Conti Epilepsy 2022

APRIL 2022
VOL. 28 NO. 2 Epilepsy

Guest Editor: Nathalie Jetté, MD, MSc, FRCPC, CSCN(EEG), FAAN, FAES, FANA
228 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
230 Evaluation of First Seizure and Newly Diagnosed Epilepsy

Elaine Wirrell, MD, FRCP(C), FAAN
261 EEG Essentials

William O. Tatum IV, DO, FAAN, FACNS, FAES
306 Neuroimaging of Epilepsy

Samuel Lapalme-Remis, MDCM, MA, FRCPC;
Dang K. Nguyen, MD, PhD, FRCPC
339 Genetic Epilepsy Syndromes

Kenneth A. Myers, MD, PhD, FRCPC, CSCN(EEG)
363 Autoimmune-Associated Seizures

Lisa Gillinder, MBBS, FRACP; Jeffrey Britton, MD, FAAN
399 Women’s Issues in Epilepsy

Esther Bui, MD, FRCP(C)
428 Seizures and Epilepsy in Childhood

Maria Gogou, MD, PhD; Judith Helen Cross, MBChB, PhD
457 Neuropsychiatric and Cognitive Comorbidities in Epilepsy

DENOTES CONTINUUM
Marco Mula, MD, PhD, FRCP, FEAN; Honor Coleman, MPsych, PhD;
AUDIO INTERVIEW
Sarah J. Wilson, PhD, FAHMS, FASSA
DENOTES VIDEO
CONTENT 483 Approach to the Medical Treatment of Epilepsy
Francesco Brigo, MD; Anthony Marson, MBChB, MD, FRCP
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

500 Update on Antiseizure Medications 2022
Bassel W. Abou-Khalil, MD, FAAN
536 Surgical Treatments for Epilepsy

George W. Culler IV, MD; Barbara C. Jobst, MD, Dr Med, FAAN
559 Management of Status Epilepticus, Refractory Status Epilepticus,

and Super-refractory Status Epilepticus
Eugen Trinka, MD, MSc, FRCP; Markus Leitinger, MD, MSc
SELF-ASSESSMENT AND CME
220 Learning Objectives and Core Competencies
603 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
605 Postreading Self-Assessment and CME Test
618 Postreading Self-Assessment and CME Test—Preferred Responses
627 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS a
Nathalie Jetté, MD, MSc, Francesco Brigo, MD

FRCPC, CSCN(EEG), FAAN, Department of Neurology,
FAES, FANA Hospital of Merano,
Guest Editor Merano-Meran, Italy
Professor of Neurology, Icahn
Relationship Disclosure: Dr Brigo reports no
School of Medicine at Mount disclosure.
Sinai, New York, New York
Unlabeled Use of Products/Investigational
Relationship Disclosure: Dr Jetté has Use Disclosure: Dr Brigo reports no
received personal compensation in the disclosure.
range of $500 to $4999 for serving as
an Associate Editor for Epilepsia. The
institution of Dr Jette has received research
support from the American Epilepsy Society, Jeffrey Britton, MD, FAAN
the National Institutes of Health, the Chair, Division of Epilepsy;
NORSE Institute and the Patient-Centered
Outcomes Research Institute. Professor of Neurology, Mayo
Clinic, Rochester, Minnesota
Use Disclosure: Dr Jette reports no Relationship Disclosure: Dr Britton has
disclosure. received personal compensation in the
range of $0 to $499 for serving as an online
course instructor for the American Clinical
Neurophysiology Society.
Bassel W. Abou-Khalil, MD,
FAAN Unlabeled Use of Products/Investigational
Use Disclosure: Dr Britton discusses
Professor of Neurology, the unlabeled/investigational use of
Vanderbilt University Medical azathioprine, cyclophosphamide, IVIg,
methylprednisolone, mycophenolate
Center, Nashville, Tennessee mofetil, prednisone, and rituximab for the
treatment of autoimmune encephalitis.
Relationship Disclosure: Dr Abou-Khalil has
served on the editorial board of Clinical
Neurophysiology. The institution of
Dr Abou-Khalil has received research
support from Biogen, Cerevel Therapeutics, Esther Bui, MD, FRCP(C)
Human Epilepsy Project, Otsuka America Assistant Professor of
Pharmaceutical, Inc, SK-Pharma, Sunovion Neurology, University of
Pharmaceuticals Inc, UCB SA, and Xenon.
Toronto; Epilepsy Fellowship
Unlabeled Use of Products/Investigational Director; Women’s Neurology
Use Disclosure: Dr Abou-Khalil discusses
the unlabeled/investigational use of
Fellowship Director; Director
cannabidiol and clobazam for the treatment of Education–Canadian League
of focal-onset seizures, gabapentin for the Against Epilepsy, Toronto,
treatment of headache and sleep disorders,
lamotrigine as a first-line treatment for
Ontario, Canada
epilepsy, perampanel for myoclonus,
Relationship Disclosure: Dr Bui reports no
primidone for the treatment of essential
disclosure.
tremor, valproate for the treatment of
generalized myoclonic and generalized
tonic-clonic seizures, and zonisamide as
Use Disclosure: Dr Bui discusses the
initial monotherapy for epilepsy.
unlabeled/investigational use of
acetazolamide, clobazam, and hormonal
therapies for the treatment of catamenial
epilepsy.
a
All relevant financial relationships have been mitigated.
222 APRIL 2022

Honor Coleman, MPsych, PhD George W. Culler IV, MD
Clinical Neuropsychologist, Assistant Professor of
Alfred Health; Lecturer, Neurology, Dartmouth-
University of Melbourne, Hitchcock Medical Center,
Melbourne, Victoria, Australia Geisel School of Medicine at
Dartmouth, Lebanon,
Relationship Disclosure: Dr Coleman has
received personal compensation for serving New Hampshire
as a research lead for the Epilepsy Foundation
of Australia. Relationship Disclosure: Dr Culler reports no
disclosure.
Use Disclosure: Dr Coleman reports no Unlabeled Use of Products/Investigational
disclosure. Use Disclosure: Dr Culler discusses
neurostimulation for the treatment of
refractory genetic/idiopathic generalized
epilepsy.
Judith Helen Cross, MBChB,
PhD
Developmental Neurosciences, Lisa Gillinder, MBBS, FRACP
University College London Service Director, Mater
Great Ormond Street Institute Advanced Epilepsy Unit, Mater
of Child Health; Department Hospital, South Brisbane,
of Neurology, Great Ormond Queensland, Australia
Street Hospital for Children Relationship Disclosure: Dr Gillinder reports
NHS Trust, London, no disclosure.
United Kingdom
Relationship Disclosure: Dr Cross holds an Use Disclosure: Dr Gillinder discusses
endowed chair at the University College the unlabeled/investigational use of
London Great Ormond Street Institute of azathioprine, cyclophosphamide, IVIg,
Child Health. The institution of Dr Cross methylprednisolone, mycophenolate
has received support from Biocodex, the mofetil, prednisone, and rituximab for the
Engineering and Physical Sciences Research treatment of autoimmune encephalitis.
Council, Epilepsy Research UK, Great Ormond
Street Hospital Charity, GW Pharmaceuticals
plc, Marinius Pharmaceuticals, Inc, the
National Institute of Health Research Great Maria Gogou, MD, PhD
Ormond Street Hospital Biomedical Research Department of Neurology,
Centre, Nutricia, Vitaflo (International) Limited,
the Waterloo Foundation, and Zogenix. Great Ormond Street Hospital
for Children NHS Trust, Great
Use Disclosure: Dr Cross discusses the
Ormond Street, London,
unlabeled/investigational use of memantine United Kingdom
for the treatment of GRIN2A-related
epilepsies, quinidine for the treatment of Relationship Disclosure: Dr Gogou reports
KCNT1-related epilepsies, and radiprodil for no disclosure.
the treatment of GRIN2B-related epilepsies.
Use Disclosure: Dr Gogou discusses the
unlabeled/investigational use of memantine
for the treatment of GRIN2A-related
epilepsies, quinidine for the treatment of
KCNT1-related epilepsies, and radiprodil for
the treatment of GRIN2B-related epilepsies.
C O N T I N U U M J O U R N A L .C O M 223

CONTRIBUTORS a (CONTINUED)
Barbara C. Jobst, MD, Dr Med, Markus Leitinger, MD, MSc

FAAN Privatdozent, Department of
Chair and Professor of Neurology, Neurointensive
Neurology, Dartmouth- Care, and Neurorehabilitation,
Hitchcock Medical Center, Christian Doppler University
Geisel School of Medicine at Hospital, Paracelsus Medical
Dartmouth, Lebanon, University, Centre for Cognitive
New Hampshire Neuroscience; Neuroscience
Institute, Christian Doppler
Relationship Disclosure: Dr Jobst has received
personal compensation of $20,000 for University Hospital Salzburg,
serving as an Associate Editor on Neurology. Centre for Cognitive
The institution of Dr Jobst has received
research support from the American Epilepsy
Neuroscience, Salzburg
Society, the Centers for Disease Control and
Prevention, the Department of Defense, the Relationship Disclosure: Dr Leitinger reports
Epilepsy Foundation, Harvard Pilgrim Health no disclosure.
Care, Inc, the National Institutes of Health,
and NeuroPace, Inc. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Leitinger discusses the
Unlabeled Use of Products/Investigational unlabeled/investigational use of antiseizure
Use Disclosure: Dr Jobst discusses medications for the treatment of status
the unlabeled/investigational use of epilepticus.
neurostimulation for the treatment of
refractory genetic/idiopathic generalized
epilepsy.
Anthony Marson, MBChB, MD,
FRCP
Samuel Lapalme-Remis, Department of Pharmacology
MDCM, MA, FRCPC and Therapeutics, University
Neurologist, Centre hospitalier of Liverpool, Liverpool,
de l’Université de Montréal; United Kingdom
Assistant Clinical Professor,
Relationship Disclosure: Dr Marson has
(Neuroscience), Université de received publishing royalties from Oxford
Montréal, Montreal, University Press.
Quebec, Canada Unlabeled Use of Products/Investigational
Use Disclosure: Dr Marson reports no
Relationship Disclosure: Dr Lapalme-Remis
disclosure.
reports no disclosure.

