla G, et al. A comparison of monotherapy with lamotrigine or carbamazepine in patients with newly
diagnosed partial epilepsy. Epilepsy Res. 2001; 46(2): 145-155.
5) Lee SA, Lee HW, Heo K, et al. Cognitive and behavioral effects of lamotrigine and carbamazepine monotherapy in patients with newly diagnosed
or untreated partial epilepsy. Seizure. 2011; 20(1): 49-54.
6) Brodie MJ, Perucca E, Ryvlin P, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology.
2007; 68(6): 402-408.
7) Rosenow F, Schade-Brittinger C, Burchardi N, et al; LaLiMo Study Group. The LaLiMo Trial: lamotrigine compared with levetiracetam in theinitial 26 weeks of monotherapy for focal and generalised epilepsy—an open-label, prospective, randomised controlled multicenter study. J Neurol
Neurosurg Psychiatry. 2012; 83(11): 1093-1098.

22

Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 1. Recommended drugs for partial seizures.
Drug name

Abbreviation

Major mechanism of action

Major adverse reactionsFirst-line drugs
Carbamazepine

CBZ

Voltage-dependent Na channel inhibition

Dizziness, diplopia, nystagmus, ataxia, drowsiness,hyponatremia, rash, cytopenia, liver dysfunction,
SJS, DIHS, TEN

Lamotrigine

LTG

Voltage-dependent Na channel inhibition

Drowsiness, dizziness, diplopia, rash, cytopenia,
liver injury, SJS, DIHS, TEN

Levetiracetam

LEV

SV2A bindingDizziness, headache, psychotic symptoms, (badmood, irritability, etc.)

Zonisamide

ZNS

Na channel blockade,Ca channel blockade,
GABA enhancement, CA inhibition

Drowsiness, lethargy, anorexia, hypohidrosis,
urolithiasis, rash, liver dysfunction

Topiramate

TPM

Na channel blockade,Ca channel blockade,
GABA A enhancement,
excitatory amino acid receptor inhibition,
CA inhibition

Drowsiness, lethargy, anorexia, hypohidrosis,
urolithiasis

Second-line drugs
Phenytoin

PHT

Voltage-dependent Na channel inhibition

Dizziness, diplopia, nystagmus, ataxia, drowsiness,rash, cytopenia, liver dysfunction, SJS, DIHS,
TEN

Gabapentin

GBP

Binds Ca channel to modulate neurotransmitter
releaseDrowsiness, dizziness, malaise, headache, diplopia,
myoclonus

Valproate

VPA

Enhancement of GABA A-mediated inhibition,
inhibition of glutamate-mediated excitability

Thrombocytopenia, obesity, alopecia, tremor,
diuresis, fibrinogen decrease, liver dysfunction,acute pancreatitis

Phenobarbital

PB

GABA A-Cl− benzodiazepine receptor, Na/Ca
channel inhibition, glutamate receptor blockade

Drowsiness, sedation, restlessness, excitability,
hyperactivity, ataxia, rash, liver dysfunction,cytopenia

Clobazam

CLB

Enhancement of GABA A-mediated inhibition

Drowsiness, salvation, ataxia, abnormal behavior,airway hypersecretion, rash

Clonazepam

CZP

Enhancement of GABA A-mediated inhibition

Drowsiness, salvation, ataxia, abnormal behavior

Perampanel

PER

Non-competitive AMPA receptor inhibition

Drowsiness, ataxia, psychotic symptom

Lacosamide

LCM

Na channel inhibition (promote slow
inactivation)

Drowsiness, ataxia

CA: carbonic anhydrase, TEN: toxic epidermal necrolysis, DIHS: drug induced hypersensitivity syndrome, SJS: Stevens-Johnson
syndrome
1. In February 2018, clobazam (Mystan), gabapentin (Gabapen), topiramate (Topina) and perampanel (Fycompa) were approved for
adjunctive use with other agents in Japan.
2. A lthough topiramate (Topina) has been approved in America and Europe for both focal and generalized seizures, this drug wasapproved only for partial seizure in Japan in February 2018.

Chapter 3

23

CQ 3-3What are the recommended drugs for new-onset generalized
epilepsy?
Summary 1-11)(1) For generalized tonic-clonic seizures, valproate is recommended as the first-line drug. Lamotrigine,
levetiracetam, topiramate, zonisamide, clobazam, phenobarbital, phenytoin, and perampanel are recommended
as second-line drugs. In women of child-bearing ages, drugs other than valproate are more recommended.
(2) For absence seizures, valproate and ethosuximide, followed by lamotrigine are recommended.
(3) For juvenile myoclonic epilepsy, valproate, clonazepam, levetiracetam, and topiramate are recommended.

Comment
For generalized seizures, the seizure control effect of valproate is superior to the other drugs. However, due to the adverse
effects of valproate, including teratogenicity and effect on neonatal IQ, drugs other than valproate should be considered for
women of child-bearing ages 9-11). During pregnancy, valproate should be avoided when possible, and if valproate is used, adose of 600 mg per day or lower is preferable.

▪ References
1) Biton V, Sackellares JC, Vuong A, et al. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.
Neurology. 2005; 65(11): 1737-1743.
2) Biton V, Di Memmo J, Shukla R, et al. Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled
study. Epilepsy Behav. 2010; 19(3): 352-358.
3) Berkovic SF, Knowlton RC, Leroy RF, et al. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007; 69(18):1751-1760.
4) Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures.
Topiramate YTC Study Group. Neurology. 1999; 52(7): 1330-1337.
5) Barrett J, Gassman C, Lim P, et al. Topiramate (RWJ-17021-000) clinical trial in primary generalised tonic-clonic seizures. 1997. http://download.
veritasmedicine.com/PDF/CR005830_CSR.pdf
6) 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.
7) 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.
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 unblinded randomised controlled trial. Lancet. 2007; 369(9566): 1016-1026.
9) Harden CJ, Meador KJ, Pennell PB, et al. Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): II.
Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of theAmerican Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009; 50(5): 1237-1246.
10) Harden CJ, Pennell PB, Koppel BS, et al. Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): III. Vitamin
K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009; 50(5): 1247-1255.
11) Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;
360(16): 1597-1605.

24

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 3-4

Which antiepileptic drugs should be avoided for generalized
epilepsies?
Summary 1)
Since carbamazepine exacerbates myoclonic seizures and absence seizures, it should not be used for idiopathic
generalized epilepsy. Phenytoin worsens tonic-clonic seizures, and gabapentin exacerbates myoclonic seizures.
Benzodiazepines occasionally exacerbates tonic seizures in Lennox-Gastaut syndrome.

Comments
Unverricht-Lundborg’s disease is a representative disease of progressive myoclonus epilepsy (PME). In a large-scale
study, treatment of Unverricht-Lundborg’s disease with phenytoin effectively controlled current seizures but worsened
survival rate 2). Phenytoin is recommended not to be used for the treatment of PME, because it induces marked cerebellar
ataxia or deteriorates cerebellar ataxia.

▪ References
1) Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia. 1998; 39(1): 5-17.
2) Eldridge R, Iivanainen M, Stern R, et al. “Baltic” myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin. Lancet. 1983;
2(8354): 838-842.

Table 1. Recommended drugs and drugs that should be used with caution for new-onset epilepsies.
Seizure typeFirst-line drugs

Second-line drug

Drugs that should be
used with caution

Partial seizure

Carbamazepine, lamotrigine,
levetiracetam, zonisamide,
topiramate

Phenytoin, valproate, clobazam,clonazepam, phenobarbital, gabapentin,
perampanel, lacosamide

Tonic clonic seizure,clonic seizure

Valproate (excluding women ofchild-bearing potential)

Lamotrigine, levetiracetam, topiramate,zonisamide, clobazam, phenobarbital,
phenytoin, perampanel

Phenytoin

Absence seizure

Valproate, ethosuximide

Lamotrigine

Carbamazepine,
gabapentin, phenytoin

Myoclonic seizure

Valproate, clonazepam

Levetiracetam, topiramate, piracetam,
phenobarbital, clobazam

Carbamazepine,
gabapentin, phenytoin

Tonic seizure,atonic seizure

Valproate

Lamotrigine, levetiracetam, topiramate

Carbamazepine,
gabapentin

Chapter 3

25

CQ 3-5

What are the recommended drugs for patients with a risk ofpsychiatric symptoms?
Summary(1) Patients with intractable epilepsy, limbic seizures, and a family history or past history of psychiatric disorders
are at risk of concomitant psychiatric symptoms. In such patients, we should be cautious with using multiple
antiepileptic drugs, rapid dose increase, and high dose administration.
(2) For patients with depressive disorder, bipolar disorder, anxiety disorder, and psychotic disorder, someantiepileptic drugs should be avoided while use of some other antiepileptic drugs may be considered inindividual patient.

Comment
Some psychiatric symptoms are caused by antiepileptic drugs, and they are sometimes overlooked 1). Antiepileptic drugs
such as ethosuximide, zonisamide, primidone, high-dose phenytoin, topiramate, and levetiracetam may cause acute psy­chosis 1, 2). Potent antiepileptic drugs given at high doses by rapid up-titration may cause forced normalization psychosis, andrapid withdrawal of benzodiazepines may induce acute psychosis. Depressive state and declined mental performancedue to phenobarbital; depressive state due to ethosuximide, clonazepam, zonisamide, topiramate, and levetiracetam; andhypomania due to clobazam have been reported 1, 2). Levetiracetam has been reported to increase aggressiveness, andlamotrigine to cause insomnia, anxiety and irritation 2).
· 
The risk of concomitant psychiatric symptoms is high in patients with intractable epilepsy, limbic seizures, and a pasthistory or family history of psychosis 3).
· 
For patients with depressive disorder, phenobarbital, zonisamide, topiramate, or levetiracetam should not be used, and useof lamotrigine may be considered 2).
· 
For patients with bipolar disorder, use of phenytoin, carbamazepine, lamotrigine, or oxcarbazepine may be considered 2).
· 
For patients with anxiety disorder, lamotrigine or levetiracetam should not be used, and use of benzodiazepines orgabapentin may be considered 2).
· 
For patients with psychiatric disorder, phenytoin, ethosuximide, zonisamide, topiramate, or levetiracetam should not be
used 2).
· To prevent antiepileptic drug-induced psychiatric symptoms, when adding or changing potent antiepileptic drug, do it
over an adequately long duration and provide guidance to patients to maintain compliance with medication 1, 4).

▪ References
1) Matsuura M, Fujiwara T, Ikeda A. Diagnostic and treatment guideline for psychotic comorbidities in adult epilepsy. Tenkan Kenkyu 2006; 24(2):74-77 (in Japanese).
2) Perucca P, Mula M. Antiepileptic drug effects on mood and behavior: Molecular targets. Epilepsy Behav. 2013; 26(3): 440-449.
3) Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associatedwith epilepsy. Epilepsia. 2011; 52(11): 2133-2138.
4) Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet. 2012; 380(9848): 1180-1192.

▪ Search formula and secondary reference sources(((“Epilepsy/drug therapy” [Majr]) AND “adverse effects” [Subheading])) OR “Anticonvulsants/adverse effects” [Majr] Filters: Randomized
Controlled Trial; Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese PubMed = 119

26

Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 1. Antiepileptic drugs that may be considered or should be avoided in patients with concomitant
psychiatric disorders.
Depressive disorder
To be avoided

PB, PRM, ZNS, TPM, LEV

Use may be considered

LTG

Bipolar disorderAnxiety disorder
LTG, LEV

PHT, CBZ, LTG, OXC

Psychiatric disorder
PHT, ESM, ZNS, TPM,LEV

CZP, CLB, GBP(For abbreviations of drugs, see Table 1 on page v of the Revised Clinical Practice Guideline For Epilepsy)(Modified from: Perucca P, Mula M. Antiepileptic drug effects on mood and behavior: Molecular targets. Epilepsy Beh. 2013; 26(3):440-449.)

Chapter 327

CQ 3-6

What are the recommended drugs when complicated withmedical diseases?
Summary 1-4)
(1) In patients complicated with renal or liver dysfunction, antiepileptic drugs should be selected considering
hepatic degradation (valproate, phenytoin, carbamazepine, phenobarbital, benzodiazepines), hepatorenal
degradation (topiramate, lamotrigine), and renal degradation (gabapentin, levetiracetam) of antiepileptic
drugs.
(2) 
There are serious concerns over deterioration of cardiac conduction abnormalities by phenytoin andcarbamazepine, as well as exacerbation of hyponatremia by carbamazepine and valproate.
(3) The effects of phenytoin and carbamazepine on immune disorders; the decline of cognitive function caused byphenobarbital, zonisamide, carbamazepine, and topiramate; and the induction of Parkinsonian symptoms byvalproate have been reported.
(4) W hen phenytoin is used in patients with hypoalbuminemia, the effect of phenytoin is augmented because free(non-albumin binding) phenytoin increases due to the reduced albumin binding rate.

Comment
Many of the existing antiepileptic drugs are metabolized by the liver. On the other hand, a number of new antiepileptic
drugs are metabolized by the kidney.
Phenytoin is the drug with the most serious concern regarding the increase in the fraction of free (non-albumin binding)drug in patients with hypoalbuminemia. Although valproate shares a similar situation, the clinical significance is less marked
compared with phenytoin. In addition, when valproate is used in combination with phenytoin, strong binding of valproate
with albumin results in further increase in free phenytoin.

▪ References
1) Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav. 2005; 7(Suppl 1): S1-64.
2) Leppik IE, Cloyd JC. General principles, epilepsy in the elderly. In: Antiepileptic drugs. 5th ed, Philadelphia: Lippincott Williams & Wilkins,
2002, p.149-158.
3) Gugler R, Shoeman DW, Huffman DH, et al. Pharmacokinetics of drugs in patients with the nephritic syndrome. J Clin Invest. 1975; 55(6): 11821189.
4) Rane A, Wilson JT. Clinical pharmacokinetics in infants and children. Clin Pharamacokinet. 1976; 1(1): 2-24.

28

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 3-7

What are the recommended drugs for elderly-onset epilepsy?
Summary(1) Carbamazepine, lamotrigine, levetiracetam, and gabapentin are recommended for partial seizures in elderly
patients without complications or comorbidities.
(2) L evetiracetam, lamotrigine, and gabapentin are recommended for partial seizures in elderly patients withcomplications or comorbidities.
(3) Lamotrigine, valproate, levetiracetam, and topiramate are recommended for generalized seizures.

Comment
A group of 593 patients (mean age 72 years) with elderly-onset epilepsy (defined as patients aged 65 years or older with
new-onset epilepsy) having seizure frequency of more than once every three months were randomly allocated to lamotrigine
150 mg/day, gabapentin 1,500 mg/day, or carbamazepine 600 mg/day, and observed for 12 months. Carbamazepine showeda slightly higher seizure control rate, whereas lamotrigine and gabapentin were superior in terms of tolerability and lower
medication dropout rate 1). A subsequent study reported that there was no difference in seizure control rate between
levetiracetam and lamotrigine 2).

▪ References
1) Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy. Neurology. 2005; 64(11): 1868-1873.
2) Werhahn KJ, Trinka E, Dobesberger J, et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset
focal epilepsy. Epilepsia. 2015; 56(3): 450-459.

Chapter 329

CQ 3-8What are the combined drugs that require special caution for
epilepsy patients?
Summary(1) Caution is required regarding decreased blood concentration and poor seizure control when antiepileptic drugs
are used in combination with an inhibitor of intestinal absorption (phenytoin with an antacid, gabapentinwith magnesium oxide) or drugs that lower the epileptic seizure threshold (Table 1) 1-3).
(2) Caution is required regarding the drug interaction effects on blood concentration by induction or inhibition ofhepatic metabolizing enzymes (Figure 1) 4).

Comment
Many of the antiepileptic drugs in current use show great interactions between the antiepileptic drugs and with otherdrugs. Given the complicated relations as shown in Figure 1, they are one of the reasons for monotherapy recommendation.
However, even with monotherapy, autoinduction of metabolic enzymes is a characteristic of carbamazepine. There is aconcern over the phenomenon of a decrease in blood concentration from approximately one month after treatment initiationor an increase in blood concentration when the drug is restarted after temporary interruption (see CQ12-4 on page 108).
Gabapentin, levetiracetam, and topiramate (200 mg/day or lower) show little interaction between antiepileptic drugs.
Drugs that lower the epileptic seizure threshold as shown in Table 1 are commonly involved in drug interaction.

▪ References
1) Ikeda A. Functional diseases and neurological/motor diseases. In: Imura Y (Ed.) Easy Guide to Internal Medicine, third Edition. Tokyo: Bunkodo
Co., Ltd. 2008. p. 826-837 (in Japanese).
2) Gilman JT. Drug interaction. In: Pellock JM, Dodson WE, Bourgenus BF eds. Pediatric Epilepsy, Diagnosis and Therapy, 2nd edition. New York:
Demos Medical Publishing. 2001. p.555-562.
3) Walley N, Sisodiya S, Goldstein DB. Pharmacogenetics and pharmacogenomics. In: Engel J Jr, Pedley T eds. Epilepsy: a comprehensive textbook,2nd edition. Philadelphia: Lippincott Williams & Wilkins, 2008. p.1497-1505.
4) Sato T, Ikeda A, Shibasaki H. Symptoms and treatment: epilepsy. In: Treatment Guide for Neurosurgery. Tokyo: Chugai Igakusha. 2002. p. 20-33(in Japanese).

Table 1. Drugs that lower the threshold of epileptic seizure.
During alcohol, barbiturate or benzodiazepines withdrawal
Anti-depressants (imipramine, amitriptyline, SSRI [mild])
Anti-psychotics (chlorpromazine, thioridazine)
Bronchodilators (aminophylline, theophylline)
Antimicrobials (carbapenems, antimicrobial and NSAID combination)
Local anesthetics (lidocaine)
Analgesics (fentanyl, cocaine)
Antitumor agents (vincristine, methotrexate)
Muscle relaxants (baclofen)
Anti-histamines(Modified from: Ikeda A. Functional diseases and neurological/motor diseases.
In: Imura Y (Ed.) Easy Guide to Internal Medicine, Third Edition, Tokyo:
Bunkodo Co., Ltd. 2008. p. 826-837.)

30Part IThe Clinical Practice Guidelines for Epilepsy 2018

Figure 1. Interactions among major antiepileptic drugs and other drugs

PHT: phenytoin, PB: phenobarbital, CBZ: carbamazepine, ZNS: zonisamide, ESM:
ethosuximide, LTG: lamotrigine, VPA: valproate, PER: perampanel
Note: The upper and lower positions between all pairs of drugs show the influence on bloodconcentration or effect. Upper position denotes increase in effect and lower position denotes
decrease in effect.
(Modified from: Sato T, Ikeda A, Shibasaki H. Other symptoms and treatment: epilepsy. In:
Treatment Guide for Neurosurgery. Tokyo: Chugai Igakusha. 2002, p. 29, Figures 1-12)

Chapter 3

31

CQ 3-9What are the precautions when switching from the original
antiepileptic drugs to generic drugs?
Summary
Patients whose seizures are well controlled are recommended not to switch from the original antiepileptic drugs to
generic drugs. When switching from original drugs to generic drugs or between generic drugs, informed consent
from the medical staffs and the patients is indispensable 1, 2).

Comment
There is no high-quality evidence that validates the therapeutic equivalence between original antiepileptic drugs andgeneric drugs. However, seizure recurrence, seizure exacerbation, and adverse effects have been reported in some patients
upon switching from original drugs to generic drugs 1, 2).

▪ References
1) The Japanese Society of Child Neurology Pharmaceutical Affairs Committee and Executive Board. Proposal from The Japanese Society of Child
Neurology: Switching from the original antiepileptic drugs to generic drugs. http://www.childneuro.jp/uploads/files/about/20080325.pdf (inJapanese)
2) The Japan Epilepsy Society. Proposal from The Japan Epilepsy Society: The use of generic drugs as antiepileptic drugs. http://square.umin.ac.jp/jes/
pdf/generic.pdf (in Japanese)

32

Part IThe Clinical Practice Guidelines for Epilepsy 2018

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

36

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

38

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 4

43Chapter 5
Drug-Resistant Epilepsy
CQ 5-1

What is the definition of drug-resistant epilepsy?
Summary
Clinically, drug-resistant epilepsy is defined as the epilepsy which cannot be controlled for a certain period (atleast 1 year or 3 times the longest interval between seizures) by using two appropriately selected antiepileptic drugs(whether as monotherapy or combination therapy), with sufficiently high blood concentrations but without adverse
events.

Comment
Since not all the epilepsies that cannot be controlled by antiepileptic drugs are intractable epilepsies (only some are
intractable), “intractable epilepsy” that was used in the previous edition is replaced by “drug-resistant epilepsy” in the 2018
edition. Some subtle seizures that do not impede daily life and recur several times a year are drug resistant, but not intractable.
Even when antiepileptic drugs fail to control seizures, if the seizure frequency is 1‒2 times a year, the patient is not indicatedfor surgery. However, if seizure frequency is 1‒2 times a month, the patient has an intractable epilepsy in whom surgicaltreatment should be considered.
The definition of drug-resistant epilepsy depends on the use situation and we have no universal definition. The ILAE
proposed the above definition so that it can be applied to various situations1). This definition is intended not only for clinicalsettings but also for purposes such as designing clinical trials, clinical research, and facilitating referral of the patients tospecialized facilities. Referral to specialized facilities is recommended if seizures are not controlled by two appropriately
selected drugs at adequately high doses.
The evidence for two drug regimens was provided by a study of 1,098 adolescent or adult patients with untreated epilepsy.
The seizure-free rate was 50% after the first drug regimen, 13% after the second regimen of monotherapy or combination
therapy, but only 5% after the third to ninth regimen of monotherapy or combination therapy. Since there is very low
possibility of achieving seizure-free status by continued drug therapy after failure of 2 regimens of antileptic drugs asmonotherapy or combination therapy, epilepsy uncontrollable by 2 appropriate drugs as monotherapy or combination
therapy can be regarded as drug resistant2).
The evidence of at least one year is based on community-based studies showing that one or more seizures in the past two
years have various impact such as psychological symptoms or disadvantages in daily life. In addition, being seizure-free forat least one year is a requirement for acquiring a driver’s license in many countries. However, in a long-term follow-up (2-22years, median 6.1 years) study of 780 adolescent-adult patients with untreated epilepsies, out of 462 patients whose seizures
were controlled for more than 1 year at the time of the final observation, 74% had seizures controlled within one year, and
11% within two years after the treatment started. In another definition, drug resistance was defined as seizures persisting
after at least two years of treatment, in addition to control failure with two drugs. This is because the possibility of drug
resistance is high if seizures are not controlled after two years of treatment3).
However, these definitions do not always apply to children, and there are many pediatric patients in whom seizures arewell controlled by three or more drug regimens. In a cohort of 613 children with epilepsy prospectively followed for 13 years
at the longest (median 9.7 years), 128 children who did not respond favorably to two drugs were treated with the third or
more drugs (median 3 drugs). After treatment for 1-14 (median 10.1) years, seizures were controlled for at least 1 year during
this period in 57% of the patients, and seizures were controlled for more than 1 year at the final observation in 38%4).
Therefore, for children, drug resistance must not be defined only by seizures not controlled by two drug regimens, or notcontrolled after 1‒2 years of treatment.
According to the guideline of the Japan Epilepsy Society for the purpose of considering surgical indication, the criterion

44

Part IThe Clinical Practice Guidelines for Epilepsy 2018

of drug-resistant epilepsy is seizures not controlled after more than 2 years of treatment even with 2‒3 kinds of appropriate
drugs5).
It should be noted that there are many patients with pseudo-drug-resistant epilepsy due to misdiagnosis (see CQ5-3 onpage 47).

▪ References
1) Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission
on Therapeutic Strategies. Epilepsia. 2010; 51(6): 1069-1077.
2) Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012; 78(20): 1548-1554.
3) Hitiris N, Mohanraj R, Norrie J, et al. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007; 75(2-3): 192-196.
4) Berg AT, Levy SR, Testa FM, et al. Remission of epilepsy after two drug failures in children: a prospective study. Ann Neurol. 2009; 65(5): 510-519.
5) Mihara T, Fijiwara T, Ikeda A, et al. Guideline on indications for epilepsy surgery. Tenkan Kenkyu. 2008; 26(1): 114-118 (in Japanese).

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015(((refractory/AL and (epilepsy/TH or epilepsy/AL)) and (definition/AL or classification/TH or classification/AL)))) and (DT = 2008:2015 and PT =excluding proceedings) = 27
No references that could serve as evidence were found in Ichushi Web.

Chapter 545

CQ 5-2

What are the true drug-resistant epilepsies in adults?
Summary
Drug-resistant epilepsies in adults include symptomatic partial epilepsies with intracranial lesions (including
cerebrovascular disorder, cerebral dysplasia, brain tumor, hippocampal sclerosis, encephalitis or encephalopathy,
and systemic diseases) on MRI and other imaging studies; cryptogenic partial epilepsies including temporal lobe
epilepsy; symptomatic generalized epilepsies with degenerative disorders such as dentatorubral pallidoluysian
atrophy (DRPLA) or metabolic disorders; various childhood onset epilepsies uncontrolled even in adulthood such as
Lennox-Gastaut syndrome; and epilepsies associated with autoimmune encephalitis.

Comment

In one study, out of a total of 2,200 outpatients (partial epilepsy 1,369 cases, generalized epilepsy 473 cases, andundetermined epilepsy 358 cases) aged 16 years and above, 1,696 patients were treated and followed for 1‒7 years. Amongthem, 45% were seizure-free for one year or longer. By epilepsy classification, the seizure-free rate was 27% in symptomatic(with a definitive cause of epilepsy) or cryptogenic (cause of epilepsy suspected but not definite) generalized epilepsy, 82% in
idiopathic generalized epilepsy, 35% in symptomatic partial epilepsy, 45% in cryptogenic partial epilepsy, and 11% in partial
epilepsy with hippocampal sclerosis. Among the partial epilepsies, seizure-free rate was 20% in temporal lobe epilepsy and
36% in non-temporal lobe epilepsy. For temporal lobe epilepsy, the seizure-free rate was 10% when accompanied byhippocampal sclerosis, and was 31% when not accompanied by hippocampal sclerosis. There was no difference in the seizurefree rate between temporal lobe epilepsy without hippocampal sclerosis and non-temporal lobe epilepsy. The seizure-free rate
was markedly low in hippocampal sclerosis, dual pathology (hippocampal sclerosis + other lesions), and cerebral dysgenesis(11%, 3% and 24%, respectively)1).
In a prospective study of 550 adolescent and adult patients with partial epilepsy treated with antiepileptic drugs, 312(57%) patients were seizure-free for at least 1 year at the last follow-up. The seizure-free rate was 42% in patients with mesial
temporal sclerosis, 78% with cerebral arteriovenous malformation, 67% with cerebral infarction, 63% with brain tumor,
57% with gliosis, 55% with cerebral atrophy, and 54% with cortical dysplasia. Patients with mesial temporal sclerosis werethe most intractable. There was no difference in seizure-free rate between patients with symptomatic partial epilepsy andthose with cryptogenic partial epilepsy2). In patients with Lennox-Gastaut syndrome (mean age 28.6 years) observed for an
average of 16 years, seizures were controlled in only 5% of the patients3).
Among 780 adolescent and adult patients newly diagnosed with epilepsy and followed long-term after treatment initiation(2–22 years, median 6.1 years), 318 (41%) patients did not achieve seizure control at least for the last 12 months of follow-up.
These patients frequently had (1) symptomatic or cryptogenic epilepsy; (2) more than 10 seizures before treatment initiation;(3) a family history of epilepsy, previous febrile convulsion, and traumatic brain injury; (4) nonadherence or irregular use ofantiepileptic drugs; and (5) prior or current psychiatric comorbidity (especially depression)4). The presence of these factors
may predict a high possibility of drug-resistant epilepsy.
Some autoimmune encephalitis-related epilepsies such as autoimmune limbic encephalitis and anti-NMDA receptor
encephalitis are highly drug-resistant and require immunotherapy5). Furthermore, although not an epilepsy, psychogenic
nonepileptic seizure is also highly drug resistant and is difficult to diagnose and treat.

▪ References
1) Semah F, Picot MC, Adam C, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology. 1998; 51(5): 1256-1262.
2) Stephan LJ, Kwan P, Brodie MJ. Does the cause of localization-related epilepsy influence the response to antiepileptic drug treatment? Epilepsia.
2001; 42(3): 357-362.
3) Yagi K. Evolution of Lennox-Gastaut syndrome: a long-term longitudinal study. Epilepsia. 1996; 37(Suppl 3): 48-51.
4) Hitiris N, Mohanraj R, Norrie J, et al. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007; 75(2-3): 192-196.
5) Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neural cell surface proteins. Neurology. 2011; 77(2):179-189.

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015(((refractory/AL and (epilepsy/TH or epilepsy/AL)) and (definition/AL or (classification/TH or classification/AL)))) and (DT = 2008:2015 and PT= excluding proceedings) = 27

46

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 5-3What are the drug-resistant epilepsies in children?
Summary
Drug-resistant epilepsies in children include epileptic encephalopathies with infant and early childhood onset,
such as West syndrome; cerebral dysplasia; chromosomal abnormalities such as 4p minus syndrome; neurocutaneous
syndromes including tuberous sclerosis; post-encephalitis/encephalopathy; post-hypoxic ischemic encephalopathies
such as severe neonatal asphyxia; epilepsy associated with cerebral degenerative/metabolic disorders; and autoimmune
encephalitis-related epilepsy.

Comment

1. Causes of drug resistanceIn one 2-year follow-up study of 381 children with newly diagnosed epilepsy, 75 patients (19.7%) were found to have drugresistant epilepsy. Neuroimaging abnormalities, some abnormalities found in clinical neurological examination, and focal
seizures were associated with drug resistance. Despite treatment of these patients with appropriate drugs for an average of
11.7 years, 49% remained drug resistant, and the resistance was mostly associated with neuroimaging abnormalities1). In
another study, among 459 patients with childhood epilepsy treated for 2‒14 years (mean 7.5 years), 87 patients (19%) were
drug resistant. The factors associated with the drug resistance were age younger than 4 years, developmental delay or motor
deficit, brain structural abnormality, and specific epileptic syndromes2).

2. Relation of drug resistance with epilepsy syndromes or underlying diseases3)
In children, there are drug-resistant epilepsies specific to age of onset4, 5). Infantile epileptic encephalopathies (including
early-stage myoclonic encephalopathy, Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, Westsyndrome, and Dravet syndrome) and early childhood onset epileptic encephalopathies (Lennox-Gastaut syndrome,
myoclonic encephalopathy in non-progressive diseases, and myoclonic absence seizure) are extremely drug resistant. In these
epilepsies, seizure control is almost impossible except for West syndrome, in which seizures could be controlled inapproximately 50% of the cases.
As in adults, seizures caused by localized cortical dysplasia in children are drug resistant, but some childhood-specificepilepsies such as epilepsies associated with unilateral megalencephaly, lissencephaly, and holoprosencephaly are markedly
severe and seizures cannot be controlled by antiepileptic drugs.
Among chromosomal abnormalities, seizures associated with ring chromosome 20 syndrome are intractable, and seizures
associated with 4p minus syndrome (Wolf-Hirschhorn syndrome) are also highly drug resistant.
Among neurocutaneous syndromes, seizures associated with Sturge-Weber syndrome and linear nevus syndrome are notcontrolled by drugs. Tuberous sclerosis is accompanied by epileptic seizures at a very high rate (approximately 85%), andmost cases are West syndrome. West syndrome caused by tuberous sclerosis responds well to vigabatrin, but rarely responds
to other antiepileptic drugs.
Epileptic seizures associated with destructive lesions in the brain caused by hypoxic ischemic encephalopathies such as
encephalitis/encephalopathy, meningitis, and severe neonate asphyxia; as well as seizures associated with neurodegenerationsin the brain such as metabolic neurological diseases and neurodegenerative diseases (including DRPLA, Krabbe disease,neuronal ceroid lipofuscinosis, and GLUT-1 deficiency) are drug resistant, and seizures related to autoimmune encephalitis
are also drug resistant in children.

▪ References
1) Wirrell EC, Wong-Kisiel LCL, Mandrekar L, et al. What predicts enduring intractability in children who appear medically intractable in the first
2 years after diagnosis? Epilepsia. 2013; 54(6): 1056-1064.
2) Ramos-Lizana J, Rodriguez-Lucenilla MI, Aguilera-Lopez P, et al. A study of drug-resistant childhood epilepsy testing the new ILAE criteria.
Seizure. 2012; 21(4): 266-272.
3) Ohtsuki Y, et al. (ed.) Clinical Practice Manual for Rare Refractory Epilepsies. Tokyo: Shindan To Chiryosha, Inc. 2013. (in Japanese)4) Bureau M, Genton P, Dravet C, et al eds. Epileptic syndromes in infancy, childhood and adolescence. Montrouge: John Libbey Eurotext, 2012.
5) Duchowny M, Cross JH, Arzimanoglou A eds. Pediatric Epilepsy. New York, McGraw Hill, 2013.

Chapter 547

Figure 1. Ages of children and specific epilepsy syndromes.

(Modified from: Bureau M, Genton P, Dravet C, et al. eds. Epileptic syndromes in infancy, childhood and adolescence.
Montrouge: John Libbey Eurotext, 2012./ Duchowny M, Cross JH, Arzimanoglou A eds. Pediatric Epilepsy. New York, McGraw
Hill, 2013.)

48

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 5-4

What is pseudo-drug-resistant epilepsy?
Summary
Pseudo-drug-resistant epilepsy arises when appropriate antiepileptic drugs are not used at adequate doses, which
may be due to misdiagnosis of the epilepsy or seizure type, wrong choice of antiepileptic drugs, wrong dosage, orpoor adherence.

Comment
When epilepsy is found to be drug resistant, it may be truly drug resistant; that is, not responding to appropriately selected
antiepileptic drugs at adequate doses, or it may be pseudo-resistant because appropriate drugs are not used at appropriate
doses.

1. In the case of inappropriate choice of drugs(1) The most common cause is misdiagnosis of non-epileptic seizures as epilepsy, such as psychogenic non-epileptic seizures(PNES), syncope, and arrhythmia. (2) Inappropriate drugs are selected due to wrong diagnosis of epilepsy syndrome or
seizure type. (3) The antiepileptic drugs are inappropriate for the correct diagnosis of seizure type or epilepsy syndrome, suchas using carbamazepine for myoclonic seizure leading to exacerbation1).
In one study in which 1,590 patients underwent simultaneous EEG-video monitoring, 32.3% were found to havepsychogenic seizures2). In another study, 46 (25%) of 184 patients treated for epilepsy did not have epilepsy, and 12 (13%) of
94 patients who were regarded as having intractable epilepsy did not have epilepsy3).

2. In the case of drug resistance despite using appropriate drugs
The cause may be due to pharmacokinetics, such as (1) the blood concentration may be low because the dose is inadequate,
or may not be much enough because not titrating the dose to the maximum tolerable level paying too much attention to thetherapeutic range of blood concentration; (2) inappropriate multidrug therapy including a combination of drugs showinginteractions (see Table 1 of CQ 12-4 on page 109) that lower the blood concentration; and (3) occurrence of drug tolerance(including benzodiazepines and acetazolamide).

3. In the case of drug resistance despite prescription of appropriate antiepileptic drugs at adequate doses
The causes may include (1) poor adherence due to a lack of understanding and motivation of epilepsy treatment by thepatient or the family, or excessive anxiety over antiepileptic drugs; (2) induction of seizures by alcohol or drug abuse, andpoor adherence; (3) inappropriate time of drug taking or irregular time of drug taking due to irregular life rhythm such asnight shift; and (4) lifestyle problem such as shift work causing disturbed circadian rhythm, sleep deprivation, and fatigue1).

▪ References
1) Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011; 365(10): 919-926.
2) Martin R, Burneo JG, Prasad A, et al. Frequency of epilepsy in patients with psychogenic seizures monitored by video-EEG. Neurology. 2003;
61(12): 1791-1792.
3) Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. Q JM. 1999;
92(1): 15-23.

Chapter 549

CQ 5-5

How to manage drug-resistant epilepsies?
Summary
The first step to manage drug-resistant epilepsy is finding the cause. After reviewing the seizure symptoms, epilepsy
diagnosis and etiology of epilepsy, assess whether the case is truly drug resistant or pseudo-resistant. In the case ofpseudo-resistance, remove the causative factors (see CQ 5-4 on page 50). In the case of true resistance, review the
drug therapy (diagnosis, choice of drugs, dose, use of antiepileptic drugs based on pharmacokinetics, rational use ofmultidrug combinations, etc.) and consider other treatment options such as surgery and immunotherapy.

Comment

1. Are the choices of drug and dose appropriate?
Confirm the seizure symptoms, medical history, situations when seizures occur, interictal EEG (sleep EEG essential), andbrain MRI. Examine the underlying disease (family history, past history, present illness, general physical findings, andneurological findings). Based on the above, determine whether the case is truly epilepsy or not, and diagnose the seizure typeand epilepsy syndrome, and investigate the etiology of epilepsy. Next, examine the type of antiepileptic drug and dose, andblood concentration. Interview, gesture mimicking seizure symptoms, and video recording by family members are useful toconfirm seizure symptoms.

2. Identification of pseudo-drug resistance and management
a. Differentiation between epilepsy and confounding seizure symptoms (see CQ1-4 on page 10, and CQ1-5 on page 11)
Confirmation of seizure symptoms (from home video if possible), interview (especially the situation of seizure occurrence),
interictal sleep EEG, and video-EEG monitoring are useful.
b. Review diagnosis of epilepsy, epilepsy syndrome and related seizure disorders, as well as seizure type
The procedures are similar to those described above (a). Juvenile myoclonic epilepsy is sometimes misdiagnosed as partial
epilepsy and treated with carbamazepine or phenytoin, which may exacerbate the seizures1).
c. Review the choice of drug and the dose
Examine whether the drug is appropriate for the epilepsy syndrome and seizure type (see Table 1 in CQ4-6 on page 42
and Table 1 in Chapter 6 on page 54), whether the drug is used sufficiently (dose and blood concentration), and whether
tolerance occurs. In the case of multidrug therapy, examine whether each drug is appropriate for the seizure type, whether
there is drug interaction that lowers blood concentration, and whether drugs with the same mechanism of action are used in
combination.
From the above information, switch to the appropriate drug, up-titrate until the maximum tolerated dose with bloodconcentration exceeding the therapeutic range, and confirm the effect. Conduct rational multidrug therapy by selecting
drugs appropriate for each seizure type, increase or decrease the doses considering drug interactions, and use drugs withdifferent mechanisms of action in the combination.
d. When poor adherence is suspected
Confirm the situation of drug taking (time of drug taking, missed doses), lifestyle and rhythm, as well as time andsituation at which seizures often occur. Monitoring blood concentration is useful for detecting habitual poor adherence.
To prevent lowered adherence, explain to the patient and the family about the following: (1) the nature of epilepsy fromthe viewpoint of epilepsy syndrome and the prognosis, (2) the necessity of treatment, (3) caution in daily life, and (4)properties of the drugs being taken (half-life, interaction with other drugs or foods, possible adverse effects and theirfrequency and severity). Also, adjust the time of drug taking considering the patient’s lifestyle such as night shift.