Use Disclosure: Dr Lapalme-Remis reports
no disclosure.
a
224 APRIL 2022

Marco Mula, MD, PhD, FRCP, Dang K. Nguyen, MD, PhD,
FEAN FRCPC
Consultant in Neurology and Neurologist, Centre hospitalier
Epileptology, Atkinson Morley de l’Université de Montréal;
Regional Neuroscience Centre, Professor (Neuroscience),
St George’s University Hospital; Université de Montréal,
Reader in Neurology, Institute Montreal, Quebec, Canada
of Medical and Biomedical
Relationship Disclosure: Dr Nguyen reports
Education, St George’s no disclosure.
University of London, London,
United Kingdom
Use Disclosure: Dr Nguyen reports no
disclosure.
Relationship Disclosure: Dr Mula has
received personal compensation in the range
of $500 to $4999 for serving on a speakers
bureau for Eisai Co, Ltd, and UCB, Inc, and for William O. Tatum IV, DO, FAAN,
serving as an Associate Editor for Epilepsy &
Behavior; has received publishing royalties FACNS, FAES
from Elsevier and Springer Publishing Professor of Neurology, Mayo
Company; and has a compensated
Clinic College of Medicine
relationship with the Korean League Against
Epilepsy and the Philippine League Against & Science; Chief, Division
Epilepsy. of Epilepsy, Mayo Clinic,
Jacksonville, Florida
Use Disclosure: Dr Mula reports no
Relationship Disclosure: Dr Tatum has
disclosure.
received personal compensation in the
range of $500 to $4999 for serving as an
Editor-in-Chief for Epilepsy & Behavior
Reports and as an expert witness for a
Kenneth A. Myers, MD, PhD, defense law firm on behalf of a patient
FRCPC, CSCN(EEG) with epilepsy with funds donated to the
Assistant Professor, Department Epilepsy Foundation of America; has
of Pediatrics, Division of Child range of $10,000 to $49,999 for serving as
Neurology, McGill University; a consultant for BioSerenity, Holberg EEG
AS, Neurelis, Inc, Zimmer Biomet; and has
Junior Scientist, Research
received publishing royalties from Demos
Institute of the McGill University and Springer Publishers. The institution of
Health Centre, Montreal, Dr Tatum has received research support
from Cerevel Therapeutics, Engage Pharma,
Quebec, Canada Esai Inc, LivaNova PLC, the Mayo Clinic,
Medtronic, and Xenon.
Relationship Disclosure: Dr Myers has
range of $500 to $4999 for serving as an
Use Disclosure: Dr Tatum reports no
academic writer with Springer Publishing
disclosure.
Company. The institution of Dr Myers has
received research support from Dravet
Canada, Fonds de recherche du Québec,
Koolen-de Vries Syndrome Foundation, The
Liam Foundation, and the Savoy Foundation.

Use Disclosure: Dr Myers discusses the
unlabeled/investigational use of clobazam
for the treatment of forms of epilepsy
other than Lennox-Gastaut syndrome and
quinidine for the treatment of epilepsy due
to KCNT1 pathogenic variants.

CONTRIBUTORS a (CONTINUED)
Eugen Trinka, MD, MSc, FRCP Sarah J. Wilson, PhD, FAHMS,

Professor, Department of FASSA
Neurology, Neurointensive Professor of Clinical
Care, and Neurorehabilitation, Neuropsychology and Pro
Christian Doppler University Vice-Chancellor (Student
Hospital, Paracelsus Medical Life), University of Melbourne,
University, Centre for Cognitive Victoria, Australia
Neuroscience, Salzburg;
Neuroscience Institute, Relationship Disclosure: Dr Wilson has
Christian Doppler University range of $0 to $499 for serving on a speakers
Hospital Salzburg, Centre bureau for Pretola Global Health Consulting
Limited. The institution of Dr Wilson has
for Cognitive Neuroscience,
received research support from the Austin
Salzburg; Department Medical Research Foundation, Australian
of Public Health, Health Research Council, Australian Government
National Health and Medical Research
Services Research and Health Council, and the Epilepsy Foundation.
Technology Assessment,
UMIT–University for Health Unlabeled Use of Products/Investigational
Use Disclosure: Dr Wilson reports no
Sciences, Medical Informatics disclosure.
and Technology, Hall in Tirol;
Karl Landsteiner Institute for
Neurorehabilitation and Space Elaine Wirrell, MD, FRCP(C),
Neurology, Salzburg, Austria FAAN
Professor of Neurology,
Relationship Disclosure: Dr Trinka has
received personal compensation in the Divisions of Child and
range of $500 to $4999 for serving as a Adolescent Neurology and
Chief Executive Officer of Neuroconsult
Ges.m.b.H and for serving as a consultant
Epilepsy, Department of
for Arvelle Therapeutics, Bial, Biogen, Neurology, Mayo Clinic,
Boehringer Ingelheim International GmbH, Rochester, Minnesota
Eisai Co, Ltd, Ever Pharma, GlaxoSmithKline
plc, GW Pharmaceuticals plc, LivaNova PLC,
Relationship Disclosure: Dr Wirrell has
Marinus Pharmaceuticals, Inc, Medtronic,
NewBridge Pharmaceuticals, Novartis AG,
range of $500 to $4999 for serving as a
Sandoz International GmbH, Sanofi, Sunovion
Consultant for BioMarin and Eisai Co, Ltd,
Pharmaceuticals Inc, Takeda Pharmaceutical
and for serving on a scientific advisory or
Company Limited, and UCB, Inc, and has
data safety monitoring board for Amicus
received research support from the Austrian
Therapeutics, Inc, Encoded Therapeutics,
Science Fund (FWF), Bayer AG, Biogen, Eisai
Inc, and Neurocrine Biosciences, Inc, and
Co, Ltd, the European Union, GlaxoSmithKline
has received publishing royalties from
plc, Novartis AG, Oesterreichische
UpToDate, Inc.
Nationalbank, Red Bull, and UCB, Inc.
Use Disclosure: Dr Wirrell reports no
Use Disclosure: Dr Trinka discusses
disclosure.
antiseizure medications for the treatment
of status epilepticus.
a
226 APRIL 2021

CONTRIBUTORS (CONTINUED)
Self-Assessment and CME Test Writers
Douglas J. Gelb, MD, PhD, James W. M. Owens Jr, MD, PhD

FAAN Associate Professor of
Professor of Neurology, Neurology, Adjunct Associate
University of Michigan, Professor of Pediatrics,
Ann Arbor, Michigan University of Washington
School of Medicine,
Relationship Disclosure: Dr Gelb has
received publishing royalties from MedLink, Seattle, Washington
LLC, Oxford University Press, and UpToDate,
Inc. Dr Gelb has received personal Relationship Disclosure: Dr Owens has
compensation in the range of $500 to $4999 received personal compensation in the
for serving as a multiple-choice question range of $500 to $4999 for serving as an
writer for Continuum. Associate Editor for Continuing Medical
Education and as a question writer for the
Unlabeled Use of Products/Investigational American Academy of Neurology. Dr Owens
Use Disclosure: Dr Gelb reports no has a noncompensated relationship as
disclosure. a member of the Accreditation Council
with the United Council for Neurologic
Subspecialties.

Use Disclosure: Dr Owens reports no
disclosure.

EDITOR’S PREFACE
An Ictal and Interictal Continuum

This issue of Continuum is devoted to the diagnosis and management
of patients with seizures and epilepsy. To accomplish this goal, I am
thankful to Dr Nathalie Jetté for accepting my invitation to serve as
guest editor of this issue and for assembling such renowned
international experts to share their expertise in epileptology with us.
The issue begins with three articles that serve as an these patients. Drs Marco Mula, Honor Coleman, and
important introduction to the rest of the issue. The Sarah J. Wilson then discuss the neuropsychiatric and
first article is by Dr Elaine Wirrell, who provides a cognitive comorbidities in epilepsy, comorbidities
detailed, state-of-the-art overview of the evaluation whose recognition and management can improve the
of the patient with a first seizure and newly quality of life of our patients with epilepsy.
diagnosed epilepsy. In the next article, Dr William O. The last four articles in this issue are devoted to the
Tatum IV provides an extensive introduction to the management of epilepsy. First, Drs Francesco Brigo
essentials of EEG with generous use of representative and Anthony Marson describe their overall evidence-
EEG tracings throughout. In the third article in this based approach to the current medical treatment of
introductory section, Drs Samuel Lapalme-Remis the focal and generalized epilepsies. Next, Dr Bassel
and Dang K. Nguyen provide a comprehensive and W. Abou-Khalil provides current information on
well-illustrated review of the neuroimaging each of the antiseizure medications available to our
of epilepsy. patients; this encyclopedic article is an update on
Dr Kenneth A. Myers next discusses the clinical previous articles he has written for Continuum that I
features, EEG findings, and management have asked him to provide as an ongoing resource for
considerations of the growing list of genetic epilepsy our readers. Drs George W. Culler IV and Barbara C.
syndromes. Drs Lisa Gillinder and Jeffrey Britton Jobst then provide a state-of-the-art review of the
then discuss the most current clinical, diagnostic, and various current surgical options available for
management issues related to the increasingly treatment of epilepsy and when they should be
recognized autoimmune-associated seizures and considered. In the final article in this issue, Drs Eugen
clarify the most current definitions of the terms Trinka and Markus Leitinger provide a detailed and
autoimmune-associated epilepsy and acute symptomatic highly illustrated review of the current definitions,
seizures secondary to autoimmune encephalitis. diagnosis, and management of status epilepticus,
Dr Esther Bui then discusses women’s issues in refractory status epilepticus, and super-refractory
epilepsy, including issues related to hormonal status epilepticus.
influences, pregnancy and the postpartum state, After reading the issue and taking the Postreading
menopause, and bone health. Next, Drs Maria Gogou Self-Assessment and CME Test written by
and Judith Helen Cross provide a detailed discussion Drs Douglas J. Gelb and James W. M. Owens Jr, and
of the diagnosis and management of seizures and edited by Dr Joseph E. Safdieh, Associate Editor and
epilepsy in childhood, including the clinical features Associate Editor of Self-Assessment and CME,
and diagnosis of the many syndromes presenting readers may earn up to 20 AMA PRA Category 1
in this age group and the various appropriate CreditsTM toward self-assessment CME or, for
therapeutic options that can be individualized for Canadian participants, a maximum of 20 hours
228 APRIL 2022

toward the Self-Assessment Program (Section 3) of Audio of each article read aloud is available for this
the Maintenance of Certification Program of the issue. Different from Continuum Audio, these are
Royal College of Physicians and Surgeons of Canada. recordings read verbatim from the print articles by
Additional credit can be obtained by listening to Dr Michael Kentris, a neurologist at the Clinical
Continuum Audio interviews associated with this and Neuroscience Institute in Dayton, Ohio. The audio
other Continuum issues, available to all subscribers, files are available to all Continuum subscribers in the
and completing tests on the Continuum Audio web AAN’s Online Learning Center at continpub.com/
platform or mobile app. Continuum Audio is also CME. I encourage you to listen and submit the survey
accredited by the Royal College of Physicians and with your feedback.
Surgeons of Canada. I would like to provide my deepest thanks to Dr
Jetté for her remarkable attention to every detail
throughout the creation and production of this issue
and to all the internationally renowned expert
authors who have provided their expertise to inform
…I am thankful to Dr Nathalie Jetté and enhance our diagnosis, management, and
for accepting my invitation to serve counseling of our many patients with seizures
and epilepsy.
as guest editor of this issue and for
—STEVEN L. LEWIS, MD, FAAN
assembling such renowned
EDITOR-IN-CHIEF
international experts to share their
expertise in epileptology with us. © 2022 American Academy of Neurology.
CONTINUUMJOURNAL.COM 229

REVIEW ARTICLE

Evaluation of First Seizure
CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
and Newly Diagnosed
Epilepsy
By Elaine Wirrell, MD, FRCP(C), FAAN
ABSTRACT
PURPOSE OF REVIEW: Thisarticle focuses on the evaluation of children and
adults who present with new-onset seizures, with an emphasis on
differential diagnosis, classification, evaluation, and management.
RECENT FINDINGS: New-onset seizures are a common presentation in neurologic

practice, affecting approximately 8% to 10% of the population. Accurate
diagnosis relies on a careful history to exclude nonepileptic paroxysmal
events. A new classification system was accepted in 2017 by the International
League Against Epilepsy, which evaluates seizure type(s), epilepsy type,
epilepsy syndrome, etiology, and comorbidities. Accurate classification
informs the choice of investigations, treatment, and prognosis. Guidelines for
neuroimaging and laboratory and genetic testing are summarized.
SUMMARY: Accurate diagnosis and classification of first seizures and

new-onset epilepsy are key to choosing optimal therapy to maximize
CITE AS: seizure control and minimize comorbidities.
CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):230–260.
Address correspondence to INTRODUCTION
A
Dr Elaine Wirrell, Mayo Clinic, 200 pproximately 8% to 10% of the population will experience a seizure,
First St SW, Rochester MN 55905,
wirrell.elaine@mayo.edu. and approximately 1 in 26 people will develop epilepsy in their
lifetime, making seizures one of the most common neurologic
RELATIONSHIP DISCLOSURE:
Dr Wirrell has received personal
problems. The epilepsies are a diverse group of conditions that
compensation in the range of share a predisposition to recurrent, unprovoked seizures. In
$500 to $4999 for serving as a addition to seizures, the majority of patients have cognitive, psychiatric, or
Consultant for BioMarin and Eisai
Co, Ltd, and for serving on a
medical comorbidities, which must be appropriately diagnosed and treated.
scientific advisory or data safety Correctly identifying the epilepsy type and syndrome, as well as the underlying
monitoring board for Amicus etiology, is critical for choosing cost-effective, yet high-yield investigations,
Therapeutics, Inc, Encoded
Therapeutics, Inc, and optimizing therapy, and understanding long-term prognosis.
Neurocrine Biosciences, Inc, and
has received publishing royalties
What Is a Seizure?
from UpToDate, Inc.
An epileptic seizure was defined by the International League Against Epilepsy
UNLABELED USE OF (ILAE) as “a transient occurrence of signs and/or symptoms due to abnormal
P R O D U C T S/ I N V E S T I G A T I O N A L
USE DISCLOSURE:
excessive or synchronous neuronal activity in the brain.”1
Dr Wirrell reports no disclosure.
What Is Epilepsy?
© 2022 American Academy Epilepsy was defined in 2005 as “a disorder of the brain characterized by an
of Neurology. enduring predisposition to generate epileptic seizures and by the neurobiologic,
230 APRIL 2022

cognitive, psychological, and social consequences of this condition.”1 In 2014, the KEY POINT
ILAE proposed a practical clinical definition for epilepsy that included any of the
● Epilepsy is defined as any
following: (1) at least two unprovoked (or reflex) seizures occurring more than of the following: (1) at least
24 hours apart, (2) one unprovoked (or reflex) seizure and a probability of two unprovoked (or reflex)
further seizures similar to the general recurrence risk (at least 60%) after two seizures occurring more
unprovoked seizures, occurring over the next 10 years, or (3) diagnosis of an than 24 hours apart, (2) one
unprovoked (or reflex)
epilepsy syndrome.2
seizure and a probability of
further seizures similar to
APPROACH TO DIAGNOSIS the general recurrence risk
A careful clinical history taken from both the patient as well as any witnesses to (at least 60%) after two
unprovoked seizures,
the clinical event(s) is the most critical aspect of making an accurate diagnosis.
occurring over the next
The questions that follow must be answered. 10 years, or (3) diagnosis of
an epilepsy syndrome.
Is This a Seizure or a Nonepileptic Event?
Multiple, nonepileptic paroxysmal events can mimic seizures, and thus, a careful
clinical assessment is required to reach an accurate diagnosis. Some of these
epilepsy mimics require prompt diagnosis to prevent adverse outcomes (ie,
prolonged QT syndrome). The patient should be asked to describe the event
from onset, including any auras or postictal symptoms. A history of
incontinence, tongue biting, or carpet burn is more suggestive of a seizure.
Terminology should be clarified; for example, the term dizziness may reflect
lightheadedness or vertigo, and an abnormal sensation in the abdomen could
reflect either nausea or an abnormal rising sensation. The physician should ask
about what the patient was doing at the onset, as well as possible triggers,
intercurrent illnesses, or medications. It is immensely helpful to speak directly to
the witness of the clinical event also, and this can be done by phone while the
patient is in the office. Observers should be asked about skin color change, motor
findings (ie, was the patient abnormally limp or stiff ), types of abnormal
movement (ie, rhythmic clonic versus irregular shaking), response to voice or
touch during the event, and any postictal confusion, sleepiness, focal weakness,
or language difficulties. If the diagnosis is suggestive of a generalized tonic-clonic
seizure, one should ask carefully about any focal features (ie, deviation of the
eyes or head) or confusion before onset. A thorough physical examination done
immediately after the seizure may show evidence of lateral tongue bites, bruises,
or other injury due to a fall or convulsive activity, and transient neurologic signs
or focal weakness suggestive of a Todd paralysis, which may provide important
information on the likely seizure localization.
Studies carried out in multiple settings have reported misdiagnosis rates
ranging from 4.6% to 30%.3 In adults, the misdiagnosis rate was higher for
patients diagnosed by nonspecialists than neurologists (19.3% versus 5.6%),4 and
the most common final diagnoses in misdiagnosed patients are cardiovascular
syncope and psychogenic nonepileptic events. Approximately 24% of children
referred with a first seizure were found to have had a nonepileptic event,5 and in
one study, 39% of children who were admitted to a tertiary epilepsy center were
found to not have epilepsy.6 Common final diagnoses in children included
nonepileptic staring spells (eg, daydreaming), psychogenic nonepileptic events,
syncope, parasomnias, and breath-holding spells. In many cases, incomplete
history taking and overinterpretation of the EEG contribute to misdiagnosis.
Common seizure mimics, typical ages at their presentation, and clinical
characteristics are listed in TABLE 1-1.

EVALUATION OF FIRST SEIZURE AND NEWLY DIAGNOSED EPILEPSY
TABLE 1-1 Common Seizure Mimics
Epilepsy mimic Clinical clues
Neonates/early infancy
Benign sleep myoclonus Myoclonus of one or more limbs or face, occurring in brief clusters lasting <3-5 seconds with
pauses of variable duration
Occurs in sleep only and abolished on waking
Otherwise normal infant
Jitteriness Affects one or more limbs, often switching sides from event to event
Often spreads in nonanatomic pattern
Increased when the infant is stimulated, startled, or crying but is suppressed when the infant is
wrapped or the affected limb is gently restrained
Infants/early childhood
Benign myoclonus of Brief jerking of one or more limbs, lasting <5 seconds each, without altered awareness
infancy
Occurs in both wakefulness and sleep
Shuddering attacks Brief stiffening with shivering-like movement, without altered awareness
Often provoked by excitement or frustration
Breath-holding spells, Triggered by pain, crying, fright

cyanotic or pallid
Child usually cries (crying may be absent with pallid breath-holding), holds their breath at the
end of expiration, then becomes briefly tonic
Associated color change (cyanotic or pallid)
Sandifer syndrome Back-arching, dystonic posturing of the limbs, and turning/tilting of the head
May be provoked by feeding and lying flat and may be alleviated with sitting up
Often seen in neurologically abnormal children
Caused by gastroesophageal reflux
Spasmus nutans Rapid eye movements, with head-tilt and nodding, but with retained awareness
Hyperekplexia Infants are hypertonic but not spastic
Excessive startle is seen with noise or touch, with flexion of limbs and neck retraction; this at
times can be associated with apnea and cyanosis
CONTINUED ON PAGE 233
232 APRIL 2022

CONTINUED FROM PAGE 232
Childhood
Stereotypies Mannerisms that may be simple (such as body-rocking, head-banging) or complex (such as
finger movements or wrist flexion/extension); these are interrupted by tactile, and at times
verbal, stimulation
May occur in normal individuals but are seen more commonly in those with autism or
intellectual disability
Self-stimulatory behavior Rhythmic hip flexion and adduction with leg-crossing, often accompanied by a distant
expression
Can be interrupted, although child may be irritable if interrupted
Benign paroxysmal vertigo Abrupt onset of anxiety, feeling off balance; child often grasps onto parent
May have associated nystagmus
Cyclic vomiting Paroxysmal events of recurrent emesis that may last hours and be interspersed with symptom-
free periods of weeks to months
Daydreaming Staring off, more likely to occur when engaged in quiet activity such as schoolwork
Can be interrupted with tactile stimulation
Parasomnias Night terrors, sleepwalking, and confusional arousals are behaviors that arise out of deep
non–rapid eye movement (REM) sleep most commonly in the first few hours after falling
asleep; they typically last >3-5 minutes and occur intermittently
These must be distinguished from nocturnal frontal lobe seizures, which are brief (typically
<2 minutes), very frequent (multiple per night), and occur throughout the night
Sleep-related rhythmic Body-rocking, rolling, or head-banging during sleep that resolve when the child awakens
movement disorders
Childhood to adulthood
Tantrums/rage attacks Tantrums are primarily seen in young children and involve relatively brief periods of behavioral
dyscontrol in response to a stimulus; consciousness is not impaired
Rage reactions occur predominantly in older children and teens and, although triggered by
minor stimuli, are characteristically out of proportion; patients are often aggressive during
these periods, which can last for ≥30 minutes
Tics Involuntary, sudden, rapid, repetitive, nonrhythmic, simple, or complex movements or

vocalizations that often occur multiple times per day
These are interruptible and can be suppressed, albeit often for only a matter of seconds
Tics abate during sleep
REM sleep disorders Abnormal motor activity typically in the later third of sleep when the individual acts out
their dreams
The individual can recall the event
The events are not as stereotypic as seizures