50Part IThe Clinical Practice Guidelines for Epilepsy 2018

3. True drug-resistant epilepsy(1) If MRI detects an intracranial lesion, evaluate for epilepsy surgery soon.
(2) Select first-line or second-line drug that is deemed appropriate, and increase the dose up to the maximum tolerated
dose. As long as adverse effects are not induced, up-titrate to blood concentrations exceeding the therapeutic range. When
adverse effect appears, reduce the dose.
Despite the above procedures, if seizures remain uncontrolled, conduct rational multidrug therapy considering interactionsof antiepileptic drugs (see Table 1 of CQ12-4 on page 109) and the mechanisms of action. Add a drug that has different
mechanism of action from the drug currently being used or a drug with multiple mechanisms of actions2). An effective
combination is to use a Na+ channel blocker and a GABAergic inhibition enhancer. Although the therapeutic effect isincreased by combining two drugs that both enhance GABAergic inhibition, or combining two glutamate receptor inhibitors(such as AMPA antagonist and NMDA antagonist), tolerability is often reduced. Combination of two Na+ channel blockers
not only has limited effectiveness, but also causes adverse effects such as exacerbating dizziness3).
(3) Consider referral to or consultation with epilepsy specialists, measurement of autoimmune antibodies, andimmunotherapies (including intravenous immunoglobulin, steroids, and immunosuppressants), and consider surgicalindication even though MRI shows no intracranial lesions.

▪ References
1) Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol. 2005; 33(4): 227-234.
2) St. Louis EK. Truly “rational” polytherapy: maximizing efficacy and minimizing drug interactions, drug load and adverse effects. Curr
Neuropharmacol. 2009; 7(2): 96-105.
3) Brodie MJ, Sills GJ. Combining antiepileptic drugs—rational polytherapy? Seizure. 2011; 20(5): 369-375.

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015(((intractable [TIAB] OR refractory [TIAB]) AND “Epilepsy/therapy” [majr])) AND “treatment outcome” [mh] Filters: Review; Publication datefrom 2008/01/01 to 2015/12/31; Humans; English; Japanese = 112

Chapter 551

CQ 5-6

What are the intellectual prognosis and social prognosis of drugresistant epilepsy?
Summary
Both intellectual and social prognoses are poorer than people without epilepsy, and there are major disadvantagesin academic, employment, and marriage aspects. These two outcomes are especially poor when seizures are notcontrolled. The rate of sudden death is also higher among people with epilepsy than the general population.

Comment

1. Socioeconomic situation
For people with drug-resistant epilepsy, even when they have no intellectual problems and are in general employment,
their work contents are sometimes restricted. In addition, if seizure occurs at work, they often lose their jobs. They also often
have difficulty in marriage. In the United States, the total household annual income of people with epilepsy is 93% of theaverage annual income of the whole population, their unemployment rate is 25%, the high school graduation rate of those
aged 25 years and above is 64% (82% in the United States in general), and the marriage rate of those aged 19 years and above
is 51% for men and 48% for women (63% and 59%, respectively, in the United States in general)1). This data is for all
epilepsies including treatable epilepsies, and these figures would be even worse in people with drug-resistant epilepsy.

2. Intellectual prognosis
In a study of 136 adults with various epilepsies who had uncontrolled seizures, WAIS-R was performed twice with aninterval of 10 years or longer. The mean verbal IQ decreased from 90.3 to 82.3, performance IQ decreased from 91.0 to 84.5,
and full scale IQ decreased from 91.0 to 84.5, and the frequency of generalized tonic-clonic seizure was most strongly related
to the cognitive decline2).

3. Social prognosis
Among 102 patients (mean age 28.6, range 15‒60 years) with Lennox-Gastaut syndrome followed long-term for 10‒20(mean 16.3) years, 12 patients worked normally, 36 worked part-time or at a sheltered workshop, and the remaining 54 were
under home care or institutionalization3). Most of the 12 patients in normal employment were seizure-free for at least 1 year
or had only tonic seizures during sleep.
Ninety-nine patients with uncomplicated childhood epilepsy (onset age younger than 16 years) followed for 27‒31 years
were compared with controls matched for sex, age, and birthplace. The relative risk of completing primary education only
was 2.1-fold, not married was 3.5-fold, no children was 3.0-fold, and unemployed was 3.8-fold4).

4. Sudden unexpected death in epilepsy (SUDEP)
SUDEP refers to death for which no cause can be found besides suffering from epilepsy.
Patients with epilepsy have high mortality rate and high SUDEP rate. The standardized mortality rate for SUDEP was
24-fold compared to the general population, accounting for 2‒17% of all-cause deaths in epilepsy patients5).
The mortality rate of 2,689 patients with chronic epilepsy who had been followed for 20 years was 2.05 times the mortality
rate of the general population in Scotland matched for sex and age6). The incidence of SUDEP per 1,000 person-years was
0.35‒1.5 cases in a population-based incidence cohort of epilepsy, but increased to 1.2‒3.8 cases in persons with chronic
epilepsy and further to 3.5‒9.3 cases in persons with intractable epilepsy. Seizure frequency is the strongest risk factor for
SUDEP, and other risk factors are onset at an early age and long duration of disease7). The risk of SUDEP increases if
generalized tonic-clonic seizures are not controlled.

52

Part IThe Clinical Practice Guidelines for Epilepsy 2018

▪ References
1) Fisher RS, Vickrey BG, Gibson P, et al. The impact of epilepsy from the patient’s perspective I: descriptions and subjective perceptions. Epilepsy Res.
2000; 41(1): 39-51.
2) Thompson PJ, Duncan JS. Cognitive decline in severe intractable epilepsy. Epilepsia. 2005; 46(11): 1780-1787.
3) Yagi K. Evolution of Lennox-Gastaut syndrome: a long-term longitudinal study. Epilepsia. 1996; 37(Suppl 3): 48-51.
4) Sillanpää M, Jalava M, Kaleva O, et al. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998; 338(24): 1715-1722.
5) Ficker DM, So EL, Shen WK, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology. 1998; 51(5): 12701274.
6) Mohanraj R, Norrie J, Stephen L, et al. Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study. Lancet
Neurol. 2006; 5(6): 481-487.
7) Tomson T, Walczak T, Sillampaa M, et al. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia. 2005; 46(Suppl11): 54-61.

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015((((intractable [TIAB] OR refractory [TIAB]) AND “Epilepsy” [majr])) AND (((“Intelligence” [Mesh] or “Intelligence Tests” [Mesh])) OR “Social
Adjustment” [mh])) AND (“prognosis” [MeSH] OR “cohort studies” [MeSH] OR “follow-up studies” [MeSH]) Filters: Publication date from2008/01/01 to 2015/12/31; Humans; English; Japanese = 36

Chapter 5

53

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.

54

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

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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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Chapter 7
Adverse Effects of Antiepileptic Drugs
CQ 7-1

What are the adverse effects of antiepileptic drugs?
Summary
Adverse effects of antiepileptic drugs comprise idiosyncratic drug reactions, dose-dependent adverse effects, andadverse effects after long-term usage.

Comment
Adverse effects of antiepileptic drugs are roughly divided into acute early idiosyncratic reactions to drugs associated withallergic mechanisms, dose-dependent inhibitory action on the nervous system, and chronic phase adverse effects seen after
long-term usage.
For idiosyncratic reactions to drugs, skin rash is a representative adverse effect occurring at a relatively high frequency.
Rare but serious adverse effects include Stevens-Johnson syndrome (SJS), drug-induced hypersensitivity syndrome (DIHS),
and toxic epidermal necrolysis (TEN). When these conditions are suspected, the suspected drug should be discontinued, anda dermatologist should be consulted. Pancytopenia, myelosuppression, and hepatic dysfunction may also be observed asadverse effects with allergic mechanisms. Most of the adverse effects due to these idiosyncratic reactions occur from 1‒2
weeks to 2‒3 months after the start of treatment. Therefore, attention should be given during the early stage of administration.
Adverse effects due to suppression of the nervous system (neurotoxic side effects) include many adverse effects such asdizziness, nystagmus, diplopia, drowsiness, nausea, anorexia, cerebellar ataxia, and psychiatric symptoms. Many of theseadverse effects are dose-dependent.
Some adverse effects are accompanied by long-term use of antiepileptic drugs, such as weight gain, hypertrichosis or hairloss, urolithiasis, cerebellar atrophy, and gingival hyperplasia. Enzyme inducers (phenytoin, carbamazepine, phenobarbital,and primidone) and valproate are risk factors of osteoporosis.
To identify adverse effects of antiepileptic drugs, systematic adverse effect screening has been reported to be useful1).
Representative adverse effects of major antiepileptic drugs are summarized in Table 1.

▪ References
1) Gilliam FG, Fessler AJ, Baker G, et al. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology.
2004; 62(1): 23-27.

▪ Search formula and secondary reference sources
PubMed search: June 26, 2015(((“Epilepsy/drug therapy” [Majr]) AND “adverse effects” [Subheading])) OR “Anticonvulsants/adverse effects” [Majr] Filters: Randomized
Controlled Trial; Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 119
Ichushi search: June 29, 2015((((((epilepsy/TH or epilepsy/AL)) and (SH = drug therapy)) and (adverse effects/AB or adverse effects/TI)) and (DT = 2008:2015 and PT = excluding
proceedings))) and (PT = Comment, review) = 94

Chapter 7

63

Table 1. Typical adverse effects of major antiepileptic drugs.
Drug

Idiosyncratic adverse effects

Carbamazepine

rash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS

Clobazamrare

Clonazepam

rare

Ethosuximide
Gabapentin
Lamotrigine

rash, pancytopenia
rarerash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS
rare
rash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS
rash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS

Levetiracetam
Phenobarbital

Phenytoin

Primidone

Valproaterash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS
pancreatitis, liver injury

Topiramate

rare

Zonisamide

rare

Rufinamide

drug-induced hypersensitivity
syndrome, SJS, status epilepticus,
aggressiveness, QT interval
shortening
attention deficit, hyperactivity
disorder, talkativeness,sleeping disorder, aggressiveness,prolonged QTrash, leukocytopenia, tachypnea,
paresthesia

Stiripentol

Sultiame

Dose-dependent adverse effects
diplopia, nystagmus, dizziness, ataxia,
drowsiness, nausea, hyponatremia, cardiac
conduction disturbance or cardiac failure,
reduced cognitive function, hearing
abnormality
drowsiness, ataxia, behavioral disorder,
salvation
drowsiness, ataxia, behavioral disorder,
salvation
drowsiness, abnormal behavior
dizziness, ataxia, drowsiness, myoclonus
drowsiness, dizziness, diplopia, excitability

drowsiness, abnormal behavior, bad mooddizziness, ataxia, drowsiness, reduced
cognitive function

Adverse effects after
long-term use
osteoporosis

weight gain

osteoporosis

diplopia, nystagmus, dizziness, ataxia,
drowsiness, peripheral neuropathy, cardiac
conduction disturbance or cardiac failure,
asterixis
dizziness, ataxia, drowsinesscerebellar atrophy,
hypertrichosis, gingival
hyperplasia, osteoporosis

thrombocytopenia, tremor, hyponatremia,
increased ammonia, Parkinson syndrome
anorexia, psychotic symptom, drowsiness,speech symptom, metabolic acidosis,
hypohidrosis
anorexia, psychotic symptom, drowsiness,speech symptom, metabolic acidosis,
hypohidrosis, reduced cognitive function
anorexia, drowsinessweight gain, hair loss,
osteoporosis
urolithiasis, weight loss

osteoporosis

urolithiasis

somnolence, insomnia, anorexia, ataxia

anorexia, drowsiness

SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, DIHS: drug-induced hypersensitivity syndrome[Before prescription, read the package inserts of individual drugs]

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Chapter 8
Status Epilepticus
CQ 8-1

What is the definition of status epilepticus?
Summary
Status epilepticus (SE) was defined as “a seizure that persists for a sufficient length of time or is repeatedfrequently enough that recovery between attacks does not occur” (International League Against Epilepsy: ILAE,
1981)1). Regarding the length of seizure, if convulsive seizure persists for 5 minutes or longer, treatment should bestarted, and if persists for 30 minutes or longer, there is a risk of long-term consequences (ILAE 2015)2).

Comment
In 2015, ILAE proposed a new definition for SE as follows: “Status epilepticus is a condition resulting either from thefailure of the mechanisms for seizure termination or from the initiation of mechanisms provoking abnormally prolonged
seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including
neuronal cell death, neuronal cell abnormality, and alteration of neuronal networks, depending on the type and duration of
seizures”2).
Although the traditional definition did not define the seizure duration, epileptic seizures usually terminate in 1 to 2
minutes in most cases. It has become clear that a prolonged seizure duration is associated with drug resistance. For thisreason, it is recommended that if the convulsive seizure lasts more than 5 minutes (t1)2, 3), the diagnosis of SE should be madeand treatment should be started. In addition, animal experiments have shown that brain damage occurs if the epileptic
discharges continue for 30–45 minutes or more. If seizure persists for more than 30 minutes (t2), there is a risk of serious
long-term consequences2).

▪ References
1) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on classification and Terminologyof the International League Against Epilepsy. Epilepsia. 1981; 22(4): 489-501.
2) Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus—Report of the ILAE Task Force on Classification of
Status Epilepticus. Epilepsia. 2015; 56(10): 1515-1523.
3) Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.
N Engl J Med. 2001; 345(9): 631-637.

▪ Search formula and secondary reference sources
PubMed search: September 12, 2008
Status Epilepticus AND (define* OR definition*) = 136
Additional PubMed search: December 8, 2015
“Status Epilepticus/classification” [Majr] OR “Status Epilepticus/etiology” [Majr] = 24
No references that could serve as evidence were found in Ichushi Web.

Chapter 865

CQ 8-2Which drugs are used for convulsive status epilepticus?
Summary
Figure 1 shows the treatment flowchart for convulsive status epilepticus.

Comment
Early status epilepticus (stage 1) is defined as convulsive seizures persisting for more than 5 minutes. Established statusepilepticus (stage 2) is defined as seizures persisting for over 30 minutes without cessation after treatment with benzodiaze­pines. Refractory status epilepticus (stage 3) is defined as seizures persisting for more than 60–120 minutes despite treat­ment with intravenous infusion or intravenous injection of antiepileptic drugs1). Treatment strategy depends on the
disease stage1-5). When seizures are not controlled even by general anesthesia and persist for more than 24 hours, the conditionis called super-refractory status epilepticus (stage 4), for which no standard treatment strategy has been established1). Nonconvulsive status epilepticus treatment generally follows those for convulsive status epilepticus, but the usefulness ofgeneral anesthesia is undetermined.

▪ References
1) Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.
Brain. 2011; 134(Pt 10): 2802-2818.
2) Brophy GM, Bell R, Claassen J, et al. Neurocritical Care Society Status Epilepticus Guideline Writing Committee. Guidelines for the evaluationand management of status epilepticus. Neurocrit Care. 2012; 17(1): 3-23.
3) Mazurkiewicz-Bełdzińska M, Szmuda M, Zawadzka M, et al. Current treatment of convulsive status epilepticus—a therapeutic protocol andreview. Anaesthesiol Intensive Ther. 2014; 46(4): 293-300.
4) Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015; 14(6): 615-624.
5) Ohsawa M. Treatment for status epilepticus. No To Hattatsu. 2007; 39(3): 185-192. (in Japanese)▪ Search formula and secondary reference sources
PubMed search: September 9, 2008
Status Epilepticus/drug therapy” AND (first-line OR first choice) = 49
Additional PubMed search: June 26, 2015(((Anticonvulsants/therapeutic use [Majr]) AND Status Epilepticus/drug therapy [Majr])) OR ((Status Epilepticus/drug therapy [Majr]) AND((first-line) OR first-choice)) = 242
No references that could serve as evidence were found in Ichushi Web.

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Figure 1. Treatment flowchart for status epilepticus (constructed from references 1‒5).

Chapter 867

CQ 8-2-(1)What treatment should be given when intravenous line has not
yet been established?
Summary
Intrarectal administration of diazepam injection solution is effective. In children, nasal / buccal administrationand intramuscular injection of midazolam are effective (not covered by medical insurance).

Comment
A small-scale prospective open study1) and a small-scale retrospective study2) have demonstrated the efficacy of intrarectal
administration of diazepam injection solution. The incidence of adverse effects including respiratory depression is low, andis safer compared to intravenous injection.
When diazepam is administered intrarectally, the beneficial effect appears within 10 minutes in most cases1, 2). However,to be effective for status epileptics, rather than suppository, gel enema preparation (not available in Japan) or injection
solution should be used. Diazepam suppository lacks fast-acting effect, and is usually not effective in controlling on-going
convulsions3).
In addition, diazepam intramuscular injection is not recommended due to the delayed onset of effect and large variabilityof time course of effects1).
The use of 10 mg (for children 0.3 mg/kg) of midazolam 0.5% injection solution (note: not 0.1% injection) is effective. Ina meta-analysis of a total of 774 children and young adults, non-intravenous midazolam was more effective than intravenous
diazepam. In an analysis of 628 patients, buccal midazolam was more effective than rectal diazepam4). In a randomized
double-blind trial of 893 patients, intramuscular midazolam (73.4%) had equivalent efficacy as intravenous lorazepam(63.4%)5). Another report suggests that intrarectal and intranasal lorazepam may also be effective6) (not available in Japan).

▪ References
1) Remy C, Jourdil N, Villemain D, et al. Intrarectal diazepam in epileptic adults. Epilepsia. 1992; 33(2): 353-358.
2) Dieckmann RA. Rectal diazepam for prehospital pediatric status epilepticus. Ann Emerg Med. 1994; 23(2): 216-224.
3) Minagawa K, Miura H, Mizuno S, et al. Pharmacokinetics of rectal diazepam in the prevention of recurrent febrile convulsions. Brain Dev. 1986;
8(1): 53-59.
4) McMullan J, Sasson C, Pancioli A, et al. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a metaanalysis. Acad Emerg Med. 2010; 17(6): 575-582.
5) Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med. 2012 ;366(7): 591-600.
6) Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children.
Cochrane Database Syst Rev. 2008; (3): CD001905.

▪ Search formula and secondary reference sources
PubMed search: September 9, 2008
Status Epilepticus/drug therapy” AND (first-line OR first choice) = 49
Additional PubMed search: June 26, 2015(((Anticonvulsants/therapeutic use [Majr]) AND Status Epilepticus/drug therapy [Majr])) OR ((Status Epilepticus/drug therapy [Majr]) AND((first-line) OR first-choice)) = 242
No references that could serve as evidence were found in Ichushi Web.

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CQ 8-2-(2)What are the drugs for stage 1 status epilepticus?
Summary
The therapeutic drug for stage 1 is intravenous diazepam or lorazepam; both drugs are benzodiazepines. However,lorazepam for injection is not available in Japan.

Comment
A prospective, randomized, double-blind study showed that intravenous injection of diazepam 10 mg controlled seizuresin 76% of the patients1). Diazepam has to be administered intravenously, not intramuscularly. Diazepam should be injectedundiluted, because it becomes turbid when diluted with normal saline or glucose. If the first injection is ineffective, additional
injection can be given after 5‒10 minutes. Pay attention to respiratory depression when giving additional injection. An
intravenous injection of diazepam usually has an anti-convulsion effect for 20 minutes2).
A prospective randomized double-blind trial in 273 children found no difference in efficacy and adverse effects between
diazepam and lorazepam3), but a meta-analysis by Cochrane review of 289 cases showed that lorazepam had a lower rate ofineffectiveness (32/130 cases for lorazepam versus 51/134 cases for diazepam, hazard ratio 0.64, 95% confidence interval
0.45‒0.9)4). Intravenous preparation of lorazepam is not available in Japan.
As an alternative to intravenous diazepam, midazolam 0.1% injection may be given, and is often used for stage 1 treatment
in children.
If the benzodiazepines are ineffective, proceed to stage 2 treatment.

▪ References
1) Leppik IE, Derivan AT, Homan RW, et al. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA. 1983; 249(11): 1452-1454.
2) Prasad K, Krishnan PR, Al-Room K, et al. Anticonvulsant therapy for status epilepticus. Br J Clin Pharmacol. 2007; 63(6): 640-647.
3) Chamberlain JM, Okada P, Holsti M, et al. Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA. 2014;
311(16): 1652-1660.
4) Prasad M, Krishnan PR, Sequeira R, et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2014; (9): CD003723.

▪ Search formula and secondary reference sources
PubMed search: September 9, 2008
Status Epilepticus/drug therapy” AND (first-line OR first choice) = 49
Additional PubMed search: June 26, 2015(((Anticonvulsants/therapeutic use [Majr]) AND Status Epilepticus/drug therapy [Majr])) OR ((Status Epilepticus/drug therapy [Majr]) AND((first-line) OR first-choice)) = 242
No references that could serve as evidence were found in Ichushi Web.

Chapter 8

69

CQ 8-2-(3)How effective is intravenous fosphenytoin for status epilepticus?
Summary
Fosphenytoin or phenytoin is used for the treatment of stage 2 status epilepticus.

Comment
Phenytoin has been used for a long time and fosphenytoin was developed to overcome the adverse effects associated withphenytoin. Therefore, fosphenytoin is easy to use in clinical practice.
While intravenous phenytoin should be injected slowly, fosphenytoin can be injected at an usual speed and reaches
effective blood concentration more rapidly. In addition, phenytoin is strongly alkaline, causing vascular pain and vasculardisorder, and its extravasation induces tissue necrosis. On the other hand, fosphenytoin is almost neutral, and rarely produces
the above adverse effects1).
The effective rate of fosphenytoin is reported to be 44‒97%, and a randomized study of 256 emergency patients showed
no difference in efficacy between phenytoin and fosphenytoin1).
Phenytoin is effective for many types of status epilepticus, except absence seizure status epilepticus and myoclonic seizure
status epilepticus2). In a meta-analysis of 8 studies with 294 patients in total, the effective rate of phenytoin was 50.2% (95%
confidence interval 43.2‒66.1%)3). Phenytoin should be injected intravenously immediately after injection of the fast-acting
diazepam, because phenytoin begins to exert its effect approximately 20 minutes after administration4, 5).
We should follow the instructions shown below when using phenytoin. Inject undiluted phenytoin into to a relatively
large blood vessel. Since there is a risk of heart failure due to cardiovascular disturbance (mainly hypotension and arrhyth­mia), inject the drug slowly while monitoring blood pressure, pulse and electrocardiogram. In addition, phenytoin causes
vascular pain and purple glove syndrome due to vascular disorder at an incidence rate of 5.9%1), and may cause tissue necrosis
due to extravasation. Care should be taken, especially for children.

▪ References
1) Thomson A. Fosphenytoin for the treatment of status epilepticus: an evidence-based assessment of its clinical and economic outcomes. Core Evid.
2005; 1(1): 65-75.
2) Shorvon S, Walker M. Status epilepticus in idiopathic generalized epilepsy. Epilepsia. 2005; 46(Suppl 9): 73-79.
3) Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: ameta-analysis of published studies. Seizure. 2014; 23(3): 167-174.
4) Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med. 1998;
339(12): 792-798.
5) Lowenstein DH. The management of refractory status epilepticus: an update. Epilepsia. 2006; 47(Suppl 1): 35-40.

▪ Search formula and secondary reference sources
PubMed search: September 21, 2008
Status Epilepticus AND (“Diazepam” OR “Phenytoin” OR “Midazolam” OR “Propofol”) = 357
Additional PubMed search: June 26, 2015(“Status Epilepticus” [Mesh]) AND “Phenytoin/therapeutic use” [Mesh] = 56
No references that could serve as evidence were found in Ichushi Web.

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CQ 8-2-(4)How effective is intravenous phenobarbital for status epilepticus?
Summary
Intravenous phenobarbital is used for the treatment of stage 2 status epilepticus.

Comment
In a prospective randomized controlled trial comparing a combination of diazepam and phenytoin versus phenobarbital,
the latter was slightly better in shortening both the duration of convulsion and the time of effect onset (average 5.5 minutes),although there was no difference in adverse effects1). In another double-blind comparative study, there was no significant
difference in seizure control between diazepam plus phenytoin and phenobarbital 2). In a meta-analysis of two studies witha total of 43 seizures, the rate of benefit of phenobarbital was 73.6% (95% confidence interval 58.3‒84.8%)3). Inject
phenobarbital intravenously after intravenous diazepam injection4), or use phenobarbital when a combination of diazepam
and phenytoin fails to control seizures5). Note that when using phenobarbital after diazepam, the frequency of respiratory
depression increases.

▪ References
1) Shaner DM, McCurdy SA, Herring MO, et al. Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus
phenobarbital and optional phenytoin. Neurology. 1988; 38(2): 202-207.
2) Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status Epilepticus. Veterans Affairs Status
Epilepticus Cooperative Study Group. N Engl J Med. 1998; 339(12): 792-798.
3) Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: ameta-analysis of published studies. Seizure. 2014; 23(3): 167-174.
4) Scottish intercollegiate guidelines network. Diagnosis and management of epilepsy in adults. A national clinical guideline. April 2003.
5) Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America’s Working Group on Status Epilepticus.
JAMA. 1993; 270(7): 854-859.

▪ Search formula and secondary reference sources
PubMed search: September 21, 2008
Status Epilepticus AND (“Diazepam” OR “Phenytoin” OR “Midazolam” OR “Propofol”) = 357
Additional PubMed search: June 26, 2015(“Status Epilepticus” [Mesh]) AND “Phenobarbital/therapeutic use” [Mesh] = 18
No references that could serve as evidence were found in Ichushi Web.

Chapter 871

CQ 8-2-(5)How effective is midazolam for status epilepticus?
Summary
Midazolam is used for treating stage 1 and stage 2 status epilepticus, or as a general anesthetic agent.

Comment
Midazolam can be used as a therapeutic agent for stage 1 and stage 2 status epilepticus or as a general anesthetic agent1, 2).
Midazolam belongs to the benzodiazepines. It is a fast-acting agent and a potent anticonvulsant. When vein access cannot
be secured, intranasal, buccal or intramuscular midazolam can be administered3). As an alternative to intravenous diazepam,
intravenous injection or continuous infusion of midazolam is an option1). Midazolam can be infused intravenously, and it
has a low risk of respiratory depression or cardiovascular disturbances. Moreover, because of its short half-life, midazolam
can be switched to other drugs (such as general anesthesia with barbiturates) when it is ineffective, without wasting time.
In a meta-analysis by Cochrane review, there were no significant differences in efficacy and adverse effects between
intravenous midazolam and intravenous diazepam4). In the pediatric clinical practice in Japan, midazolam has been used
as a therapeutic agent for stage 1 status epilepticus5). In addition, midazolam has been reported to be effective for nonconvulsive status epilepticus uncontrolled by diazepam and phenytoin6).

▪ References
1) Singhi S, Murthy A, Singhi P, et al. Continuous midazolam versus diazepam infusion for refractory convulsive status epilepticus. J Child Neurol.
2002; 17(2): 106-110.
2) Claassen J, Hirsch LJ, Emerson RG, et al. Treatment of refractory Status epilepticus with pentobarbital, propofol, or midazolam: a systematic review.
Epilepsia. 2002; 43(2): 146-153.
3) McMullan J, Sasson C, Pancioli A, et al. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a metaanalysis. Acad Emerg Med. 2010; 17(6): 575-582.
4) Prasad M, Krishnan PR, Sequeira R, et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2014; (9): CD003723.
5) Ohsawa M. Treatment for status epilepticus. No To Hattatsu. 2007; 39(3): 185-192 (in Japanese).
6) Claassen J, Hirsch LJ, Emerson RG, et al. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus.
Neurology. 2001; 57(6): 1036-1042.

▪ Search formula and secondary reference sources
PubMed search: September 21, 2008
Status Epilepticus AND (“Diazepam” OR “Phenytoin” OR “Midazolam” OR “Propofol”) = 357
Additional PubMed search: June 26, 2015(“Status Epilepticus” [Mesh]) AND “Midazolam/therapeutic use” [Mesh] = 41
No references that could serve as evidence were found in Ichushi Web.

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CQ 8-2-(6)How effective is intravenous levetiracetam for status epilepticus?
Summary
Intravenous levetiracetam is effective as a therapeutic agent for stage 2 status epilepticus. However, this drug is notcovered by medical insurance in Japan.

Comment
Levetiracetam has a mechanism of action different from those of other antiepileptic drugs1). This drug is fast-acting, withfew adverse effects including respiratory depression and cardiovascular disturbances1-3), and interaction with other drugs isalso uncommon1).
Comparative studies of levetiracetam with intravenous phenytoin4) and intravenous lorazepam5) have reported equivalent
efficacy among them. In a systematic review of 7 retrospective studies with a total of 141 cases, the effective rate was 52‒94%.
In another systemic review of 3 prospective studies with 100 cases, the effective rate was 44–75%2). In a meta-analysis of 8
studies with 204 cases, the effective rate was 68.5%3).

▪ References
1) Deshpande LS, Delorenzo RJ. Mechanisms of levetiracetam in the control of status epilepticus and epilepsy. Front Neurol. 2014; 5: 11.
2) Zelano J, Kumlien E. Levetiracetam as alternative stage two antiepileptic drug in status epilepticus: a systematic review. Seizure. 2012; 21(4): 233-236.
3) Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: ameta-analysis of published studies. Seizure. 2014; 23(3): 167-174.
4) Alvarez V, Januel JM, Burnand B, et al. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia.
2011; 52(7): 1292-1296.
5) Misra UK, Kalita J, Maurya PK. Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study. J Neurol. 2012;
259(4): 645-648.

▪ Search formula and secondary reference sources
PubMed search: December 14, 2015(“Status Epilepticus” [Mesh]) AND “levetiracetam/therapeutic use” [Mesh] = 193
No references that could serve as evidence were found in Ichushi Web.

Chapter 873

CQ 8-3

How effective is general anesthesia for refractory statusepilepticus?
Summary
Administer general anesthesia as early as possible for refractory status epilepticus. As general anesthetic agent,
midazolam, propofol, thiopental or thiamylal can be used.

Comment
Refractory status epilepticus is defined as status epilepticus that is not controlled by stage 1 (such as diazepam) and stage
2 therapeutic drugs (such as fosphenytoin).
Refractory status epilepticus develops in 31–43% of patients with status epilepticus1). When seizures are not controlled bystage 1 and stage 2 therapeutic agents, we should administer general anesthetic agent immediately. When convulsive statusepilepticus persists for more than 30 minutes, irreversible changes occur in the brain. Based on this result, it is reasonable touse general anesthesia when seizures persist for approximately 30 minutes. However, there is no high quality evidence for thetiming to start anesthesia, which general anesthetic agent to use, the depth of anesthesia, or the duration of anesthesia. There
are no clear recommendation standards for the above issues2).
For general anesthesia, midazolam (see CQ 8-2-(5) on page 72), propofol or barbiturate is used.
Propofol has a potent antiepileptic effect and is effective in many patients. Moreover, it is fast-acting with a short half-life,
and there is no waste of time when switching to other anesthetics. Its lethal adverse effects have been reported, but the risk
is low when used at doses not exceeding 5 mg/kg/hour3) and terminated within 48 hours2). However, general anesthesia withpropofol is contraindicated for children.
Thiopental and thiamylal belong to the barbiturates. Thiopental4) is fast-acting, but takes a long time to arouse after its
cessation. The frequency of adverse effects (including hypotension and infections) during anesthesia is high. Thiamylal has asimilar profile as thiopental.
In terms of controlling convulsive seizures, thiopental is superior to propofol and midazolam, but there is no association
between these anesthetics and prognosis of disease4). In a meta-analysis by Cochrane review of only one single-blind trial of
24 cases, there was no clear difference in efficacy between thiopental and propofol5).

▪ References
1) Rossetti AO, Logroscino G, Bromfield EB. Refractory status epilepticus: effect of treatment aggressiveness on prognosis. Arch Neurol. 2005;
62(11): 1698-1702.
2) Rossetti AO. Which anesthetic should be used in the treatment of refractory status epilepticus? Epilepsia. 2007; 48(Suppl 8): 52-55.
3) van Gestel JP, Blussé van Oud-Alblas HJ, Malingre M, et al. Propofol and thiopental for refractory status epilepticus in children. Neurology. 2005;
65(4): 591-592.
4) Parviainen I, Kälviäinen R, Ruokonen E. Propofol and barbiturates for the anesthesia of refractory convulsive status epilepticus: pros and cons.
Neurol Res. 2007; 29(7): 667-671.
5) Prabhakar H, Kalaivani M. Propofol versus thiopental sodium for the treatment of refractory status epilepticus. Cochrane Database Syst Rev. 2015;(6): CD009202.

▪ Search formula and secondary reference sources
PubMed search: September 9, 2008
Status Epilepticus AND (general anesthesia) = 48
Additional PubMed search: June 26, 2015(“Status Epilepticus” [Mesh]) AND ((“Anesthesia, General” [Mesh]) OR “general anesthesia” [TIAB]) = 9
No references that could serve as evidence were found in Ichushi Web.

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CQ 8-4

Does EEG monitoring during status epilepticus have clinicalsignificance?
Summary
Electroencephalographic monitoring during status epilepticus is useful.

Comment
When seeing patients with suspected status epilepticus, record EEG in parallel with treatment. The EEG examination isuseful in (1) exclusion of non-epileptic seizures such as psychogenic nonepileptic seizures (PNES), (2) differentiation between
generalized seizures and partial seizures, (3) diagnosis of nonconvulsive status epilepticus (NCSE), (4) evaluation of brain
function, and (5) prediction of prognosis.
PNES is not a malingering disorder, and it may cause not only incontinence or self-injury, but also any other symptoms,
and some patients with PNES require mechanical ventilator1, 2). EEG recording during or immediately after seizure is usefulfor a definitive diagnosis. When examining patients with suspected PNES, record EEG as far as possible concurrent withtreatment (see Chapter 14 on page 123).
For evaluation of treatment, we should confirm not only the clinical improvements but also reduction of epileptic
discharges on EEG. A report demonstrated that after anesthesia was stopped, 48% of the clinically controlled patients still
had subtle convulsion or electrical status on EEG3).
Many reports have shown that in status epilepticus, maintaining flat EEG3, 4) or burst suppression pattern5) with deep
anesthesia using general anesthetic agents improves the final outcome.
Continuous EEG monitoring is useful for the diagnosis of NCSE6, 7). EEG monitoring for over 6 hours can detect
abnormal findings in 82% of NCSE8) (not covered by medical insurance). In addition, the occipitally dominant background
EEG activity has been reported to be related to clinical outcome9).

▪ References
1) Meierkord H, Will B, Fish D, et al. The clinical features and prognosis of pseudoseizures diagnosed using video-EEG telemetry. Neurology. 1991;
41(10): 1643-1646.
2) Holtkamp M, Othman J, Buchheim K, et al. Diagnosis of psychogenic nonepileptic status epilepticus in the emergency setting. Neurology. 2006;
66(11): 1727-1729.
3) DeLorenzo RJ, Waterhouse EJ, Towne AR, et al. Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus.
Epilepsia. 1998; 39(8): 833-840.
4) Krishnamurthy KB, Drislane FW. Depth of EEG suppression and outcome in barbiturate anesthetic treatment for refractory status epilepticus.
Epilepsia. 1999; 40(6): 759-762.
5) Shorvon S, Baulac M, Cross H, et al. The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London
Colloquium on Status Epilepticus. Epilepsia. 2008; 49(7): 1277-1285.
6) Claassen J, Taccone FS, Horn P, et al. Recommendations on the use of EEG monitoring in critically ill patients: consensus statement from theneurointensive care section of the ESICM. Intensive Care Med. 2013; 39(8): 1337-1351.
7) Sutter R, Kaplan PW. Electroencephalographic criteria for nonconvulsive status epilepticus: synopsis and comprehensive survey. Epilepsia. 2012;
53(Suppl 3): 1-51.
8) Claassen J, Mayer SA, Kowalski RG, et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology.
2004; 62(10): 1743-1748.
9) Alvarez V, Drislane FW, Westover MB, et al. Characteristics and role in outcome prediction of continuous EEG after status epilepticus: Aprospective observational cohort. Epilepsia. 2015; 56(6): 933-941.

▪ Search formula and secondary reference sources
PubMed search: September 7, 2008
Status Epilepticus AND “Electroencephalography” = 178
Additional PubMed search: June 29, 2015((Status Epilepticus [majr]) AND “Electroencephalography” [Mesh]) AND ((“Monitoring, Physiologic” [Mesh]) OR monitor*) = 89
No references that could serve as evidence were found in Ichushi Web.

Chapter 875

Chapter 9
Surgical Treatment for Epilepsy
CQ 9-1

Which kinds of epilepsies (syndromes) are indications for
surgical treatment?
Summary
The following five epilepsies (syndromes) can be treated with surgery: (1) mesial temporal lobe epilepsy, (2) partial
epilepsy with responsible organic lesions detected, (3) partial epilepsy without detectable organic lesions, (4) partial
epilepsy due to extensive lesions within one hemisphere, and (5) intractable epilepsy with atonic seizures.

Comment
We consider that patients with epilepsy are candidates for surgical treatment when the epileptogenic zone can be
determined by examinations, and resection of the epileptogenic zone is expected to result in no or acceptable sequelae. The
above five epilepsy syndromes are treatable by surgery (surgically remediable syndromes)1). (1) Mesial temporal lobe epilepsy(MTLE), especially MTLE with hippocampal sclerosis (HS) (MTLE-HS), is considered to be the best indication for surgicaltreatment as an independent syndrome, and significant seizure control is predicted 2-4). (2) For partial epilepsy, when a lesion
is detected by diagnostic imaging and is resectable, we consider surgical treatment. Thermocoagulation surgery is effective
for gelastic seizures induced by hypothalamic hamartoma5). (3) Even when no lesion is depicted on MRI, surgical treatment
may be indicated if the epileptogenic zone can be detected by EEG and functional neuroimaging. (4) Partial epilepsy causedby extensive lesions in unilateral hemisphere is included as a candidate for surgical treatment. Since the arrest or regressionof psychomotor development is often induced in patients who have intractable epilepsy with infancy or early childhood
onset, early surgical treatment is recommended6). (5) Corpus callosotomy is effective for atonic seizures.

▪ References
1) Engel J Jr, Cascino GD, Shields WD. Surgically remediable syndromes. In: Engel J Jr, Pedley TA, eds. Epilepsy: A Comprehensive Textbook, 2nd
ed. Philadelphia; Wolters Kluwer/Lippincott Williams & Wilkins; 2007. p.1761-1769.
2) Wieser HG; ILAE Commission on Neurosurgery of Epilepsy. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis.
Epilepsia. 2004; 45(6): 695-714.
3) Wiebe S, Blume WT, Girvin JP, et al; Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled
trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001; 345(5): 311-318.
4) Téllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain. 2005;
128(Pt 5): 1188-1198.
5) Kameyama S, Shirozu H, Masuda H, et al. MRI-guided stereotactic radiofrequency thermocoagulation for 100 hypothalamic hamartomas. J
Neurosurg. 2016; 124(5): 1503-1512.
6) González-Martánez JA, Gupta A, Kotagal P, et al. Hemispherectomy for catastrophic epilepsy in infants. Epilepsia. 2005; 46(9): 1518-1525.

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CQ 9-2

Is temporal lobe resection effective for drug-resistant temporal
lobe epilepsy?
Summary
The effectiveness and safety of temporal lobe resection have been established for drug-resistant temporal lobe
epilepsy, and it is a treatment that should be considered for complex partial seizures that impede daily living. This
treatment is particularly effective when localized temporal lobe lesions are depicted on MRI.

Comment
The results of surgical treatment for temporal lobe epilepsy have been accumulated from major epilepsy centers around theworld since the 1990’s1). In 2001, the superiority of surgical treatment to drug treatment was demonstrated by a randomized
controlled trial (RCT)2). In 2003, the American Academy of Neurology together with the American Epilepsy Society andthe American Association of Neurological Surgeons published guidelines stating that “Patients with disabling complex
partial seizures, with or without secondarily generalized seizures, who have failed appropriate trials of first-line antiepileptic
drugs should be considered for referral to an epilepsy surgery center”3).
The rate of freedom from seizures that impede daily living in patients who underwent surgery was 60–80% if MRI
detected localized temporal lesions related to seizures, and the rate was approximately 50% if MRI detected no lesions4).
Apart from hippocampal sclerosis, localized lesions responsible for epilepsy include benign tumors such as ganglioglioma,
dysembryoplatsic neuroepithelial tumor and diffuse astrocytoma; cavernous malformations; and cerebral cortical dysplasia.
Postoperative complications such as speech disturbance, memory impairment, hemiparesis, and visual field defect may
occur, but the incidence is low5). Memory impairment after medial temporal lobe resection may involve various degrees ofverbal memory loss if there is no hippocampal atrophy on the language dominant side, but in patients with hippocampal
atrophy and below average preoperative memory, there is no change in verbal memory after surgery3).
Temporal lobe resection has been shown to be highly effective and safe in patients with drug-resistant temporal lobe
epilepsy, and is an established therapy. However, it takes more than 10 years on average from diagnosis to surgery. To
address this issue, epileptologists in the United States performed a randomized controlled trial (RCT) and recommended
that when two trials with appropriate antiepileptic drugs failed, surgery should be conducted at an early stage without
waiting for years6).
Comparison between surgical and medical treatments involves an inherent limitation of the low level of evidence. The
evaluation bias always occurs because blinding of medical and surgical treatments is impossible (see Systematic Review
Digest on page 148). If surgical treatment is believed to be clearly effective, randomization becomes an ethical concern.
Furthermore, we often have further difficulty in accomplishing a clinical trial since subject recruitment is challenging. Thisis shown by the fact that the randomized trial of Engel et al.6) was terminated prematurely. No comparative trials have beenreported, probably because long-term comparative studies are especially difficult to complete. In a case series report, the rateof seizure recurrence after surgery was several percent per year, and the seizure-free rate was approximately 50% after 10
years7).
Regarding the surgical methods, in addition to the classical standard anterior temporal lobe resection, various
approaches to the medial temporal lobe have been proposed. Anterior temporal lobectomy is superior to selective
amygdalohippocampectomy in seizure outcome8), 9). The superiority of selective resection for postoperative cognitive function
has not been shown so far. For patients with high risk of postoperative memory impairment, new therapies such as multiple
hippocampus transection, laser ablation and hippocampal electrical stimulation therapy have been proposed, and evaluationof these methods is awaited.

Chapter 977▪ References
1) McIntosh AM, Wilson SJ, Berkovic SF. Seizure outcome after temporal lobectomy: current research practice and findings. Epilepsia. 2001; 42(10):1288-1307.
2) Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001; 345(5): 311-318.
3) Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality
Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Associationof Neurological Surgeons. Neurology. 2003; 60(4): 538-547.
4) Téllez-Zenteno JF, Hernández Ronquillo L, Moien-Afshari F, et al. Surgical outcomes in lesional and non-lesional epilepsy: a systematic review andmeta-analysis. Epilepsy Res. 2010; 89(2-3): 310-318.
5) Hader WJ, Tellez-Zenteno J, Metcalfe A, et al. Complications of epilepsy surgery: a systematic review of focal surgical resections and invasive EEG
monitoring. Epilepsia. 2013; 54(5): 840-847.
6) Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012; 307(9):922-930.
7) de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
Lancet. 2011; 378(9800): 1388-1395.
8) Hu WH, Zhang C, Zhang K, et al. Selective amygdalohippocampectomy versus anterior temporal lobectomy in the management of mesial temporal
lobe epilepsy: a meta-analysis of comparative studies. J Neurosurg. 2013; 119(5): 1089-1097.
9) Josephson CB, Dykeman J, Fiest KM, et al. Systematic review and meta-analysis of standard vs selective temporal lobe epilepsy surgery. Neurology.
2013; 80(18): 1669-1676.

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CQ 9-3What are the indications for chronic intracranial EEG(long-term intracranial EEG) in presurgical evaluation?
Summary
There is no clear criterion for the indication of chronic intracranial EEG as a presurgical evaluation for epilepsy
surgery. The current consensus is described below, but it may be changed by the advances and widespread use of otherpresurgical examinations.

Comment
Although there is no clear criterion for the indication of chronic intracranial EEG, this examination has been regarded asa gold standard for determining the epileptogenic zone and the extent of resection area since over 50 years ago1).
The consensus to date for the indications includes: (1) patients with partial epilepsy diagnosed by seizure symptoms andother noninvasive examinations (including positron emission tomography and magnetoencephalography) even without any
localized lesion detected by MRI; (2) patients with localized lesions demonstrated by MRI, which are inconsistent with theepileptogenic zones localized by other noninvasive examinations, or in whom multiple epileptogenic zones are suggested bynoninvasive examinations; (3) regardless of the presence or absence of localized lesions on MRI, patients with epileptogenic
lesions near the functional area, in whom high-resolution focus localization and brain function mapping are required1, 2).
Chronic subdural EEG recording is often omitted when noninvasive examination results are consistent with anatomical
findings in patients with mesial temporal lobe epilepsy associated with unilateral hippocampal sclerosis or partial epilepsy
with localized neocortical lesions. Also, this examination is often omitted in a standard extensive resection (including
callosotomy) (especially in children). Furthermore, this examination is usually not done before corpus callosotomy for
generalized seizures.
There are two types of intracranial electrodes: subdural electrodes that are placed on the brain surface and depth electrodes
placed inside the brain. In the former case, electrodes are placed by craniotomy; and in the latter, electrodes are stereotaticallyimplanted. We have no conclusion about their superiority, and both are used when necessary3).
Even though the required recording period has not been established, the recording is done for usually 1–4 weeks in many
institutions. While it usually takes more than two weeks to perform an adequate examination, the incidence of wound
infection or intracranial infection increases as the placement period increases. Complications of chronic intracranial EEG
recording include infection, cerebrospinal fluid leak, and focal neurologic symptoms. The incidence rate is 8.3% (7.7% cured
within 3 months, 0.6% prolonged)4).
In EEG analyses, in addition to conventional visual inspection, new analytical methods are available using signal
processing for a broader frequency range. For functional brain mapping, in addition to the classical electrical stimulation
method, new method is available to identify the high-frequency oscillations during a task. However, the superiority of these
new analytical methods has not been established5, 6).

▪ References
1) Nair DR, Burgess R, McIntyre CC, et al. Chronic subdural electrodes in the management of epilepsy. Clin Neurophysiol. 2008; 119(1): 11-28.
2) Wetjen NM, Marsh WR, Meyer FB, et al. Intracranial electroencephalography seizure onset patterns and surgical outcomes in nonlesional
extratemporal epilepsy. J Neurosurg. 2009; 110(6): 1147-1152.
3) Taussig D, Montavont A, Isnard J. Invasive EEG explorations. Neurophysiol Clin. 2015; 45(1): 113-119.
4) Hader WJ, Tellez-Zenteno J, Metcalfe A, et al. Complications of epilepsy surgery: a systematic review of focal surgical resections and invasive EEG
monitoring. Epilepsia. 2013; 54(5): 840-847.
5) Gloss D, Nolan SJ, Staba R. The role of high-frequency oscillations in epilepsy surgery planning. Cochrane Database Syst Rev. 2014; (1): CD010235.
6) Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. Lancet Neurol. 2014; 13(11): 1114-1126.

Chapter 9

79

CQ 9-4

How to determine the timing of considering surgical treatment?
Summary
When seizures have continued even after two or more regimens of appropriately selected antiepileptic drugs given
as monotherapy or combination therapy, classify such epilepsy with uncontrolled seizures for a certain period as
drug-resistant epilepsy, and consider surgical treatment. The “certain period” of persistent seizures is considered to
be one year or longer (or a period at least three times the pre-treatment interval between seizures). Earlier surgery
should be considered in children.

Comment
The ILAE1) defines drug-resistant epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and usedantiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom for anadequate period”. An adequate period without seizures may be considered as at least one year (or a minimum of three times
the pre-treatment inter-seizure interval) without seizure recurrence. For adults, surgical treatment should be considered
promptly when epilepsy is judged to be drug resistant. For childhood, early surgery is desirable considering functional andsurvival outcomes. The ILAE Commission on Neurosurgery2) also recommends early surgery. The goal of surgical treatment
is not only to eliminate seizures but also to improve quality of life. Intellectual impairment and psychiatric disorder are notexclusion criteria for surgical indication. In children, it is known that psychomotor development improves when seizures arecontrolled after surgical treatment (treatable epileptic encephalopathy)3).

▪ References
1) Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission
on Therapeutic Strategies. Epilepsia. 2010; 51(6): 1069-1077.
2) Binnie CD, Polkey CE. Commission on Neurosurgery of the International League Against Epilepsy (ILAE) 1993-1997: recommended standards.
Epilepsia. 2000; 41(10): 1346-1349.
3) Berkovic SF, Arzimanoglou A, Kuzniecky R, et al. Hypothalamic hamartoma and seizures: a treatable epileptic encephalopathy. Epilepsia. 2003;
44(7): 969-973.

80Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 9-5

Is surgical treatment effective even for drug-resistant epilepsies
in children?
Summary
The surgical treatment is widely used for children with drug-resistant epilepsy and is recommended as a treatment
by international experts despite no high-grade evidence supporting its efficacy. Epilepsy syndromes in children are
diverse, and poorly controlled epileptic seizures may affect cognitive and behavioral developments. Therefore,
presurgical evaluation should be performed at an appropriate timing in a specialized hospital or center.

Comment
The outcome of surgical treatment for drug-resistant epilepsy in children is better than that in adults, especially when alesion is confirmed pathologically or by MRI1). However, there is no high-grade evidence for it, and the ILAE recommends
the treatment based on expert consensus2).
The conspicuous features of epilepsy surgery in children include a high proportion of multilobar resection andhemispherectomy (including callsotomy), and cerebral cortical dysplasia as a common etiology. Surgical resection of localized
cortical dysplasia results in a high rate of seizure-free outcome3, 4).
Children are affected by diverse epilepsy syndromes, and poor control of epileptic seizures has a risk of worsening cognitiveand behavioral developments. Therefore, presurgical evaluation should be performed at an appropriate timing in a specialized
hospital or center3). Good seizure control by surgery sometimes improves developmental outcomes, especially in the case of
infants treated with hemispherectomy4).
In children with severe epilepsy showing localized lesions or hemispheric lesions, good outcome may be obtained evenwhen EEG demonstrates extensive bilateral epileptic abnormalities.

▪ References
1) Téllez-Zenteno JF, Hernández Ronquillo L, Moien-Afshari F, et al. Surgical outcomes in lesional and non-lesional epilepsy: a systematic review andmeta-analysis. Epilepsy Res. 2010; 89(2-3): 310-318.
2) Cross JH, Jayakar P, Nordli D, et al. Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the
Subcommission for Pediatric Epilepsy Surgery. Epilepsia. 2006; 47(6): 952-959.
3) Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. Lancet Neurol. 2014; 13(11): 1114-1126.
4) Spencer S, Huh L. Outcomes of epilepsy surgery in adults and children. Lancet Neurol. 2008; 7(6): 525-537.

Chapter 981

CQ 9-6

What is the risk of psychiatric symptoms after epilepsy surgery?
Summary(1) The risk of psychiatric symptoms after epilepsy surgery is high in patients with a past history or a family historyof psychiatric symptoms (including anxiety, depression, and psychosis) before epilepsy surgery, and in those inwhom seizures persist after surgery.
(2) Explain to patients before surgery the possibility of psychiatric symptoms after epilepsy surgery.
(3) For early detection and early treatment of psychiatric symptoms, we should follow the patients carefully for
approximately 6 months to 1 year.

Comment
It is desirable that all patients treated with epilepsy surgery should receive psychiatric evaluation before surgery1). A pasthistory of psychiatric disease is not a contraindication for surgery under the condition that psychiatric intervention is given.
The frequency of de novo postsurgical psychiatric symptoms such as anxiety, depression and psychosis, including mild
conditions such as adaptation disorder, is 1.1‒18.2%2). Presurgical psychiatric complications frequently exacerbate or recur
up to one year after surgery. Regular close psychiatric follow-up after surgery leads to good outcome.
Risk factors for psychiatric symptoms such as anxiety, depression, and psychosis after epilepsy surgery are residual seizures
after surgery and presence of a family history or past history of psychiatric condition before surgery. In surgically treatedpatients with temporal lobe epilepsy, the rate of de novo depression after surgery is 4‒18%, occurring 3‒12 months after
surgery and lasting for 1 to 11 months. The rate of de novo anxiety disorder occurring after surgery is 3–26%, showing apeak in the first month after surgery. The rate of de novo psychiatric disorders developing after surgery is 1.1%, and theoccurrence of psychiatric disorders is not related to the postsurgical seizure control or laterality of the resected hemisphere3).
In patients with favorable seizure outcome (seizure-free) after surgery, the outcome of psychiatric symptoms is alsofavorable, but in rare cases adaptation disorder may occur. A hypothesis of “burden of normality” has been proposed to
explain this phenomenon. It may be a kind of reaction of cured epilepsy patients to their new situation, that they should takeon various social obligations that have been neglected while they were affected by epilepsy4).
Treatment is basically the same as the usual treatment for psychiatric symptoms. In patients who did not receive any
explanation about the risk of postsurgical psychiatric symptoms before surgery, the patients and families often react to or
resist the involvement of psychiatrists after surgery. Therefore, participation of a psychiatrist in the treatment team before
surgery is desirable.

▪ References
1) Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associatedwith epilepsy. Epilepsia. 2011; 52(11): 2133-2138.
2) Macrodimitris S, Sherman EM, Forde S, et al. Psychiatric outcomes of epilepsy surgery: a systematic review. Epilepsia. 2011; 52(5): 880-890.
3) Cleary RA, Baxendale SA, Thompson PJ, et al. Predicting and preventing psychopathology following temporal lobe epilepsy surgery. Epilepsy
Behav. 2013; 26(3): 322-334.
4) Ferguson SM, Rayport M. The adjustment to living without epilepsy. J Nerv Ment Dis. 1965; 140: 26-37.

▪ Search formula and secondary reference sources
Search formula
epilepsy [majr] AND mental disorders [majr] AND therapy [sh] Filters: Clinical Trial; Meta-Analysis; Multicenter Study; Randomized Controlled
Trial; Publication
PubMed = 86

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CQ 9-2

Should temporal lobe resection be added to drug therapy in
drug-resistant temporal lobe epilepsy?
Recommendation
We recommend temporal lobectomy in addition to drug therapies in patients with drug-resistant epilepsy (GRADE
2D) (weak recommendation, very low level of evidence).
• Supplementary note: In the GRADE system, when the evidence level is “very low”, in principle it is not possible
to grade “strong recommendation”. Since temporal lobe resection is highly effective with a low incidence ofadverse effects, almost all the panelists supported “strong recommendation”, but due to the constraint of the
GRADE system, the final grading was “weak recommendation”.

1. Background, priority of the problem
For drug-resistant epilepsy, adding further new drugs has limited effect. The temporal lobe resection is expected to achieve
seizure-free condition despite its invasiveness.

2. Comment

Evidence summary
There were 2 randomized controlled trials (RCTs) (total 118 patients) on the effectiveness of temporal lobe resection versus
medical therapy for drug-resistant epilepsy1, 2). With regard seizure outcome, the relative risk was 20.57 (95% confidence
interval 4.24‒99.85) and the number needed to treat (NNT: indicating the number of persons needed to treat to achieve theoutcome for one person) was 4, showing superiority of temporal lobe resection. Neither of the two RCTs mentioned decreaseof antiepileptic drugs after surgery. Death rate did not differ between two groups.
The relative risk of surgical complications was 12.33 (95% confidence interval 1.67‒90.89), and was higher in the temporal
lobe resection group. Death, memory impairment, and psychiatric symptoms were not significantly different between thetwo groups. Quality of life (QOL) improvement was superior in the temporal lobe resection group.

3. Panel meeting

3-1. What is the overall quality of evidence across outcomes?
Since it was not possible to mask the intervention, the risk of bias was high overall in the collected studies. Bias for death
was considered not serious, while that for the other outcomes was considered serious and was downgraded one rank.
Inconsistency and non-directness of the results were without question and considered not serious. For imprecision, confidence
intervals crossed the clinical decision threshold in many items, and was downgraded one or two ranks. Publication bias could
not be judged because of the small number of studies. Consequently, the level of evidence for the outcomes was as follows:“low” for seizure freedom, death, surgical complications, and quality of life improvement; and “very low” for memory
impairment and psychiatric symptoms. The overall level of evidence was “D (very low)”.
* For surgical therapy, since blinding of the control group is difficult, the level of evidence is generally low.

3-2. How is the balance between benefits and harms?
Temporal lobe resection can be expected to control seizures. As a result, antiepileptic drugs are possibly reduced although
it is not shown in RCT. The incidence of serious adverse effects was low. Therefore, the risk of temporal lobe resection isconsidered to be smaller as compared to its benefit.

3-3. What about patients’ values and preference?
Some patients may feel resistance in to receive invasive surgical therapy, but the beneficial effect of seizure-free producedby the surgery outweighs the resistance to the invasive procedure. There is perhaps no significant uncertainty or variability
in value among the patients.

Chapter 983

3-4. What is the balance between net benefit and cost or resources?
The medical insurance fee scale for epilepsy surgery using a microscope (including temporal lobe resection) is 131,630
points (as of January 11, 2018). The surgery is conducted under general anesthesia and requires neurosurgeons.
However, through reducing antiepileptic drugs, decreasing hospitalization duration accompanying reduced seizures, andenabling more active social activities, epilepsy surgery is expected to lead to saving in the long term. For this reason, the cost
can be considered negligible.

3-5. Recommendation grading
During the discussions at the panel meeting, temporal lobe resection was expected to eliminate seizures, and overall thecost of the surgery could be considered negligible. Even taking the adverse effects into account, the surgery was supported
by panelists.
At the panel meeting, many panelists supported a recommendation grade of “strong recommendation”. However, in the
GRADE system, when the evidence level is “very low”, in general we are not able to grade “strong recommendation”. For thisreason, the final grading was “weak recommendation”.

4. Descriptions in other related guidelines
In Japan, the Japan Epilepsy Society published the “Guideline on indications for epilepsy surgery”3) in 2008, and“Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy”4) in 2010.
The “Guideline on indications for epilepsy surgery” recommends surgical treatment for mesial temporal lobe epilepsy at asuitable timing, stating that “since surgical results are superior in cases of mesial temporal lobe epilepsy with a localizedorganic lesion or with extensive lesions in unilateral hemisphere, consider surgical treatment from an early stage and do not
miss the timing of surgery”. The “Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy” also
follows the above recommendation, stating that “patients should be selected in accordance with the guideline on indications
for epilepsy surgery”.
In overseas countries, the Quality Standards Subcommittee of the American Academy of Neurology, the American
Epilepsy Society, and the American Association of Neurological Surgeons published a guideline5) in 2003. The guideline
states that “drug-resistant epilepsy should be considered for referral to an epilepsy surgery center” and that “patients whomeet established criteria for an anteromesial temporal lobe resection and who accept the risks and benefits of this procedure
should be offered surgical treatment”.

5. Treatment monitoring and evaluation
Monitoring and evaluation during the perioperative period of treatment are generally performed by a neurosurgeon. After
this period, although a neurosurgeon is not necessarily required to monitor and evaluate the patients, follow-up and support
for the patients should be provided.

6. Possibility of future researchSome memory-preserving or minimally invasive surgery may be developed in the future. In addition, we would like toknow the surgical outcomes and adverse events over a longer follow-up period because the observation periods of the two
RCTs were 1 year1) and 2 years2).

7. RCT reports reviewed for this CQ
Wiebe 20011), Engel 20122)

8. List of appendices (to be shown later)
Appendix CQ9-2-01. Flow diagram and literature search formula
Appendix CQ9-2-02. Risk of bias summary
Appendix CQ9-2-03. Risk of bias graphAppendix CQ9-2-04. Forest plot
Appendix CQ9-2-05. Summary of findings (SoF) table
Appendix CQ9-2-06. Evidence-to-decision table

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

▪ References
1) Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001; 345(5): 311-318.
2) Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012; 307(9):922-930.
3) Mihara T, Fujiwara T, Ikeda A, et al. Guideline on indications for epilepsy surgery. Tenkan Kenkyu. 2008; 26(1): 114-118 (in Japanese).
4) Watanabe E, Fujiwara T, Ikeda A, et al. Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy. Tenkan Kenkyu. 2006;
27(3): 412-416 (in Japanese).
5) Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality
Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Associationof Neurological Surgeons. Neurology. 2003; 60(4): 538-547.

Chapter 985

Chapter 10
Stimulation Therapy for Epilepsy
CQ 10-1

Is vagus nerve stimulation therapy effective for drug-resistant
epilepsy?
Summary
Vagus nerve stimulation (VNS) is one of the non-pharmacological, accommodative therapies for epilepsy, in which
an implantable electrical stimulator activates the left cervical vagal nerve intermittently to reduce or attenuate drugresistant epileptic seizures. This method is covered by medical insurance, but implementation of the treatment
requires certification.

Comment
Vagus nerve stimulation (VNS) is used as an adjunctive accommodative treatment for patients with drug-resistant epileptic
seizure, who are not indicated for epileptic surgery with craniotomy, or who do not respond adequately to the surgical treatment.
The first evidence for the efficacy of VNS was based on two randomized controlled trials (RCTs) conducted in the UnitedStates in the 1990s1, 2). In RCTs of therapies that require surgical treatment and implantation procedure, we usually havedifficulties in including an appropriate control group. However, in these two RCTs, efficacy was compared with a shamstimulation (low level stimulation) control group. In the sham stimulation group, an implantation procedure was performedin the same manner as in the treatment group, but the stimulation intensity was so low that it almost had no effect (active
control group) even though the patients feel something (Table 1). In patients aged 12 years or above with drug-resistantpartial seizures, the mean seizure reduction rate 3 months after surgery was 25‒28% in the high-level stimulation group and
6‒15% in the low-level stimulation group (see Systematic Review Digest on page 162). Furthermore, as a more clinicallyoriented comparative study, an RCT was conducted to compare best medical therapy (BMT) alone with a combination of
BMT and VNS (BMT + VNS), and significantly greater improvement of health-related QOL was achieved by a combinationof VNS and BMT3).
Although the effectiveness of VNS increases on long-term continued administration4, 5), RCT for long-term treatment isdifficult to establish because of the ethical issue, and only a limited number of patients can be recruited. The study by Ryvlin
et al.3) was initially planned for a two-year follow-up period, but the study was terminated prematurely due to difficulties inpatient recruitment. We should take this limitation into consideration when evaluating the outcome assessment in systematic
review. Regarding the long-term effect, many reports have indicated that seizure reduction rate by VNS for 2 years isapproximately 50%, and the responder rate (seizure reduction ≥ 50%) is mostly reported to be approximately 50%.
In addition to RCT, many investigations such as registry research and case series have demonstrated the seizure reduction
effect of VNS5, 6), and the VNS has been established as an accommodative treatment for drug-resistant epilepsy. This
treatment has been covered by medical insurance from 2010 in Japan, although it was delayed as compared with other countries.
Some studies have reported the effectiveness of VNS in children or for generalized seizures7, 8). In Japan, there are no
restrictions regarding seizure type and age for the use of VNS. However, since RCT has not been performed, indications
have to be decided cautiously when used in children or for generalized seizures. Adverse effects associated with VNS include
cough, hoarseness, throat discomfort, and swallowing disturbance, but the occurrence rate decreases during continuationof VNS2, 3).
In addition to the accommodative effects on epileptic seizures, VNS was reported to be efficacious against concomitant
symptoms such as cognitive dysfunction and affective disorder seen in patients with epilepsy 9-11). However, it should be notedthat the primary end point of those studies was the effect of VNS on epileptic seizures, and the effect on concomitant
symptoms was not the main objective.

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▪ References
1) A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology. 1995; 45(2): 224-230.
2) Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.
Neurology. 1998; 51(1): 48-55.
3) Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal
epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia. 2014; 55(6): 893-900.
4) Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation
Study Group E01-E05. Neurology. 1999; 53(8): 1731-1735.
5) Elliott RE, Morsi A, Kalhorn SP, et al. Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomesand predictors of response. Epilepsy Behav. 2011; 20(1): 57-63.
6) Elliott RE, Morsi A, Tanweer O, et al. Efficacy of vagus nerve stimulation over time: review of 65 consecutive patients with treatment-resistant
epilepsy treated with VNS > 10 years. Epilepsy Behav. 2011; 20(3): 478-483.
7) Elliott RE, Rodgers SD, Bassani L, et al. Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. J
Neurosurg Pediatr. 2011; 7(5): 491-500.
8) Orosz I, McCormick D, Zamponi N, et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347
children. Epilepsia. 2014; 55(10): 1576-1584.
9) Clark KB, Naritoku DK, Smith DC, et al. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci.
1999; 2(1): 94-98.
10) Elger G, Hoppe C, Falkai P, et al. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000; 42(2-3):
203-210.
11) Harden CL, Pulver MC, Ravdin LD, et al. A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav. 2000;
1(2): 93-99.

Table 1. Stimulation conditions used in RCTs of VNS.
High-level stimulation
Current (milliamperes)*

Reference 1995
0.25‒3.0

Reference 1998
1.3**

Frequency (Hz)
Pulse width (microseconds)
ON time (seconds)
OFF time (minutes)

20‒50
500
30‒90
5‒10

30
500
30
5

Magnet mode

used

used

Low-level stimulation
Reference 1995
0.25–2.75
1 or 213030
60–180
not used

Reference 1998
1.2**
1
130
30
180
used****: At high-level stimulation, current was set at the highest tolerable level for each patient. At low-level stimulation,
current was set at the lowest level that could be sensed by the patient.
**: Mean value of final current***: Current at magnet mode was set at 0.
(Data excerpted from: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medicallyintractable seizures. Neurology. 1995; 45(2): 224-230. / Handforth A,, DeGiorgio CM, Schachter SC, et al. Vagus
nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology. 1998; 51(1): 48-55.

Chapter 10

87

CQ 10-3

Is intracranial electrical stimulation therapy with implanted
electrodes effective for epilepsy?
Summary
Shot-term (1‒3 months) efficacy of stimulation of the anterior nucleus of thalamus and responsive stimulation of
the seizure onset zone has been shown for partial seizures. Although a limited number of reports have also indicatedthe long-term efficacy of these methods and the effectiveness of other intracranial stimulation methods (hippocampus,
paracentral thalamic nucleus, and cerebellum), evidence is not sufficient and further verification is required.

Comment
Many patients do not achieve freedom from seizure even with appropriate drug therapies and surgical treatments. In
recent years, intracranial electrical stimulation therapy with implanted electrodes has attracted attention as a treatment forthese patients. However, as of December 2017, intracranial electrical stimulation therapy with implanted electrodes has notbeen approved in Japan.
Stimulation of the anterior nucleus of thalamus is performed by stimulating bilateral anterior nuclei of the thalamus
intermittently using an implanted stimulator. For partial seizures in adults, the median seizure reduction rate is 40% after
three months of treatment1). The effect may last for 5 years2). Adverse events include subjective depressive symptoms andmemory impairment.
Responsive stimulation of the seizure onset zone is performed by implanting deep or subdural electrodes at 1‒2 epileptogenic
zones, which automatically detect seizure onset and initiate stimulation. For partial seizures in adults, the mean seizure
reduction rate is 38% after 3 months of treatment3). The effect may last for 5 years4). Adverse events include intracranial
hemorrhage and wound infection.
Multiple institutes have reported the efficacy of hippocampal stimulation for temporal lobe epilepsy, but the number ofcases is limited5-9).

▪ References
1) Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;
51(5): 899-908.
2) Salanova V, Witt T, Worth R, et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015;84(10): 1017-1025.
3) Morrell MJ; RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.
Neurology. 2011; 77(13): 1295-1304.
4) Bergey GK, Morrell MJ, Mizrahi EM, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.
Neurology. 2015; 84(8): 810-817.
5) Boon P, Vonck K, De Herdt V, et al. Deep brain stimulation in patients with refractory temporal lobe epilepsy. Epilepsia. 2007; 48(8): 1551-1560.
6) Velasco AL, Velasco F, Velasco M, et al. Electrical stimulation of the hippocampal epileptic foci for seizure control: a double-blind, long-term followup study. Epilepsia. 2007; 48(10): 1895-1903.
7) McLachlan RS, Pigott S, Tellez-Zenteno JF, et al. Bilateral hippocampal stimulation for intractable temporal lobe epilepsy: impact on seizures andmemory. Epilepsia. 2010; 51(2): 304-307.
8) Bondallaz P, Boëx C, Rossetti AO, et al. Electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe
epilepsy. Seizure. 2013; 22(5): 390-395.
9) Cukiert A, Cukiert CM, Burattini JA, et al. Seizure outcome after hippocampal deep brain stimulation in a prospective cohort of patients withrefractory temporal lobe epilepsy. Seizure. 2014; 23(1): 6-9.

▪ Search formula and secondary reference sources
PubMed search: December 11, 2014
epilepsy AND treatment AND brain stimulation AND clinical trial = 184
Sprengers M, Vonck K, Carrette E, et al. Deep brain and cortical stimulation for epilepsy (Review). The Cochrane Library 2014, Issue 6.

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CQ 10-1

Should vagus nerve stimulation therapy be added to drug
therapies for drug-resistant temporal lobe epilepsy?
Recommendation
We suggest to add vagus nerve stimulation to drug therapies (GRADE 2D) (weak recommendation, very low levelof evidence).
• Supplementary note: In principle, vagus nerve stimulation is considered for patients with no indication for
curative surgery. Implantation of the vagus nerve stimulation device involves surgery under general anesthesia
in an experienced hospital. After implantation, the patients need to be followed in the hospital where theoperation was performed or other facilities by experts with experience in stimulator control.

1. Background, priority of the problem
In patients with drug-resistant epilepsy in whom seizures are not controlled even after trials of two appropriate antiepileptic
drugs, further addition of drugs has only limited effect. Vagus nerve stimulation added to antiepileptic drug therapy is
expected to provide additive effect of seizure frequency reduction. Because vagus nerve stimulation is less invasive and has
lower seizure control effect as compared with brain surgery with craniotomy, it may be selected as a treatment option inpatients with no indication for curative neurosurgery.

2. Comment

Evidence summary
Only one randomized controlled trial (RCT) examined the effectiveness of vagus nerve stimulation adjunct to best
medical practice (BMP) (intervention group) versus BMP alone (control group) for drug-resistant epilepsy1). We therefore
considered also to use observational studies. However, because the outcomes of those studies, such as reduced seizure
frequency and mood change, are susceptible to placebo effect, we determined to use the single RCT.
Regarding efficacy, the relative risk for 50% seizure frequency reduction was 1.34 (95% confidence interval 0.59‒3.04),
and NNT (number needed to treat: indicating the number of persons needed to treat to achieve the outcome for one person)
was 25. As for mood changes, there were no significant differences between the intervention group and control group in thescores for several scales: QOLIE-89 (89-item Quality of Life in Epilepsy Inventory), CES-D (Center for Epidemiologic
studies Depression scale), and NDDI-E (Neurological Disorders Depression Inventory in Epilepsy scale). Regarding moodchanges, the only scale showing a statistically significant difference was the 7-point evaluation scale CGI-I (Clinical Global
Impression of Impression Important Scale), but the difference was only 0.5 (95% confidence interval 0.99‒0.01), showing asmall effect. For serious adverse events, vocal cord paralysis and brief respiratory arrest occurred only in the intervention
group, but were transient with no sequelae. There was no significant difference in the adverse event of dysphonia between theintervention group and the control group.
It should be noted that the selected RCT was prematurely terminated by the sponsor due to a low recruitment rate,
because many study candidates did not accept randomization of the treatment. Therefore, the study may be underpoweredfor detection of the outcome.

3. Panel meeting

3-1. What is the overall quality of evidence across outcomes?
In the study reviewed, the risk of bias was high overall, which was judged as serious for all the outcomes, and was
downgraded by one rank. The inconsistency of results was not downgraded because of only one study used. The indirectness
was judged as not serious and without any problems. As for imprecision, the confidence intervals in many analyses crossed
the clinical decision threshold, and it was hence downgraded by one or two ranks. As for publishing bias, there was only one
study, and therefore was not downgraded. Consequently, the level of evidence for the outcomes was as follows: “very low” forseizure frequency ≤ 50%, serious adverse events, and dysphonia; and “low” for the other outcomes. The overall level ofevidence was “very low”.

Chapter 1089

3-2. What is the balance between benefits and harms?
Since there was only one RCT, the certainty of the effect estimate was low, and it was difficult to consider the balance
between benefits and harms.

3-3. What about patients’ values and preferences?
The importance of outcomes has great inter-individual differences, and it should be diverse. It should be noted that somepatients place importance on the reduction of seizure frequency, while others regard the risk of adverse effects to be more
important.

3-4. What is the balance between net benefit and cost or resources?
The electrode implantation for VNS surgery is conducted under general anesthesia. Vagus nerve stimulation is covered by
medical insurance, and the medical insurance fee scale for implantation is 24,350 points, and that for exchange is 4,800
points (as of January 11, 2018). The reoperation should be done once every few years for replacement of the power generator
because of degradation of the condenser. Considering the effectiveness for refractory epilepsy and the above-mentioned
factors, the cost was judged to be moderate.

3-5. Recommendation grading
During the discussions at the panel meeting, considering the moderate burden and cost, and the few alternative treatment
options available, the panelists concluded that it was reasonable to use this treatment method despite a certain amount ofharm, burden and cost. The unanimous decision was “to propose implementing vagus nerve stimulation for drug-resistant
epilepsy”. As an additional consideration, the patients’ families at the panel meeting expressed the following opinion: “Wedesire to overcome social constraints. If there is any method to solve this, please include it as one of the options.”

4. Descriptions in other related guidelines
In Japan, the “Practice guideline of vagus nerve stimulation therapy for epilepsy”2) was published by the Japan Epilepsy
Society in 2012, which states that “VNS has accommodative effect on drug-resistant epileptic seizures [recommendation
grade A]”. Also, the American Academy of Neurology released a guideline update entitled “Vagus nerve stimulation for thetreatment of epilepsy” in 2013. This guideline update describes the possibilities of the effectiveness of vagus nerve stimulation
appearing several years after VNS operation, the effectiveness in children [rate of > 50% seizure reduction: 55% (95%
confidence interval 50‒59%)], and an increased risk of infection in children compared to adults [odds ratio 3.4 (95%
confidence interval 1.0‒11.2)].
According to the guidelines in Japan and overseas and the recommendation from the ILEA, the indication for vagus nerve
stimulation is, in principle, patients who have no indication for curative neurosurgery2-4).

5. Treatment monitoring and evaluation
Vagus nerve stimulation treatment requires adjustment of the stimulation conditions, management of complications, andsolving equipment troubles. Epilepsy specialists or doctors trained by the specialists should perform monitoring andevaluation after the operation based on expert knowledge.

6. Possibility of future research
The RCT reviewed for this CQ had high risk of bias. Therefore, it is desirable to have more RCTs with better quality. In
addition, further research focusing on how to identify good responders and the effects on status epilepticus is needed in the
future.

7. RCT reports reviewed for this CQ
Ryvlin 20141)

90Part IThe Clinical Practice Guidelines for Epilepsy 2018

8. List of appendices (to be shown later)
Appendix CQ10-1-01. Flow diagram and search formula for references
Appendix CQ10-1-02. Risk of bias summary
Appendix CQ10-1-03. Risk of bias graphAppendix CQ10-1-04. Forest plot
Appendix CQ10-1-05. Summary of findings (SoF) table
Appendix CQ10-1-06. Evidence-to-decision table▪ References
1) Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal
epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia. 2014; 55(6): 893-900.
2) Kawai K, Sugai K, Akamatsu N, et al. Guideline on implementation of vagus nerve stimulation therapy for epilepsy. Tenkan Kenkyu. 2012; 30(1):68-72 (in Japanese).
3) Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the
Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013; 81(16): 1453-1459.
4) Cross JH, Jayakar P, Nordli D, et al. Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the
Subcommission for Pediatric Epilepsy Surgery. Epilepsia. 2006; 47(6): 952-959.