Periodic leg movements Repetitive stereotyped flexion of toes, ankles, knees, and hips
in sleep
Resolve with waking
Postural orthostatic Episodic periods of lightheadedness, chest pain, blurred vision, abdominal pain
tachycardia syndrome
(POTS) or orthostatic Comes on with standing and resolves with sitting/lying down
intolerance
Panic attacks Brief episodes, lasting minutes only with sudden feeling of impending doom, accompanied by
shortness of breath, choking sensation, palpitations, chest pain, paresthesia, dizziness,
sweating, trembling, and feeling faint
Patient is very frightened but aware
No postictal sleepiness/confusion
Narcolepsy/cataplexy Excessive daytime sleepiness, cataplexy (loss of tone in response to strong emotion),
hypnagogic hallucinations, and sleep paralysis
Migraine with aura Most common aura is visual, typically in one visual field, and is characteristically a scintillating
scotoma, which is then followed by a migraine headache
Visual phenomena with occipital seizures are more commonly colored and of various shapes
Hemiplegic migraine Aura of focal weakness with or without speech disturbance; visual symptom and paresthesia
onset before typical migrainelike headache
Often family history is positive
Psychogenic Two main symptomatologies: (1) unresponsive periods without motor phenomena or (2) motor
nonepileptic spells phenomena with bizarre, irregular jerking and thrashing
Often prolonged >15-30 minutes
Often minimal postictal phase
Frequent and refractory from onset
Paroxysmal kinesiogenic Brief (<1 minute) attacks of abnormal movement, triggered by a sudden voluntary movement
dyskinesia
The movements are most commonly dystonic but may be choreiform
Affects limbs on one or both sides
No altered awareness
Family history may be present
Episodic ataxia Autosomal dominant
Brief episodes of cerebellar ataxia triggered by sudden movement, emotion, or illness
May have associated dysarthria, nystagmus, titubation, and nausea
234 APRIL 2022

Adults
Transient ischemic Sudden onset of focal neurologic symptoms that typically reflect loss of function (ie, paresis,
attacks speech problems, etc), which then resolve completely within 24 hours, and usually within
30-60 minutes
Seizures more commonly present with positive symptoms due to an excess of neuronal
discharge (visual: flashing lights, zigzag shapes, lines, shapes, objects; somatosensory: pain,
paresthesia, or motor features, eg, clonic activity); transient ischemic attacks most commonly
involve loss or reduction of neuronal function (eg, loss of vision, hearing, sensation,
or limb power)
Any age
Vasovagal syncope Typically triggered by prolonged standing, dehydration, change in posture, warm environment,
or emotional upset (ie, blood draw)
Preceded by lightheadedness, blurred vision, ringing in the ears, pallor, diaphoresis, abdominal
discomfort
Loss of tone, which may be followed by brief myoclonic jerks or tonic posturing
Rapid return to awareness but lightheadedness may remain for a brief period thereafter
Cardiac syncope–long Sudden loss of consciousness with pallor, atonia, or tonic posturing
QT
Often triggered by fright, exercise, surprise, and immersion in water
Family history of syncope may be present
Neurogenic syncope Headache and sensory symptoms associated with collapse

(Chiari malformation,
colloid cyst of the third Exacerbated by straining
ventricle)

CASE 1-1 illustrates the importance of relying on a careful history and avoiding
overinterpretation of EEG.
In some cases, confident differentiation of a seizure from a nonepileptic event
may not be possible as specific historical details may be lacking. In the absence of
other compelling data, careful follow-up to clarify the diagnosis before initiation
of antiseizure medication is recommended.
If a Seizure, Is This Provoked or an Acute Symptomatic Seizure Versus an

Unprovoked Seizure?
Provoked seizures are due to identifiable causes such as toxins, drugs, or
metabolic factors. Most people with provoked seizures have a history of
confusion or behavior change that precedes the seizure and often persists beyond
the typical postictal phase. Additionally, provoked seizures are usually
generalized convulsive events, as opposed to focal seizures. Details of use or
abrupt cessation of any prescription medication or drug of abuse, including
alcohol, should be queried. Abrupt withdrawal of benzodiazepines, barbiturates,
or alcohol may lead to seizures. Young children may accidentally ingest
medications or toxins in the home, and thus, a careful inventory of all such
agents in the home is critical. Details of any chronic medical condition that could
lead to metabolic disturbances, such as diabetes or kidney disease, should be
sought. Careful assessment of vital signs and other clinical findings may point to
a specific toxidrome. Laboratory screening including serum glucose, electrolytes,
renal and liver function, and urine toxicology should be considered as patients
with provoked seizures may require urgent therapy to address the underlying
cause and prevent further brain injury (eg, hypoglycemia). In most cases of
provoked seizures, prophylactic antiseizure medication is not required. The basic
mechanisms by which toxins lead to provoked seizures are (1) increased
excitation, (2) decreased inhibition, or (3) withdrawal of central nervous system
depressants,7 and these categories are outlined in TABLE 1-2.
Acute symptomatic seizures result from an acute brain process such as
encephalitis, stroke, or traumatic brain injury. The history and physical
examination often provide important clues to the underlying diagnosis, and these
patients typically present with other neurologic findings consistent with their
brain injury, such as focal deficits and abnormal vital signs including fever.
Seizure symptomatology often reflects the location of the acute brain process,
and seizures usually are focal in onset. With acute symptomatic seizures, specific
treatment targeted to the underlying brain process may be required; however,
patients may additionally need short-term antiseizure medication
If This Is an Unprovoked Seizure, Does This Person Have Epilepsy?

Several studies have shown that a significant minority of patients presenting
with an alleged first, unprovoked seizure have actually experienced prior
seizures. It is typically the first convulsive seizure that brings the patient to
medical attention, whereas other seizures including absence, myoclonic, or
focal seizures without motor manifestations may have previously occurred but
have not been recognized. Correctly identifying these events is critical to making
a correct diagnosis of epilepsy. Thus, patients and their families should be
carefully questioned about any episodes of unresponsive staring, isolated quick
body jerks, and symptoms of nocturnal seizures such as unexplained tongue
biting or incontinence. Confirming a diagnosis of epilepsy as opposed to a single
236 APRIL 2022

seizure may have implications for the initiation of prophylactic KEY POINTS
antiseizure medication.
● A careful history taken
CASE 1-2 illustrates how the EEG can sometimes confirm a diagnosis of
from both the patient as
epilepsy, as opposed to a single unprovoked seizure, and thus alter well as any witnesses to the
recommendations for treatment. event(s) is the most critical
aspect in distinguishing a
seizure from a nonepileptic
If This Is Epilepsy, What Type Is This?
paroxysmal event.
The ILAE published a revised classification of seizure types (FIGURE 1-3) and
epilepsies (FIGURE 1-4) in 2017.8-10 These frameworks provide a mechanism to ● It is the first convulsive
understand the possible seizures patients have, what other seizure types they may seizure that typically brings
develop, potential triggers, underlying etiology, and prognosis. Furthermore, the patient to medical
attention. Many people
classification also informs the risk of important comorbidities, including learning presenting with a “first
disorders, intellectual disability, psychiatric disorders, and mortality. seizure” have a history of
prior seizures, which may
SEIZURE TYPE. The first level of classification is the seizure type, which is divided not have been recognized,
and thus have epilepsy.
into focal, generalized, and unknown onset. A generalized-onset seizure engages
bilateral brain networks from onset, whereas a focal seizure begins within one
region or hemisphere. Generalized-onset seizures are classified into motor or
nonmotor types, the latter comprising various subtypes of absence seizures.
Focal seizures are subdivided based on awareness (aware versus impaired
awareness) and motor symptoms (motor: tonic, clonic, atonic, or myoclonic
activity; nonmotor: behavior arrest, cognitive, emotional, sensory, or autonomic
features). Importantly, a focal seizure may evolve to bilateral convulsive activity,
and thus, one must carefully probe for auras or other focal features that preceded
a generalized tonic-clonic seizure.
Both focal impaired-awareness seizures, as well as absence seizures, may
present with staring spells. Important distinguishing features between these
seizure types are shown in TABLE 1-3.
EPILEPSY TYPE. The second level of classification focuses on epilepsy type, which is
based on the type(s) of seizures the patient is having. Epilepsy types are divided
into generalized, focal, combined generalized and focal, or unknown. A diagnosis of
generalized epilepsy would be made in a patient who has one or more types of
generalized seizures, which would include tonic, tonic-clonic, absence,
myoclonic, or atonic as well as generalized spike-and-wave discharge on EEG.
One needs to be cautious with a patient with a generalized tonic-clonic seizure
and normal EEG as it is unclear if that seizure was truly generalized in onset or
evolved to a bilateral tonic-clonic seizure.
Conversely, a diagnosis of focal epilepsy would be made if a patient has had one
or more types of focal-onset seizures, which could include focal to bilateral tonic-
clonic seizures. In most cases of focal epilepsy, the interictal EEG will show focal
epileptiform discharge; however, this EEG finding is not required to make a
diagnosis of focal epilepsy.
Less commonly but importantly, there are some patients who have both
generalized and focal seizures who have generalized and focal epilepsy. This
subgroup is most common in some of the early-onset, drug-resistant epilepsies
such as Lennox-Gastaut syndrome or Dravet syndrome. These patients have a
history of both generalized and focal seizure types, and their interictal EEG may
show both generalized and focal discharges; however, epileptiform activity is not
required for this diagnosis and is made on clinical grounds.