Chapter 10

91

CQ 10-2

When conducting vagus nerve stimulation for
drug-resistant epilepsy, which intensity of stimulation(high or low) should we use?
Recommendation
When conducting vagus nerve stimulation (VNS) for drug-resistant epilepsy, we suggest to use high intensity
stimulation rather than low intensity stimulation (GRADE 1C) (strong recommendation, low level of evidence).
• Supplementary note: Adjustment of stimulation conditions should be conducted in the hospital where theelectrode implantation was performed or in a hospital/institution where VNS specialist is present.

1. Background, priority of this issue
The efficacy of vagus nerve stimulation is known to depend on the stimulation conditions. The intensity of stimulation
should be adjusted while monitoring its therapeutic effect and adverse effects. Therefore, it is necessary to clarify whether
high intensity stimulation or low intensity stimulation is superior when conducting VNS.
In addition, as mentioned in CQ 10-1 “Should vagus nerve stimulation therapy be added to drug therapies for drugresistant temporal lobe epilepsy?”, we have difficulty in performing comparison between real VNS and sham VNS (with nostimulation). Therefore, there is an increase in randomized controlled trials (RCTs) using low intensity stimulation as shamstimulation (placebo stimulation or pseudo-stimulation) to compare with high intensity stimulation.
There is one Cochrane Review1) on a similar clinical question. This review shows that high intensity stimulation has
superior therapeutic effect, while treatment withdrawal is rare both when using high and low intensity stimulation.

2. Comment

Evidence summary
There were 4 RCTs that examined the efficacy of vagus nerve stimulation therapy for drug-resistant epilepsy2‒5).
For efficacy, the relative risk for seizure frequency ≤ 50% was 1.74 (95% confidence interval 1.14‒2.65) and NNT (number
needed to treat: indicating the number of persons needed to treat to achieve the outcome for one person) was 10. For adverse
events, low level stimulation was significantly superior in dysphonia and hoarseness (relative risk 2.06, 95% confidence
interval 1.34‒3.17) and dyspnea (relative risk 2.43, 95% confidence interval 1.29‒4.57). Treatment withdrawal, cough, andpain did not differ significantly between high level and low level stimulations.

3. Panel meeting

3-1. What is the quality of evidence about the overall outcomes?
In all the studies collected, the risk of bias was low overall, and the level was not downgraded for all the outcomes. For
inconsistency of the results, I2 was 32% for only dysphonia / hoarseness. Since the effect estimate differed between studies,
heterogeneity was considered high. Inconsistency was thus considered serious and was downgraded one rank. There was noproblem with indirectness, and was judged not serious. As for imprecision, the confidence intervals in many analyses crossed
the clinical decision thresholds, and hence was downgraded by one or two ranks. Regarding publication bias, there were only
four studies, and therefore was not downgraded. Consequently, the level of evidence for the outcomes was as follows:“moderate” for seizure frequency ≤ 50%, cough, and dyspnea; “low” for treatment withdrawal, dysphonia / hoarseness, andpain. The overall level of evidence was “low”.

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3-2. What is the balance between benefits and harms?
High level stimulation was superior to low level stimulation for the outcome of seizure frequency ≤ 50%. Among theadverse events, dysphonia/hoarseness and dyspnea showed lower rates in low level stimulation, but since there was no
significant difference in treatment withdrawal between two groups, there must be few adverse events serious enough to cause
treatment withdrawal. According to expert opinion, many adverse events are reversible and can be controlled by adjusting
the stimulation current intensity. Taken together, we decided that high level stimulation is probably superior in terms of thebalance between benefits and harms.

3-3. What about patients’ values and preferences?
We concluded that there is probably no significant uncertainty and variability in patient’s values and preferences because
high level stimulation is more effective than low level stimulation, and although adverse events are more prevalent in highlevel stimulation, they are reversible and can be controlled by adjusting the stimulation current.

3-4. What is the balance between net benefit and cost or resources?
Adjustment of stimulation intensity can be done by placing the programming wand over the subcutaneously implanted
generator; thus resources and costs are negligible. However, reoperation is needed every few years to replace the generator
when the battery runs out of power. Battery consumption is higher for high level stimulation than for low level stimulation.
Based on these, it was decided that high level stimulation costs moderately more as compared to low level stimulation.

3-5. Recommendation grading
In the discussions at the panel meeting, high level stimulation was considered superior in efficacy, and adverse effects were
acceptable because most of them were presumably at a level that would not cause treatment withdrawal. As for burden andcost, high level stimulation was expected to consume more battery power, requiring more frequent generator exchange.
Based on the above arguments, despite considerable adverse events that did not cause treatment withdrawal as well as theincreased burden and cost, we finally unanimously recommended using high level stimulation, considering the highly
anticipated seizure control effect.

4. Descriptions in other related guidelines
In Japan, the “Guideline on implementation of vagus nerve stimulation therapy for epilepsy”6) was published by the Japan
Epilepsy Society in 2012, which states that “In principle, initiate VNS two weeks after implantation. Start with low
stimulation intensity and then gradually increase the intensity while monitoring the adverse effects [recommendation grade C]”.
In 2013, the American Academy of Neurology released a guideline update entitled “Vagus nerve stimulation for thetreatment of epilepsy”7). There is no recommendation for high level or low level stimulation in that guideline. However, it
states that whether stimulation at a higher frequency is more likely to reduce seizures than usual stimulation remains
unknown.

5. Treatment monitoring and evaluation
For adjusting stimulation intensity, we need a system which is capable of managing complications and coping withequipment troubles.

6. Future research issues
Further research on the optimal intensity of stimulation is needed. In addition, other than stimulus intensity, there is no
RCT on supplementary techniques such as magnet stimulation, which will be a future research subject. It is also desirable toelucidate the mechanisms underlying the subgroup with high response and develop evaluation methods to identify thesesubjects.

7. RCT reports reviewed for this CQ
Michael 19932), VNS study Group 19953), Handforth 19984), Klinkenberg 20125)

Chapter 10938. List of appendices (to be shown later)
Appendix CQ10-2-01. Flow diagram and search formula for references
Appendix CQ10-2-02. Risk of bias summary
Appendix CQ10-2-03. Risk of bias graphAppendix CQ10-2-04. Forest plot
Appendix CQ10-2-05. Summary of findings (SoF) table
Appendix CQ10-2-06. Evidence-to-decision table▪ References
1) Panebianco M, Rigby A, Weston J, et al. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2015; (4): CD002896.
2) Michael JE, Wegener K, Barnes. Vagus nerve stimulation for intractable seizures: one year follow-up. J Neurosci Nurs. 1993; 25(6): 362-366.
3) The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractableseizures. The Vagus Nerve Stimulation Study Group. Neurology. 1995; 45(2): 224-230.
4) Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.
Neurology. 1998; 51(1): 48-55.
5) Klinkenberg S, Aalbers MW, Vles JS, et al. Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. Dev Med
Child Neurol. 2012; 54(9): 855-861.
6) Kawai K, Sugai K, Akamatsu N, et al. Guideline on implementation of vagus nerve stimulation therapy for epilepsy. Tenkan Kenkyu. 2012; 30(1):68-72 (in Japanese).
7) Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the
Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013; 81(16): 1453-1459.

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Chapter 11
Termination of Epilepsy Treatment
CQ 11-1

How many years after seizure remission should treatment
termination be considered?
Summary
In children, consider treatment termination after seizures have remitted for at least 2 years.
In adults, more cautious consideration should be given, but in the case of a desire of child-bearing, actively consider
dose reduction and termination.

Comment
Termination of epilepsy treatment is one of the most difficult clinical decisions. Although much evidence has been
accumulated, there is no clear consensus on the timing of treatment termination.
In children, some epilepsy syndromes have good prognosis (= idiopathic partial epilepsy). To avoid adverse effects of longterm treatment with antiepileptic drugs on cognitive and behavioral development, the benefits of treatment termination are
great. In adults, such subgroup with good prognosis has not been reported, and the risk of seizure recurrence by drug
termination is higher than in the case of childhood-onset epilepsy1). Because social factors such as employment and driving
license have great impact on the decision in adults, more careful consideration is required. In women whose seizures are in
remission, a desire of child-bearing is a good opportunity to consider treatment termination. If seizure recurs in the processof treatment withdrawal, the seizure is controlled by restarting therapy in most cases, although the seizure control may bedifficult in some patients2). We should make a final decision on treatment termination individually by comprehensively
considering various conditions of each patient (in particular, the presence or absence of a poor prognostic factor) together
with respect for the intentions of the patients and their families.
As for the timing of treatment termination in children, there is a Cochrane review that compared an early treatment
withdrawal group (seizure remission for less than 2 years) and a late treatment withdrawal group (seizure remission for morethan 2 years)3). In this analysis, the early treatment withdrawal group had a higher risk of seizure relapse than the latetreatment withdrawal group, with a relative risk of 1.32 (1.02–1.70). Particularly, in patients with partial seizure or EEG
abnormality, the risk of relapse was even higher; the relative risk of early withdrawal was 1.52 (0.95–2.41), and that of late
withdrawal was 1.67 (0.95–3.00). There is no reliable evidence on generalized seizures. In children, there is little risk of
relapse if treatment is terminated after 2 years or longer of seizure remission.
In adults, there is no evidence that compares early and late treatment termination. According to the results of a randomized
controlled trial of 1,013 adult epilepsy patients who had seizure remission for more than 2 years, the complete remission rate
was 78% in the patients who continued treatment, and 59% in those who withdrew treatment after 2 years of follow-up4).
The most important factor influencing seizure relapse was the duration of seizure remission.

▪ References
1) Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs: a meta-analysis. Neurology. 1994; 44(4): 601-608.
2) Schmidt D, Löscher W. Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinicalexperience. Acta Neurol Scand. 2005; 111(5): 291-300.
3) Sirven J, Sperling MR, Wingerchuk DM. Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database
Syst Rev. 2015; (2): CD001902.
4) Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients inremission. Lancet. 1991; 337(8751): 1175-1180.

Chapter 1195▪ Search formula and secondary reference sources
PubMed search: December 13, 2015((“epilepsy” [MeSH Terms] OR “epilepsy” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH Terms]
OR “therapeutics” [All Fields])) AND termination [All Fields] = 383. Finally the above references were included.

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CQ 11-2

Does the risk of seizure recurrence differ depending on seizure
type, epilepsy type, or epilepsy syndrome?
Summary
The risk of seizure recurrence differs depending on epilepsy syndrome.

Comment
According to a prospective study on treatment termination in 264 children with epilepsy by Shinnar et al.1), seizures
recurred in 95 children (36%) during the follow-up period (average 58 months). In this study, among the epilepsy syndromes,
no recurrences occurred in 14 children with idiopathic partial epilepsy (benign childhood epilepsy with centrotemporal
spikes, benign Roland epilepsy), while seizures recurred in all 4 children with juvenile myoclonic epilepsy (JME)2).
Meanwhile, in a long-term follow-up (median 44.6 years) study of 66 patients with JME, 39 patients (59.1% of all patients)
remained seizure-free for over 5 years (22.9 ± 10. 9 years), 11 of whom (16.7% of all patients) had no antiepileptic drugs forover 5 years3). Thus, the results are inconsistent among reports.
The above findings suggest that the diagnosis of epilepsy syndrome is critical when considering termination of treatment.
However, there are few epilepsy syndromes in which a definite prognosis can be predicted. For the other epilepsy syndromes,
the risk of seizure relapse is relative, and evidence is poor. In addition, many patients cannot be classified under one specificepilepsy syndrome. At least, the recurrence rate is higher in symptomatic epilepsy than in idiopathic epilepsy [relative risk
1.81 (1.21–2.70)]1).
There is not enough evidence on the risk of seizure recurrence for each of the seizure types. According to a study fromJapan that analyzed the recurrence and clinical features of 556 patients with childhood-onset epilepsy who discontinued
antiepileptic drug therapy, 80 patients (14.4%) had recurrence, and the rate was especially high in those who stopped drugs
after adolescence2). By epilepsy type, the rates were high in adolescent- or adult-onset idiopathic generalized epilepsy (31.3%),
symptomatic localization-related epilepsy (25.2%), and cryptogenic or symptomatic generalized epilepsy (19.2%).

▪ References
1) Shinnar S, Berg AT, Moshé SL, et al. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol. 1994; 35(5):534-545.
2) Yamatani M, Konishi T, Matsuzawa J, et al. Relapse of seizure after withdrawal of antiepileptic drug treatment in childhood epilepsy: age-dependent
factors. No To Hattatsu. 2000; 32(1): 15-20 (in Japanese with English abstract).
3) Senf P, Schmitz B, Holtkamp M, et al. Prognosis of juvenile myoclonic epilepsy 45 years after onset: seizure outcome and predictors. Neurology.
2013; 81(24): 2128-2133.

▪ Search formula and secondary reference sources
PubMed search: December 13, 2015((((“epilepsy” [MeSH Terms] OR “epilepsy” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH
Terms] OR “therapeutics” [All Fields])) AND (“recurrence” [MeSH Terms] OR “recurrence” [All Fields])) OR (“recurrence” [MeSH Terms] OR“recurrence” [All Fields] OR “relapse” [All Fields])) AND ((“risk factors” [MeSH Terms] OR (“risk” [All Fields] AND “factors” [All Fields]) OR “riskfactors” [All Fields] OR (“risk” [All Fields] AND “factor” [All Fields]) OR “risk factor” [All Fields]) AND type [All Fields] AND (“syndrome”[MeSH Terms] OR “syndrome” [All Fields])) = 349. Finally the above references were included.

Chapter 11

97

CQ 11-3

Is there an optimal dose reduction speed of antiepileptic drugs?
Summary
There is no reliable evidence for recommendation of the optimal speed for dose reduction of antiepileptic drugs forboth children and adults.

Comment
According to a Cochrane review1) that verified the risk of seizure relapse in a rapid withdrawal group that terminatedtreatment within a tapering period of 3 months and a slow withdrawal group with a longer tapering period, there was nosuch study in adults. There were several studies in children. However, no conclusion could be derived because of issues suchas deficient methodology and insufficient sample size. Even in children, there is no evidence that can be reflected in guideline.
In principle, we should taper the dose gradually. Abrupt cessation of the antiepileptic drugs has the risk of causing
unexpected rebound seizure or status epilepticus. Especially, phenobarbital and clonazepam should be tapered carefully.

▪ References
1) Ranganathan LN, Ramaratnam S. Rapid versus slow withdrawal of antiepileptic drugs. Cochrane Database Syst Rev. 2006; (2): CD005003.

▪ Search formula and secondary reference sources
PubMed search: December 13, 2015(“epilepsy” [MeSH Terms] OR “epilepsy” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH Terms]
OR “therapeutics” [All Fields]) AND (“anticonvulsants” [Pharmacological Action] OR “anticonvulsants” [MeSH Terms] OR “anticonvulsants” [AllFields] OR “anticonvulsant” [All Fields]) AND (“appointments and schedules” [MeSH Terms] OR (“appointments” [All Fields] AND “schedules”[All Fields]) OR “appointments and schedules” [All Fields] OR “schedule” [All Fields]) AND withdrawal [All Fields] AND discontinuation [AllFields] = 27. Finally the above reference was included.

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CQ 11-4

What are the poor prognostic factors in treatment termination?
Summary
The risk of seizure recurrence is high in patients with adolescent-onset epilepsy, symptomatic epilepsy, and EEG
abnormalities.
In adult-onset epilepsy, the following factors increase the risk of recurrence: (1) taking two or more drugs at theonset of dose reduction, (2) a history of tonic-clonic seizure, (3) a history of myoclonic seizure, and (4) neurologicalabnormalities.

Comment
Berg and Shinnar1) conducted a detailed meta-analysis on the predictors of poor prognosis related to treatment
withdrawal in childhood and adult epilepsy. The risk of recurrence in the first year after tapering of antiepileptic drug was
0.25 (0.21–0.30) and the risk of recurrence in the second year was 0.29 (0.24–0.34). The risk factors were as follows.
Adolescent onset epilepsy had a higher recurrent risk compared to childhood onset epilepsy [relative risk 1.79 (1.46–1.81)].
Adult onset epilepsies had a higher recurrent risk compared to childhood onset epilepsies [relative risk 1.34 (1.00–1.81)].
Symptomatic epilepsy had a higher recurrent risk compared to idiopathic epilepsy [relative risk 1.55 (1.21–1.98)]. Especially,
symptomatic epilepsy with motor symptoms had a higher risk of recurrence compared to idiopathic epilepsy [relative risk
1.79 (1.13–2.83)]. Patients with abnormal EEGs had a relative risk of 1.45 (95% CI, 1.18 to 1.79) compared to those withnormal EEGs. There was no adequate evidence regarding the degree of abnormalities in EEG.
In a randomized controlled trial (RCT) of 1,013 adult epilepsy patients who had been seizure-free for more than 2 years,
the risk of recurrence was higher in patients who took two or more drugs or those with a history of tonic-clonic seizure2).
Based on this study, a prognostic index for recurrence of seizures after remission of epilepsy was developed3). A study on theconsequences of treatment termination in adult epilepsy pointed out that recurrence rate was higher in patients withneurological signs4).
According to a review on recurrence after treatment termination in adults and children5), seizures remitted again in mostof the patients by restarting the drugs, but in 19% of the patients (mean of 14 studies, 95% CI: 15–24%), remission was not
obtained by resuming the drugs, and 23% of them became refractory. The factors inducing intractable recurrence included
symptomatic etiology, partial epilepsy, and cognitive impairment.

▪ References
1) Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs: a meta-analysis. Neurology. 1994; 44(4): 601-608.
2) Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomised study of antiepileptic drug withdrawal in patients inremission. Lancet. 1991; 337(8751): 1175-1180.
3) Medical Research Council Antiepileptic Drug Withdrawal Study Group. Prognostic index for recurrence of seizures after remission of epilepsy.
BMJ. 1993; 306(6889): 1374-1378.
4) Lossius MI, Hessen E, Mowinckel P, et al. Consequences of antiepileptic drug withdrawal: A randomized, double-blind study (Akershus Study).
Epilepsia. 2008; 49(3): 455-463.
5) Schmidt D, Löscher W. Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinicalexperience. Acta Neurol Scand. 2005; 111(5): 291-300.

▪ Search formula and secondary reference sources
PubMed search: December 13, 2015(“epilepsy” [MeSH Terms] OR “epilepsy” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH Terms]
OR “therapeutics” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “treatment” [All Fields] OR “therapeutics” [MeSH
Terms] OR “therapeutics” [All Fields]) AND (“prognosis” [MeSH Terms] OR “prognosis” [All Fields]) AND outcome [All Fields] AND termination[All Fields] = 83. Finally the above references were included.

Chapter 1199

CQ 11-5

Should driving be avoided during dose reduction of antiepileptic
drugs?
Summary
The Road Traffic Act revised in 2013 and later contains no regulation concerning driving motor vehicles duringdose reduction of antiepileptic drugs.
The “Guidelines for assessing fitness of driving for people with epilepsy”1) produced by the Japan Epilepsy Society
Legal Issue Committee in 2001 claimed the following: When antiepileptic drugs are being reduced or stopped
following the instructions of a doctor, the patients are prohibited from driving a motor vehicle during the period ofdose reduction and for three months after the end of dose reduction. Thereafter, the “Proposal for Epilepsy andDriving”2) also produced by the same Committee proposed no driving and observation for 6 months after the end ofdose reduction or termination of treatment, except when there is sufficient evidence that there is no risk of recurrence(long seizure-free period, small total number of attacks, epilepsy syndrome with low risk of recurrence, patients withgood prognosis after epilepsy surgery).

▪ References
1) Japan Epilepsy Society Legal Issue Committee. Guidelines for assessing fitness of driving for people with epilepsy. Tenkan Kenkyu. 2001; 19(2):140-141 (in Japanese).
2) Japan Epilepsy Society Legal Issue Committee. “Proposal for epilepsy and driving” (2014) http://square.umin.ac.jp/jes/images/jes-image/driveteigen2.
pdf (in Japanese).

▪ Search formula and secondary reference sources
PubMed search: December 13, 2015(“epilepsy” [MeSH Terms] OR “epilepsy” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH Terms]
OR “therapeutics” [All Fields]) AND (“automobile driving” [MeSH Terms] OR (“automobile” [All Fields] AND “driving” [All Fields]) OR“automobile driving” [All Fields]) AND (“jurisprudence” [MeSH Terms] OR “jurisprudence” [All Fields] OR “law” [All Fields]) = 93. Finally theabove references were included.

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Chapter 12
Drug Concentration Monitoring
CQ 12-1

When should serum concentrations of antiepileptic drugs bemonitored?
Summary
Measurement of serum concentrations of antiepileptic drugs is useful for the following purposes: (1) to establish
individual therapeutic ranges when the desired seizure control is obtained; (2) to diagnose adverse effects; (3) toevaluate adherence at the time of poor seizure control or breakthrough seizure; (4) to adjust doses in situations ofpharmacokinetic changes (such as in children, elderly patients, comorbid disorders, and change in dosage form); (5)to adjust doses when change in pharmacokinetics is predicted (such as during pregnancy and addition or removal ofdrugs having interactions); and (6) to adjust doses of drugs having dose-dependent pharmacokinetics (particularly
phenytoin).

Comment
Monitoring serum concentrations of antiepileptic drugs is useful in deciding patient’s medication regimen, if monitoringis done for a clear purpose and the results are interpreted properly along with other clinical factors. Serum concentrations ofantiepileptic drugs should not be monitored routinely without intended purposes. However, they should be measured when
there are clinical needs (Table 1)1).
The reference range of serum concentrations of a certain drug is not the same as its therapeutic range. The lower limit of
the reference range of serum concentrations is the concentration being more likely to produce an insufficient therapeutic
effect, and the upper limit is the concentration being more often associated with adverse effects. That is, the serum
concentrations of antiepileptic drugs within the reference range (so-called effective serum concentrations) indicate thatthey are expected to be effective with fewer adverse effects in most of the patients1).
The therapeutic range of serum concentrations for a certain patient is the range within which that patient has the best
seizure control. In most of the patients, the therapeutic range is within or overlaps with the reference range. However,treatment may be effective even when the serum concentration is lower than the reference range in some cases, or conversely
may be effective only when the concentration is higher than the reference range in other cases, because of large interindividual variability of the therapeutic range. Therefore, it is important to know the therapeutic range for each patient. The
dose should not be increased if the patient remains seizure-free at serum concentration lower than the reference range. On
the other hand, the dose might be increased to above the reference range if the patient has residual seizures without any
adverse effects. The reference range of serum concentration differs depending on age, epilepsy syndrome, and seizure type1, 2).
The reference range is determined based on the lowest serum concentration (the trough value, which is measured before
drug taking in the morning). However, it is difficult to measure the trough value in outpatient clinic, and serum concentration
measured at our clinics is usually higher than the trough. Therefore, it is not a concern if the measured value exceeds theupper limit of the therapeutic range. We should interpret the blood concentration considering the blood sampling time, thedrug taking time, and the time of maximum concentration (Tmax) of each drug (Table 1 in CQ 12-2 on page 104).
Antiepileptic drug exists in two forms in the blood: a protein-bound form and a free form. In patients with hypoproteinemia,
pregnancy, hepatic disorders or renal disorders, the amount of drug in the free form is larger than that in healthy subjects
even when the measured serum concentration is the same, and the efficacy and adverse effects are not the same as in normal
controls. Although the free form possesses antiepileptic effect, measurement of free form is not covered by medical insurance.
In general, the total serum concentrations of antiepileptic drugs, including both protein-bound form and free form, aremeasured and recorded.

Chapter 12  

101▪ References
1) Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the
Subcommission on Therapeutic Drug Monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008; 49(7): 1239-1276.
2) Johannessen SI, Patsalos PN. Individual approach to laboratory monitoring of antiepileptic drugs. In: Wyllie E, Gidal BE, Goodkin HP, et al eds.
Willie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015. p.568-573.

Table 1. General indications for monitoring blood concentrations of antiepileptic drugs.
1. A fter initiation of treatment or after dose adjustment, when the clinician decides to aim at a target concentration
for that patient.
2. Once the desired seizure control state has been achieved, to establish the “individual therapeutic range.”
3. To determine the magnitude of a dose increase, particularly with antiepileptic drugs showing dose-dependent
pharmacokinetics (most notably, phenytoin).
4. W hen there are uncertainties in the differential diagnosis of signs or symptoms suggesting drug-related adverse
reaction, or when adverse effect is difficult to assess clinically (young children, patients with mental disability).
5. When seizures persist despite an adequate dosage.
6. W hen change in pharmacokinetics (consequently, required dose also change) is suspected, due to age,pregnancy, comorbidity, or drug interaction.
7. To assess changes in steady state drug concentration when a change in drug formulation or change to genericformulation is made.
8. When there is an unexpected change in clinical response.
9. To conform adherence when poor compliance is suspected.
(Modified from: Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs—best practice guidelines fortherapeutic drug monitoring: a position paper by the Subcommission on Therapeutic Drug Monitoring, ILAE
Commission on Therapeutic Strategies. Epilepsia. 2008: 49(7); 1239: 1276.)

102Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 12-2

Serum concentration monitoring is useful for which drugs?
Summary
The reference ranges of serum concentrations have been established for carbamazepine, phenytoin, phenobarbital,
primidone, valproate, and ethosuximide. Serum concentration monitoring is useful for these drugs. However, forsome other drugs, the serum concentration monitoring is not very useful because the reference ranges have notdetermined for them or they show remarkable fluctuations in serum concentration (Tables 1 and 2)1-5).

Comment
Because there are large interindividual variabilities in epileptogenesis and response to a given antiepileptic drug, it isdifficult to find a general therapeutic range of serum concentrations applicable to all patients. However, it is known that
there exists a range of serum concentrations at which seizures are controlled and dose-dependent adverse effects are rarely
seen in most of the patients. This range is called the “reference range” (so-called effective blood concentration).
Even for drugs with no established general reference ranges, serum concentration measurement is useful for comparisons
within an individual patient. Benzodiazepines play a role as an anti-convulsant by binding with benzodiazepine receptors
in the brain. Because the number of benzodiazepine receptors varies from person to person, it is difficult to determine thereference blood concentration range for all persons. The reference ranges for clobazam, nitrazepam and diazepam have notbeen reported. However, repetitive serum concentration measurements in one patient are useful for monitoring adverse
effects such as drowsiness in that patient.
Phenytoin is a drug showing big fluctuations in serum concentration, which requires attention. Because of the non-linear
relationship between dosage and serum concentration and the narrow therapeutic window, measurement of serum
concentration is critical for setting the optimal dosage. Especially, a rapid rise in serum concentration occurs at high doses1).
The serum concentration of lamotrigine decreases drastically when used concomitantly with enzyme-inducing drugs(phenytoin, carbamazepine, phenobarbital, and primidone), increases greatly when used in combination with valproate, anddeclines significantly during pregnancy. Serum level of carbamazepine decreases within 1–3 months after start of treatment,
due to enzyme self-induction. Therefore, serum concentration has to be monitored shortly after treatment initiation.

▪ References
1) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015, p.376-700.
2) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015,
p.593-768.
3) Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge: Cambridge University Press, 2010.
4) Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 Edition. Tokyo: Jiho Inc., 2015 (in Japanese).
5) Johannessen SI, Johannessen-Landmark C, Perucca E. Pharmacokinetic optimization of therapy. In: Shorvon S, Perucca E, Engel J Jr eds. The
treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015, p.124-138.

Chapter 12  

103

Table 1. Therapeutic ranges of blood levels and pharmacokinetics of major antiepileptic drugs.
Maintenance dosea
Generic name(abbreviation)

Phenobarbital

PB

Primidone
Carbamazepine
Phenytoinf

PRM
CBZ
PHT

Valproate

Acetazolamide
Potassium bromide

VPA
VPA-R
ESM
CZP
NZP
CLB
CLBh
AZM
KBr

Gabapentin
Topiramate
Lamotriginei

GBP
TPM
LTG

sustained release

Ethosuximide
Clonazepam
Nitrazepam
ClobazamN-desmethyl

Adult
(mg)

Child
(mg/kg)

Dose increaserange

T1/2: elimination half-lifec (h)
Blood
conc.
Adult
reference
Adult Child
with
b
range
Child
(mg) (mg/kg) (µg/mL) monoenzyme
therapy
inducerd
almostunchanged

Tmax: peaktimec (h)
Adult

Child

10–26ealmostunchanged
7.5–16g

10–13
days

5–8
days

(1) with VPA(2) with enzyme inducerd(3) with (1) and (2)Levetiracetamj
Rufinamide
Stiripentol
Vigabatrin
Perampanel
Lacosamidem

LEV
RFNk
STP
VGB
PER l
LCM

by weight by weight

8–12l
200–400m

a: In children, the younger the age, the higher the dose per kg body weight is required to obtain a given blood concentration, themaintenance dose is higher, and half-life and peak time are shorter. In adolescents, pharmacokinetics are almost the same as adults.
b: If effective, blood concentration can stay low, or can be increased to higher than the therapeutic range as long as there is no adverse
effect.
c: This is the time for the concentration to decrease by half from the peak. The time until blood concentration decreases by one-half afteradministration is peak time + half-life. Half-life and peak time are in principle determined for monotherapy with drug taking after
meal. In combination therapy, half-life is shortened when the combination lowers blood level through interaction, and is prolonged
when the combination increases blood concentration (see “Interaction” in CQ 12-4 on page 109). Peak time is shortened significantlywith drug is taken when fasting.
d: Enzyme-inducing drugs: PB, PRM, CBZ and PHT. Increase drug metabolism in the liver, concomitant use shortens half-life oforiginal drug.
e: Value at the time when self-induction is completed (3–4 weeks after starting)f: For PHT, the higher the blood level, the longer is the half-life. L: low dose (blood level around 5 μg/mL), H: high dose (blood level
10 μg/mL or above)
g: Peak time of VPA sustained release preparation varies depending on the dosage form: 5 to 10 h for Selenica® R fine granule, 7.5 to 10 hfor Depakene® R tablet, and 13 to 16 h for Selenica® R tablet.
h: N-DMCLB is a metabolite of CLB. N-DMCLB has anticonvulsive action of approximately 1/4 strength of that of CLB. Whenclassified by CLB:N-DMCLB concentration ratio into three groups of approximately 1:2‒3 (10% of the subjects), around 1:10 (80%),
and around 1:50–100 (10%), drowsiness occurs at a higher rate as the CLB:NDMCLB concentration ratio increases.
i: In Japan, monotherapy use is approved only for partial seizure (including secondarily generalized seizures) and tonic clonic seizure in
16 year-old and above. To prevent rash (especially Stevens‒Johnson syndrome), follow the instructions in the package insert concerning
the initial dose, the dose increase range and the maximum dose of LTG.
j: Monotherapy use only for 4 year-old and above with partial seizure.

104

Part IThe Clinical Practice Guidelines for Epilepsy 2018

k: Covered by insurance for 4 year-old and above. Starting dose to maximum dose is as follows: 15 to < 30 kg in weight: 200‒1,000 mg,
30 to < 50 kg: 400‒1,800 mg, 50 to < 70 kg: 400‒2,400 mg, ≥ 70 kg: 400‒3,200 mg. Dose increase range is: 15 to < 30 kg: ≤ 200 mg,
and ≥ 30 kg: ≤ 400 mg. Official abbreviation is undecided and RUF is also commonly used.
l: Covered by insurance for 12 year-old and above. Official abbreviation is undecided and PRP is also commonly used.
m: Covered by insurance for 6 year-old and above.
(Compiled from: Shorvon S, Perucca E, Engel J Jr, eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015,
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds.: Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015, p.593‒768. / Patsalos PN, Bourgeois BFD: The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010. / Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 edition. Tokyo: Jiho Inc., 2015.)

Table 2. Usefulness of measuring blood concentration.
Usefulness
Very useful
UsefulUseful to certain extent
Limited or undetermined

Antiepileptic drugs
Phenytoin, lamotrigine
Carbamazepine, phenobarbital, valproate, ruﬁnamide,
perampanel
Primidone, ethosuximide, zonisamide, topiramate
Clonazepam, clobazam, diazepam, nitrazepam,
acetazolamide, gabapentin, levetiracetam, potassium
bromide, stiripentol, vigabatrin, lacosamide(Compiled from: Johannessen SI, Johannessen-Landmark C, Perucca E. Pharmacokinetic
optimization of therapy. In: Shorvon S, Perucca E, Engel J Jr, eds. The treatment of
epilepsy, 4th ed. Chichester: Wiley Blackwell, 2015, p.124‒138.)

Chapter 12  

105

CQ 12-3

Is serum concentration monitoring a requisite in the treatmentof patients with hepatic or renal dysfunction?
Summary
Since the pharmacokinetics of antiepileptic drugs may alter in patients with hepatic or renal dysfunction, conduct
treatment based on serum concentrations of drugs. Dialysis reduces serum drug concentrations.

Comment
Antiepileptic drugs are mainly metabolized by the liver and excreted by the kidney. But the ratio of hepatic metabolism
and renal excretion varies depending on the drug. In patients with liver or kidney disorders, pay attention to the increase inserum concentrations of antiepileptic drugs, bearing in mind the metabolism and excretion routes and the ratio of hepatic
metabolism and renal excretion for each drug. Then, the doses should be reduced if necessary. For drugs that are metabolized
by the liver, serum concentrations do not change markedly in acute hepatitis since metabolic enzymes do not decrease, but
serum concentrations rise in cirrhosis because metabolic enzyme and hepatic blood flow are both reduced. In patients treatedwith hemodialysis, the blood levels of some drugs decrease, therefore consider dose increment1) (Table 1)2-4).

▪ References
1) Singh G. Management of medical comorbidity associated with epilepsy. In: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4thedition. Chichester: Wiley Blackwell, 2015, p.245-258.
2) Spina E, Italiano D. Drug interactions. In: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell,2016. p.344-359.
3) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015. p.376-700.
4) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015.
p.593-768.

106Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 1. Metabolic and excretion routes of major antiepileptic drugs, and dose adjustment ofantiepileptic drugs in the case of hepatic and renal impairment.

Phenytoin
Carbamazepine
Valproate
Phenobarbital
Primidone
Clobazam
Clonazepam
Zonisamide
Ethosuximide
Potassium bromide
Gabapentin
Topiramate
Lamotrigine
Levetiracetam
Rufinamide
Stiripentol
Vigabatrin
Perampanel
Lacosamide

Hepatic
metabolism (%)
90
90
85
55
45‒60
> 90
> 90
70
70
0
0
< 25
90
<3
85
75
10
70
30

Renal
excretion (%)
<2
<1
<5
25
20‒25
<1
<1
< 30
20
100
100
75
10
70
2
25
90
30
40

Adjustment during liver
impairment
Dose reduction
Dose reduction
Dose reduction
Slight dose reduction‒No need
Slight dose reduction‒No need
Dose reduction
Dose reduction
Dose reduction
Dose reduction
No needNo needNo need
Dose reduction
No need
Dose reduction
Dose reduction
No need e
Dose reduction
Dose reduction

Adjustment during
kidney impairment
No needNo needNo needSlight dose reduction
Slight dose reduction
No need e
No needSlight dose reduction
No need
Dose reduction
Dose reduction
Dose reduction
No need
Dose reduction
No needNo need
Dose reduction
No needSlight dose reduction(Compiled from: Spina E, Italiano D. Drug interactions. In: Shorvon S, Perucca E, Engel J Jr. eds. The treatment of epilepsy,
4th edition. Chichester: Wiley Blackwell, 2016. p.344‒359. / Shorvon S, Perucca E, Engel J Jr. eds. The treatment of epilepsy,
4th edition. Chichester: Wiley Blackwell, 2015. p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatmentof Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015. p.593‒768.)

Chapter 12  

107

CQ 12-4

What are the drugs that interact with antiepileptic drugs?
Summary 1-5)
When addition or removal of a given non-antiepileptic drug results in an increase in seizures or adverse effects,
suspect drug interaction with the antiepileptic drugs being used and consider measurement of serum concentrationsof the antiepileptic drugs. Conversely, when an antiepileptic drug is being added or removed, pay attention to thepossibility that the therapeutic effects of other drugs may alter, which may result in some changes in comorbid
symptoms.

Comment
Drug interactions include interactions between antiepileptic drugs (Table 1)1-3), interactions between antiepileptic drugs
and psychotropic drugs (Tables 2 and 3)1-5), and interactions between antiepileptic drugs and general drugs other thanpsychotropic drugs (Tables 4 and 5)1-5). Pay special attention when patients are complicated with psychiatric disease ordevelopmental disorder, or elderly people taking various drugs because of comorbidities.
Among antibiotics, clarithromycin and erythromycin inhibit the metabolism of carbamazepine, resulting in a large
increase in serum concentration of carbamazepine, causing dizziness, vertigo, and severe drowsiness. Carbapenem antibiotics(panipenem‒betamipron, meropen, imipenem‒cilastatin, doripenem, biapenem, tebipenem) are contraindicated when
taking valproate, as they significantly lower the serum concentration of valproate.
For antithrombotic drugs, warfarin used with phenytoin mutually increase the serum concentrations of each other, andthe blood level of rivaroxaban is lowered by carbamazepine, phenytoin or phenobarbital (see CQ 3-8 on page 30).

▪ References
1) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015. p.376-700.
2) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer,
2015. p.593-768.
3) Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge: Cambridge University Press, 2010.
4) Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 edition. Tokyo: Jiho Inc., 2015 (in Japanese).
5) Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika (Japanese Journal of Pediatric Medicine) 2014; 46(9):1242-1247 (in Japanese).