CASE 1-1 A 13-year-old girl presented with recurrent spells of lightheadedness

without vertigo. These occurred more commonly when she stood up too
quickly. She had two more severe events, one during a discussion on frog
dissection in biology class and another while she was getting her blood
drawn. Her examination was normal.
Her EEG was interpreted as showing independent bitemporal sharp
waves in drowsiness and sleep. She was diagnosed with focal epilepsy
and was started on oxcarbazepine. Her lightheadedness persisted, and
she had two more spells; one was just before a subsequent EEG when the
EEG technician was rubbing the girl’s head, and the other was after she
skinned her knee. During these spells, she was said to feel “woozy,” look
pale, and drop slowly to the ground. She lost consciousness and
remained limp for about 30 seconds, then gradually recovered over about
2 to 5 minutes.
She underwent video-EEG monitoring, during which time the EEG
technician rubbed the girl’s head to induce her spell. The EEG (FIGURE 1-1)
was found to be consistent with syncope, due to a cardiac cause, as
opposed to seizure. Careful review of her initial EEG showed 14 and 6
positive spikes as opposed to bitemporal sharp waves, which are a
normal variant and not epileptiform.
COMMENT This case exemplifies that a careful history taken from both the patient as
well as any witness to the event is the most critical aspect in distinguishing
a seizure from a nonepileptic paroxysmal event. A diagnosis of epilepsy
cannot be made solely by relying on EEG findings.
238 APRIL 2022

FIGURE 1-1
Successive EEG tracings of the events of the patient in CASE 1-1. Note the ECG lead in red at
the bottom of the recording. There is artifact at P4. Initially, sinus bradycardia can be
seen (A), followed by asystole (B), and then resumption of heart rate (C). The initial EEG
change is diffuse delta slowing, which occurs after 8 seconds of asystole, and is caused by
a lack of brain perfusion. This is followed by overall suppression of activity, which reverts
to diffuse slowing once the heart rate is again restored.

The term unknown is used if information is inadequate to determine the

epilepsy type.
EPILEPSY SYNDROME. An epilepsy syndrome is a characteristic cluster of clinical

and EEG features that may be supported by specific etiologic findings.
Syndromes often have age-dependent presentations and specific comorbidities.
Many carry important implications for the choice of specific therapy and
prognosis, and we are seeing an increased focus on drug trials in
defined syndromes.
The ILAE has convened a task force to provide definitions for the various
syndromes, and their educational website provides an excellent resource for the
diagnosis of epilepsy syndromes.11 An epilepsy syndrome is identifiable in
approximately one-quarter of epilepsy cases beginning in infants and children
but is less frequent in adult-onset epilepsy. TABLE 1-4 provides an overview of
some of the more common epilepsy syndromes, along with their clinical and EEG
features and long-term prognosis.
The 2017 classification defined the term developmental and epileptic
encephalopathy to describe epilepsies that are associated with underlying
encephalopathy, where both the underlying etiology (developmental) and the
TABLE 1-2 Categories of Toxins Causing Provoked Seizures
Category Mechanism Other clinical findings Examples

Increased excitation
Stimulants Increased release of dopamine, Anxiety, delusions, delirium, Cocaine

serotonin, norepinephrine, and/or diaphoresis, hypertension,
epinephrine or blocking their tachycardia, hyperthermia, Amphetamines
reuptake hyperreflexia, mydriasis,
Phenethylamines
piloerection
Bath salts
ECG monitoring should be
considered for QRS and QTc Serotonergic agents
prolongation and arrhythmias
Bupropion
Venlafaxine
Synthetic cannabinoids
Phencyclidine
Cholinergic Binding of nicotinic or muscarinic DUMBBELS (defecation, Organophosphates

agents receptors or inhibiting urination, miosis, bradycardia,
acetylcholinesterase bronchospasm, emesis, Nicotine
lacrimation, and salivation)
Nerve gases (sarin and VX)
Glutamate Binding of N-methyl-D-aspartate Somnolence, hallucinations, Domoic acid (shellfish poisoning)

agonists (NMDA), α-amino-3-hydroxy-5- delirium, nausea and vomiting,
methyl-4-isoxazole propionic acid diarrhea, salivation Amanita muscaria mushroom
(AMPA), or kainate receptors ingestion
240 APRIL 2022

frequent seizures and epileptiform discharges (epileptic) are felt to contribute to
the encephalopathy.10 Although this term can be applied to people at any age, the
developmental and epileptic encephalopathies most commonly have an onset
early in life. Developmental and epileptic encephalopathies can be defined by
epilepsy syndrome (ie, infantile epileptic spasms syndrome, Dravet syndrome,
Lennox-Gastaut syndrome) or by etiology. In most cases, developmental and
epileptic encephalopathies are correlated with a high risk of lifelong, drug-
resistant seizures, variable degrees of intellectual disability (often severe), and
multiple other medical and behavioral comorbidities.
The idiopathic generalized epilepsies collectively account for approximately
15% to 20% of all epilepsies and are made up of four syndromes: childhood
absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and
generalized tonic-clonic seizures alone, with juvenile myoclonic epilepsy being
the most prevalent among this group. These epilepsies typically affect
developmentally normal children and young adults and present with varied types
of generalized seizures. The main seizure type(s) and typical age at presentation
vary among the syndromes. In many cases, complete seizure control may be
achieved with medication, and in childhood absence epilepsy, remission often
occurs by adolescence.
Category Mechanism Other clinical findings Examples
Increased excitation or withdrawal of central nervous system (CNS) depressants
γ-Aminobutyric Blockage of GABA-ergic neurons or Tremor, tachycardia, Tramadol

acid (GABA) abrupt withdrawal of CNS hypertension, diaphoresis,
antagonists depressants nausea, anxiety, irritability, Antibiotics: isoniazid (depletes
insomnia, hallucinations pyridoxine, which inhibits GABA
synthesis from glutamate),
penicillin, cephalosporins,
carbapenems, fluoroquinolones
Abrupt withdrawal of GABA-

ergic agents such as alcohol,
benzodiazepines, baclofen,
barbiturates
Antidepressants and
antipsychotics including tricyclic
antidepressants, selective
serotonin reuptake inhibitors
(SSRIs), phenothiazines
Decreased CNS inhibition
Histamine Antagonism at histamine receptors Confusion, ataxia, Histamine antagonists including

antagonists hallucinations, delirium, dry diphenhydramine, doxylamine,
mucous membranes, mydriasis hydroxyzine, chlorpheniramine
Adenosine Antagonism of adenosine Cardiac dysrhythmias Theophylline, caffeine

antagonists
ECG = electrocardiogram.

CASE 1-2 A 19-year-old woman presented with her first generalized convulsive
seizure. She had been up late the night before and had a 3-minute
generalized tonic-clonic seizure, which was witnessed by her roommate,
approximately 10 minutes after getting up for work the next day. She
denied any aura. During the seizure, she lost bladder continence and bit
the side of her tongue. Her examination 2 hours after the seizure was
unremarkable, and her basic metabolic panel was normal.
Her paternal aunt had epilepsy as a young adult, which was well
controlled with medication.
On EEG (FIGURE 1-2), she was found to have generalized polyspike-and-
wave discharge and had several myoclonic jerks with clinical correlate
occurring spontaneously as well as with photic stimulation.
She admitted to episodes of hand-twitching in the morning that caused
her to spill her tea but had attributed that to nervousness. Based on the
history and EEG, she was diagnosed with juvenile myoclonic epilepsy, and
antiseizure medication was initiated.
FIGURE 1-2
Routine EEG (bipolar montage, 15 μV/mm) of the patient in CASE 1-2 shows a generalized
polyspike-and-wave discharge which correlates with a witnessed myoclonic jerk. This
example occurred spontaneously; however, these were also triggered with photic
stimulation.
COMMENT This case emphasizes that it is the first convulsive seizure that typically
brings the patient to medical attention. Many patients presenting with a
“first seizure” have a history of prior seizures that may not have been
recognized and, thus, have epilepsy. In this case, the patient described
hand-twitching in the morning, which was consistent with early-morning
myoclonus.
242 APRIL 2022

KEY POINT
● A diagnosis of an
epilepsy syndrome is
possible in approximately
one-quarter of epilepsy
cases beginning in infancy
and childhood but is less
frequently found in adults.
Diagnosis of a specific
syndrome provides key
information to assist with
choosing optimal
investigations and
treatment and for
providing accurate
prognosis.
FIGURE 1-3
Classification of seizure types by the International League Against Epilepsy (ILAE).
a
These could be focal or generalized, with or without alteration of awareness.
b
Because of inadequate information or inability to place in other categories.
Reprinted with permission from Fisher RS, et al, Epilepsia.8 © 2017 International League Against Epilepsy.
Another important syndrome group is the self-limited focal epilepsies of

childhood, which comprise self-limited neonatal epilepsy, self-limited infantile
epilepsy, self-limited epilepsy with autonomic seizures, and self-limited
epilepsy with centrotemporal spikes. Depending on the syndrome, seizures have
an onset anywhere from the neonatal period through late childhood but remit
with time.
CASE 1-3 illustrates how defining the epilepsy syndrome can help choose cost-
effective investigations and therapies and provide an accurate prognosis.
What Is the Etiology?

One of the main questions people with new-onset seizures have is “What has
caused this?” The range of possible etiologies for seizures is diverse, and a careful
investigation to determine the underlying cause is needed.
The causes of epilepsy are defined in the six following groups.
STRUCTURAL. Epilepsy is said to have a structural cause if a structural brain

change is present that results in epilepsy. Structural causes may be
developmental abnormalities, such as focal cortical dysplasia or polymicrogyria,
or acquired brain processes, such as infection, stroke, trauma, or tumor. In most
cases, structural abnormalities will be visible on MRI but may require specific
epilepsy protocols.