108

Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 1. Interactions between epileptic drugs.
Added drug
VPA
PB
CBZ
PHT
ZNS
CZP
CLB
ESM
AZM
GBP
TPM
LTG
LEV
RFN
STP
VGB
PER
LCM

Blood concentration of the original antiepileptic drug
VPA PB CBZ PHT ZNS CZP CLB ESM AZM GBP TPM LTG LEV RFN STP VGB PER LCM
↑↑
↓a
↓b
↓
↓
↑
→
↓
↑↑
→
↑↑
↓
↓
→↓
↓
↓
↓
↓
→
↓↓
↓↓
↓
↓↓
↓↓
↓
↓↓ ↑↓→
↑
↓
↓
↓
↓↓
→
↓↓
↓↓
↓
↓
↓↓
→
↓↓
↓
↓↓
↑↓
↓↓
↓↓
↓
↓
↓↓
→
↓↓
↓↓
↓
↓↓
↓↓
→
↓↓
↓
c
→ →
→
→
↑
→
↓
→
→
→
↑↑
↑
↑d
↑↑
→
→
↑
↓
→
→
↑
→
→
↑
↑
→
→
→
→
→
→
→
→
→
→
→
↓
→
→
↑
→
→
→
↓
→
→
→
→
↓
→
→
→
→
→
→
→
→
→
→
→
→
→
→
↑
↓
↑
→
↓
↑
↑
↑↑
↑↑
↑↑
→
→
→
↓
→
↓
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→

Blood level: ↑ increase, ↑↑ marked increase, ↓ decrease, ↓↓ marked decrease, → unchanged.
In the case of marked increase or marked decrease, consider decrease or increase dose of the original antiepileptic drug.
a: Although total concentration decreases, CBZ‒epoxide increases and the effect is augmented, no need to increase dose.
b: Although total concentration decreases, free drug increases and the effect is augmented, no need to increase dose.
c: CBZ-epoxide increases.
d: Both CBZ and CBZ-epoxide increase
PRM is metabolized to PB and is the same as PB, therefore is omitted.
(Compiled from: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010)

Chapter 12  

109

Table 2. Effects of psychotropic drugs on antiepileptic drugs (AED).
AED
PB
PRM
CBZ
PHT
VPA
CLB
NZP
ZNS
KBr
LTG
TPM

Blood concentrationof AED
↑
↑
↑
↑
↑
↑
↑
↑
↓
↑
↑
↓
↑

Psychotropic drugs that influence AED
Tricyclic antidepressant, zotepine, methylphenidate, tetracyclic antidepressant
Tricyclic antidepressant, zotepine, phenothiazines, methylphenidate
Quetiapine, chlorpromazine, paroxetine, haloperidol, fluvoxamine, risperidone
Tricyclic antidepressant, trazodone, fluvoxamine, methylphenidate, tetracyclic antidepressant
Chlorpromazine, tricyclic antidepressant, sertraline
Haloperidol , phenothiazines, fluvoxamine
Phenothiazines
Adverse effects increased by tricyclic antidepressantRisperidone
Phenothiazines (drowsiness, attention, concentration, reduced reflex movement worsened)
Sertraline
Olanzapine, risperidone (somnolence enhanced)
Amitriptyline, lithium*: Tricyclic antidepressants: imipramine, amitriptyline, nortriptyline, and amoxapine. Tetracyclic antidepressants: maprotiline andmianserin. Phenothiazines: chlorpromazine, levomepromazine, fluphenazine, and propericiazine.
**: CZP, AZM, ESM, GBP, LEV, RFN, STP, VGB, LCM: no description.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

Table 3. Effects of antiepileptic drugs (AED) on psychotropic drugs.
AED
PB
PRM
CBZ
PHT
VPA
CZP
CLB
NZP
ZNS
KBr
TPM
RFN

Blood concentration
Psychotropic drugs that are influenced by AEDof psychotropic drugs
Tricyclic antidepressant, zotepine, phenothiazines, tetracyclic antidepressant↑Olanzapine, chlorpromazine, tricyclic antidepressant, paroxetine , haloperidol, tetracyclic↓
antidepressant, risperidone
Tricyclic antidepressant, zotepine, phenothiazines↑
Lithium↑
Aripiprazole, alprazolam, tricyclic antidepressant, sertraline, trazodone, paliperidone, paroxetine,↓
haloperidol , phenothiazines, tetracyclic antidepressant, risperidone
Tricyclic antidepressant, trazodone, fluvoxamine, tetracyclic antidepressant↑Quetiapine, tricyclic antidepressant, trazodone, paroxetine , tetracyclic antidepressant↓Aripiprazole, chlorpromazine, tricyclic antidepressant, paroxetine↑
Effect of phenothiazines enhanced↑
Haloperidol, phenothiazines↑
Phenothiazines↑
Adverse effects of tricyclic antidepressant increased↑↑
Phenothiazines (drowsiness, attention, concentration, reduced reflex movement worsened↑)
Amitriptyline, haloperidol, lithium↑
Risperidone↓
Triazolam↓*: Tricyclic antidepressants: imipramine, amitriptyline, nortriptyline, and amoxapine. Tetracyclic antidepressants: maprotiline andmianserin. Phenothiazines: chlorpromazine, levomepromazine, fluphenazine, and propericiazine**: AZM, ESM, GBP, LTG, LEV, STP, VGB, LCM: no description.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 4. Effects of general drugs other than psychotropic drugs on antiepileptic drugs (AED).

PB

Blood
concentration of
AED
↑
↓

PRM

contraindicated
↑

AED

CBZ

↑

↓

↑
PHT
↓
↑
VPA
↓

CZP

↑
↓
↑

CLB

↑

NZP

TPM

↑
↑
↓
↑
↓
↑

LTG

↓

PER

↑

ESM

AZM
GBP

General drugs other than psychotropic agents that influence AED
Chloramphenicol, antihistamines (hydroxyzine, diphenhydramine ), selegiline
Antacid
In the case of PB elixir: cyanamide, disulfiram (enhance alcohol reaction)
Selegiline, antihistamines
Azole antifungals (including miconazole, fluconazole, and itraconazole), isoniazid, omeprazole, Ca
channel blockers (including verapamil, amlodipine, nifedipine, and benidipine), quinupristin/
dalfopristin, chloramphenicol, salicylic acid, ciprofloxacin, cimetidine, diltiazem, sulfamethoxazoletrimethoprim, selegiline, danazol, darunavir , telaprevir, bicalutamide, verapamil, macrolide
antibiotics (including erythromycin, clarithromycin, and josamycin), ritonavir
Aminophylline, efavirenz, antacid, theophylline, rifampicin
Azole antifungals (including miconazole, fluconazole, itraconazole, and voriconazole), amiodarone,aminophylline, allopurinol, isoniazid, omeprazole, chloramphenicol, cyclosporine, disulfiram,
cimetidine, diltiazem, sulfamethoxazole-trimethoprim, tacrolimus, ticlopidine, theophylline,
nelfinavir, para-amino-salicylic acid, fluorouracil-based preparations (including tegafur preparations
and doxifluridine), fosfluconazole, warfarinAminophylline, salicylic acid, diazoxide, cisplatin, theophylline, nelfinavir, pyridoxine, vinca alkaloids(including vincristine), rifampicin
Isoniazid, salicylates (including aspirin), cimetidine, macrolide antibiotics (including erythromycin,
clarithromycin, and josamycin)
Carbapenem antibiotics (panipenem-betamipron, meropen, imipenem-cilastatin, doripenem,
biapenem, tebipenem), cholestyramine, cisplatin, naproxen, methotrexate, rifampicin
Isoniazid
Rifampicin
Selegiline
Cimetidine, drugs metabolized by CYP3A4 (including rifampicin), CYP3A4 inhibitors (including
ritonavir, corticosteroid preparations, and macrolide antibiotics), selegiline
Cimetidine, selegiline
High-dose aspirin
Ammonium chloride
Cimetidine, naproxen, morphine
Antacid (aluminum hydroxide, magnesium hydroxide)
Hydrochlorothiazide
Acetaminophen, atazanavir, oral contraceptives (including ethinylestradiol and norethisterone),ritonavir, rifampicin, lopinavir-ritonavir combination
Ketoconazole*: ZNS, KBr, LEV, RFN, STP, VGB, LCM: no description.
**: Underlined parts denote concomitant use contraindicated.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

Chapter 12  

111

Table 5. Effects of antiepileptic drugs (AED) on general drugs other than psychotropic drugs.
AED

Blood concentrationof general drugs
↑

PB
↓

↑

PRM

↓
↑

CBZ

↓

↑

PHT

↓

↑
↑
↑
↑
↑
↑
↓
↑
↓
↓
↓

VPA
CZP
CLB
NZP
AZM
TPM
LTG
RFN
PER

General drugs other than psychotropic agents that are influenced by AED
Including thiazide hypotensive diuretics (orthostatic hypotension↑), selegiline, antihistamines(hydroxyzine, diphenhydramine)
Azelnidipine, aminophylline, imatinib, irinotecan, HIV protease inhibitors (including indinavir,
saquinavir, nelfinavir, and lopinavir), chloramphenicol, cyclosporine, tacrolimus, theophylline,
doxycycline, PDE5 inhibitors (sildenafil, tadalafil, vardenafil), felodipine, corticosteroids (including
dexamethasone), flecainide, verapamil, voriconazole, montelukast etc., estrogen-progestogenpreparations (including norgestrel and ethinylestradiol), rivaroxaban, warfarin
Antihistamines, thiazide hypotensive diuretics (including trichlormethiazide) (orthostatic
hypotension↑), selegiline
Doxycycline
Isoniazid (enhance hepatoxicity), cyclophosphamide, selegiline
Acetaminophen, aprepitant, aminophylline, albendazole, alprazolam, itraconazole, HIV proteaseinhibitors (including saquinavir, indinavir, nelfinavir, and lopinavir), etravirine, efavirenz, eplerenone,
eletriptan, ondansetron, caspofungin, anticancer drugs (axitinib, irinotecan, imatinib, gefitinib,
sunitinib, sorafenib, dasatinib, tamibarotene, temsirolimus, toremifene, nilotinib, lapatinib),
dienogest, digoxin, dihydropyridine calcium antagonists (including nifedipine, felodipine, andnilvadipine), sildenafil, solifenacin, tadalafil, dabigatran etexilate, theophylline, telaprevir, doxycycline,
donepezil, tramadol, nondepolarizing muscle relaxant (including vecuronium), corticosteroids(including prednisolone and dexamethasone), buprenorphine, praziquantel, flecainide, fosaprepitant,voriconazole, maraviroc, mirabegron, meglumine, immunosuppressants (cyclosporine, tacrolimus,
everolimus), estrogen-progestogen preparations, rivaroxaban, rilpivirine, warfarin
Warfarin
Azelnidipine, aminophylline, itraconazole, imatinib, irinotecan, indinavir, ondansetron, quinidine,
hypoglycemic agents (insulin, oral hypoglycemic agents), thyroid hormone preparations (including
levothyroxine), saquinavir, cyclosporine, disopyramide, tacrolimus, tadalafil, theophylline,deferasirox, doxycycline, nisoldipine, nifedipine, nelfinavir, nondepolarizing muscle relaxant(including vecuronium and pancuronium), PDE5 inhibitors (tadalafil, sildenafil, vardenafil),felodipine, corticosteroids (including dexamethasone), praziquantel, flecainide, verapamil,
voriconazole, mexiletine, estrogen / gestagen preparations (including norgestrel andethinylestradiol), rivaroxaban, warfarin
Warfarin
Selegiline
Drugs metabolized by CYP3A4 (including rifampicin), selegiline
Selegiline
ACTH, antihypertensive drugs, digitalis preparations (digoxin)
Metformin
Oral contraceptives (including ethinylestradiol and norethisterone), digoxin, pioglitazone
Oral contraceptives (including ethinylestradiol and norethisterone)
Oral contraceptives (including ethinylestradiol and norethisterone)
Oral contraceptives (including ethinylestradiol and norethisterone)
Oral contraceptives (including ethinylestradiol, and norethisterone)*: ZNS, ESM, KBr, LEV, STP, VGB, LCM: no description. However, STP has potent inhibitory effect on drug metabolic enzymes in theliver, and may increase the blood concentrations of various drugs.
**: Underlined parts denote concomitant use contraindicated.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

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Chapter 13
Epilepsy and WomenCQ 13-1

What kind of advice and information should be provided
regarding pregnancy and childbirth for women with epilepsy?
Summary
For women with epilepsy, comprehensive counseling including guidance about pregnancy and childbirth should
be provided in consideration of women’s life cycle. Specifically, encourage adolescents to understand the basic andpractical knowledge regarding pregnancy and childbirth as well as the knowledge about epilepsy including daily life
and importance of treatment. Also, recommend planned pregnancy and childbirth to make these life events possible
with the lowest risk. In patients who need to continue antiepileptic medication, it is desirable to select a drug withlower teratogenic risk and conduct appropriate dose adjustment to control seizures before pregnancy.

Comment
For women of childbearing age, it is desirable for the attending doctor to comprehensively assess the patient’s capability ofdaily living based on the severity of epilepsy, environmental factors, and presence or absence of coexisting disability, anddiscuss with the family members, pediatrician and other health personnel to make a reasonable decision about the possibilityof pregnancy and childbirth and to develop a plan for medication adherence1-3). Specifically, health professionals should
provide advice and guidance to all women with childbearing potential starting from adolescence (junior high school
students), at the timings appropriate to women’s life cycle such as marriage and pregnancy, and recommend planned
pregnancy and childbirth with strengthened cooperation from the family.
Regarding antiepileptic drugs (AEDs) during pregnancy and childbirth, we should be careful with the following points:(1) prescribe monotherapy in principle, (2) use the lowest required dose, (3) select AED with as low teratogenicity as possible,and (4) watch out for fluctuation in blood concentration of AED during pregnancy2, 3). Pay attention to the change in seizure
frequency at each stage of pregnancy and childbirth, and aim at optimal AED therapy considering the balance between
seizure control and reduction of risk to pregnancy and childbirth. In addition, give detailed explanations in advance on
general precautions concerning pregnancy and childbirth, effects of AED on fetus and neonate, the course after childbirth,
genetic inheritance of epilepsy, and development of the child. Table 1 summarizes the measures to be taken concerning
pregnancy and childbirth.
Although there is no clear difference in the rate of infants with congenital malformations between women with epilepsy
not taking AEDs and the general population4, 5), the frequency of congenital malformations in infants born from womentaking AEDs during pregnancy is 4‒10%, which is roughly 2‒3 times higher than the frequency of 2‒5% in the general
population. The teratogenic risk varies depending on the AED being taken2, 5, 6). On the other hand, AEDs taken when notpregnant or AEDs taken by male patients have little effect on the fetus2).
The types of congenital malformation are similar to those found in the general population, with high frequencies of cleft
lip, cleft palate and cardiac anomalies. There are no clear differences among AEDs for minor anomalies, with one exceptionof spina bifida which is more often induced by valproate and carbamazepine2).
When using oral contraceptives for planned pregnancy, explain their interactions with AEDs (phenobarbital, phenytoin,carbamazepine, and lamotrigine reduce the effect of contraceptives). We should recommend the patients to consult with anobstetrician or gynecologist for proper guidance about pills containing estrogen of 50 μg or more and other contraceptive
methods2, 7).
Furthermore, the experience of pregnancy and childbirth has great significance for women (and their families) in their
lifetime. Therefore, we should follow the patients always considering psychological features.

Chapter 13113

In clinical practice, we may use charts such as that shown in Figure 1 to highlight points that require special attention ateach stage of pregnancy, and also the drug adjustment plan.

▪ References
1) Winterbottom J, Smyth R, Jacoby A, et al. The effectiveness of preconception counseling to reduce adverse pregnancy outcome in women withepilepsy: What’s the evidence? Epilepsy Behav. 2009; 14(2): 273-279.
2) Kaneko S, Kan R, Tanaka M, et al. Treatment guideline for women of childbearing potential with epilepsy. Report of Japan Epilepsy Society
Guideline Development Committee. Tenkan Kenkyu. 2008; 25: 27-31 (in Japanese).
3) Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications.
Epilepsia. 2013; 54(3): 405-414.
4) Fried S, Kozer E, Nulman I, et al. Malformation rates in children of women with untreated epilepsy: a meta-analysis. Drug Saf. 2004; 27(3): 197-202.
5) Veiby G, Daltveit AK, Engelsen BA, et al. Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy. J
Neurol. 2014; 261(3): 579-588.
6) Meador K, Reynolds MW, Crean S, et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of publishedpregnancy registries and cohorts. Epilepsy Res. 2008; 81(1): 1-13.
7) Perucca E, Battino D, Tomson T. Gender issues in antiepileptic drug treatment. Neurobiol Dis. 2014; 72(Pt B): 217-223.

▪ Search formula and secondary reference sources
Search for the previous version of CQ13-1
PubMed search: June 28, 2015
epilepsy [mesh] AND (pregnancy [mesh] OR pregnant) AND “patient education” = 34
Ichushi search: June 28, 2015((epilepsy/MTH) and ((pregnancy/TH or pregnancy/AL)) and ((patient education/TH or patient education/AL))) and (PT = excluding proceedings)= 12
PubMed search: June 28, 2015
epilepsy [majr] AND (pregnancy [majr] OR Delivery, Obstetric [mesh] OR lactation [mesh])Filters: Publication date from 2008/01/01 to 2015/12/31;
Humans; English; Japanese = 96
Ichushi search: June 28, 2015((epilepsy/MTH) and ((pregnancy/TH or pregnancy/AL) or (childbirth/TH or childbirth/AL) or (breastfeeding/TH or breastfeeding /AL))) and(DT = 2008:2015 and PT = excluding proceedings) = 136

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Table 1. Major measures for epilepsy patients of childbearing potential.
Before pregnancy(1) Adherence building with patient/family
Conduct detailed counseling from before pregnancy
Counseling items:· Basic knowledge of childbirth and pregnancy for
women with epilepsy· Daily life and medication guidance· Recommendation of planned pregnancy and childbirth· Whether pregnancy and childbirth are realistic:
explain importance of family cooperation· If necessary, also consider specialized psychologicalsupport(2) Doctor’s judgement after consultation with patient· Possibility of dose reduction, adjustment or
discontinuation of antiepileptic drugs (AED)· If drug taking is continued, use monotherapy at thelowest required dose possible· If using multiple drugs, pay attention to the combination
Combination to be avoided: valproate +carbamazepine or phenytoin + primidone +phenobarbital
Valproate should be avoided if possible; if must be
given, use sustained release formulation aiming at adose of 600 mg/day or less.
· Folic acid supplement from before pregnancy (approx.
0.4 mg/day)· Collaboration with obstetrics/gynecology and pediatrics
departments (cooperation from before pregnancy toafter delivery preferable)

During pregnancy
Regular visits and medication· Increase AED dose only when symptoms worsen despite
regular drug taking· Measure α fetoprotein and folic acid levels at least once
before pregnancy and as appropriate thereafter· α fetoprotein measurement at around 16 weeks’ gestation· Perform fetal monitoring such as ultrasound at 18 weeks’gestation· In patients with generalized tonic-clonic seizures, pay
attention to premature labor
At birth and puerperium· In general, natural birth is possible· Pay attention to seizure worsening due to irregular drug taking
before and after parturition
After birth· Adjust AED dose if blood level fluctuates after childbirth· Breastfeeding is possible in principle (consider both motherand child factors comprehensively)

Figure 1. Points that require attention for pregnancy and childbirth(Translated and modified from original figure of Ikeda A. Department of Epilepsy, Movement Disorders andPhysiology, Kyoto University School of Medicine

Chapter 13

115

CQ 13-2

What is to be noted for antiepileptic medication in women atchildbearing age?
Summary
When pregnancy is expected, try to control seizures with antiepileptic monotherapy if possible. Also, select drugs
with careful consideration for the risk of teratogenicity and cognitive impairment in children as well as the efficacy
for seizure control. Also pay attention to dose adjustment.

Comment
In antiepileptic drug treatment, multidrug therapy has higher risk for teratogenicity than monotherapy, and the rates andtypes of malformation also vary depending on the types of drugs used in combination1-3). When antiepileptic medication isneeded during pregnancy, aim at monotherapy as far as possible from before pregnancy and select drugs with low
teratogenicity risk. The risk of major malformations for various antiepileptic drug are shown in Table 13). Levetiracetam andlamotrigine have a low incidence of congenital malformation when used as monotherapy3-5). Carbamazepine also has arelatively low induction rate of malformation. Phenytoin, phenobarbital, and topiramate have slightly higher malformationinduction rates4). Valproate has a higher malformation induction rate than the other drugs.
We should take note of the following point: even for antiepileptic drugs with low teratogenic risk when used alone, whenthese drugs are used in combination, the teratogenic risk increases depending on the combination2, 4, 6). For polytherapy,
valproate, phenytoin, and phenobarbital are known to be drugs that increase the risk of teratogenicity when used in
combination2, 6). Study has also shown that the teratogenic risk is increased when phenytoin or carbamazepine is used in
combination with certain drugs including barbiturates (such as valproate + carbamazepine, and phenytoin + primidone +phenobarbital)2).
In children born from a mother taking valproate during pregnancy, decrease of IQ (full scale IQ, especially verbal IQ)
was found in a dose-dependent manner (especially at high doses of 1,000 mg/day or higher)7). The incidence of autism
spectrum disorders also increased by prenatal exposure to valproate8). When using valproate, in addition to the highteratogenic risk, the risk of cognitive dysfunction and behavioral disorder in children should also be noted. When valproateneeds to be taken unavoidably, we should prescribe it at a dose of 600 mg/day or lower as much as possible7, 9). Use of asustained release formulation is desirable aiming to stabilize blood concentration2). International guidance also recommends
that caution should be taken in the decision to prescribe valproate to pregnant women9).
Regarding perampanel and lacosamide that have been launched on the market recently in Japan, there is currently
insufficient data concerning human pregnancy and childbirth.

▪ References
1) Borgelt LM, Hart FM, Bainbridge JL. Epilepsy during pregnancy: focus on management strategies. Int J Womens Health. 2016; 8: 505-517.
2) Kaneko S, Kan R, Tanaka M, et al. Treatment guideline for women of childbearing potential with epilepsy. Report of Japan Epilepsy Society
Guideline Development Committee. Tenkan Kenkyu. 2008; 25: 27-31 (in Japanese).
3) Tomson T, Xue H, Battino D. Major congenital malformations in children of women with epilepsy. Seizure. 2015; 28: 46-50.
4) Vajda FJ, O’Brien TJ, Lander CM, et al. The teratogenicity of the newer antiepileptic drugs-an update. Acta Neurol Scand 2014; 130(4): 234-238.
5) Cunnington MC, Weil JG, Messenheimer JA, et al. Final results from 18 years of the International Lamotrigine Pregnancy Registry. Neurology.
2011; 76(21): 1817-1823.
6) Meador K, Reynolds MW, Crean S, et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of publishedpregnancy registries and cohorts. Epilepsy Res. 2008; 81(1): 1-13.
7) Meador KJ, 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.
8) Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA.
2013; 309(16): 1696-1703.
9) Tomson T, Marson A, Boon P, et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015; 56(7):1006-1019.

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Table 1. The prevalence of major congenital malformations caused by taking antiepileptic drugs.
EURAP
NAAPR
UKIre
AUS
NMBR
SMBR

VPA
9.7%
(98/1,010)
9.3%(30/323)
6.7%(82/1,220)13.8%(35/253)
6.3%(21/333)
4.7%(29/619)

CBZ
5.6%(79/1,402)
3.0%(31/1,033)
2.6%(43/1,657)
5.5%(19/346)
2.9%(20/685)2.7%(38/1,430)

LTG
2.9%
(37/1,280)
1.9%(31/1,562)
2.3%(49/2,098)
4.6%(14/307)
3.4%(28/833)
2.9%(32/1,100)PB
7.4%(16/217)
5.5%(11/199)

PHT
5.8%(6/103)
2.9%(12/416)
3.7%(3/82)
2.4%(1/41)

7.4%(2/27)
6.7%(8/119)LEV
1.6%(2/126)
2.4%(11/450)0.7%(2/304)2.4%(2/84)
1.7%(2/118)(0/61)

OXC
3.3%(6/184)2.2%(4/182)

5.9%(1/17)
1.8%(1/57)
3.7%(1/27)

TPM
6.8%(5/73)
4.2%(15/359)
4.3%(3/70)
2.4%(1/42)
4.2%(2/48)
7.7%(4/52)(Abbreviations: VPA: valproate, CBZ: carbamazepine, LTG: lamotrigine, PB: phenobarbital, PHT: phenytoin, LEV:
levetiracetam, OXC: oxcarbazepine (not approved in Japan as of January 2018), TPM: topiramate)
EURAP: European and International Registry of Antiepileptic Drugs in Pregnancy, NAAPR: North American Antiepileptic
Drugs and Pregnancy Registry, UKIre: UK and Irish Epilepsy and Pregnancy Registry, AUS: Australian Register of Antiepileptic
Drugs in Pregnancy), NMBR: Medical Birth Registry of Norway, SMBR: Swedish Medical Birth Register(Modified from: Tomson T, Xue H, Battino D. Major congenital malformations in children of women with epilepsy. Seizure.
2015;28:46-50.)

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117

CQ 13-3

Is folic acid supplementation needed?
Summary
Folic acid supplementation is useful to prevent the occurrence of neural tube defect.

Comment
Some antiepileptic drugs are known to lower blood folic acid levels1-3). In particular, when valproate or carbamazepine
is administered, supplementation of folic acid at an appropriate dose (0.4‒0.6 mg/day)3, 4) is desirable to reduce the risk ofneural tube closure defect. It has also been reported that folic acid mitigates the adverse effect of antiepileptic drugs on IQ
of children5).
For administration, use of ready-made folic acid preparations or multivitamin preparations containing folic acid may beconsidered1, 3).

▪ References
1) Wilson RD; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada and The Motherrisk Program. Pre-conceptional
vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube
defects and other congenital anomalies. J Obstet Gynaecol Can. 2007; 29(12): 1003-1013.
2) Wlodarczyk BJ, Palacios AM, George TM, et al. Antiepileptic drugs and pregnancy outcomes. Am J Med Genet A. 2012; 158A(8): 2071-2090.
3) Harden CL Pennell PB, Koppel BS. Practice Parameter update: management issues for women with epilepsy—focus on pregnancy (an evidencebased review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology
Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009; 73(2): 142-149.
4) Lifestyle-related Disease Control Office, Department of Community Health and Health Promotion Nutrition, Ministry of Health, Labour andWelfare. Promotion of appropriate information provision on the intake of folic acid by women of childbearing age for reducing the risk of neuraltube closure defect. http://www1.mhlw.go.jp/houdou/1212/h1228-1_18.html (in Japanese)5) Meador KJ, Baker GA, Browning N. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective
observational study. Lancet Neurol. 2013; 12(3): 244-252.

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 13-4

Is it useful to monitor serum concentrations of antiepileptic
drugs during pregnancy?
Summary
Since serum concentrations of antiepileptic drugs may change from the pre-pregnant values during pregnancy, it
is desirable to conduct therapeutic drug monitoring (TDM) as necessary.

Comment
Serum concentrations of antiepileptic drugs may change during pregnancy. For example, serum concentration oflamotrigine may decrease to approximately 40% of the pre-pregnant level1, 2). Even though levetiracetam has a low serum
protein binding rate, its serum concentration may decrease by 50% or more during pregnancy3, 4). Therefore, it is necessary
to prevent the attenuation of seizure control effect of drugs by adjusting the doses appropriately based on serum concentrations
measured at various appropriate times during pregnancy and at childbirth, using the optimal concentrations of antiepileptic
drugs before pregnancy as the baseline level. On the other hand, it is important to prevent the adverse effects due to increase
in serum concentrations after childbirth.
Attention should be paid to the interpretation of serum concentrations of protein-bound drugs such as phenytoin andvalproate, because even when the total blood concentration shows a low value, the concentration of free drug may be
increased due to decreased serum protein during pregnancy. Since the therapeutic effect of antiepileptic drug is mainly
provided by the free drug, dosage should not be increased unnecessarily even when the total serum concentration decreases.
If a reduction of free drug concentration is confirmed and seizures worsen despite good medication adherence, then consider
increasing the dose of the drug5).

▪ References
1) De Haan GJ, Edelboek P, Segers J, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology. 2004;
63(3): 571-573.
2) Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency. Neurology.
2008; 70(22 Pt 2): 2130-2136.
3) Reisinger TL, Newman M, Loring DW, et al. Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy.
Epilepsy Behav. 2013; 29(1): 13-18.
4) Wlodarczyk BJ, Palacios AM, George TM, et al. Antiepileptic drugs and pregnancy outcomes. Am J Med Genetics A. 2012; 158A(8): 2071-2090.
5) Røste LS, Taubøll E. Women and epilepsy: review and practical recommendations. Expert Rev Neurother. 2007; 7(3): 289-300.

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119

CQ 13-5

Are women with epilepsy more likely to have complications
during pregnancy?
Summary
Although the rate of complications is almost unchanged, some complications are increased slightly.

Comment
Injury caused by falls during seizure as well as intracranial hemorrhage, venous thrombosis, sinus thrombosis, and is­chemic stroke attack could occur during pregnancy. Their frequencies are low and statistical figures are unknown1-3). There
are few reports on premature rupture of membrane and umbilical cord abnormalities as complications at delivery. Over
90% of mothers affected by epilepsy have normal pregnancy and delivery.
According to a recent systematic review, the rates of complications including spontaneous abortion, preterm labor,
perinatal hypertension, and postpartum hemorrhage, as well as the proportion requiring caesarean section were slightly
higher in mothers with epilepsy than control mothers, but the incidence of events requiring intensive care was not different
between these two groups4).

▪ References
1) Kaplan PW, Norwitz ER, Ben-Menachem E, et al. Obstetric risks for women with epilepsy during pregnancy. Epilepsy Behav. 2007; 11(3): 283-291.
2) Meador KJ, Pennell PB, Harden CL, et al. Pregnancy registries in epilepsy: a consensus statement on health outcomes. Neurology. 2008; 71(14):1109-1117.
3) Aylward RL. Epilepsy: a review of reports, guidelines, recommendations and models for the provision of care for patients with epilepsy. Clin Med(Lond). 2008; 8(4): 433-438.
4) Viale L Allotey J, Cheong-See F, et al. Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis. Lancet. 2015;
386(10006): 1845-1852.

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CQ 13-6

Can women with epilepsy have a natural delivery?
How are seizures treated during delivery?
Summary
In general, women with epilepsy can have a natural delivery. Seizures during delivery can be treated by the general
strategy for epilepsy.

Comment
In most cases the patient gives birth by normal delivery1-4). In general, there is no indication for caesarean section, but
caesarean section may be conducted depending on concomitant symptoms3). Vacuum-assisted delivery should be avoided3).
Guide patients to continue regular drug taking as far as possible until birth1-4). If seizures occur during labor, they can be
managed by the general strategy for seizures, but if necessary, administration of benzodiazepines is recommended.
We should pay attention to the withdrawal seizures in neonates because it sometimes occurs in neonates3).

▪ References
1) Røste LS, Taubøll E. Women and epilepsy: review and practical recommendations. Expert Rev Neurother. 2007; 7(3): 289-300.
2) Harden CL, Hopp J, Ting TY, et al. Practice Parameter update: Management issues for woman with epilepsy—Focus on pregnancy (an evidencebased review): Obstetrical complication and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics andTechnology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009; 73(2): 126-132.
3) Kanemoto K, Kumatani S. Epilepsy treatment during pregnancy. Shinkei Naika. 2004; 61(1): 40-43 (in Japanese).
4) EURAP Study Group. Seizure control and treatment in pregnancy: observations from the EURAP epilepsy pregnancy registry. Neurology. 2006;
66(3): 354-360.

Chapter 13

121

CQ 13-7

Can women taking antiepileptic drugs breastfeed a baby?
Summary
They can breastfeed a baby.

Comment
Breastfeeding is in principle possible even when taking antiepileptic drugs. However, pay attention to the fact thatantiepileptic drugs are transferred from maternal blood to breast milk at different rates1-3).
When breastfeeding, observe symptoms in neonates such as withdrawal seizures, somnolence, hypotonia, and poor
suckling, considering the transfer rate of the antiepileptic drug to breast milk and the half-life of the antiepileptic drug inthe infant3). When these symptoms appear, manage in a flexible manner such as refraining from breastfeeding and measuring
the serum concentration in the neonate3). Table 1 shows the breast milk transfer rates of various antiepileptic drugs.
In any case, make realistic decision about breastfeeding based on a comprehensive assessment giving priorities to thechild’s mental and physical growth and the mother’s wish. In addition, during the breastfeeding period, provide adequate
care and guidance on daily life, including sleep deprivation and fatigue due to childcare.

▪ References
1) Harden CL, Pennell PB, Koppel BS, et al. Practice Parameter update: management issues for women with epilepsy—focus on pregnancy (anevidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding. report of the Quality Standards Subcommittee and Therapeutics andTechnology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009; 73(2): 142-149.
2) Røste LS, Taubøll E. Women and epilepsy: review and practical recommendations. Expert Rev Neurother. 2007; 7(3): 289-300.
3) Kikuchi T, Yoshida S. Effect of child exposure to antiepileptic drugs via transfer of drugs to breast milk. In: Kaneko S, ed. The Course on Epilepsy,
3rd revised edition. Tokyo: Shinkoh Igaku Shuppansha Co., Ltd. 2012. p.215-218 (in Japanese).

Table 1. Breast milk transfer rates of various AEDs and half-life of AEDs in neonates.
AED
CBZ
CLB0.
CZP
DZP
ESM
GBP
LEV
LTG
OXC
PB
PHT
PRM
TPM
VPA
ZNS

Transplacental transfer
rate of AED
0.69–0.78
1.7–7.5
0.59
1.2–2.0
0.97
1.74 (1.3–2.1)
1.14 (0.56–2.0)
0.9 (0.6–1.3)
0.92–1.0
0.7–1.0
0.86–1.0
0.88–0.99
0.95 (0.85–1.06)
1.59–1.71
0.92

Breast milk transfer rate of AED
0.36–0.41
13–0.36
1.0–3.0
0.5
0.86–1.36
0.7–1.3
1.0–3.09
0.61 (0.5–0.77)
0.5–0.65 1
0.36–0.46
0.06–0.19
0.72
0.67–1.1
0.01–0.1
0.41–0.93

Half-life of AED in neonate(hours)
8–36
17–31
13–33
31
32–38
14
16–18
24
7–22
100–500
15–105
7–60
24
30–60
61–109Transplacental transfer rate = AED concentration in umbilical cord blood/AED concentration in maternal blood
Breast milk transfer rate = AED concentration in breast milk/AED concentration in maternal blood(Modified from: Kikuchi T, Yoshida S. Effect of child exposure to antiepileptic drugs via transfer of drugs to breast
milk. In: Kaneko S, ed. The Course on Epilepsy, 3rd revised edition. Tokyo: Shinkoh Igaku Shuppansha Co., Ltd. 2012.
p.215-218.)

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Chapter 14
Diagnosis of psychogenic nonepileptic seizures
CQ 14-1

How are psychogenic nonepileptic seizures differentiated fromepileptic seizures?
Summary(1) Even in the presence of clinical symptoms suggesting psychogenic nonepileptic seizures (PNES), PNES cannot
be diagnosed based on those symptoms alone.
(2) A diagnosis of PNES can be made by an experienced doctor, who confirms typical PNES semiology without any
EEG abnormal findings immediately before, during, and immediately after the seizure in an ictal video-EEG
recording.
(3) However, ictal video-EEG recording may not provide decisive findings for the diagnosis of simple partial
seizures and seizures arising from supplementary motor area, orbital frontal cortex, or cingulate gyrus.
(4) Even if a definite diagnosis of PNES has been established for one of the seizure types in a patient, we should
avoid a hasty conclusion that all other seizures are PNES in the same patient.

Comment
Psychogenic non-epileptic seizures (PNES) are paroxysmal psychosomatic symptoms resembling epileptic seizures, which
is not explainable by already accepted pathophysiological mechanisms. PNES are found in 5‒20% of patients who first visit
a hospital for suspected epilepsy, and in 15‒30% of patients diagnosed with intractable epilepsy with an indication forsurgery1). The male to female ratio varies depending on the subject population; PNES are female-dominant in patients withneither concomitant mental retardation (intellectual disability) nor epilepsy, but show no definite gender difference inpatients with concomitant mental retardation or epilepsy. The frequencies of concomitant mental retardation vary from 17
to 37% depending on report. In PNES with concomitant epileptic seizures or mental retardation, direct inducing factors areoften present. Therefore, we should take detailed history of the patient’s living conditions and focus on any changes inlifestyle just before the onset of PNES. On the other hand, in PNES with neither concomitant epilepsy nor mental
retardation, we should seek advice from psychiatrists and clinical psychologists because the life history such as family
relationship is often critical in those patients.
Typical seizure semiology suggesting PNES includes (1) long duration of seizure, (2) fluctuating symptoms during
seizure, (3) asynchronous (left-right) body movements, (4) pelvic thrusting, (5) side-to-side swinging of the head and body,(6) closed eyes during seizure, (7) crying during seizure, (8) memory recall of seizure event, (9) no postictal confusion, and(10) seizures appear to occur during sleeping, but EEG findings show an arousal state2).
However, no symptoms can lead to a definite diagnosis on their own, and the above symptoms should be considered as
reference findings.
In the case of suspected PNES, we should confirm the diagnosis over time while following the clinical symptoms as wellas performing environmental adjustment and psychotherapy.
Urinary incontinence and tongue biting have been reported during seizures in patients with PNES, although the incidence
is low3). Therefore, incontinence and tongue biting do not exclude a diagnosis of PNES4).
Abnormally high prolactin concentration within 10‒20 minutes after the attack indicates the unlikeliness of PNES5).
There are four levels of certainty for a diagnosis of PNES, ranging from possible to documented. Table 1 shows the criteria
for the four levels5). Descriptions from a witness of seizure or a video of the actual seizure with routine EEG finding lead toa “possible”, “probable” or “clinically established” diagnosis, while a “documented” diagnosis requires visit to a specialized
hospital equipped with simultaneous ictal video-EEG recording.

Chapter 14

123

The main purpose of admission for making a definite diagnosis is to record ictal video-EEG. Moreover, the hospitalization
also provides medical staff a chance to observe the actual seizures.
In the case of dose reduction or cessation of antiepileptic drugs at the hospital, we should pay attention to the following
risks: manifestation of epileptic seizures that have been controlled until the reduction of drugs, withdrawal seizures inpatients treated with phenobarbital and benzodiazepines for a certain period, and induction of status epilepticus.

▪ References
1) Kanemoto K, Fujiwara T, Ikeda A, et al. Diagnosis and treatment guideline for psychogenic non-epileptic seizure (so-called pseudo-seizures).
Tenkan Kenkyu. 2009; 26(3): 478-482 (in Japanese).
2) Avbersek A, Sisodiya S. Does the primary literature provide support for clinical signs used to distinguish psychogenic non-epileptic seizures fromepileptic seizures? J Neurol Neurosurg Psychiatry. 2010; 81(7): 719-725.
3) Oliva M, Pattison C, Carino J et al. The diagnostic value of oral lacerations and incontinence during convulsive “seizures”. Epilepsia. 2008; 49(6):962-967.
4) Oto M, Conway P, McGonigal A, et al. Gender differences in psychogenic non-epileptic seizure. Seizure. 2005; 14(1): 33-39.
5) LaFrance WC Jr, Baker GA, Duncan R, et al. Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach: areport from the International League Against Epilepsy Nonepileptic Seizures Task Force. Epilepsia. 2013; 54(11): 2005-2018.