FIGURE 1-4
Classification of the epilepsies by the International League Against Epilepsy.
Reprinted with permission from Scheffer IE, et al, Epilepsia.10 © 2017 International League Against Epilepsy.
TABLE 1-3 Distinguishing Features Between Focal Impaired Awareness and Absence
Seizures
Focal impaired awareness Absence
Frequency (in Typically less than daily to monthly Often daily or more
untreated patients)
Duration Usually minutes Usually <10-30 seconds
Postictal state Usually present with confusion and possible Absent

language dysfunction if affects dominant
temporal lobe
Other possible Often contralateral head or eye deviation, May have bilateral oral or manual automatisms with
clinical features contralateral dystonic posturing with more prolonged absence seizures
ipsilateral automatisms
Interictal EEG in Normal, focal slowing, or focal discharges Usually see generalized spike-and-wave discharge on
untreated patients routine EEG, which may activate with hyperventilation
or photic stimulation
Other associated May evolve to bilateral tonic-clonic seizure May have associated myoclonic or generalized tonic-
seizure types clonic seizures
244 APRIL 2022

GENETIC. Epilepsy is considered genetic if it is caused by a known or presumed KEY POINTS
genetic variant. In some cases of genetic epilepsy, a clear pathogenic variant
● Genetic causes of
in a single gene can be identified, such as KCNQ2, CDKL5, or STXBP1. These epilepsy are increasingly
single-gene disorders are often, but not always, associated with drug-resistant, recognized. In some cases,
early-onset developmental and epileptic encephalopathies. Some of these genes such as the idiopathic
may lead to structural brain changes (ie, ARX, TSC1, or TSC2) whereas others generalized epilepsies,
inheritance is polygenic, and
can result in metabolic alterations that contribute to seizures (ie, SLC2A1
pathogenic variants are
or ALDH7A1). typically not found on gene
Another large group of genetic epilepsies includes the idiopathic generalized panels. In other cases,
epilepsies. In these conditions, family studies have documented a strong particularly in early-onset
developmental epileptic
genetic predisposition, although a single causal gene is typically not found.
encephalopathies,
Rather, the underlying etiology is felt to be polygenic, with or without inheritance is monogenic,
environmental factors. and pathogenic variants are
identified on epilepsy gene
INFECTIOUS. Infectious etiologies are the most common worldwide cause of panels or whole-exome
sequencing.
epilepsy but are more prevalent in developing nations. An infectious etiology
implies that epilepsy and seizures are core symptoms of the disorder, and ● Increasingly, specific
examples include neurocysticercosis, human immunodeficiency virus (HIV), antibodies are being
cerebral malaria, or congenital infections such as Zika virus or cytomegalovirus. detected in people with
autoimmune encephalitis
Infectious etiology should not be used to describe acute symptomatic seizures that that result in acute
occur during brain infection, such as encephalitis or meningitis. symptomatic seizures.
These should be
METABOLIC. A metabolic etiology implies that epilepsy and seizures are the result distinguished from immune-
mediated epilepsies in
of biochemical changes that result from a known metabolic disorder. Some
which an enduring
metabolic disorders are critical to identify early because they have a specific predisposition to seizures is
therapy that will stop seizures and often prevent further developmental decline. present.
Examples are glucose transporter disorder, which is treatable with a ketogenic
diet, or a disorder of creatine metabolism, which is often treatable with high-dose ● Despite advances in
neuroimaging and genetics,
supplemental creatine. Many metabolic disorders also have an underlying approximately 40% of
genetic etiology. people with new-onset
epilepsy have no known
IMMUNE. An immune epilepsy implies that epilepsy directly results from the etiology found.
underlying immune disorder. A recent report by the ILAE Autoimmune and
Inflammation Task Force distinguishes immune-mediated epilepsy, where an
enduring predisposition to seizures is present, from acute symptomatic seizures
secondary to autoimmune encephalitis.12 Examples of immune epilepsy include
Rasmussen syndrome or glutamic acid decarboxylase 65 (GAD65)-associated
epilepsy.
UNKNOWN. The more extensive the investigations, the more likely a cause is to be
found. However, even after exhaustive investigations, no clear etiology can be
found in approximately one-third to one-half of patients with new-onset
unprovoked seizures.13,14
Some causes will fit into more than one etiologic category, and these should be
combined if needed. For example, tuberous sclerosis complex results in
structural brain changes leading to epilepsy but is caused by a pathogenic variant
in TSC1 or TSC2. Thus, it would be considered to have a structural-genetic
etiology. Glucose transporter deficiency results in hypoglycorrhachia but, in
most cases, is caused by a pathogenic variant of SLC2A1 and, thus, should be
considered to have genetic-metabolic etiology.

TABLE 1-4 Common Epilepsy Syndromes
Usual age Common

Syndrome at onset Seizure type(s) Interictal EEG comorbidities Prognosis
Focal epilepsy syndromes
Self-limited First month of Focal clonic or tonic Usually normal None Epilepsy remits by
neonatal epilepsy life, most in seizures which may 6 months with
first week evolve to bilateral normal
tonic-clonic development
Self-limited 3-20 months Focal impaired Usually normal Usually none; Most remit by
infantile epilepsy awareness or focal cases due to early preschool
clonic seizures, which PRRT2 variants years with normal
may evolve to may develop a development
bilateral tonic-clonic movement
disorder
Self-limited 2-9 years Focal autonomic High-amplitude None Remission by later

epilepsy with seizures (often focal or multifocal childhood
autonomic retching or vomiting) discharges that
seizures with or without increase in sleep
(Panayiotopoulos impaired awareness
syndrome)
Self-limited 3-12 years Focal seizures with High-amplitude None Remission by early
epilepsy with dysarthria, sialorrhea, centrotemporal adolescence
centrotemporal and unilateral tonic or discharges that
spikes clonic movement of increase in sleep;
the lower face; may normal background
evolve to bilateral
tonic-clonic seizures
in sleep
Sleep-related Childhood Focal motor seizures Often normal but Often none but Often drug-
hypermotor and with hyperkinetic or frontal discharges may have responsive;
epilepsy adolescence asymmetric tonic or may be seen mostly cognitive and surgery may be an
dystonic features, in sleep attentional option if drug-
occurring problems due to resistant
predominantly in disrupted sleep
sleep
Mesial temporal 2 years Focal aware or Often focal slowing Memory High incidence of
lobe epilepsy through impaired awareness or discharges in problems and drug resistance
with hippocampal adulthood seizures with features frontotemporal depression but may become
sclerosis referable to mesial leads seizure-free after
temporal lobe resective surgery
(autonomic: ie, rising or thermoablation
epigastric sensation;
cognitive: déjà vu or
jamais vu; emotional:
fear; or sensory
symptoms: olfactory
or gustatory)
246 APRIL 2022

Usual age Common

Generalized epilepsy syndromes
Childhood 3-10 years Typical absence Generalized 3-Hz Learning Two-thirds remit
absence seizures occurring spike-and-wave problems, typically by later
epilepsy multiple times per day discharge; most attention deficit childhood or
untreated patients hyperactivity adolescence; may
have a recorded disorder (ADHD) evolve to juvenile
seizure on EEG myoclonic
epilepsy if it does
not remit
Juvenile 8-19 years Typical absence Generalized 3-Hz Learning Often controlled
absence seizures; spike-and-wave problems, ADHD with antiseizure
epilepsy approximately 80% discharge; most medications, but
will also develop untreated patients remission is rare
generalized tonic- have a recorded
clonic seizures seizure on EEG
Juvenile Adolescence Myoclonic seizures; Generalized ADHD, Often controlled

myoclonic to young most also have polyspike-and-wave depression, with antiseizure
epilepsy adulthood generalized tonic- discharge, often anxiety medications, but
clonic seizures, and a activated with remission is rare
minority have brief photic stimulation
absence seizures
Epilepsy with Adolescence Generalized tonic- >3-Hz generalized ADHD, Often controlled
generalized to young clonic seizures only spike and wave or depression, with antiseizure
tonic-clonic adulthood polyspike and anxiety medications, but
seizures alone wave remission is rare
Epilepsy 2-14 years Eyelid myoclonia, 3- to 6-Hz Mild cognitive Eyelid myoclonia
with eyelid many patients also generalized delay, ADHD, is often drug-
myoclonia have typical absence polyspike or anxiety, resistant; remission
and generalized polyspike-and-slow- depression is possible but rare
tonic-clonic seizures wave, often
triggered by eye
closure or photic
stimulation
Myoclonic 2-12 years Myoclonic absence 3-Hz generalized Mild cognitive Remits in
absence seizures; generalized spike and wave delay, ADHD, approximately
epilepsy tonic-clonic seizures time-locked with anxiety, 40% of cases
may be seen in myoclonic jerks depression
some cases

Usual age Common

Focal and generalized epilepsy syndromes
Genetic epilepsy Childhood Autosomal dominant Usually normal but Usually none Usually remits
with febrile with incomplete may show with age
seizures plus penetrance; febrile generalized or focal
seizures, which may discharge
persist after 6 years,
other focal or
generalized seizures
Developmental and epileptic encephalopathies
Early infantile <3 months Tonic and/or Severely abnormal Moderate or Usually drug-
developmental myoclonic with diffuse slowing, greater resistant and
and epileptic multifocal intellectual lifelong
encephalopathy discharges, and/or disability,
burst suppression hypotonia
Gelastic seizures Usually in Gelastic seizures with Often normal Developmental Drug-resistant
with infancy or mirthless laughter delay and (unless treated
hypothalamic preschool behavior with surgery)
hamartoma years problems
common long-
term; may have
precocious
puberty
Infantile epileptic 1-24 months Clusters of epileptic Severely abnormal; High risk of High risk of
spasms spasms usually high- intellectual drug-resistant
syndrome amplitude disability epilepsy; may
background slowing evolve to focal/
with focal or multifocal epilepsy
multifocal discharge or Lennox-Gastaut
or hypsarhythmia syndrome
Dravet syndrome 1-20 months Often prolonged, Usually normal at Normal Drug-resistant
hemiconvulsive, or onset development at and lifelong
generalized tonic- onset, but with
clonic seizures with time all develop
fever intellectual
disability
248 APRIL 2022

Usual age Common

Epilepsy with Preschool Myoclonic-atonic Slow background Most are normal Two-thirds remit
myoclonic-atonic age seizures are with high-amplitude at onset, but but may have mild
seizures characteristic; other generalized spike cognitive and attention or
seizure types and wave attention cognitive
including generalized concerns can be concerns;
tonic-clonic, absence, seen and often 1/3 do not remit
myoclonic, atonic, and worsen during and often have
occasionally tonic periods of more more severe
seizures may also frequent learning and
occur seizures attention
problems
Lennox-Gastaut Mostly Tonic seizures;may Slow background Intellectual Drug-resistant and

syndrome preschool to also have other with high-amplitude, disability (often lifelong
school age; seizure types generalized slow moderate to
adolescent including generalized (<2.5 Hz) spike severe),
onset is rare tonic-clonic, and wave; behavior
myoclonic, atonic, generalized problems
atypical absence, or paroxysmal fast
focal seizures activity in sleep
Rasmussen Usually Focal/hemispheric Hemispheric Progressive Drug-resistant;

syndrome childhood seizures that increase background slowing hemispheric often seizures
in severity and and interictal dysfunction; resolve after
frequency with time discharge acquired hemispherotomy
and may culminate in hemiparesis,
epilepsia partialis visual field
continua deficit and
possible
language
deficits (if
dominant
hemisphere)
Developmental Late Usually focal motor, EEG shows Plateauing or Continuous spike
and/or epileptic preschool or which may evolve to significant activation regression in and wave in sleep
encephalopathy school age bilateral tonic-clonic of spike discharges cognition, typically resolves
with spike-and- seizures; some in sleep, with near behavior, or by adolescence;
wave activation patients may have continuous (usually motor function however,
in sleep other seizure types >50%) slow spike and with continuous depending on
and rarely, no seizures wave in slow sleep spike-and-wave etiology, seizures
may be seen pattern may persist
Progressive Any age Progressive Progressive Cognitive Progressive

myoclonus worsening of background slowing decline; decline with time;
epilepsies myoclonic seizures and/or increased progressive myoclonus is
with time; often epileptiform cerebellar signs drug-resistant
emergence of other discharges
seizure types
including generalized
tonic-clonic seizures

What Are the Associated Comorbidities?