▪ Search formula and secondary reference sources(((psychogenic AND (nonepileptic OR non-epileptic)) OR PNES) AND (therapy [sh] OR psychotherapy [mh]) Filters: Publication date from2008/01/01 to 2015/12/31; English; Japanese
PubMed = 92
psychogenic seizures
Cochrane = 3

Table 1. Levels of certainty for diagnosis of PNES.
Diagnostic Level
Possible
Probable

Clinically established

Documented

Source of information
By witness or self-reported descriptions

EEG
No epileptic activities on routine or sleepdeprived interictal EEG
Clinician-confirmed semiology typical of PNES As above
by reviewing a video recording or seeing actualattackClinician having much experience with epilepsy No epileptic activities on routine or Holter
patients confirmed semiology typical of PNES EEG recorded at the attack with semiology
by reviewing a video recording or seeing actual resembling epileptic seizures (epileptic EEG
attack, but not on ictal EEG
activities would be expected in case of true
epileptic seizure)
Confirmed by clinician having much experience No epileptic activities on video-EEG recordedwith epilepsy patients on ictal video-EEG
immediately before, during or immediately
after the attack with typical PNES symptoms(Modified from: LaFrance WC Jr, Baker GA, Duncan R, et al. Minimum requirements for the diagnosis of psychogenic
nonepileptic seizures : a staged approach : a report from the International League Against Epilepsy Nonepileptic Seizures Task
Force. Epilepsia. 2013; 54(11): 2005-2018.)

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CQ 14-2

How are psychogenic nonepileptic seizures treated?
Summary(1) The management of psychogenic nonepileptic seizures (PNES) includes: (1) clearly disclose the diagnosis tothe patient as a good news, without nuance of condemnation, (2) explain no need for antiepileptic drug, (3) list
up the factors that induce seizure and the factors that perpetuate symptoms, (4) offer psychiatric evaluation, (5)implement individual psychotherapy and family psychotherapy, and (6) consider the use of psychotropic drugs
in patients with mood disorder, anxiety disorder, and somatization disorder.
(2) In principle, antiepileptic drugs are tapered and stopped, but this involves risks such as transient deteriorationof the psychological state or manifestation of epileptic seizures masked by antiepileptic drugs.
(3) W hen associated with mental retardation (intellectual disability), disclose the diagnosis to the patient and thefamily, and at the same time adjust the social and psychological environments.
(4) W hen PNES coexist with true epileptic seizures, explain in detail to the patients and their family which typeof seizure is PNES and which type is epileptic seizure.

Comment(1) Even in patients with PNES confirmed by ictal video-EEG, all the seizures are not necessarily PNES. Considering thispoint, we should initially explain it to the patients as follows, “Attacks due to emotional problems, not real epilepsy,
may coexist with attacks due to epilepsy”1).
	  In an RCT recruiting patients (IQ 70 or above) without coexisting epileptic seizures who had PNES attacks morethan twice a month, cognitive behavioral therapy (CBT) for 4 months significantly reduced the seizure frequency
with a moderate or greater effect size, and the odds ratio of seizure control for at least 3 months was 3.1252).
	  In patients who have taken antiepileptic drugs for long periods of time, some feel that epilepsy is their major
problem in life because they believe “they cannot get a job due to epilepsy” and “they cannot have children because of
epilepsy”. These patients may have severe psychological disturbance due to loss of identity. Negating the diagnosis of
epilepsy needs to go hand in hand with formation of new identity.
	  Showing the data of ictal video-EEG recorded during seizure to the patient and family is often educational andeffective. However, care has to be taken not to convey a value judgment that PNES are false seizures. Most of the
PNES are not malingering disorders, but are seizures caused by endogenous conflict.
	  When referring a patient to a psychiatrist, the message to the patient and family has to be carefully worded so as
not to be perceived as sending them away from one’s care, such as, “To exclude all possible disorders and to try all
possible treatments, let’s also ask the psychiatrist to give us some advice.” It is desirable to follow the patient by both
departments for at least a certain period of time.
(2) In principle, antiepileptic drugs are reduced in dose and stopped3). Particularly at the cessation of drugs, it is necessary
to explain in advance to the patient and family about the possibility of emergence of epilepsy seizures controlled by
medications so far or appearance of withdrawal syndrome1).
	  When the patient and family are very anxious about seizure relapse during dose reduction or cessation of antiepileptic
drugs, or when the family has difficulties in coping with urgent situations such as emergency hospital visit, then shortterm inpatient treatment is indicated.
If the patient and family request inpatient treatment because they worry about frequent seizures, explain to themthat he/she will be hospitalized as a part of psychotherapy in collaboration with the psychiatrist. We should try to
prevent long-term hospitalization.
(3) When the patient has coexisting mental retardation (intellectual disability), explain and disclose the diagnosis to thepatient and family and at the same time adjust the psychological and social environments. Full-fledged psychotherapy
accompanied by introspection is often difficult to conduct. Listen carefully to the situations leading to PNES, such as
loss of parents who protected the patient, big changes in workplace, and human relation at work1).
	  Maintain an environment that does not encourage gain from illness, such as getting help from many staff members
when seizures occur or admission to a hospital when the patient shows PNES. We should adjust the environment sothat the patient can receive appropriate attention and protection even without showing PNES.

Chapter 14125	  Disclosure of PNES coexisting with epileptic seizures is more easily accepted by the patient and family, because
the presence of PNES does not entail changes in the basic treatment framework such as transfer to another department
and cessation of medications.
(4) When PNES coexist with true epileptic seizures, explain in detail to the patient and family which type of seizure is
PNES and which type is epileptic seizure. For the antiepileptic drugs, reduce the doses and change to monotherapy if
possible.

▪ References
1) Kanemoto K, Fujiwara T, Ikeda A, et al. Diagnosis and treatment guideline for psychogenic non-epileptic seizure (so-called pseudo-seizures).
Tenkan Kenkyu. 2009; 26(3): 478-482 (in Japanese).
2) Goldstein LH, Chalder T, Chigwedere C, et al. Cognitive-behavioral therapy for psychogenic nonepileptic seizures: a pilot RCT. Neurology. 2010;
74(24): 1986-1994.
3) Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associatedwith epilepsy. Epilepsia. 2011; 52(11): 2133-2138.

▪ Search formula and secondary reference sources(((psychogenic AND (nonepileptic OR non-epileptic)) OR PNES) AND (therapy [sh] OR psychotherapy [mh]) Filters: Publication date from2008/01/01 to 2015/12/31; English; Japanese
PubMed = 92
psychogenic seizures
Cochrane = 3

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Chapter 15
Psychotic Symptoms of Epilepsy
CQ 15-1

What kinds of psychosis accompany epilepsy and what are theirtreatments?
Summary(1) The majority of psychoses associated with epilepsy are interictal psychoses including alternative psychosis andpostictal psychosis.
(2) For treatment of psychosis, use antipsychotic drugs according to symptoms as for schizophrenia, and if someantiepileptic drugs are suspected to be the cause, consider dose reduction and discontinuation.
(3) A fter remission of psychotic symptoms, taper the antipsychotic agents carefully. In patients with a long
duration of psychotic symptoms, taper gradually from 1‒2 months after complete remission.
(4) For postictal psychosis, administer benzodiazepine or a sedating antipsychotic drug to induce sleep during thelucid interval after seizure clustering or during the manic state just before emergence of psychotic symptoms.

Comment(1) Psychosis (psychotic disorder or psychiatric symptoms) is a state of obviously abnormal behaviors such as delusions,pronounced hallucinations with lack of insight, or disorganized languages, disorganized behavior, and catatonic
behavior. In a meta-analysis1), the frequency of psychosis associated with epilepsy was 5.6% (95% CI: 4.8‒6.4%, odds
ratio 7.8) among all patients with epilepsy, and 7% (95% CI: 4.9‒9.1%) among patients with temporal lobe epilepsy.
The frequency of interictal psychosis was 5.2% (95% CI: 3.3‒7.2%) and that of postictal psychosis was 2% (95% CI:
1.2‒2.8%). Preictal psychosis and ictal psychosis are rare.
	  Interictal psychosis2) is delusional psychosis with strong emotional change, sometimes accompanied by first-rank
symptoms typical of schizophrenia such as feeling of being manipulated, but unlike schizophrenia, emotions arepreserved.
	  Alternative psychosis2) is a subtype of interictal psychosis with various emotional symptoms and delusions occurring
when seizures are controlled. The EEG often shows forced normalization (paradoxical normalization), but EEG
examination is not a requisite for the diagnosis. Alternative psychosis sometimes occurs when seizures disappear
following epilepsy surgery3).
	  Postictal psychosis2) occurs after seizure clustering (rarely after a single seizure). After a lucid interval of 24 to 48
hours, visual hallucination, auditory hallucination, or delusion occurs within one week. Various hallucination-delusion
states accompanied by emotional changes last from a few days to a few weeks (usually 1‒2 weeks).
(2) For the treatment of psychosis, antipsychotic agents are used as for schizophrenia4). Many antiepileptic drugs induce
hepatic metabolic enzymes and attenuate the effects of antipsychotic agents. Therefore, high-dose antipsychotics may
be needed5). If antiepileptic drugs are suspected to have induced psychotic symptoms, consider dose reduction anddiscontinuation of the antiepileptic drugs4, 5).
(3) After remission of psychotic symptoms, reduce the doses of antipsychotic agents carefully. In patients with prolonged
psychotic symptoms, reduce doses gradually from 1‒2 months after complete remission5).
(4) During the lucid interval after seizure clustering or during the manic state, administration of benzodiazepine or asedating antipsychotic drug to induce sleep may prevent the postictal psychosis or mitigate psychotic symptoms4).

Chapter 15

127▪ References
1) Clancy MJ, Clarke MC, Connor DJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry. 2014;
14: 75.
2) Krishnamoorthy ES, Trimble MR, Blumer D. The classification of neuropsychiatric disorders in epilepsy: a proposal by the ILAE Commission on
Psychobiology of Epilepsy. Epilepsy Behav. 2007; 10(3): 349-353.
3) González Mingot C, Gil Villar MP, Calvo Medel D, et al. Epileptic peri-ictal psychosis, a reversible cause of psychosis. Neurologia. 2013; 28(2):81-87.
4) Matsuura M, Fujiwara T, Ikeda A, et al. Diagnosis and treatment guideline for psychotic complications of adult epilepsy. Tenkan Kenkyu. 2006;
24(2): 74-77 (in Japanese).
5) Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associatedwith epilepsy. Epilepsia. 2011; 52(11): 2133-2138.

▪ Search formula and secondary reference sources
epilepsy [majr] AND mental disorders [majr] AND therapy [sh] Filters: Clinical Trial; Meta-Analysis; Multicenter Study; Randomized Controlled
Trial; Publication
PubMed = 86

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 15-2

How to manage depression and suicide-related behaviors
associated with epilepsy?
Summary(1) Treat epilepsy-associated depression with individualized psychotherapy and antidepressants.
(2) The first-line antidepressants are new antidepressants such as SSRI and SNRI.
(3) A fter recovery from the first episode of depression, carefully taper and discontinue antidepressant. After
recovery from the second or subsequent depression episode, continue antidepressant even after recovery.
(4) For patients with a history of depression, when tapering antiepileptic drugs which also have mood-stabilizing
effect, carefully taper those drugs.
(5) A ntiepileptic drugs may increase suicide-related behaviors. Provide information to patients and their families
regarding the negative psychotropic effects of antiepileptic drugs. Consult with experts in mental health forhigh risk patients.

Comment(1) In a meta-analysis of epilepsy and depression1), the overall prevalence of active (current or in the past year) depression
was 23.1% (95% CI: 20.6‒28.3%), with an odds ratio of 2.77 (95% CI: 2.09‒3.67). The lifetime prevalence was
13.0% (95% CI: 5.1‒33.1%) with an odds ratio of 2.20 (95% CI: 1.07–4.51).
	  Treatments include individualized supportive psychotherapy, psychoeducation, cognitive behavioral therapy(CBT), and antidepressants2). According to systematic reviews3, 4), antidepressants and CBT are effective. Especially,
CBT tailored to individual patient is useful.
(2) The first-line antidepressants are new antidepressant that are less likely to exacerbate seizures, such as a selective
serotonin reuptake inhibitor (SSRI) and serotonin‒noradrenaline reuptake inhibitor (SNRI). Start with a low dose to
reduce adverse effects and increase until the therapeutic effect appears.
	  Among SSRIs, enzyme inhibitors such as fluvoxamine may increase serum concentrations of antiepileptic drugs.
	  When lithium carbonate is used in combination with antiepileptic drugs, adverse effects such as seizure exacerbationand neurotoxicity may occur. Pay special attention to encephalopathy when combined with carbamazepine.
(3) For the first depression episode, continue antidepressants for around 6 months even after recovery. From the secondor subsequent depression episode, continue antidepressants for around 2 years after recovery.
(4) In patients with a history of mood disorder, carefully taper antiepileptic drugs with mood-stabilizing effect(carbamazepine, oxcarbazepine, valproate, and lamotrigine) when tapering those drugs.
(5) Provide information to patients and families regarding the negative psychotropic effect of antiepileptic drugs.
Especially, pay attention to suicidal ideation in patients with a history of mental disorders.
	  In patients with a history of suicidal ideation, avoid antiepileptic drugs that induce depression. In patients with ahistory of episodic behavioral disorders, pay attention to the manifestation of depression in association with a seizurefree state, and consult a mental health expert for patients at high risk of these symptoms2).
	  A systematic review reported no sufficient evidence for a significant association between antiepileptic drugs andsuicide-related behaviors5). However, expert consensus from the ILEA Task Force on Therapeutic Strategies proposed
the followings.6) (1) Although some antiepileptic drugs may induce psychiatric symptoms and lead to suicidal tendency,
its rate is very low and the actual suicidal risk is yet to be established. (2) Suicide in epilepsy is multifactorial. Even inpatients with some suicide risk factors, treatment should not be withdrawn. (3) When starting or switching antiepileptic
drugs, we (attending doctors) should tell patients to report any mode changes and suicidal ideation when they appear.
(4). In clinical trials, information on psychiatric adverse effects caused by antiepileptic drugs should be collected,
including family and past history of psychiatric disorders, past history of suicidal behaviors, and screening result using
a suicide scale.

Chapter 15

129▪ References
1) Fiest KM, Dykeman J, Patten SB, et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology. 2013; 80(6): 590-599.
2) Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associatedwith epilepsy. Epilepsia. 2011; 52(11): 2133-2138.
3) Mehndiratta P, Sajatovic M. Treatments for patients with comorbid epilepsy and depression: A systematic literature review. Epilepsy Behav. 2013;
28(1): 36-40.
4) Gandy M, Sharpe L, Perry KN. Cognitive behavior therapy for depression in people with epilepsy: a systematic review. Epilepsia. 2013; 54(10):1725-1734.
5) Ferrer P, Ballarín E, Sabaté M. Antiepileptic drugs and suicide: a systematic review of adverse effects. Neuroepidemiology. 2014; 42(2): 107-120.
6) Mula M, Kanner AM, Schmitz B, et al. Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic
Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia. 2013; 54(1): 199-203.

▪ Search formula and secondary reference sources
epilepsy AND (mental disorders OR depression OR mood OR suicide) Cochrane = 303
epilepsy [majr] AND (depress* OR suicide) Filters: Clinical Trial; Meta-Analysis; Multicenter Study; Randomized Controlled Trial; Publication
date from 2008/01/01 to 2015/12/31; English; Japanese
PubMed = 104

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

Chapter 16
Acute Symptomatic Seizures
CQ 16-1

What is the definition of acute symptomatic seizure?
Summary
Acute symptomatic seizures are seizures that occur in close temporal association with acute central nervous systemdisorders, which include metabolic, toxic, structural, infectious, or inflammatory disorders.

Comment
The Commission on Epidemiology and Prognosis of the ILAE defined acute symptomatic seizures as “seizures occurringin close temporal association with an acute systemic, metabolic, or toxic encephalopathy or in association with an acutecentral nervous system disorder (infection, stroke, head injury, or acute alcohol intoxication or withdrawal)”1). This definition
was also adopted by Beghi et al.2).
Among acute symptomatic seizures, convulsive seizures mostly occur only once, but may be repeated or even develop to
status epilepticus. Convulsive seizures may recur when the above disorders relapse.
Acute symptomatic seizure is clearly distinguished from epileptic seizure unprovoked by organic disorders (see CQ 1-1 onpage 2).

▪ References
1) Guidelines for epidemiologic studies on epilepsy. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Epilepsia.
1993; 34(4): 592-596.
2) Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010; 51(4): 671-675.

▪ Search formula and secondary reference sources
PubMed search: November 28, 2008
Acute symptomatic seizure = 222
Additional PubMed search: May 7, 2015
Acute symptomatic seizure (Filters: Clinical Trial; Multicenter Study; Randomized Controlled Trial; Systematic Reviews; Meta-Analysis;)= 28
No references that could serve as evidence were found in Ichushi Web.

Chapter 16

131

CQ 16-2

What are the causes of acute symptomatic seizures?
Summary
The etiologies of acute symptomatic seizures include cerebrovascular disease, central nervous system infection,acute immune-mediated encephalopathies, head injury, metabolic or systemic disease, intoxication, withdrawal,
post-neurosurgical operation, demyelinating disease, post-radiation therapy, and overlap of several etiologies.

Comment
The major etiologies for acute symptomatic seizures are shown in Table 11-4).
Acute symptomatic seizures differ from epilepsy in having clearly identifiable etiologies, having high mortality rates dueto the acute diseases, and requiring short-term treatment with antiepileptic drugs4, 5). Acute symptomatic seizures often occur
in the neonates and the elderly, similarly to epilepsy.

▪ References
1) Annegers JF, Hauser WA, Lee JR, et al. Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935-1984. Epilepsia. 1995; 36(4): 327-333.
2) Huang CC, Chang YC, Wang ST. Acute symptomatic seizure disorders in young children—a population study in southern Taiwan. Epilepsia. 1998;
39(9): 960-964.
3) Murthy JM, Yangala R. Acute symptomatic seizures-incidence and etiological spectrum: a hospital-based study from South India. Seizure. 1999;
8(3): 162-165.
4) Leung H, Man CB, Hui AC, et al. Prognosticating acute symptomatic seizures using two different seizure outcomes. Epilepsia. 2010; 51(8): 1570-1579.
5) Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010; 51(4): 671-675.

▪ Search formula and secondary reference sources
PubMed search: November 28, 2008
Acute symptomatic seizure = 222
Additional PubMed search: May 7, 2015
Acute symptomatic seizure (Filters: Clinical Trial; Multicenter Study; Randomized Controlled Trial; Systematic Reviews; Meta-Analysis;)= 28
No references that could serve as evidence were found in Ichushi Web.

Table 1. Major acute symptomatic seizures.
Cerebrovascular disease
CNS infection
Immune-mediatedencephalopathies
Head injury
Metabolic or systemic disorders

Intoxication

Withdrawal
Post-neurosurgical operation
Demyelinating disease
Post-radiotherapy
Multiple etiologies

132

Part I

Seizure occurring within 7 days of cerebrovascular attack
Seizure occurring in the acute phase of CNS infection
See CQ16-6 (page 161)
Seizure occurring within 7 days of head trauma
Seizure occurring in association with systemic diseases including electrolyte imbalance,
hypoglycemia, non-ketotic hyperglycemia, uremia, hypoxic encephalopathy, hepatic
encephalopathy, hypertensive encephalopathy, eclampsia, posterior reversible encephalopathy
syndrome (PRES), systemic lupus erythematosus (SLE), and mitochondrial encephalopathy
Seizure occurring when taking narcotics (such as cocaine), prescribed drugs (such asaminophylline and imipramine), dangerous drugs, drug overdose, environmental pollution(such as carbon monoxide, lead, camphor, and organophosphorus), and alcohol (such as acutealcohol intoxication).
Seizure occurring within 1‒3 days after discontinuation of alcohol and drugs (such as barbiturate
and benzodiazepines) in patients who are addicted to those agents
Seizure occurring immediately after intracranial surgery
Seizure occurring in the acute phase of acute disseminated encephalomyelitis or multiple sclerosis
Seizures occurring within 24 hours after radiation exposure
Seizure related to several concomitant conditions

The Clinical Practice Guidelines for Epilepsy 2018

CQ 16-3

How to manage patients with acute symptomatic seizures?
Summary
In patients with acute symptomatic seizures, we promptly measure vital signs including consciousness level, takehistory, perform general and neurological examinations, and continue to perform these procedures.

Comment
Figures 1 and 2 show the flow chart of clinical investigation of patients suspected of acute symptomatic seizures.
In patients with convulsion, we first perform procedures to prevent injury or aspiration. Check vital signs and consciousness
level, and perform respiratory and circulatory management if needed. Suspect inflammatory disease if the patient has afever; and consider hypertensive encephalopathy, posterior reversible encephalopathy syndrome (PRES), or eclampsia if thepatient has severe hypertension. In the case of status epilepticus, start treatment for status epilepticus (see Chapter 8).
For history taking, we should obtain information about symptoms at seizure attack, history of trauma, diseases under
treatment (for example, hypoglycemia if receiving insulin injection for diabetes), current medications (for example, drug
intoxication if taking massive dose of drug), alcohol drinking history (alcohol dependence, acute alcohol intoxication orwithdrawal), and possibility of pregnancy.
For general physical examination, check for injury, incontinence, bite wound, skin conditions (color, rash, cyanosis, etc.),
breath odor, and tachypnea. If arrhythmia, cardiac murmur, or cyanosis is present, consider the possibility of syncope,
cerebral embolism or heart failure1).
For neurological examinations, first check the level of consciousness, then suspect meningitis or encephalitis if meningeal
irritation signs are present, brain tumor or cerebrovascular disease if focal neurological signs are present, and hypocalcemia
if Trousseau signs or Chvostek signs are present.

▪ References
1) National Collaborating Centre for Primary Care. The diagnosis and management of the epilepsies in adults and children in primary and secondarycare. 2004.

▪ Search formula and secondary reference sources
PubMed search: November 28, 2008
Acute symptomatic seizure = 222
Additional PubMed search: May 7, 2015
Acute symptomatic seizure (Filters: Clinical Trial; Multicenter Study; Randomized Controlled Trial; Systematic Reviews; Meta-Analysis;)= 28
No references that could serve as evidence were found in Ichushi Web.

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133

Figure 1. Procedures of investigation for patients suspected of acute symptomatic seizures, and examples.
Convulsive seizure, seizure with lossof consciousness
Vital sign (conscious state)evaluation

Respiratory and circulatory management as necessary, treatment for status epilepticus

Medical history

Situation of seizure, past history including trauma, diseases being treated, drugs being
used, drinking history, pregnancy, etc.

General physical examination

Injury, incontinence, bite, skin color, breath odor, tachypnea, etc.
Arrythmia, heart murmur, cyanosis

Neurological examinations

Level of impaired consciousness, meningeal irritation sign, focal neurological signs,
Trousseau signs, Chvostek signs

Other examinations

Blood tests, head CT or MRI, EEG, ECG, chest X ray, etc.
If necessary, cerebrospinal fluid examination

Treatment

Treatment of underlying disease
Antiepileptic drugs in case of high probability of relapse

Figure 2. Flowchart for diagnosis of acute symptomatic seizures.

Situation-related seizure: seizure induced only in the presence of inducing factor.
Isolated seizure: unprovoked seizure occurring once in the lifetime.
Broken line in figure suggests the possibility of transition in some cases.
Note: “Epileptiform” in the figure signifies symptoms caused by a state of excessive activationin the brain, and does not necessarily mean seizure symptoms of epilepsy as a chronic disease.
(Modified from: Ikeda A, Shibazaki H. Convulsion; differentiation between syncope andepilepsy. In: Sugimoto T, Omata M (ed.) Differential Diagnosis in Internal Medicine, 2ndedition. Tokyo: Asakura Publishing Co. Ltd. 2003. p.87‒96)

134

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CQ 16-4

What kinds of examination are needed for acute symptomatic
seizures?
Summary
Conduct blood test, brain CT or MRI, EEG, electrocardiogram, and chest X-ray, and perform cerebrospinal fluid
examination if necessary.

Comment
Check for hypoglycemia, hypocalcemia, hyponatremia, high creatinine (uremic encephalopathy), high ammonia (hepatic
encephalopathy), antinuclear antibody [systemic lupus erythematosus (SLE) and vasculitis], and antibodies of immunemediated encephalopaties1). Brain CT or MRI is critical for the diagnosis of brain tumor, brain abscess, brain granuloma,
and cerebrovascular disease2, 3). Perform cerebrospinal fluid examination if meningitis or encephalitis is suspected in febrilepatients with headache or impaired consciousness.

▪ References
1) National Collaborating Centre for Primary Care. The diagnosis and management of the epilepsies in adults and children in primary and secondarycare. 2004.
2) Harden CL, Huff JS, Schwartz TH, et al. Reassessment: neuroimaging in the emergency patient presenting with seizure (an evidence-based review):
report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007; 69(18): 1772-1780.
3) Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review):
report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007;
69(21): 1966-2007.

▪ Search formula and secondary reference sources
PubMed search: November 28, 2008
Acute symptomatic seizure = 222
Additional PubMed search: May 7, 2015
Acute symptomatic seizure (Filters: Clinical Trial; Multicenter Study; Randomized Controlled Trial; Systematic Reviews; Meta-Analysis;)= 28
No references that could serve as evidence were found in Ichushi Web.

Chapter 16

135

CQ 16-5

How to treat acute symptomatic seizures?
Summary
For acute symptomatic seizures, treat the underlying disease and start antiepileptic drugs if there is a highprobability of seizure recurrence.

Comment
If seizure persists, treat as for status epilepticus (see Chapter 8). In the case of a highly probable seizure recurrence in theacute phase, intravenous injection of fosphenytoin, phenytoin, levetiracetam or phenobarbital is useful for patients who havedifficulties in taking oral antiepileptic drugs1, 2). Conventional oral antiepileptic drugs are useful for patients capable of oral
intake3-5).
Avoid chronic prophylactic use of antiepileptic drugs and stop their administration after a short period, because continuous
administration does not prevent transition to epilepsy2).

▪ References
1) Minicucci F, Muscas G, Perucca E, et al. Treatment of status epilepticus in adults: guidelines of the Italian League against Epilepsy. Epilepsia. 2006;
47(Suppl 5): 9-15.
2) Koppel BS. Treatment of acute and remote symptomatic seizures. Curr Treat Options Neurol. 2009; 11(4): 231-241.
3) Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia. 2001; 42(4):515-524.
4) Marson AG, Williamson PR, Clough H, et al. Carbamazepine versus valproate monotherapy for epilepsy: a meta-analysis. Epilepsia. 2002; 43(5):505-513.
5) Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectivenessas initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006; 47(7): 1094-1120.

▪ Search formula and secondary reference sources
PubMed search: November 28, 2008
Acute symptomatic seizure = 222
Additional PubMed search: May 7, 2015
Acute symptomatic seizure (Filters: Clinical Trial; Multicenter Study; Randomized Controlled Trial; Systematic Reviews; Meta-Analysis;)= 28
No references that could serve as evidence were found in Ichushi Web.

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 16-6

How to diagnose and treat anti-NMDA receptor encephalitis?
Summary(1) If acute symptomatic seizures are suspected to be caused by anti-NMDA receptor encephalitis, perform brain
MRI and cerebrospinal fluid examination and consider to measure anti-NMDA receptor antibody. Perform asystemic search for the presence of neoplastic disorders including ovarian teratoma.
(2) A fter starting appropriate circulatory and respiratory management, consider surgical resection of the tumor
in the early stage if paraneoplastic syndrome is suspected. Also consider steroid pulse therapy, high-dose
intravenous immunoglobulin therapy, plasmapheresis, and immunosuppressants (currently not covered by
medical insurance).

Comment
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is more prevalent in young women. It initially manifests
diverse psychiatric symptoms such as emotional disorder, memory impairment, hallucination, and delusion; and later shows
convulsive seizures and involuntary movements such as dyskinesia, respiratory failure, and autonomic nervous system
symptoms1, 2). Convulsive seizures may be the initial symptom3).
Brain MRI shows high signal intensity regions in mesial temporal lobe, cerebral cortex, and cerebellum on T2-weighted
images. Cells and proteins increase in cerebrospinal fluid. However, these abnormal findings are absent in some cases1, 2).
Measurement of autoantibodies including anti-NMDA receptor antibody in blood and cerebrospinal fluid specimens isrequisite for the diagnosis1, 2). However, these tests can be done only in a limited number of facilities. Systemic search formalignancies is recommended because tumors such as ovarian teratoma may be involved in the pathophysiology1, 2, 4).
We should consider early surgical resection of a tumor when its involvement is suspected1, 2). When acute anti-NMDA
receptor antibody encephalitis is strongly suspected, consider steroid pulse therapy, high-dose immunoglobulin therapy,
plasmapheresis, and immunosuppressants1, 3, 4). There is no high level evidence for the choice of treatment method.

▪ References
1) Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol.
2008; 7(12): 1091-1098.
2) Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor
encephalitis: an observational cohort study. Lancet Neurol. 2013; 12(2): 157-165.
3) Viaccoz A, Desestret V, Ducray F, et al. Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology. 2014;82(7): 556-63.
4) Iizuka T, Sakai F, Ide T, et al. Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal. Neurology. 2008; 70(7):504-511.

▪ Search formula and secondary reference sources
PubMed search: December 11, 2014
“anti-n-methyl-d-aspartate receptor encephalitis” [MeSH Terms] OR (“anti-n-methyl-d-aspartate” [All Fields] AND “receptor” [All Fields] AND“encephalitis” [All Fields]) OR “anti-n-methyl-d-aspartate receptor encephalitis” [All Fields] OR (“anti” [All Fields] AND “nmdar” [All Fields]
AND “encephalitis” [All Fields]) OR “anti nmdar encephalitis” [All Fields] = 399 Among the 399 papers, the above references were reviewed.
No references that could serve as evidence were found in Ichushi Web.

Chapter 16137

Chapter 17
Epilepsy and Genetics
CQ 17-1

Relation between epilepsy and genetics
Summary
When a parent has epilepsy, the frequency of the patient’s children developing epilepsy is 4–6%, which is 2–3
times higher than that in the general population. However, the frequency varies depending on the cause of epilepsy.
There is no clear pattern of inheritance for epilepsy in general.

Comment
The genetic factor plays a small role in the pathogenesis of epilepsy in general1). Therefore, we should take care not to giveexcessive anxiety to patients and their families and not to lead them to misunderstand the negative impact of the genetic
factor.
In some patients, family history reveals definite inheritance patterns (epilepsy syndrome) such as autosomal dominant andrecessive inheritance, or sex-linked inheritance. However, the inheritance pattern is undetermined in most of the patientswith epilepsy. The familial prevalence and the rate of EEG abnormalities differ even for the same epilepsy syndrome,
suggesting multifactorial inheritance pattern involving many overlapping factors. The incidence rate of epilepsy indescendants of the patients is 6%, which is clearly higher than the incidence for people aged up to 20 years in the general
population (1‒2%). When the mother has epilepsy or when one of the parents has absence seizures, the incidence rate is
further increased to 8–9%2). In addition, epilepsy occurs relatively frequently in siblings of patients with epilepsy. In the casethat the onset age of the proband is under 15 years, the incidence rate of epilepsy in siblings by 20 years of age is 3‒5%2).
Moreover, the incidence rate increases to 5‒15% in the proband’s siblings when the EEG of the proband shows generalized
spike-and-wave complex, or when the proband’s parent is (or both parents are) affected by epilepsy2).
Regarding febrile convulsion, while the prevalence in children is 7‒11% (4% in other countries), the prevalence increases
to 20‒25% in siblings of patients with febrile convulsion. Also, children with febrile convulsion will eventually have nonfebrile convulsion (epilepsy) at a higher rate when their parents are affected by epilepsy3, 4).

▪ References
1) Genetics Commission of International League Against Epilepsy. Things you want to know. https://www.ilae.org/files/dmfile/GeneticsPamphlet-2013.pdf
2) Hauser WA, Hesdorffer DC. Facts about epilepsy. New York: Demos press, 1999. p.1-16.
3) Granstrom ML, Gaily E, Beck-Mannagetta G. Febrile convulsions, epileptic seizures and EEG abnormalities in offspring of epileptic mothers. In:
Beck-Mannagetta G, Anderson VE, Doose H, Janz D eds. Genetics of epilepsies, Berlin: Springer-Verlag, 1989. p.137-141.
4) Clinical Practice Guideline for Febrile Convulsion Development Committee (ed.), The Japanese Society of Child Neurology (supervision). Clinical
Practice Guideline for Febrile Convulsion 2015. Tokyo: Shindan To Chiryou Sha, Inc. 2015 (in Japanese).

▪ Search formula and secondary sources for reference
PubMed search: June 28, 2015
No. of references 63 “epilepsy/genetics [majr] AND heredity [mesh] Sort by: Relevance Filters: Publication date from 2008/01/01 to 2015/12/31;
Humans; English; Japanese”
Ichushi search: June 28, 2015
No. of references 100, ((epilepsy/MTH) and ((genetic test/TH or genetic test/AL))) and (PT = excluding proceedings)

138

Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 17-2

Current situation of genetic research and genetic testing for
epilepsy
Summary
Various mutations have been identified in many epilepsy syndromes. However, genetic diagnosis has clinicalsignificance in only a few epilepsy syndromes. Identification of gene abnormalities leads to a definite diagnosis only
for progressive myoclonic epilepsy, Angelman syndrome, Rett syndrome, and Dravet syndrome.

Comment
The causative genetic abnormalities for various epilepsy syndromes are shown in Table 11, 2), and those for progressive
myoclonic epilepsy (PME) are shown in Table 23). When Dravet syndrome is suspected, gene testing is useful because thefindings from the SCN1A genetic test may help us determine the treatment strategy and provide genetic counseling at an
earlier stage than when diagnosis is obtained from only clinical symptoms4).
On the other hand, based on the current knowledge about genetic research on epilepsy, genetic results cannot accurately
predict the prognosis (for example, patients with the same SCN1A mutation may have different phenotypes). Moreover, evenwhen the genetic test result is negative, it does not exclude the possibility of having an unknown causative gene or a geneunidentifiable by conventional sequence analyses such as copy-number polymorphisms. It should be noted that genetic tests
have only limited usefulness for exclusion diagnosis.
Furthermore, many genetic tests are not covered by medical insurance at present, making it difficult to be used as a routine
test in the clinical practice.

▪ References
1) Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilepsies—report of the ILAE Genetics Commission. Epilepsia. 2010; 51(4): 655-670.
2) Ishii A. Molecular genetics of Dravet syndrome and GEFS+ : The spectrum of epilepsies caused by mutations of SCN1A and other genes. Igaku No
Ayumi. 2015: 253(7); 561-567 (in Japanese).
3) Nakayama T. Molecular genetics of progressive myoclonic epilepsy. Igaku No Ayumi. 2015: 253(7); 584-588 (in Japanese).
4) Hirose S, Scheffer IE, Marini C, et al. Genetics Commission of the International League Against Epilepsy. SCN1A testing for epilepsy: applicationin clinical practice. Epilepsia. 2013; 54(5): 946-952.

▪ Search formula and secondary sources for reference
PubMed search: June 28, 2015
No. of references: 21, “epilepsy/genetics [majr] AND genes [mesh] Filters: Review; Publication date from 2008/01/01 to 2015/12/31; Humans;
English; Japanese”
Ichushi search: June 28, 2015
No. of references: 27, ((epilepsy/MTH) and ((gene/TH or gene/AL))) and (PT = review)

Chapter 17  

139

Table 1. Causative genes identified in various epilepsy syndromes.
Epilepsy syndrome
Benign familial neonatal seizures
Benign familial neonatal-infantile
seizures
Benign infantile epilepsy
Ohtahara syndrome
Infantile spasms (atypical Rett
syndrome / West syndrome)
X-linked infantile spasms
Severe myoclonic epilepsy of
infancy (Dravet syndrome)

Locus
20q13.3
8q24
2q23-q24.3

Gene
KCNQ2
KCNQ3
SCN2A

Product
K V7.2(K channel)
K V7.3(K+ channel)
Na+ channel α2 subunit

16p11.2
9q34.1
Xp22.13
Xp22

PRRT2
STXBP1ARX
STK9/CDKL5

Proline-rich transmembrane protein 2
Syntaxin binding protein 1
Aristaless related homeobox
Cyclin-dependent kinase-like 5

Xp22.132q24
2q24.3
5q34-q35
9q34.1

Aristaless related homeobox
Na+ channel α1 subunit
GABA A receptor γ2 subunit
GABA A receptor α1 subunit
Chromodomain helicase DNA binding protein 2
Syntaxin binding protein 1
Nav1.1(Na+ channel)
Na+ channel β1 subunit
GABA A receptor γ2 subunit
GABA A receptor δ subunit
Na+ channel α9 subunit
Syntaxin 1B
GABA A receptor γ2 subunit+

Genetic epilepsy with febrile
seizures plus (GEFS+)

2q24
19q13.1
5q34

Childhood absence epilepsy (withfebrile seizures plus)
PCDH19-related epilepsy limited
to females
Early-onset absence epilepsy(glucose transporter-1 deficiency
syndrome)
Juvenile myoclonic epilepsy

5q34

ARX
SCN1A
GABRG2GABRA1CHD2STXBP1SCN1ASCN1BGABRG2
GABRD
SCN9A
STX1B
GABRG2

Xq22

PCDH19Protocadherin 19

1p35-p31.1

SLC2A1GLUT1

5q34-q35
6p12-p11
20q13.2-q13.3
1q21
8p21
10q24

GABRA1EFHC1CHRNA4CHRNB2CHRNA2LGI1GABAA receptor α1 subunit
EF-hand domain-containing protein 1
nACh receptor α4 subunitnACh receptor β2 subunitnACh receptor α2 subunit
Leucine rich glioma inactivated 1

10q22

KCNMA1

KCa1.1(K+ channel)

19p13

CACNA1A

Cav2.1(Ca 2+ channel)

12p13

KCNA1

Kv1.1(K+ channel)

1p21-23

ATP1A2

Sodium-potassium ATPase

15q11-13

Loss including
UBE3A
MECP2
FOXG1

(UBE3A)

Autosomal dominant nocturnal
frontal lobe epilepsy
Autosomal dominant lateral
temporal epilepsy (autosomal
dominant epilepsy with auditory
features)
Generalized epilepsy andparoxysmal dyskinesia
Absence epilepsy and episodic
ataxia type 2
Focal epilepsy and episodic ataxia
type 1
Familial hemiplegic migraine andepilepsyAngelman syndrome
Rett syndrome

Xp28
14q12

Methyl-CpG-binding protein-2
Forkhead box protein G1(Partially modified from: Ottman R, Hirose S, Jain S, et al. Genetic testing in the epilepsies—report of the ILAE Genetics Commission.
Epilepsia. 2010; 51(4): 655-670.)

140Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 2. Causative genes in progressive myoclonic epilepsy (PME).
Name of disease

Onset age(years)Clinical symptoms

Locus

Gene

Neuronal ceroid lipofuscinosis (NCL)*
Infantile NCL

0.5‒2

Vision loss, microcephaly, epilepsy, regression

Late Infantile NCL)

2‒4

Vision loss, epilepsy, myoclonus

Juvenile NCL

4‒10

Vision loss, epilepsy

Adult NCL

12‒50

Epilepsy, ataxia, dementia

All ages

Myoclonus, cerebella ataxia, epilepsy

Dentatorubral-pallidoluysian atrophy(DRPLA)
Mitochondrial encephalomyopathy(MERRF)

Unverricht-Lundborg disease (ULD)

PME with K+ channel abnormality
Lafora disease

1p34.2
11p15.4
16p11.2
20q13.33
13q22.3
15q23
4q28.2
8p23.3
Not Mapped
11p15.5
17q21.31
11q13.2
7q11.21
12p13.31

5‒42
Short stature, hearing loss, cardiomyopathy mtDNA(mostly in
mtDNA
childhood)
mtDNA
mtDNA
13q34
6‒16
Myoclonus, epilepsy, no or mild
21q22.3
intellectual disability
12q12
4q21.117q21.32
6‒14
9.5‒18

Resembling Unverricht-Lundborg disease
Epilepsy, myoclonus, regression

11p15.1
6q24.3
6p22.3

CNL1
CNL2
CNL3
CNL4
CNL5
CNL6
CNL7
CNL8
CNL9
CNL10
CNL11
CNL13
CNL14
ATN1
MT-TK
MT-TL1
MT-TF
MT-T1
CARS2
CSTB
PRICKLE1
SCARB2
GOSR2
KCNC1
EPM2A
EPM2B

* The loci and responsible genes for NCL are identified from all NCL, and does not correspond to each clinical subcategory.
(Partially modified from: Nakayama T. Molecular genetics of progressive myoclonic epilepsy. Igaku No Ayumi. 2015: 253(7); 584-588.)

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141

Chapter 18
Advice and Information for Patients
CQ 18-1

What kinds of advice should be given to patients?
Summary
Provide the following information to patients with epilepsy (and their families), or inform them of the methods toobtain such information.
(1) General knowledge about epilepsy(2) Caution in daily life(3) Types of epileptic seizures(4) Effects and adverse effects of antiepileptic drugs, and method of drug taking(5) How to cope with epileptic seizures and risk of seizures(6) Psychological problems about epilepsy(7) Support system and organizations for epilepsy(8) Legal knowledge on driver’s license(9) Matters concerning education and employment(10) Pregnancy and childbirthComment
Regarding advice to patients, explain the above contents depending on the situation of individual patients1).

▪ Reference1) Couldridge L, Kendall S, March A. A systematic overview—“a decade of research”. The information and counselling needs of people with epilepsy.
Seizure. 2001; 10(8): 605-614.

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CQ 18-2

How to give advice on driver’s license?
Summary(1) It is desirable to explain matters about driving when a person is newly diagnosed with epilepsy or at the first
visit.
(2) Provide information about epilepsy written in the Road Traffic Act and the Act on Punishment of Acts Inflicting
Death or Injury on Others by Driving a Motor Vehicle.
(3) Give advice on whether or not to drive a car following the domestic law on driving.

Comment
It is desirable to explain matters about driving a motor vehicle to patients with epilepsy when they are newly diagnosed
with the disease or at their first visit.
We should give the patients information about an outline of the items related to epilepsy in the Road Traffic Act and the
Act on Punishment of Acts Inflicting Death or Injury on Others by Driving a Motor Vehicle, as shown below.
(1) Do not drive a vehicle when the patients are under the condition in which they may not be able to drive normally, suchas due to overwork, illness, medication, or other reasons (Road Traffic Act Article 66, with penalty).
(2) The Public Safety Commission will not issue a driving licenses to persons with epilepsy (Road Traffic Act Article 90).
However, this restriction does not apply when there is no risk of seizure that will hinder driving. The required criterion
is that seizure that impairs consciousness or movement during the awake state has not occurred for a period of 2 years(operation standards for issuing license by the Public Safety Commission, Table 1).
(3) A patient should declare the disease condition accurately when obtaining or renewing the driver’s license (partiallyrevised law of Road Traffic Act, with penalty).
(4) If the driver’s license was revoked due to illness but later the patient recovers to a state capable of re-acquiring thelicense, the written test and the practical test will be exempted (partially revised law of Road Traffic Act).
(5) For epilepsy with a risk of recurrence of seizures that impair consciousness or movement, if a patient, despite being
under influence of the above condition (with a risk of hindering normal driving) and consequently not able to drive
normally, drives a motor vehicle and causes death or injury, a penalty will be imposed which is heavier than that for
professional negligence resulting in death (Act on Punishment of Acts Inflicting Death or Injury on Others by Driving
a Motor Vehicle).
In giving advice on whether or not to drive a car, in principle provide guidance in accordance with domestic laws (Table 1).
For items without legal provisions, provide appropriate medical guidance, such as the following.
(1) “There is no risk of seizure” in the Act is usually interpreted as “the risk is considerably low” rather than “the risk ofseizure is zero”.
(2) Even after seizures has not occurred for 2 years, instruct the patient not to drive during periods when the risk of seizure
relapse is judged medically to be high, such as after changing antiepileptic drugs, under poor physical condition, orlack of sleep.
(3) W hen epilepsy is newly diagnosed or when seizure relapses after a certain seizure-free period, even if the patient stillretains the driver’s license, he/she is in “a state of not able to drive normally”. Therefore, advise the patient not to drivefor 2 years.
(4) At the first attack which is not diagnosed as epilepsy, instruct the patient not to drive for a certain period (for example,
6 months).

For reference
According to the revised Road Traffic Law and operation standards enforced on June 1, 2014, a driver’s license is permitted
if a patient with epilepsy meets the prescribed conditions. Whether a license is issued is determined by the Public Safety
Commission based on a doctor’s medical report or a special fitness screening. Regarding epilepsy and driver’s license, there
is a detailed comment in the Q&A regarding the revised Road Traffic Act on the website of the Japan Epilepsy Society1).
If there is any question, contact the “Inquiry Desk for Fitness of Driving” installed in prefectural driver’s license centers, orChapter 18

143

recommend patients to consult the driver’s license center.
From 2014, when a patient is diagnosed to be in a state subject to denial of driver’s license provided by the Operation
Standards of the Road Traffic Act, and the patient is found to possess a driver’s license and is actually driving, it is possible
to report the case to the Public Safety Commission on a voluntary basis. Regarding notification, the Japan Epilepsy Society(Table 2) and the Japan Medical Association have published notification guidelines2, 3).

▪ References
1) Japan Epilepsy Society Legal Issue Committee. Q&A on the revised Rood Traffic Act. (2014) http://square.umin.ac.jp/jes/images/jes-image/140912_
RoadTrafficLaw.pdf (in Japanese)
2) Japan Epilepsy Society Legal Issue Committee. Guideline on doctor’s notification for epilepsy. http://square.umin.ac.jp/jes/images/jes-image/140910JES_GL.pdf (in Japanese)
3) Japan Medical Association. Guideline on voluntary notification from doctors who diagnosed the diseases manifesting given symptoms based on the
Road Traffic Act. (2014) http://dl.med.or.jp/dl-med/teireikaiken/20140910_1.pdf (in Japanese)

Table 1. Criteria for permission or denial of license related to specific diseases.
(1) License is not denied in the following cases.
A. If no seizure has occurred within the past 5 years, and a doctor has made a diagnosis to the effect that “there is no risk of seizure
occurring in the future”
B. If no seizure has occurred within the past 2 years, and a doctor has made a diagnosis to the effect that “there is no risk of seizure
occurring in the next x years”
C. If, after 1-year follow-up, a doctor has made a diagnosis to the effect that “seizure is limited to simple partial seizure without
impaired consciousness or movement, and there is no risk of worsening of symptoms in the future.”
D. If, after 2-year follow-up, a doctor has made a diagnosis to the effect that “seizure only occurs during sleep, and there is no riskof worsening of symptoms in the future.”(2) In the case that a doctor has made a diagnosis to the effect that “it is expected that a diagnosis corresponding to (1) above can bemade within 6 months,” license shall be withheld or suspended for 6 months. (Based on the diagnosis of a doctor, if it is recognizedthat a withholding or suspension period shorten than 6 months is sufficient, that period shall be set as the withholding or
suspension period)
During the period of withholding or suspension, issue order to take fitness screening or submit medical report.
① When the result of fitness screening or the medical report is consistent with (1) above, license is not denied.
② If the content is “Eventually, a diagnosis corresponding to (1) above cannot be made, but because there was a special circumstanceof ○ ○ during the period, it is expected that a diagnosis corresponding to (1) above can be made within another 6 months”,
then the license shall be withheld or suspended for another 6 months. (Based on the diagnosis of a doctor, if it is recognizedthat a withholding or suspension period shorten than 6 months is sufficient, that period shall be set as the withholding or
suspension period).
③ For other cases, the license shall be denied or cancelled.
(3) For other cases, the license shall be denied or cancelled.
(4) For cases corresponding to item (1) (A) above, a special fitness screening test shall be conducted after a certain period (x year).
(5) The Japan Epilepsy Society currently expresses the opinion that at this point in time, except those who have had no seizures
related to epilepsy without medication for the past 5 years and no risk of relapse in the future, usually persons with epilepsy do nothave the fitness for the licenses to drive mid-sized vehicles [except mid-sized vehicles (limited to 8 t)] and large vehicles, and forclass II license. When persons corresponding to this category apply for these licenses or apply for renewal, even they are not subject
to ruling as in (2) and (3) above, they should be given explanation of the opinion and recommended to reconsider the license
application or renewal application for the time being, and to utilize the application revocation system.

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Table 2. Japan Epilepsy Society Legal Issue Committee. Guideline on doctor’s notification for epilepsy(1) If a patient is diagnosed as in a state subject to denial of a driver’s license shown in the Operation Standards of the Road Traffic Act,and if the patient is found to possess a driver’s license and is actually driving, try to persuade the patient not to drive.
(2) Explain to the patient the possibility that when applying or renewing a driver’s license, if the patient is diagnosed as in a state
subject to denial of a driver’s license shown in the Operation Standards, the Public Safety Commission will refuse, cancel, withholdor suspend the license. Also, recommend the patient to report the symptoms accurately to the Public Safety Commission. Explainthat if he/she intentionally conceal symptoms that interfere with driving or acquires/renews the license by making a false
declaration, it is possible that he/she will be penalized for violation of the Road Traffic Act (penal provision: imprisonment up to
1 year or a fine of up to 300,000 yen).
(3) In the case that the risk of traffic accident caused by a patient is judged to be extremely high (for example, the risk is consideredhigh if, in addition to the number of seizures, there is a history of traffic accidents or irregular drug taking), and the patient isfound to be actually driving despite sufficient persuasion to stop driving, assess the situation comprehensively and consider
notification to the Public Safety Commission. However, when submitting a notification, pay close attention to avoid damaging thedoctor-patient relationship, with the result that the patient avoids reporting his/her medical condition accurately or receiving
proper medical care.
(4) Refer to the guidelines of the Japan Medical Association for specific notification procedures to the Public Safety Committee.

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CQ 9-2 Digest Edition
CQ 9-2

Should temporal lobe resection be added to drug therapy in
drug-resistant temporal lobe epilepsy?
Recommendation
We recommend temporal lobectomy in addition to drug therapies in patients with drug-resistant epilepsy (GRADE
2D) (weak recommendation, very low level of evidence).
• Supplementary note: In the GRADE system, when the evidence level is “very low”, in principle it is not possible
to grade “strong recommendation”. Since temporal lobe resection is highly effective with low incidence of adverse
effects, almost all the panelists supported “strong recommendation”, but due to the constraint of the GRADE
system, the final grading was “weak recommendation”.

1. Background, priority of the problem
For drug-resistant epilepsy, adding further new drugs has limited effect. The temporal lobe resection is expected to achieve
seizure-free condition despite its invasiveness.

2. Comment

Evidence summary
There were 2 randomized controlled trials (RCT) (total 118 patients) on the effectiveness of temporal lobe resection for
drug-resistant epilepsy1, 2). With regard seizure outcome, the relative risk was 20.57 (95% confidence interval 4.24‒99.85)
and the number needed to treat (NNT: indicating the number of persons needed to treat to achieve the outcome for one
person) was 4, showing superiority of temporal lobe resection. Neither of the two RCTs mentioned decrease of antiepileptic
drugs after surgery. Death rate did not differ between two groups.
The relative risk of surgical complications was 12.33 (95% confidence interval 1.67‒90.89), and was higher in the temporal
lobe resection group. Death, memory impairment, and psychiatric symptoms were not significantly different between thetwo groups. Quality of life (QOL) improvement was superior in the temporal lobe resection group.

3. Panel meeting

3-1. What is the overall quality of evidence across outcomes?
Since we were not able to mask the intervention, the risk of bias was high overall in the collected studies. Bias for death
was considered not serious, while that for the other outcomes was considered serious and was downgraded one rank.
Inconsistency and non-directness of the results were without question and considered not serious. For imprecision, confidence
intervals crossed the clinical decision threshold in many items, and was downgraded one or two ranks. Publication bias
could not be judged because of the small number of studies. Consequently, the level of evidence for the outcomes was asfollows: “low” for seizure freedom, death, surgical complications, and quality of life improvement; and “very low” for memory
impairment and psychiatric symptoms. The overall level of evidence was “D (very low)”.
* For surgical therapy, since blinding of the control group is difficult, the level of evidence is generally low.

3-2. How is the balance between benefits and harms?
Temporal lobe resection can be expected to control seizures. As a result, antiepileptic drugs are possibly reduced although
it is not shown in RCT. The incidence of serious adverse effects was low. Therefore, the risk of temporal lobe resection isconsidered to be smaller compared to its benefit.

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3-3. What about patients’ values and preference?
Some patients may feel resistant to receive invasive surgical therapy, but the beneficial effect of seizure-free produced by
the surgery outweighs the resistance to the invasive procedure. There is perhaps no significant uncertainty or variability invalue among the patients.

3-4. What is the balance between net benefit and cost or resources?
The health insurance fee scale for epilepsy surgery using a microscope (including temporal lobe resection) is 131,630
points (as of January 11, 2018). The surgery is conducted under general anesthesia and requires neurosurgeons.
However, through reducing antiepileptic drugs, decreasing hospitalization duration accompanying reduced seizures, andenabling more active social activities, epilepsy surgery is expected to lead to saving in the long term. For this reason, the cost
can be considered negligible.

3-5. Recommendation grading
During the discussions at the panel meeting, temporal lobe resection was expected to eliminate seizures, and overall thecost of the surgery could be considered negligible. Even taking the adverse effects into account, the surgery was supported
by panelists.
At the panel meeting, many panelists supported a recommendation grade of “strong recommendation”. However, in the
GRADE system, when the evidence level is “very low”, in general we are not able to grade “strong recommendation”. For thisreason, the final grading was “weak recommendation”.

4. Descriptions in other related guidelines
In Japan, the Japan Epilepsy Society published the “Guideline on indications for epilepsy surgery”3) in 2008, and“Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy”4) in 2010.
The “Guideline on indications for epilepsy surgery” recommends surgical treatment for mesial temporal lobe epilepsy at asuitable timing, stating that “since surgical results are superior in cases of mesial temporal lobe epilepsy with a localizedorganic lesion or with extensive lesions in unilateral hemisphere, consider surgical treatment from an early stage and do not
miss the timing of surgery”. The “Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy” also
follows the above recommendation, stating that “patients should be selected in accordance with the guideline on indications
for epilepsy surgery”.
In overseas countries, the Quality Standards Subcommittee of the American Academy of Neurology, the American
Epilepsy Society, and the American Association of Neurological Surgeons published a guideline5) in 2003. The guideline
states that “drug-resistant epilepsy should be considered for referral to an epilepsy surgery center” and that “patients whomeet established criteria for an anteromesial temporal lobe resection and who accept the risks and benefits of this procedure
should be offered surgical treatment”.

5. Treatment monitoring and evaluation
Monitoring and evaluation during the perioperative period of treatment are generally performed by a neurosurgeon. After
this period, although a neurosurgeon is not necessarily required to monitor and evaluate, follow-up and support should be
provided to the patients.

6. Possibility of future researchSome memory-preserving or minimally invasive surgery may be developed in the future. In addition, we would like toknow the surgical outcomes and adverse events over a longer follow-up period because the observation periods of the two
RCT were 1 year1) and 2 years2).

7. RCT reports reviewed for this CQ
Wiebe 20011), Engel 20122)

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8. List of appendices (to be shown later)
Appendix CQ9-2-01. Flow diagram and literature search formula
Appendix CQ9-2-02. Risk of bias summary
Appendix CQ9-2-03. Risk of bias graphAppendix CQ9-2-04. Forest plot
Appendix CQ9-2-05. Summary of Findings (SoF) table
Appendix CQ9-2-06. Evidence-to-Decision table▪ References
1) Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001; 345(5): 311-318.
2) Engel J Jr, McDermott MP, Wiebe, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012; 307(9):922-930.
3) Mihara T, Fujiwara T, Ikeda A, et al. Guideline on indications for epilepsy surgery. Tenkan Kenkyu. 2008; 26(1): 114-118 (in Japanese).
4) Watanabe E, Fujiwara T, Ikeda A, et al. Guideline on diagnosis and surgical indications of mesial temporal lobe epilepsy. Tenkan Kenkyu. 2006;
27(3): 412-416 (in Japanese).
5) Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality
Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Associationof Neurological Surgeons. Neurology. 2003; 60(4): 538-547.

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Appendix CQ 9-2-01.

Flow diagram and literature search formula

Literature search
PICO
P: Patients with drug-resistant epilepsy
I: Temporal lobe resection added to drug therapy
C: Compared with drug therapy alone
O: Are seizures eliminated or reduced?
Are antiepileptic drugs reduced or discontinued?
Is there increase in death related to surgery?
Are there increases in complications (medical/neurological) related to surgery?
Is memory (IQ, memory) lowered?
Is QOL (including psychiatric symptoms) improved?

▪ Search formula
PubMed search: September 28, 2016
#1 Search ((“drug resistant epilepsy” [mesh] OR ((epilepsy OR seizures OR convulsions) AND (intractable OR refractory OR resistant))#2 Search (“anterior temporal lobectomy” OR (temporal lobe AND surgery [sh]))#3 Search (randomized controlled trial[pt] OR meta-analysis[pt] OR randomized OR blind OR observation* OR cohort OR “follow-up” OR cross
OR case OR series OR prospective OR retrospective OR placebo OR trial)#4 (#1 AND #2 AND #3)
Cochrane CENTRAL search: September 28, 2016
(epilepsy OR seizures) AND “temporal lobe” AND surgery

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CQ9-2. Flow diagram of literature search (modified PRISMA 2009)

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Appendix CQ9-2-02 and -03.   Risk of bias summary
Risk of bias graphs

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Appendix CQ9-2-04.   Forest plot

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Appendix CQ9-2-05.   Summary of Findings (SoF) table
Patients: Patients with drug resistant epilepsy
Intervention: Temporal lobe resection + drug therapy
Comparison: Drug therapy

OutcomeSeizure freedom

Expected absolute effect*(95% confidence interval)
Risk of vagus
Risk of drug
nerve stimulation
therapy+ drug therapy
16 (per 1,000)
327 (per 1,000)(67–1,000)0 (per 1,000)

Relative effect:risk ratio(RR)(95% confidence
interval)

No. ofpatients(No. ofstudies)

RR 20.57(4.24–9.85)

118(2 RCTs)0 (per 1,000)(0–0)
5 (per 1,000)(0–126)Not estimable(0 RCTs)⊕⊕⃝⃝
Lowa,b
‒

RR 0.33(0.01–7.95)

118(2 RCTs)

⊕⊕⃝⃝
Lowc

Quality ofevidence(GRADE)

Reduction/discontinuationof antiepileptic drugs
Death

16 (per 1,000)

Surgical complications

0 (per 1,000)0 (per 1,000)(0–0)

RR 12.33(1.67–90.89)

118(2 RCTs)⊕⊕⃝⃝
Lowa.bMemory impairment

0 (per 1,000)0 (per 1,000)(0–0)

RR 12.00(0.71–202.18)

26(1 RCT)⊕⃝⃝⃝
Very lowa,cPsychiatric symptoms

225 (per 1,000)

200 (per 1,000)(86–466)

RR 0.89(0.38–2.07)

80(1 RCT)⊕⃝⃝⃝
Very lowa,b

QOL improvement: change
in QOLIE-89 (89-item
Quality of Life in Epilepsy
Inventory) mental healthscore (range of QOLIE-89:
0‒100)

Mean QOL
improvement(change in
QILIE-89) was 0

QOL improvementby temporal lobe
resection + drug
therapy was 8.6
times higher (0.14‒
17.06 higher) thandrug therapy group‒38(1 RCT)⊕⊕⃝⃝
Lowa,dComment*Risk (and 95% confidence interval) in the intervention group was estimated based on the risk in the control group and the effect due tointervention (and 95% confidence intervals).
Grades of quality of evidence according to the GRADE Working Group:
High:
High certainty of the effect estimate. True effect is near the effect estimate.
Moderate: Moderate certainty of the effect estimate. The effect estimate is considered to be near the true effect, but further research
may change the effect estimate.
Low:
There is limitation in the certainty of the effect estimate. Although the effect estimate may be near the true effect, further
research is very likely to change the effect estimate.
Very low: Very low certainty of the effect estimate. The true effect is very likely to be different from the effect estimate.
: because masking was not done, which affected the outcomes: because although confidence interval of effect estimate does not cross the clinical decision threshold of appreciable benefit or that ofappreciable harm, it does not satisfy the criteria for optimal information size (OIS).
c: because confidence interval of effect estimate crosses the clinical decision thresholds of both appreciable benefit and appreciable harmd: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable benefit, but not the clinical decisionthreshold of appreciable harm
a

b

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Appendix CQ 9-2-06.   Evidence-to-Decision table
Evaluation table of recommendation decision criteria
Study population: Patients with drug-resistant temporal lobe epilepsy
Intervention: Temporal lobe resection (added to drug therapy)
CRITERIAJUDGEMENTS

PROBLEMDESIRABLEEFECTSUNDESIRABLE
EFFCETSIs there apriority problem?
More serious
problems andmore urgent
problems havehigher priority- No- Probably no- Probably yes- Yes- Varies- Don’t know

How substantial
are the desirable
anticipatedeffects?

- Trivial- Small- Moderate- Large- Varies- Don’t know

How substantial
are theundesirable
anticipatedeffects?

- Large- Moderate- Small- Trivial- Varies- Don’t know

CERTAINTY OF
THE EVIDENCE

What is theoverall certaintyof this evidence?

VALUESIs thereimportantuncertainty
about orvariability in
how much people
value the main
outcomes?

Does thebalance between
desirable andundesirable
effects favor theintervention or
the comparison?

- Very low- Low- Moderate- High- No included studies- Important
uncertainty orvariability- Probably important
uncertainty orvariability- Probably noimportant uncertainty
or variability- No important
uncertainty andvariability

BALANCE OF EFFECTS- Control is superior- Control is probably
superior- Control andintervention areequivalent- Intervention isprobably superior- Intervention issuperior- It depends- Don’t know

ADDITIONALCONSIDERATIONSRESEARCH EVIDENCE
For drug resistant epilepsy, the effect of further adding new drugs is limited.
Temporal lobe resection is a treatment that can be expected to achieve seizure
freedom.

The relative importance or values of the main outcomes of interest:
Relative
importance

Certainty of theevidence (GRADE)

Seizure freedom

CRITICAL⊕⊕⃝⃝
LOW

Reduction/discontinuationof antiepileptic drugs

CRITICALDeathCRITICAL⊕⊕⃝⃝
LOW

Surgical complications

CRITICAL⊕⊕⃝⃝
LOW

Memory impairment

CRITICAL⊕⃝⃝⃝
VERY LOW

Psychiatric symptoms

CRITICAL⊕⃝⃝⃝
VERY LOWQOL improvement

CRITICAL⊕⊕⃝⃝
LOW

Outcome

It depends on patient.
Memory impairment canbe predicted to someextent. One RCT (Wiebe
2001) reported transient
asymptomatic visual defectin 22 of 40 patients.
Surgery generally has
evidence with low
certainty due to difficulties
with blinding.

Summary of findings
OutcomeNo temporallobe
resection

Temporallobe
resection

Difference(95% CI)

Relative
effect (RR)
(95% CI)

Seizure freedom

1.6%

32.7%
(6.7 to100.0)

31.1% more
(5.1 more to156.9 more)

RR 20.57(4.24 to99.85)

Death

1.6%

0.5% (0.0
to 12.6)

1.1% fewer(1.6 fewer
to 11 more)

RR 0.33(0.01 to7.95)

Surgicalcomplications

0.0%

0.0% (0.0
to 0.0)0.0% fewer(0 fewer to
0 fewer)

RR 12.33(1.67 to90.89)

Memoryimpairment

0.0%

0.0% (0.0
to 0.0)0.0% fewer(0 fewer to
0 fewer)

RR 12.00(0.71 to202.18)

Psychiatric
symptoms

22.5%

20.0%
(8.6 to46.6)

2.5% fewer(14 fewer to24.1 more)

RR 0.89(0.38 to2.07)

QOL
improvement

Mean
QOL
improvement
was 0

-

MD 8.6higher (0.14higher to
17.06
higher)-Reduction/
discontinuationof antiepilepticdrugs

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Summary: With regard seizure outcome, relative risk was 20.57 (95%
confidence interval 4.24‒99.85) and NNT was 4. No study on the outcome ofantiepileptic drug reduction was found. There was no significant increase indeath due to surgery. Surgical complications was increased with relative risk of
12.33 (95% confidence interval 1.67‒90.89), and included stroke and infection.
Other than these, Wiebe et al, reported transient visual defect in approximately
one-half of patients in surgery group. Memory impairment tended to increase
when temporal lobe resection was added to drug therapy but there was no
significant difference. The main psychiatric symptom was depression, but there
was no significant difference between with and without temporal lobe resection.
Quality of life (QOL) was superior in the group with add-on temporal lobe
resection.
COST ANDRESOURCEACCEPTABILITYFEASIBILITY160

How large are
the required
resources (cost)?

- High cost
- Moderate cost
- Negligible- Moderate saving- Large saving- Varies- Don’t know

The health insurance fee scale for epilepsy surgery using a microscope (including
temporal lobe resection) is 131,630 points (as of January 11, 2018). The surgery
is conducted under general anesthesia and requires a neurosurgeon. However,through reducing antiepileptic drugs, hospitalization decreases accompanying
reduced seizures, and more active social activities are possible. these are expected
to lead to saving in the long term.

Is the option
acceptable to key
stakeholders?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Access to facility capable of surgery is required, but is possible.

Is the option
feasible toimplement?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Feasible in specialized facilities. To find hospitals capable of surgery, consult thefollowing websites:
1. The Japan Neurosurgical Society http://jns.umin.ac.jp/
2. Epilepsy Surgery Society of Japan http://plaza.umin.ac.jp/~jess/
3. The Japan Epilepsy Society http://square.umin.ac.jp/jes/Part II

Systematic Review Digest

Recommendation decision table
Type of recommendation
Judgment

Strongrecommendation
against theintervention

Conditional
recommendation
against theintervention

Conditional
recommendation for
either the intervention
or the comparison

Conditional
recommendation for
the intervention

Strongrecommendation
for the intervention

○

○

○

●

○

Recommendation

Addition of temporal lobe resection to drug therapy is recommended for drug-resistant temporal lobe epilepsy.
(GRADE 2D, strength of recommendation “weak recommendation” / certainty of evidence “very low”)

Justification

Question (CQ): Should temporal lobe resection be added to drug therapy for drug resistant temporal lobe epilepsy?
Patients (P): Patients with drug resistant epilepsy
Intervention (I): Temporal lobe resection (added to drug therapy)
Comparison (C): Continued drug therapy only
Outcome (O): Seizure freedom, death, surgical complications
Summary of evidence: Systematic review identified 2 RCTs (118 subjects). Relative risk of freedom from seizure due totemporal lobe resection was 20.57 (95% confidence interval 4.24‒99.85) and NNT was 4. No studies investigating theoutcome of antiepileptic drug reduction was found. There was no significant increase in death due to surgery.
Complications related to surgery were increased with relative risk of 12.33 (95% confidence interval 1.67‒90.89), andincluded stroke and infection. Other than these, Wiebe et al, reported transient visual defect in approximately one-halfof patients in surgery group. Memory impairment tended to increase when temporal lobe resection was added to drug
therapy, but there was no significant difference. The main psychiatric symptom was depression, but there was no
significant difference between with and without temporal lobe resection. Quality of life (QOL) was superior in the groupwith add-on temporal lobe resection.
Certainty of evidence: Since masking of the intervention was impossible, the risk of bias in the studies collected was highoverall. Bias for death was considered not serious, while that for other outcomes was considered serious and downgraded
one rank. Inconsistency and non-directness of the results were without question, and not serious. For imprecision,confidence intervals crossed the clinical decision threshold in many cases, and was downgraded one or two ranks.
Publication bias could not be judged because of the small number of studies. Consequently, the certainty of evidence forthe outcomes was as follows: “low” for seizure freedom, death, surgical complications, and QOL improvement; and “verylow” for memory impairment and psychiatric symptoms. The overall certainty of evidence was “D (very low)”.
Judgment of benefits and harms, burden, and cost:
Surgical invasiveness is high. However, the merit of freedom from seizure in patients with drug resistant epilepsy is great,
and the efficacy is also high.
Recommendation:
Addition of temporal lobe resection to drug therapy is proposed for drug resistant temporal lobe epilepsy.
(strength of recommendation “weak recommendation” / certainty of evidence “very low”)
Additional considerations:
According to GRADE, when the certainty of evidence is “very low”, in principle it is not possible to rank “strong
recommendation”. Since temporal lobe resection is expected to be highly effective with low incidence of adverse effects,
the opinion of almost all of the panelists was “strong recommendation” at the panel meeting, but due to the constraint of
the GRADE system, the final grade was “weak recommendation”.

Subgroup
No RCTs comparing surgical methods were identified.
considerations.
Consider how to set
criteria for patient
population or intervention,
which may change therecommendation statement
Implementation
Selection of the optimal surgical method depending on the cause is necessary.
considerations.
Follow-up and support after surgery are necessary.
In clinical practice,problems such as feasibility
and tolerability may arise.
Monitoring andevaluation.
What kind of monitoringis necessary during
implementation? Is
evaluation necessary
before or after publication?
Research possibilities.
What are the unclear
points in judgment that
require future research?

There is room for further research on the development of memory-preserving, minimally invasive surgery. In addition,
the observation periods of the two RCT were 1 year and 2 years, and there is accumulating interest on the data of surgicaloutcomes and adverse events over a longer period of follow-up.

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CQ 10-1 Digest Edition
CQ 10-1

Should vagus nerve stimulation therapy be added to drug
therapies for drug-resistant temporal lobe epilepsy?
Recommendation
We suggest to add vagus nerve stimulation to drug therapies (GRADE 2D) (weak recommendation, very low levelof evidence).
• Supplementary note: In principle, vagus nerve stimulation is considered for patients with no indication for
curative surgery. Implantation of the vagus nerve stimulation device involves surgery under general anesthesia
in an experienced hospital. After implantation, the patients need to be followed in the hospital where operation
was performed or other facilities, by experts with experience in stimulator control.

1. Background, priority of the problem
In patients with drug-resistant epilepsy in whom seizures are not controlled even after trials of two appropriate antiepileptic
drugs, further addition of drugs has only limited effect. Vagus nerve stimulation added to antiepileptic drug therapy is
expected to provide additive effect of seizure frequency reduction. Because vagus nerve stimulation is less invasive and has
lower seizure control effect compared to brain surgery with craniotomy, it may be selected as a treatment option in patientswith no indication for curative neurosurgery.

2. Comment

Evidence summary
Only one randomized controlled trial (RCT) examined the effectiveness of vagus nerve stimulation for drug-resistant
epilepsy1). We therefore considered to use observational studies together. However, because outcomes of those studies, suchas reduced seizure frequency and mood change, are susceptible to placebo effect, we determined to use a single RCT.
Regarding efficacy, the relative risk for 50% seizure frequency reduction was 1.34 (95% confidence interval 0.59‒3.04),
and NNT (number needed to treat: indicating the number of persons needed to treat to achieve the outcome for one person)
was 25. As for mood changes, there were no significant differences between the intervention group and control group in thescores for several scales: QOLIE-89 (89-item Quality of Life in Epilepsy Inventory), CES-D (Center for Epidemiologic
studies Depression scale), and NDDI-E (Neurological Disorders Depression Inventory in Epilepsy scale). Regarding moodchanges, the only scale showing a statistically significant difference was the 7-point evaluation scale CGI-I (Clinical Global
Impression of Impression Important Scale), but the difference was only 0.5 (95% confidence interval 0.99‒0.01), showing asmall effect. For serious adverse events, vocal cord paralysis and brief respiratory arrest occurred only in the intervention
group, but were transient with no sequelae. There was no significant difference in the adverse event of dysphonia between theintervention group and the control group.
It should be noted that the selected RCT was prematurely terminated by the sponsor due to a low recruitment rate,
because many study candidates did not accept randomization of the treatment. Therefore, the study may be underpoweredfor detection of the outcome.

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3. Panel meeting

3-1. What is the overall quality of evidence across outcomes?
In the study reviewed, the risk of bias was high overall, which was judged as serious for all the outcomes, and was
downgraded by one rank. The inconsistency of results was not downgraded because of only one study used. The indirectness
was judged as not serious and without any problems. As for imprecision, the confidence intervals in many analyses crossed
the clinical decision threshold, and it was hence downgraded by one or two ranks. As for publishing bias, there was only one
study, and therefore was not downgraded. Consequently, the level of evidence for the outcomes was as follows: “very low”
for seizure frequency ≤ 50%, serious adverse events, and dysphonia; and “low” for the other outcomes. The overall level ofevidence was “very low”.

3-2. What is the balance between benefits and harms?
Since there was only one RCT, the certainty of the effect estimate was low, and it was difficult to consider the balance
between benefits and harms.

3-3. What about patients’ values and preferences?
The importance of outcomes has great inter-individual differences, and it should be diverse, It should be noted that somepatients place importance on the reduction of seizure frequency, while others regard the risk of adverse effects to be more
important.

3-4. What is the balance between net benefit and cost or resources?
The electrode implantation for VNS surgery is conducted under general anesthesia. Vagus nerve stimulation is coveredby health insurance, and the health insurance fee scale for implantation is 24,350 points, and that for exchange is 4,800
points (as of January 11, 2018). The reoperation should be done once every few years for replacement of the power generator
because of degradation of the condenser. Considering the effectiveness for refractory epilepsy and the above-mentioned
factors, the cost was judged to be moderate.

3-5. Recommendation grading
During the discussions at the panel meeting, considering the moderate burden and cost, and the few alternative treatment
options available, the panelists concluded that it was reasonable to use this treatment method despite a certain amount ofharm, burden and cost. The unanimous decision was “to propose implementing vagus nerve stimulation for drug-resistant
epilepsy”. As an additional consideration, the patients’ families at the panel meeting expressed the following opinion: “Wedesire to overcome social constraints. If there is any method at all, please include it as one of the options.”

4. Descriptions in other related guidelines
In Japan, the “Practice guideline of vagus nerve stimulation therapy for epilepsy”2) was published by the Japan Epilepsy
Society in 2012, which states that “VNS has accommodative effect on drug-resistant epileptic seizures [recommendation
grade A]”. Also, the American Academy of Neurology released a guideline update entitled “Vagus nerve stimulation for thetreatment of epilepsy” in 2013. This guideline update describes the possibilities of the effectiveness of vagus nerve stimulation
appearing several years after VNS operation, the effectiveness in children [rate of > 50% seizure reduction: 55% (95%
confidence interval 50‒59%)], and an increased risk of infection in children compared to adults [odds ratio 3.4 (95%
confidence interval 1.0‒11.2)].
According to the guidelines in Japan and overseas and the recommendation from the ILEA, the indication for vagus nerve
stimulation is in principle patients who have no indication for curative neurosurgery2-4).

5. Treatment monitoring and evaluation
Vagus nerve stimulation treatment requires adjustment of the stimulation conditions, management of complications, andsolving equipment troubles. Epilepsy specialists or doctors trained by the specialists should perform monitoring andevaluation after the operation based on specialist knowledge.

6. Possibility of future research
The RCT reviewed for this CQ had high risk of bias. Therefore, it is desirable to have more RCTS with better quality. In
addition, research focusing on how to identify good responders and the effects on status epilepticus is needed in the future.

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7. RCT report reviewed for this CQ
Ryvlin 20141)

8. List of appendices (to be shown later)
Appendix CQ10-1-01. Flow diagram and literature search formula
Appendix CQ10-1-02. Risk of bias summary
Appendix CQ10-1-03. Risk of bias graphAppendix CQ10-1-04. Forest plot
Appendix CQ10-1-05. Summary of Findings (SoF) table
Appendix CQ10-1-06. Evidence-to-Decision table▪ References
1) Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal
epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia. 2014; 55(6): 893-900.
2) Kawai K, Sugai K, Akamatsu N, et al. Guideline on implementation of vagus nerve stimulation therapy for epilepsy. Tenkan Kenkyu. 2012; 30(1):68-72 (in Japanese).
3) Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the
Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013; 81(16): 1453-1459.
4) Cross JH, Jayakar P, Nordli D, et al. Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the
Subcommission for Pediatric Epilepsy Surgery. Epilepsia. 2006; 47(6): 952-959.

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Appendix CQ 10-1-01.    Flow diagram and literature search formula

CQ 10-1 Literature search
PICO
P: Patients with drug resistant epilepsy (children as subgroup)
I: Vagus nerve stimulation added to drug therapy
C: Compared with drug therapy alone
O: Are seizures controlled (25, 50, 75%)?
Is there a decrease in treatment continuation rate?
Is there an increase in dysphonia/hoarseness?
Is there an increase in coughing?
Is there an increase in pain?
Is mood improved (= mood change)?

▪ Search formula
PubMed search: September 28, 2016
#1 Search ((“drug resistant epilepsy” [mesh] OR ((epilepsy OR seizures OR convulsions) AND (intractable OR refractory))))#2 Search (“vagus nerve stimulation” [mesh] OR (“vagal nerve” AND stimulation) OR (“vagus nerve” AND “electric stimulation therapy”))#3 Search (randomized controlled trial [pt] OR meta-analysis [pt] OR randomized OR blind OR observation* OR cohort OR “follow-up” OR cross
OR case OR series OR prospective OR retrospective OR placebo OR trial)#4 (#1 AND #2 AND #3)
Cochrane CENTRAL search: September 28, 2016
(epilepsy OR seizures) AND vagus nerve stimulation

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CQ10-1. Flow diagram of literature search (modified PRISMA 2009)

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Appendix CQ10-1-02 and -03.    Risk of bias summary
Risk of bias graphs

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Appendix CQ10-1-04.   Forest plot

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Appendix CQ10-1-05.    Summary of Findings (SoF) table
Patients: Patients with drug-resistant epilepsy
Intervention: Vagus nerve stimulation (VNS) + drug therapy
Comparison: Drug therapy

Outcome12-month seizure
frequency ≤50%

Expected absolute effect*(95% confidence interval)
Risk of vagus nerve
Risk of drug
stimulation + drug
therapy
therapy
Study subject population
241 (per 1,000)
323 (per 1,000)(142–734)
Low risk population
120 (per 1,000)
161 (per 1,000)(71–365)
High risk population
480 (per 1,000)
643 (per 1,000)(283–1,000)
Mood change
Mean mood change(QOLIE-89): 0 (QOLIE-89) in vagus
nerve stimulation + drug
therapy group was 1.3
higher (1.56‒4.16) thandrug therapy group

Mood after 12 months:
change in QOLIE-89(89-item Quality of Lifein Epilepsy Inventory)
mental health score(range of QOLIE-89:
0‒100)
Mood after 12 months:
Mood changechange in CES-D (Centre (CES-D): 0
for Epidemiologic Studies
Depression scale) score(range of CED-D: 0‒60)

Mean mood change(CES-D score) in vagus
nerve stimulation + drug
therapy group was 2.7
lower (6.54‒1.14) thandrug therapy group
Mood after 12 months:
Mood change
Mean mood changechange in NDDI-E(NDDI-E): 0(NDDI-E score) in(Neurological Disorders
vagus nerve stimulation
Depression Inventory in+ drug therapy group
Epilepsy scale) score
was 0.8 lower(range of NDDI-E: 6‒24)(2.26‒0.66) than drug
therapy group
Mood after 12 months:
Mood change
Mean mood changechange in CGI-I (Clinical (CHI-I): 0(CHI-I score) in vagus
Global Impression of
nerve stimulation + drug
Improvement scale) score
therapy group was 0.5(range of CGI-I: 1‒7)
lower (0.99‒0.01) thandrug therapy group
Serious adverse events
Study subject population
52 (per 1,000)
93 (per 1,000)(23–369)
Low risk population
25 (per 1,000)
45 (per 1,000)(11–178)High risk population
100 (per 1,000)
179 (per 1,000)(45–713)Dysphonia
0 per 1,000
0 per 1,000(0 to 0)Relative effect:risk ratio (RR)
(95% confidence
interval)

No. ofpatients(No. ofstudies)

Quality ofevidence(GRADE)

RR 1.34(0.59–3.04)

60(1 RCT)⊕⃝⃝⃝
Very low a,b‒60(1 RCT)⊕⊕⃝⃝
Low a,c‒60(1 RCT)⊕⊕⃝⃝
Low a,d‒60(1 RCT)⊕⊕⃝⃝
Lowa,c‒60(1 RCT)⊕⊕⃝⃝
Low a,c

RR 1.79(0.45–7.13)

112(1 RCT)⊕⃝⃝⃝
Very low a,b

RR 4.69
0.23–93.70)

60(1 RCT)⊕⃝⃝⃝
Very low a,b

Comment*Risk (95% confidence interval) in the intervention group was estimated based on the risk in the control group and the effect due tointervention (and 95% confidence intervals).

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Grades of quality of evidence according to the GRADE Working Group:
High:
High certainty of the effect estimate. True effect is near the effect estimate.
Moderate: Moderate certainty of the effect estimate. The effect estimate is considered to be near the true effect, but further research
may change the effect estimate.
Low:
There is limitation in the certainty of the effect estimate. Although the effect estimate may be near the true effect, further
research is very likely to change the effect estimate.
Very low: Very low certainty of the effect estimate. The true effect is very likely to be different from the effect estimate.
: because masking was not done, which affected the outcome.
: because confidence interval of effect estimate crosses the clinical decision thresholds of both appreciable benefit and appreciable harm.
c: because although confidence interval of effect estimate does not cross the clinical decision threshold of appreciable benefit or that ofappreciable harm, it does not satisfy the criteria for optimal information size (OIS).
d: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable benefit, but does not cross the clinicaldecision threshold of appreciable harm.
a

b

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Appendix CQ 10-1-06.   Evidence-to-Decision table
Evaluation table of recommendation decision criteria
Study population: Patients with drug resistant temporal lobe epilepsy
Intervention: vagus nerve stimulation
CRITERIA

ADDITIONALCONSIDERATIONSPROBLEMJUDGEMENTSRESEARCH EVIDENCE

Is there a priority
problem?
More serious
problems andmore urgent
problems havehigher priority- No- Probably no- Probably yes- Yes- Varies- Don’t know

For drug-resistant epilepsy in which seizures cannot be controlled even with
two regimens of appropriate antiepileptic drugs, the effect of adding further
drugs is limited. By adding vagus nerve stimulation (VNS) to antiepileptic
drugs, the effect of lowering the seizure frequency is expected. Compared withbrain surgery by craniotomy, VNS is minimally invasive and may be selected as
one of the treatment options.

How substantial
are the desirable
anticipatedeffects?

- Trivial- Small- Moderate- Large- Varies- Don’t know

DESIRABLE EFECTS
UNDESIRABLE EFFCETS

How substantial
are theundesirable
anticipatedeffects?

CERTAINTY OF THE
EVIDENCE

What is theoverall certaintyof the evidenceof effects?

- Large- Moderate- Small- Trivial- Varies- Don’t know

- Very low- Low- Moderate- High- No included
studies

The relative importance or values of the main outcomes of interest:
Outcome Relative

Relative
importance

Certainty of theevidence (GRADE)

Seizure frequency ≤50%

CRITICAL⊕⃝⃝⃝
VERY LOW

Mood: change in QOLIE-89(89-item Quality of Life in
Epilepsy Inventory) mental
health score

CRITICAL⊕⊕⃝⃝
LOW

Mood: change in CES-D(Centre for Epidemiologic
Studies Depression scale)

CRITICAL⊕⊕⃝⃝
LOW

Mood: change in NDDI-E(Neurological Disorders
Depression Inventory in
Epilepsy scale)

CRITICAL⊕⊕⃝⃝
LOW

Mood: change in CGI-I(Clinical Global Impressionof Improvement scale)

CRITICAL⊕⊕⃝⃝
LOW

Serious adverse events

CRITICAL⊕⃝⃝⃝
VERY LOW

Dysphonia

CRITICAL⊕⃝⃝⃝
VERY LOW

Summary of findings

OutcomeDrugtherapy

Vagus nerve
stimulation(VNS) + drug
therapy

Seizure frequency≤ 50%

241 per
1,000

323 per 1,000(142 to 734)

82 more per
1,000 (from99 fewer to
492 more)

120 per
1,000

161 per 1,000(71 to 365)

41 more per
1,000 (from49 fewer to
245 more)

480 per
1,000

643 per 1,000(283 to 1,000)

163 more per
1,000 (from197 fewer to
979 more)

Mood: change in
QOLIE-89(89-item Qualityof Life in Epilepsy
Inventory) mental
health score

Relative
effect
(RR)(95% CI)

Difference(95% CI)

RR 1.34(0.59 to3.04)

MD 1.3higher (1.56
lower to 4.16
higher)Relative risk for seizure
frequency ≤ 50% byintervention was 1.34
(0.59‒3.04), and NNT
was 25. For mood change,
the effect was small for all
the scales.

In the intervention group(31 patients), serious
adverse events occurred in
5 patients, 2 (40%) ofwhom had vocal cordparalysis and 1 had brief
respiratory arrest, but all
recovered completely.
Therefore, from RCT, therelative risk of significant
undesirable effects occurringin clinical practice isestimated to be smaller
than 1.79 (0.45–7.13).

-

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VALUESIs thereimportantuncertainty
about orvariability in
how much people
value the main
outcomes?

Does the balance
betweendesirable andundesirable
effects favor theintervention or
the comparison?

BALANCE OF EFFECTS
COST ANDRESOURCEACCEPTABILITYFEASIBILITY

176- Important
uncertainty orvariability- Probably
importantuncertainty orvariability- Probably noimportantuncertainty orvariability- No important
uncertainty andvariability- Control is superior- Control is probably
superior- Control andintervention areequivalent- Intervention isprobably superior- Intervention issuperior- It depends- Don’t know

Mood: change in
CES-D (Centre
for Epidemiologic
Studies Depression
scale)

MD 2.7lower (6.54
lower to 1.14
higher)Mood: change in
NDDI-E(Neurological
DisordersDepression
Inventory in
Epilepsy scale)

MD 0.8lower (2.26
lower to 0.66
higher)Mood: change in
CGI-I (ClinicalGlobal Impressionof Improvement
scale)

MD 0.5lower (0.99
lower to 0.01
lower)

Serious adverse
event

Dysphonia

52 per
1,000

93 per 1,000(23 to 369)

41 more per
1,000 (from28 fewer to
317 more)

25 per1,000

45 per 1,000(11 to 178)

20 more per
1,000 (from14 fewer to
153 more)

100 per
1,000

179 per 1,000(45 to 713)

79 more per
1,000 (from55 fewer to
613 more)

0 per
1,000

0 per 1,000 (0to 0)

0 fewer per
1,000 (from0 fewer to 0
fewer)

Individuals differ in theway they attach importanceto outcomes. Some patientsplace importance on the
reduction of seizure
frequency, while others
regard the risk of adverse
effects to be more important.

RR 1.79(0.45 to7.13)

RR 4.69(0.23 to93.70)

Summary: Only one RCT was extracted from the literature search, and thisRCT was prematurely terminated by the sponsor due to a low enrollment rate,
which resulted primarily from the strong views expressed by candidates towardrandomization. Therefore, there is a possibility that the study was underpoweredfor detecting the outcome. The relative risk for reduction of seizure frequency to≤ 50% was 1.34 (0.59‒3.04).
The relative risk for mood change was 1.3 (−1.56‒4.16) for QOLIE-89, −2.7(−6.54‒1.14) for CES-D, −0.8 (−2.26‒0.66) for NDDI-E, and −0.5 (−0.99‒0.01)
for CGI-I.
The relative risk for serious adverse events was 1.79 (0.45‒7.13). Although there
was no significant difference, the result suggests a possibility of increase in risk.
However, vocal cord paralysis and brief respiratory arrest seen only in theintervention group were transient.

How large are
the resource
requirement(cost)?

- High cost
- Moderate cost
- Negligible- Moderate saving- Large saving- Varies- Don’t know

Is the option
acceptable to key
stakeholders?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Is the option
feasible toimplement?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Part II

The implantation surgery is conducted under general anesthesia. Vagus nerve
stimulation is covered by health insurance, and the health insurance fee scale
for implantation is 24,350 points, and that for exchange is 4,800 points (as ofJanuary 11, 2018). Also, it is necessary to replace the generator once every few
years when the battery runs out, which requires reoperation. The cost of
exchange is approximately ¥2,000,000 (covered by health insurance).

In the past, there were several prefectures that did not have vagus nerve
stimulation device implantation facility or guidance/management facility, andaccess to treatment was poor in some regions. However, currently the criteria foradjusting doctor have been relaxed and access has improved. If the environmentof access to device implantation facility and guidance/management facility
continues to improve, adjustment of stimulation condition is feasible.

Systematic Review Digest

A list of facilities that can
provide this therapy isposted on the Society
website.

Recommendation decision table
Type of recommendation
Judgment

Strongrecommendation
against theintervention

Conditional
recommendation
against theintervention

Conditional
recommendation for
either the intervention
or the comparison

Conditional
recommendation for
the intervention

Strongrecommendation
for the intervention

◯

◯

◯

●

◯

Recommendation

Addition of vagus nerve stimulation on drug therapy is proposed for drug resistant epilepsy. (GRADE 2D, strength ofrecommendation “weak recommendation” / certainty of evidence “very low”)

Justification

Question (CQ): Should vagus nerve stimulation be used for drug resistant epilepsy?
Patient (P): Drug resistant epilepsy
Intervention (I): Vagus nerve stimulation (added to drug therapy)
Comparison (C): Drug therapy
Outcome: Seizure frequency ≤ 50%, mood improvement (QOLIE-8, CES-D, NDDI-E, CGI-I), serious adverse events,
dysphonia
Summary of evidence: Systematic review identified 1 RCT (96 subjects). When seizure frequency ≤ 50% is the outcome,relative risk due to intervention was 1.34 (95% confidence interval 0.59‒3.04). For mood change, the result differeddepending on the evaluation scale, but the effect was small.
Certainty of evidence: The study collected had a high overall bias risk which was judged as serious for all the outcomes,
and was downgraded by 1 rank. For inconsistency of results, there was only one study, and therefore was not downgraded.
There was no problem with indirectness and was judged not serious. As for imprecision, the confidence intervals in many
analyses crossed the clinical decision threshold; hence was downgraded by one or two ranks. As for publishing bias, there
was only one study, and therefore was not downgraded. Consequently, the certainty of evidence for the outcomes was asfollows: “very low” for seizure frequency ≤ 50%, serious adverse events, and dysphonia; and “low” for the other outcomes.
The overall certainty of evidence was “very low”.
Judgment of benefits and harms, burden and cost:
Since there was only 1 RCT, the certainty of effect estimate was low, and it was difficult to judge the balance between
benefits and harms. Among the serious adverse events, vocal cord paralysis and brief respiratory arrest that occurred onlyin the intervention group were transient with no sequelae. Burden and cost are moderate. Considering that there are notmany treatment options, it is appropriate to implement the therapy with expectation of the effectiveness even at theexpense of harms, burden and cost.
Recommendation:
Addition of vagus nerve stimulation on drug therapy is proposed for drug resistant epilepsy. (strength of recommendation“weak recommendation” / certainty of evidence “very low”.
Additional considerations:
At the panel meeting, the patient’s families expressed the following opinion: “There is desire to overcome social constraints.
If there is any method at all, please include it as one of the options.”

Subgroup
considerations.
Consider how to set
criteria for patient
population or intervention,
which may change therecommendation statement

In children, no RCT comparing with and without vagus nerve stimulation was found. In addition, the 2013 guidelines
update of the American Academy of Neurology [Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline
update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of theAmerican Academy of Neurology. 2013; 81(16): 1453-1459.] analyzed 14 non-RCT studies (481 subjects). The rate of ≥50% seizure reduction was 55% (95% confidence interval 51‒59%) and the seizure-free rate was 7% (95% confidence
interval 5‒10%). However, the heterogeneity between studies was very large. The same guideline update suggests that therisk of infection is higher in children (odds ratio 3.4, 95% confidence interval 1.0‒11.2) than in adults.

Implementationconsiderations.
In clinical practice,problems such as feasibility
and tolerability may arise.

To initiate therapy, access to vagus nerve stimulation device implantation facility and guidance/management facility
becomes an issue. Patient should be given explanation that surgery is necessary before therapy can be initiated, and that
it is not possible to predict beforehand whether it will be effective for any patient. Indication judgment and stimulation
device implantation are performed by or under the guidance of a doctor specializing in epilepsy surgery, who is both aJapan Epilepsy Society board-certified specialist and a Japanese Neurosurgical Society board-certified specialist.
Adjustment of the stimulation conditions after therapy initiation as well as follow-up of therapeutic effect and adverse
events are conducted by or under the guidance of a Japan Epilepsy Society board-certified specialist, or a board-certified
specialist of the Japanese Society of Child Neurology, Japanese Society of Neurology, Japanese Society of Psychiatry, orJapanese Neurosurgical Society [Japan Epilepsy Society Criteria for VNS Qualification (enforced on January 8, 2010,
revised on July 1, 2014 and June 26, 2016)].

Monitoring andevaluation.
What monitoring isnecessary during
implementation? Is
evaluation of effectnecessary before or after
publication?

Implementation of vagus nerve stimulation requires a system that allows adjustment of the stimulation conditions,interventions for complications, and correction of equipment troubles. Monitoring and evaluation are conducted by
specialists or physicians who have received guidance from the specialists.

Research possibilities.
What are the unclear
points in judgment that
require future research?

RCT with better quality is desirable. In addition, research focusing on identifying good responders and the effects on
status epilepticus is needed in the future.

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CQ 10-2

Digest Edition

CQ 10-2

When conducting vagus nerve stimulation for
drug resistant epilepsy, which intensity of stimulation(high or low) should we use?
Recommendation
When conducting vagus nerve stimulation for drug-resistant epilepsy, we suggest to use high intensity stimulation
rather than low intensity stimulation (GRADE 1C) (strong recommendation, low level of evidence).
• Supplementary note: Adjustment of stimulation conditions should be conducted in the hospital where theelectrode implantation was performed or in a hospital/institution where VNS specialist is present.

1. Background, priority of this issue
The efficacy of vagus nerve stimulation is known to depend on the stimulation conditions. The intensity of stimulation
should be adjusted while monitoring its therapeutic effect and adverse effects. Therefore, it is necessary to clarify whether
high intensity stimulation or low intensity stimulation is superior when conducting VNS.
In addition, as mentioned in CQ 10-1 “Should vagus nerve stimulation therapy be added to drug therapies for drugresistant temporal lobe epilepsy?”, we have difficulty in performing comparison between real VNS and sham VNS (with nostimulation). Therefore, there is an increase in randomized controlled trials (RCTs) using low intensity stimulation as shamstimulation (placebo stimulation or pseudo-stimulation) to compare with high intensity stimulation.
There is one Cochrane Review1) on a similar clinical question. This review shows that high intensity stimulation has
superior therapeutic effect, while treatment withdrawal is rare both when using high and low intensity stimulation.

2. Comment

Evidence summary
There were 4 RCTs that examined the efficacy of vagus nerve stimulation therapy for drug-resistant epilepsy2‒5).
For efficacy, the relative risk of seizure frequency ≤ 50% was 1.74 (95% confidence interval 1.14‒2.65) and NNT (number
needed to treat: indicating the number of persons needed to treat to achieve the outcome for one person) was 10. For adverse
events, low level stimulation was significantly superior in dysphonia and hoarseness (relative risk 2.06, 95% confidence
interval 1.34‒3.17) and dyspnea (relative risk 2.43, 95% confidence interval 1.29‒4.57). Treatment withdrawal, cough, andpain did not differ significantly between high level and low level stimulations.

3. Panel meeting

3-1. What is the quality of evidence about the overall outcomes?
In all the studies collected, the risk of bias was low overall, and the level was not downgraded for all the outcomes. For
inconsistency of the results, I2 was 32% for only dysphonia / hoarseness. Since the effect estimate differed between studies,
heterogeneity was considered high. Inconsistency was thus considered serious and was downgraded one rank. There was noproblem with indirectness, and was judged not serious. As for imprecision, the confidence intervals in many analyses crossed
the clinical decision thresholds, and hence was downgraded by one or two ranks. Regarding publication bias, there were only
four studies, and therefore was not downgraded. Consequently, the level of evidence for the outcomes was as follows:“moderate” for seizure frequency ≤ 50%, cough, and dyspnea; “low” for treatment withdrawal, dysphonia/ hoarseness, andpain. The overall level of evidence was “low”.

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3-2. What is the balance between benefits and harms?
High level stimulation was superior to low level stimulation for the outcome of seizure frequency ≤ 50%. Among theadverse events, dysphonia/hoarseness and dyspnea showed lower rates in low level stimulation, but since there was no
significant difference in treatment withdrawal between two groups, there must be few adverse events serious enough to cause
treatment withdrawal. According to expert opinion, many adverse events are reversible and can be controlled by adjusting
the stimulation current intensity. Taken together, we decided that high level stimulation is probably superior in terms of thebalance between benefits and harms.

3-3. What about patients’ values and preferences?
We concluded that there is probably no significant uncertainty and variability in patient’s values and preferences because
high level stimulation is more effective than low level stimulation, and although adverse events are more prevalent in highlevel stimulation, they are reversible and can be controlled by adjusting the stimulation current.

3-4. What is the balance between net benefit and cost or resources?
Adjustment of stimulation intensity can be done by placing the programming wand over the subcutaneously implanted
generator; thus resources and costs are negligible. However, reoperation is needed to replace the generator every few years
when the battery runs out. Battery consumption is higher for high level stimulation than for low level stimulation. Based onthese, it was decided that high level stimulation costs moderately more as compared to low level stimulation.

3-5. Recommendation grading
In the discussions at the panel meeting, high level stimulation was considered superior in efficacy, and adverse effects were
acceptable because most of them were presumably at a level that would not cause treatment withdrawal. As for burden andcost, high level stimulation was expected to consume more battery power, requiring more frequent generator exchange.
Based on the above arguments, despite considerable adverse events that did not cause treatment withdrawal as well as theincreased burden and cost, we finally unanimously recommended using high level stimulation, considering the highly
anticipated seizure control effect.

4. Descriptions in other related guidelines
In Japan, the “Guideline on implementation of vagus nerve stimulation therapy for epilepsy”6) was published by the Japan
Epilepsy Society in 2012, which states that “In principle, initiate VNS two weeks after implantation. Start with low stimulation
intensity and then gradually increase the intensity while monitoring the adverse effects [recommendation grade C]”.
In 2013, the American Academy of Neurology released a guideline update entitled “Vagus nerve stimulation for thetreatment of epilepsy”. There is no recommendation for high level or low level stimulation in that guideline. However, it
states that whether stimulation at a higher frequency is more likely to reduce seizures than usual stimulation remains
unknown.

5. Treatment monitoring and evaluation
For adjusting stimulation intensity, we need a system which is capable of managing complications and coping withequipment troubles.

6. Future research issues
Further research on the optimal intensity of stimulation is needed. In addition, other than stimulus intensity, there is no
RCT on supplementary techniques such as magnet stimulation, which will be a future research subject. It is also desirable toelucidate the mechanisms underlying the subgroup with high response and develop evaluation methods to identify thesesubjects.

7. RCT reports reviewed for this CQ
Michael 19932), VNS study Group 19953), Handforth 19984), Klinkenberg 20125)

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8. List of appendices (to be shown later)
Appendix CQ10-2-01. Flow diagram and search formula for references
Appendix CQ10-2-02. Risk of bias summary
Appendix CQ10-2-03. Risk of bias graphAppendix CQ10-2-04. Forest plot
Appendix CQ10-2-05. Summary of Findings (SoF) table
Appendix CQ10-2-06. Evidence-to-Decision table▪ References
1) Panebianco M, Rigby A, Weston J, et al. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2015; (4): CD002896.
2) Michael JE, Wegener K, Barnes. Vagus nerve stimulation for intractable seizures: one year follow-up. J Neurosci Nurs. 1993; 25(6): 362-366.
3) The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractableseizures. The Vagus Nerve Stimulation Study Group. Neurology. 1995; 45(2): 224-230.
4) Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.
Neurology. 1998; 51(1): 48-55.
5) Klinkenberg S, Aalbers MW, Vles JS, et al. Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. Dev Med
Child Neurol. 2012; 54(9): 855-861.
6) Kawai K, Sugai K, Akamatsu N, et al. Guideline on implementation of vagus nerve stimulation therapy for epilepsy. Tenkan Kenkyu. 2012; 30(1):68-72 (in Japanese).
7) Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the
Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013; 81(16): 1453-1459.

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Appendix CQ10-2-01.   Flow diagram and literature search formula

CQ 10-2

Literature search

PICO
P: Patients with drug-resistant epilepsy (children as subgroup)
I: Vagus nerve stimulation at high level stimulation
C: Compared with vagus nerve stimulation at low level stimulation
O: Are seizures controlled (25, 50, 75%)?
Is there a decrease in treatment continuation rate?
Is there an increase in dysphonia/hoarseness? / and cough?
Is there an increase in dyspnea?
Is there an increase in pain?

▪ Search formula
PubMed search: September 28, 2016
#1 Search ((“drug resistant epilepsy” [mesh] OR ((epilepsy OR seizures OR convulsions) AND (intractable OR refractory))))#2 Search (“vagus nerve stimulation” [mesh] OR (“vagal nerve” AND stimulation) OR (“vagus nerve” AND “electric stimulation therapy”))#3 Search (randomized controlled trial [pt] OR meta-analysis [pt] OR randomized OR blind OR observation* OR cohort OR “follow-up” OR cross
OR case OR series OR prospective OR retrospective OR placebo OR trial)#4 (#1 AND #2 AND #3)
Cochrane CENTRAL search: September 28, 2016
(epilepsy OR seizures) AND vagus nerve stimulation

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CQ10-2. Flow diagram of literature search (modified PRISMA 2009)

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Appendix CQ10-2-02 and -03.   Risk of bias summary
Risk of bias graphs

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Appendix CQ10-2-04.  Forest plot

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Appendix CQ10-2-05.    Summary of Findings (SoF) table
Patients: Patients with drug-resistant epilepsy
Intervention: High level stimulation
Comparison: Low level stimulation

OutcomeSeizure frequency ≤ 50%

Expected absolute effect*(95% confidence interval)
Risk of low level Risk of high levelstimulation
stimulation
144 (per 1,000)
251 (per 1,000)(165–382)

Relative effect:risk ratio (RR)
(95% confidence
interval)

No. ofpatients(No. ofstudies)

Quality ofevidence(GRADE)

RR 1.74(1.14–2.65)

373(4 RCTs)⊕⊕⊕⃝
Moderatea

Treatment withdrawal

10 (per 1,000)

26 (per 1,000)(5–129)RR 2.51(0.50–12.61)

375(4 RCTs)

⊕⊕⃝⃝
Lowb

Dysphonia/hoarseness251 (per 1,000)

518 (per 1,000)(337–797)

RR 2.06(1.34–3.17)

334(3 RCTs)⊕⊕⃝⃝
Lowc,dCough

291 (1,000)

315 (per 1,000)(233–425)

RR 1.08(0.80–1.46)

334(3 RCTs)⊕⊕⊕⃝
Moderated

Dyspnea74 (1,000)

179 (per 1,000)(95–336)

RR 1.08(0.80–1.46)

312(2 RCTs)⊕⊕⊕⃝
ModeratedPain

239 (1,000)

239 (per 1,000)(163–352)

RR 1.00(0.68–1.47)

312(2 RCTs)

⊕⊕⃝⃝
Lowb

Comment*Risk (95% confidence interval) in the intervention group was estimated based on the risk in the control group and the effect due tointervention (and 95% confidence intervals).
Grades of quality of evidence according to the GRADE Working Group:
High:
High certainty of the effect estimate. True effect is near the effect estimate.
Moderate: Moderate certainty of the effect estimate. The effect estimate is considered to be near the true effect, but further research
may change the effect estimate.
Low:
There is limitation in the certainty of the effect estimate. Although the effect estimate may be near the true effect, further
research is very likely to change the effect estimate.
Very low: Very low certainty of the effect estimate. The true effect is very likely to be different from the effect estimate.
: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable benefit: because confidence interval of effect estimate crosses the clinical decision thresholds of both appreciable benefit and appreciable harm.
c: because I2 = 32%; effect estimates differ among studies, heterogeneity is probably highd
: because confidence interval of effect estimate crosses the clinical decision threshold of appreciable harm
a

b

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Appendix CQ 10-2-06.  Evidence-to-Decision table
Evaluation table of recommendation decision criteria
Study population: Patients with drug-resistant temporal lobe epilepsy
Intervention: vagus nerve stimulation
CRITERIA

ADDITIONALCONSIDERATIONSPROBLEMDESIRABLEEFECTSJUDGEMENTSRESEARCH EVIDENCE

Is there a priority
problem?
More serious
problems andmore urgent
problems havehigher priority- No- Probably no- Probably yes- Yes- Varies- Don’t know

Vagus nerve stimulation is known to have different effects depending on thestimulation conditions. The intensity of stimulation should be adjusted while
monitoring the therapeutic effect and adverse effects.

How substantial
are the desirable
anticipated effects?

- Trivial- Small- Moderate- Large- Varies- Don’t know

How substantial
are the undesirable
anticipated effects?

- Large- Moderate- Small- Trivial- Varies- Don’t know

The relative importance or values of the main outcomes of interest:

UNDESIRABLE EFFCETS

OutcomeRelative
importance

Certainty of the evidence(GRADE)

Seizure frequency ≤ 50%

CRITICAL⊕⊕⊕⃝
MODERATE

Treatment withdrawal

CRITICAL⊕⊕⃝⃝
LOW

Dysphonia, hoarseness

CRITICAL

⊕⊕⃝⃝
LOW

Cough

CRITICAL⊕⊕⊕⃝
MODERATE

Dyspnea

CRITICAL⊕⊕⊕⃝
MODERATE

Pain

CRITICAL⊕⊕⃝⃝
LOW

Summary of findings

CERTAINTY OF
THE EVIDENCE

What is theoverall certaintyof the evidenceof effects?

VALUESIs there important
uncertainty aboutor variability in
how much people
value the main
outcomes?

- Very low- Low- Moderate- High- No included
studies- Important
uncertainty orvariability- Probably
importantuncertainty orvariability- Probably noimportantuncertainty orvariability- No important
uncertainty andvariability

Relative
effect (RR)
(95% CI)

Low levelstimulation

High levelstimulation

Difference(95% CI)

Seizurefrequency≤ 50%

144 per
1,000

251 per 1,000(165 to 382)

107 moreper 1,000(from 20
more to 238
more)

RR 1.74(1.14 to2.65)

Treatment
withdrawal

10 per1,000

26 per 1,000(5 to 129)

15 moreper 1,000(from 5 fewer
to 119 more)

RR 2.51(0.50 to12.61)

Dysphonia/
hoarseness251 per
1,000

518 per 1,000(337 to 797)

267 moreper 1,000(from 85
more to 46
more)

RR 2.06(1.34 to
3.17)

Cough

291 per
1,000

315 per 1,000(233 to 425)

23 moreper 1,000(from 58
ewer to 134
more)

RR 1.08(0.80 to1.46)

Dyspnea

74 per
1,000

179 per 1,000(95 to 336)

105 moreper 1,000(from 21
more to 263
more)

RR 2.43(1.29 to
4.57)

Pain

239 per
1,000

239 per 1,000(163 to 352)

0 fewer
per 1,000(from 77
fewer to 112
more)

RR 1.00(0.68 to
1.47)

OutcomeCQ 10-2Comparison between highand low level stimulation
was examined, because
research comparing with vs.
without vagus stimulation
is difficult to implement
due to issues in research
execution
The relative risk of seizure
frequency ≤50% for highlevel stimulation was 1.74
(1.14‒2.65), and wassignificantly superior to
low level.

Significant differences
between high level and low
level stimulation wereobserved for dysphonia/
hoarseness (relative risk
2.06, 1.34 to 3.17) anddyspnea (relative risk 2.43,
1.29 to 4.57). However, therelative risk of treatment
withdrawal was 2.51 (0.50
to 12.61), with no significant
difference between highlevel and low levelstimulation. It can beinferred that there are few
adverse events serious
enough to cause treatment
discontinuation. Adverse
effects are reversible andcan be controlled byadjusting electric current.

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BALANCE OF EFFECTS
COST ANDRESOURCEACCEPTABILITYFEASIBILITY

190

Does the balance
between desirable
and undesirable
effects favor theintervention or
the comparison?

- Control is superior- Control is probably
superior- Control andintervention areequivalent- Intervention isprobably superior- Intervention issuperior- It depends- Don’t know

Summary: High frequency stimulation is significantly superior for the outcomeof seizure frequency ≤ 50% (relative risk 1.74, 1.14‒2.65). For adverse events,
low level stimulation was significantly superior for dysphonia/hoarseness(relative risk 2.06, 1.34‒3.17) and dyspnea (relative risk 2.43, 1.29‒4.57).
Treatment withdrawal, cough, and pain did not differ significantly between two
groups.

How large are
the resource
requirement(cost)?

- High cost
- Moderate cost
- Negligible- Moderate saving- Large saving- Varies- Don’t know

Stimulation intensity can be adjusted by manipulating the programming wandlocated above the subcutaneously implanted generator, and resources and costs
are negligible. However, it is necessary to replace the generator once every few
years when the battery runs out, requiring exchange with a cost or about¥2,000,000 (covered by health insurance). Battery consumption is higher forhigh level stimulation than for low level stimulation.

Is the option
acceptable to key
stakeholders?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Is the option
feasible toimplement?

- No- Probably no- Probably yes- Yes- Varies- Don’t know

Part IIIn the past, there were several prefectures that did not have vagus nerve stimulation
device implantation facility or guidance/management facility, and access totreatment was poor in some regions. However, currently the criteria for adjusting
doctor have been relaxed and access has improved.
If the environment of access to device implantation facility and guidance/
management facility continues to improve, adjustment of stimulation condition
is feasible.

Systematic Review Digest

A list of facilities that can
provide this therapy isposted on the Society
website.

Recommendation decision table
Type of recommendation
Judgment

Strongrecommendation
against theintervention

Conditional
recommendation
against theintervention

Conditional
recommendation for
either the intervention
or the comparison

Conditional
recommendation for
the intervention

Strongrecommendation
for the intervention

◯

○

◯

◯

●

Recommendation

When conducting vagus nerve stimulation for drug resistant epilepsy, high level stimulation rather than low levelstimulation is recommended (GRADE 1C, strength of recommendation “strong recommendation”/certainty ofevidence “low”.

Justification

Question (CQ): When conducting vagus nerve stimulation for drug resistant epilepsy, should high-level stimulation or
low-level stimulation be used?
Patients (P): Patients with drug-resistant epilepsy who were implanted a vagal nerve stimulating device.
Intervention (I): High level stimulation
Comparison (C): Low level stimulation
Outcomes (O): Seizure frequency ≤50%, treatment withdrawal, dysphonia/hoarseness, cough, dyspnea, pain
Summary of evidence: Systematic review identified four RCTs (375 patients). For seizure frequency ≤50%, high levelstimulation was significantly superior (relative risk 1.74, 1.14‒2.65) [NNT 10]. Among adverse events, significant
differences were observed for dysphonia/ hoarseness (relative risk 2.06, 1.34‒3.17) and dyspnea (relative risk 2.43,
1.29‒4.57). The relative risk of treatment withdrawal was 2.51 (0.50‒12.61), with no significant difference between highlevel stimulation and low level stimulation groups.
Certainty of evidence: In all the studies collected, the risk of bias was low overall, and was not downgraded for all theoutcomes. For inconsistency of the results, I2 was 32% for only dysphonia and hoarseness. Since the effect estimate
differed between studies, heterogeneity was considered high. Inconsistency was thus considered serious and was
downgraded one rank. There was no problem with indirectness, which was not serious. As for imprecision, the confidence
intervals in many analyses crossed the clinical decision thresholds, and hence was downgraded by one or two ranks.
Regarding publication bias, there were only four studies, and therefore was not downgraded. Consequently, the certaintyof evidence for the outcomes was as follows: “moderate” for seizure frequency ≤50% cough, and dyspnea; and “low” fortreatment withdrawal, dysphonia/ hoarseness, and pain. The overall certainty of evidence was “low”.
Judgment of benefits and harms, burden and cost:
In 4 RCTs, high level stimulation was significantly superior for the outcome of seizure frequency ≤50% outcome. Amongthe adverse events, dysphonia/ hoarseness (relative risk 2.06, 1.34‒3.17) and dyspnea (relative risk 2.43, 1.29‒ 4.57) weresignificantly more frequent in high level stimulation, but both were transient. There was no significant difference intreatment withdrawal between two groups (relative risk 2.51, 0.50‒12.61). As for the burden and cost, it is expected thathigh level stimulation consumes more battery power and requires a higher frequency of generator exchange. Taking theabove into consideration, despite adverse events that do not lead to treatment withdrawal and the possibility of increases
in burden and cost, it is worth trying high level stimulation in anticipation of seizure control.
Recommendation:
When conducting vagus nerve stimulation for drug resistant epilepsy, high level stimulation rather than low levelstimulation is recommended (strength of recommendation “strong recommendation”/certainty of evidence “low”).
Additional considerations:Due to the problems with research execution, it is difficult to realize comparative study of vagus nerve stimulation versus
no stimulation. Therefore, there is an increase in RCT comparing high level stimulation versus low level stimulation.
Low level stimulation is generally treated as sham stimulation (placebo group). On the other hand, theoretically there
exists an argument: the fact that low level stimulation is harmful may account for the therapeutic effect observed whencompared with high level stimulation.

Subgroup considerations.
Consider how to set criteria
for patient population orintervention, which may
change therecommendation statement

There was one RCT in children (Klinkenberg 2012). The relative risk of 50% reduction of seizure frequency for high levelstimulation was 1.19 (0.94‒1.44), with no significant difference compared to low level stimulus. On the other hand, therelative risk of treatment withdrawal was 1.90 (1.75‒2.06) and was significantly higher. However, since the observation
period in this RCT was only 20 weeks, and therapeutic effect can be expected with prolonged treatment, this finding
alone cannot be used as evidence for withholding treatment.

Implementationconsiderations.
In clinical practice,problems such as feasibility
and tolerability may arise.

High level stimulation usually refers to the intensity of stimulation used in treatment. On the other hand, low levelstimulation refers to control stimulation (so-called sham stimulation) in which the stimulation frequency, pulse width,and stimulation frequency are set at low levels.
There may be a problem in the case of poor access to vagus nerve stimulation device implantation facility and guidance/
management facility due to changing residence and other reasons.

Monitoring andevaluation.
What monitoring isnecessary for
implementation? Is
evaluation of effectnecessary before or after
publication?

For adjustment of stimulation intensity, a system has to be in place to respond to complications and to cope withequipment troubles. The frequency of hospital visit is about once a month after implantation surgery, and once every 3months when the condition is stabilized.

Research possibilities.
What are the unclear
points in judgment that
require future research?

Further studies are needed to examine the optimal intensity of stimulation, elucidate the characteristics of subgroupdemonstrating high efficacy, and develop methods to identify the high responders. Also, apart from adjusting stimulation
intensity, there are no RCTs on other supplementary techniques such as magnet stimulation, which is a topic of future
research.

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