The ILAE has recognized the importance of comorbidities in its core definition of
epilepsy as “a disorder of the brain characterized by an enduring predisposition to
generate epileptic seizures and by the neurobiologic, cognitive, psychological, and
social consequences of this condition.”1 Thus, management of people with epilepsy
must address cognitive and psychological comorbidities in addition to seizures. It is
increasingly recognized that such comorbidities are the rule, rather than the
exception, and they can have an even greater impact on quality of life than seizures.
Cognitive disorders are common and often precede seizure onset.15 Their
etiology is multifactorial and may include the underlying pathology that has led
to epilepsy, the impact of frequent seizures and epileptiform discharges, or
treatment-related effects (side effects of antiseizure medications or epilepsy
surgery). Furthermore, other neuropsychiatric disorders such as attention deficit
hyperactivity disorder and mood disorders are also more prevalent and often
precede seizure onset.16,17 These are critical to identify early, as they are treatable
and can significantly worsen cognitive function if left untreated.
FURTHER INVESTIGATIONS
The diagnosis of a first seizure and epilepsy is a clinical one in nearly all cases.
While the clinical history is the most critical piece of the puzzle, other
CASE 1-3 A 9-year-old boy, who was previously well, presented to the emergency
department with his first witnessed generalized tonic-clonic seizure that
occurred around 6:30 AM. His mother was getting ready for work and
heard a choking sound from her son’s room. She found him having a
generalized convulsive seizure that lasted approximately 3 minutes. He
had bitten his tongue. An ambulance was called, and he was taken to the
emergency department. His neurologic examination on arrival showed
paresis of the left arm and face, which rapidly resolved within 30 minutes.
Brain MRI was normal.
He had no significant medical history and was an excellent student. He
did admit to having two brief episodes over the past 6 months where he
woke up in the early morning and felt that he was drooling, his left mouth
was numb, and he could not speak clearly, although he was otherwise
alert. These resolved within 1 minute, and the family had attributed these
to a normal sleep variant.
His EEG in wakefulness showed occasional right centrotemporal
discharges; however, these became significantly more frequent in sleep
(FIGURE 1-5).
Based on the clinical history and EEG, he was diagnosed with self-
limited epilepsy with centrotemporal spikes. The family was reassured
that he would outgrow this seizure disorder, typically in the next 1 to
2 years. They were provided teaching on seizure safety and counseled on
the low risk of sudden unexpected death in epilepsy (SUDEP) and
associated cognitive concerns. They elected to withhold daily
medication. He had no further seizures over the subsequent 2 years and
continued to do well in school.
250 APRIL 2022

investigations may provide supportive data to confirm epilepsy or may yield
information on the underlying cause.
The American Academy of Neurology has developed an evidence-based
guideline for the management of a first seizure in adults18 and a practice
parameter for evaluating a first nonfebrile seizure in children.19
EEG
Studies have shown that between 18% and 56% of children and 12% and 50% of
adults presenting with new-onset seizures have an epileptiform abnormality
found on routine EEG.20 An EEG is recommended as part of the neurodiagnostic
evaluation in both children and adults with an apparent first unprovoked seizure
because it may impact management decisions.18,19
The diagnostic yield appears highest if the EEG can be done in the first
24 hours21; however, background findings such as focal slowing may be
seen transiently after a seizure as postictal phenomena and then resolve.
Thus, the presence of focal slowing in that time frame should not be assumed
to be due to an underlying structural change. Most studies have also shown
that the yield of EEG after a period of sleep deprivation is higher, particularly
for those with focal discharges. In patients presenting to the emergency
department with a first seizure who fully recover to neurologic baseline
FIGURE 1-5
Initial sleep EEG (30 μV/mm and 30 mm/s) from the patient in CASE 1-3 showing very frequent
right centrotemporal sharp waves, consistent with a diagnosis of self-limited epilepsy with
centrotemporal spikes.
This case illustrates how the accurate diagnosis of a specific syndrome COMMENT
provides key information to assist with choosing optimal investigations and
treatment and for providing accurate prognosis.

and are otherwise well, an EEG can typically be performed on an

outpatient basis.
Interpretation of EEG must be done in the context of the clinical history
because approximately 3% of people without epilepsy may show epileptiform
discharges, and thus, an abnormal EEG does not equate to epilepsy. Additionally,
caution must be taken to not overinterpret normal variants as pathogenic
(FIGURE 1-6).22 In young children, vertex sharp waves may appear spiky and lead
to misdiagnosis of central spikes, and hypnagogic hypersynchrony may be
misinterpreted as generalized spike and wave. In adolescents and adults, wicket
waves and rhythmic temporal theta of drowsiness are often miscalled as
FIGURE 1-6
Examples of normal EEG variants which are often misinterpreted as “epileptiform.” A, EEG
from a 4-year-old girl with a history of a single febrile seizure shows hypnagogic
hypersynchrony. B, EEG from an 11-year-old boy with a past history of childhood absence
epilepsy, now in remission, shows rhythmic temporal theta of drowsiness (also known as
rhythmic midtemporal theta of drowsiness) waveforms during light sleep, initially in the right
temporal (arrow) and later in the left temporal regions (arrowhead).
252 APRIL 2022

temporal epileptiform discharges. Thus, interpretation by a qualified KEY POINTS
electroencephalographer is key.
● Cognitive and psychiatric
Although it is relatively uncommon to detect clinical events during recording comorbidities are common
of routine EEG, both epileptic and nonepileptic events may be captured. In most in people with epilepsy and
laboratories, one channel is dedicated to ECG, which allows screening for often predate seizure onset.
potential cardiac arrhythmias. Psychogenic nonepileptic events may also be seen The causes are
multifactorial, but they are
on routine EEG; video recording during routine recordings can be helpful in
critical to diagnose and treat
appreciating their symptomatology. Activation parameters done during the as they often have an even
routine EEG typically involve both hyperventilation, which often triggers greater impact than seizures
absence seizures in those with untreated childhood or juvenile absence epilepsy, on quality of life.
and photic stimulation, which may trigger myoclonic seizures in someone with
● An EEG is indicated in all
juvenile myoclonic epilepsy. Detection of these more subtle seizure types often patients with new-onset,
points to a specific syndrome and typically would mandate initiation of unprovoked seizures. Care
prophylactic antiseizure medication. must be taken to avoid
The EEG may also help with determining the epilepsy type. Focal epilepsy is misinterpreting normal
variants as epileptogenic.
suggested if the EEG shows focal epileptiform discharges or focal slowing. In The EEG assists with
contrast, generalized spike-and-wave discharges would be consistent with a determination of seizure and
generalized epilepsy. Some epilepsy syndromes have a unique EEG signature. For epilepsy type, choice of
example, finding independent, high-amplitude centrotemporal spikes, which are further investigations, and
prognosis regarding the risk
activated in sleep, in a neurotypical, school-aged child with a history of early- for seizure recurrence.
morning convulsive seizures would support a diagnosis of self-limited epilepsy
with centrotemporal spikes. Conversely, an otherwise well 18-year-old woman
who presents with a single, early-morning generalized tonic-clonic seizure, and
who has generalized polyspike and wave triggered by photic stimulation, most
likely has juvenile myoclonic epilepsy.
The EEG may also help guide the need for other investigations. In most cases,
focal epileptiform discharges and/or focal slowing may suggest a diagnosis of an
underlying lesion.
Finally, the EEG provides information on the risk of seizure recurrence.
Approximately 40% to 50% of people who have a first unprovoked seizure will
experience a recurrence within the next 2 years.20 A systematic review in adults
with a first seizure reported that an EEG with epileptiform abnormalities was
associated with a relative rate increase for seizure recurrence at 1 to 5 years of 2.16
(95% confidence interval [CI], 1.07 to 4.38) compared with that in patients
without EEG abnormalities.18 Studies in children with a first seizure have shown
the risk of recurrence increases from 27% to 42% if the EEG is normal to 60% to
71% if the EEG shows epileptiform abnormalities.20
Prolonged video-EEG monitoring is rarely required after a first seizure.
However, such monitoring should be considered to exclude frequent subtle
seizures or status epilepticus in those who do not show recovery to baseline
neurologic function within 60 minutes, have fluctuating levels of consciousness,
or have unexplained focal neurologic findings.
Neuroimaging
The Commission on Neuroimaging of the ILAE has recommended that all
patients with epilepsy should undergo MRI, except those with a clearly defined,
drug-responsive idiopathic generalized epilepsy syndrome (childhood absence
epilepsy, juvenile absence epilepsy, or juvenile myoclonic epilepsy) or self-
limited focal epilepsy of childhood (self-limited epilepsy with centrotemporal
spikes or self-limited epilepsy with autonomic seizures).23,24

Patients with new-onset seizures with associated focal neurologic deficits,

fever, persistent headache, cognitive changes, or a recent history of head trauma
should be considered for urgent imaging, which is more commonly done by
CT given its ease of access. However, imaging with MRI is preferable to CT
because MRI avoids radiation exposure and enhances the detection of lesions. CT
has low sensitivity for detecting many small cortical epileptogenic lesions
including focal cortical dysplasia, mesial temporal sclerosis, low-grade gliomas,
or cavernous malformations, as well as lesions in the base of the skull such as the
orbitofrontal or mesial temporal regions. However, CT is more sensitive than MRI
for calcified lesions or bone lesions. Approximately 10% of adults with new-onset,
unprovoked seizures are found to have a clinically relevant structural lesion on
neuroimaging, and these individuals have a higher risk of seizure recurrence than
those without imaging abnormalities (relative risk, 2.44; 95% CI, 1.09 to 5.44).18
In patients who have returned to their neurologic baseline, who have no focal
neurologic deficits and for whom no other concern is present, MRI can be
obtained on an outpatient basis. An epilepsy protocol MRI with adequate spatial
resolution and multiplanar reformatting will enhance the yield of detection of
lesions.25 Other functional neuroimaging methods, such as positron emission
tomography (PET) or single-photon emission computed tomography (SPECT),
and magnetoencephalography (MEG) are often considered in cases of drug-
resistant, focal epilepsy and have little role in the evaluation of new-onset
seizures.
If a lesion is found on MRI, one must establish, using both clinical and
electrophysiologic data, whether it is indeed the underlying etiology for the
seizures. Small T2 hyperintensities, arachnoid cysts, or small meningiomas are
often coincidental as opposed to causal.
In children younger than 3 years of age, ongoing brain myelination often limits
the detection of lesions such as cortical dysplasia.26 In such cases, MRI studies
should be reviewed by a pediatric neuroradiologist, and consideration should be
given to repeating the MRI after the age of 3 years if seizures persist.
Laboratory Studies
Other laboratory studies may be indicated in a person with new-onset seizures.
ROUTINE BLOOD AND URINE STUDIES. Routine laboratory screening of patients with
new-onset seizures, with complete blood cell count, glucose, electrolytes including
calcium and magnesium, blood urea nitrogen, and creatinine, is commonly
done to exclude provoked seizures but has an overall low yield.19,27 Clinical
circumstances that may suggest a higher likelihood of underlying provoked
seizures include failure to return to baseline alertness, vomiting, diarrhea,
dehydration, failure to thrive, certain underlying medical conditions (eg,
diabetes), or medication exposures. More detailed screening for inborn errors
of metabolism should be considered in children who have concerning clinical
features, in addition to the seizures, including developmental plateauing or
regression, paroxysmal decompensation with altered consciousness, vomiting
or unusual odors with minor infectious illnesses, or unexplained organomegaly.
Such testing could include glucose, bicarbonate, alanine transaminase (ALT),
aspartate transaminase (AST), serum for amino acids, ammonia, lactate, pyruvate,
carbohydrate-deficient transferrin, very long chain fatty acids, and urine for
organic acids, mucopolysaccharides, oligosaccharides, and creatine metabolites.
254 APRIL 2022

TOXICOLOGY. Toxicology screening is not mandated in all cases but should be KEY POINTS
strongly considered if toxin exposure or substance abuse is a concern or if the
● Neuroimaging is
clinical findings are suggestive of a possible exposure (TABLE 1-2). recommended for all
patients with new-onset,
LUMBAR PUNCTURE. Lumbar puncture should be considered if the clinical picture unprovoked seizures,
is suggestive of possible meningitis, encephalitis, or subarachnoid hemorrhage except those with a well-
defined, drug-responsive
but is of limited value otherwise. A lumbar puncture should be considered in the
idiopathic generalized
presence of new, unexplained fever with seizures, encephalopathy, or meningeal epilepsy or self-limited
signs such as nuchal rigidity. Patients who are immunocompromised may also focal epilepsy of childhood.
have abnormal CSF results without overt clinical evidence of a brain infection. In patients who have
returned to their neurologic
Febrile seizures are relatively common, affecting 2% to 5% of children
baseline and for whom there
between the ages of 6 months and 5 years. Recommendations regarding the need are no concerns for an acute
for lumbar puncture have been published by the American Academy of neurologic process, urgent
Pediatrics.28 In children aged 6 months to 5 years presenting with a simple febrile CT is not needed. Rather,
seizure, defined as a duration of less than 15 minutes, without focal features and MRI can be obtained on an
outpatient basis.
without recurrence within a 24-hour period, a lumbar puncture should be
performed if meningeal signs are present or if the history or examination ● Routine blood and urine
suggests central nervous system infection. It should be considered an option for studies are commonly
infants aged 6 to 12 months who are deficient in either Haemophilus influenzae or obtained but of low yield in
patients with new-onset,
Streptococcus pneumonia immunization (or if immunization status cannot be unprovoked seizures.
determined) or in children who have received antibiotics, which may mask
clinical symptoms of intracranial infection. Although no guidelines have been ● A lumbar puncture should
determined for children with complex febrile seizures, in the absence of febrile be considered if the clinical
picture is suggestive of
status epilepticus, the risk of brain infection is low,29 and lumbar punctures
possible meningitis,
should be performed selectively. However, in children presenting with encephalitis, or
convulsive febrile status epilepticus, a lumbar puncture should be performed subarachnoid hemorrhage
because the risk of meningitis is approximately 17%.30 but is otherwise is of low
In the presence of possible increased intracranial pressure or new focal yield.
neurologic symptoms or signs, a brain imaging study should precede the

lumbar puncture.
AUTOIMMUNE TESTING. Neuronal antibodies may be associated with acute

symptomatic seizures because of an autoimmune encephalitis but are exceedingly
rare in new-onset epilepsy. A recent review of this topic noted several clinical
features that should suggest an autoimmune etiology, including a characteristic
onset (frequent, drug-resistant seizures), other associated features (cognitive
and/or behavioral dysfunction, dysautonomia, movement disorders such as
orofacial dyskinesias), and specific seizure types (faciobrachial dystonic
seizures).12 Serum and CSF autoimmune studies should be strongly considered in
the presence of suggestive clinical features but are of low yield in their absence.
GENETIC TESTING. Understanding of the genetic contributions to epilepsy has

markedly expanded over the past 20 years, with large-scale molecular genetic
studies leading to identification of an increasing number of novel epilepsy genes
(FIGURE 1-731). Although genetic testing should be selectively considered, it is not
recommended for most patients with new-onset epilepsy.
The report of the ILAE Genetics Commission suggests that the clinical utility
of testing should be evaluated before genetic testing. Testing should be
considered if the result will likely lead to a change in the procedures used for
evaluation or a change in the optimal treatment choice or prognosis and if it will

FIGURE 1-7
Significant growth in the past 20 years of the understanding of epilepsy genetics.
Reprinted with permission from Helbig I, et al, Epilepsia.31 © 2016 International League Against Epilepsy.
likely influence a decision about reproduction.32 Additionally, the social or

psychological impact on the patient must be considered.
Genetic testing is of the highest yield in infants and young children with
developmental and epileptic encephalopathies of unknown cause, with
approximately one-third to one-half of these patients having a pathogenic
variant found.33,34 Genetic testing should also be considered in patients whose
examination or other investigations point to a probable genetic cause. This
includes individuals with findings on neuroimaging suggestive of a genetic-
structural cause (ie, tuberous sclerosis complex or double cortex) or those with
imaging or laboratory findings suggestive of a genetic-metabolic etiology (eg,
mitochondrial disorders, Batten disease, or glucose transporter deficiency).35,36
The implications of genetic testing may be significant and should be discussed
with the family by a genetic counselor or other knowledgeable health care
provider before initiation of testing. These include the following:
u Medical implications: some genes may have implications for symptoms other than
epilepsy, and these implications may also extend to relatives of the person being tested
u Reproductive implications: the risk of passing on an abnormal variant
u Psychological implications: the impact of potentially carrying an abnormal variant that
could result in disease in oneself or increase risk of disease in one’s child
u Insurance and financial implications
Several possible genetic investigations, including karyotype, chromosomal

microarray, single-gene sequencing, epilepsy gene panel, and whole-exome or
256 APRIL 2022

whole-genome sequencing, and, in certain cases, specific clinical features, may KEY POINTS
drive the choice for a particular test. For example, in a 3-year-old child with
● All patients with new-
global developmental delay, absent speech, disrupted sleep, a happy demeanor, onset, unprovoked seizures
and new-onset epilepsy, whose EEG is found to have a notched delta appearance, must be counseled about
focused testing for Angelman syndrome will likely be pursued. However, in lifestyle issues, seizure
many cases, the phenotype does not suggest a specific gene. A recent meta- safety, and what to do if
further seizures occur.
analysis that assessed cost-effectiveness of various genetic tests commonly used
Water safety is of utmost
in patients with epilepsy suggested that either an epilepsy gene panel or whole- importance. Showers are
exome sequencing study should be the initial test ordered in such cases.37 safe; however, bathing or
swimming alone is not
recommended.
Management
In any individual presenting with a first unprovoked seizure or new-onset ● Although immediate
epilepsy, counseling on lifestyle issues, seizure safety, and what to do if further initiation of antiseizure
seizures occur must be provided. Although the risk of recurrence will depend on medication after a first
several factors, including underlying cause and EEG findings, in general, the unprovoked seizure does
reduce the risk of
highest risk of recurrence is in the first 1 to 2 years after the seizure. recurrence, it does not
The most important lifestyle modification that is indicated for all patients with impact long-term epilepsy
new-onset, unprovoked seizures pertains to safety around water. Although outcome or quality of life.
showers are generally safe, being in a bathtub or swimming alone is not
recommended. Patients should also be counseled about other safety issues such
as avoiding excessive heights. Other potential restrictions may be required based
on their occupation or participation in certain sports.38
For people who have had seizures that alter their awareness, guidance
regarding driving varies depending on the place of residence. The Epilepsy
Foundation website has a list of updated driving laws for each state.39
Patients should also understand the importance of managing seizure triggers.
Sleep deprivation is a common trigger for many epilepsy types, and thus,
regulating sleep hygiene is important. Overall, patients benefit from regular
mealtimes and a healthy diet, regular exercise, and management of emotional
stress and mood disorders. Other triggers can be specific for certain epilepsies,
such as flashing lights, or, in some cases, even eating or reading. Some women
have a catamenial pattern to seizures, and fever or intercurrent illness may also
trigger seizures in susceptible individuals.
Some patients may benefit from having a seizure rescue medication that could
be used if they have a prolonged seizure or cluster of seizures. This is particularly
important in those who live a considerable distance from emergency medical
services or those with a history of a previous seizure emergency. Patients and
their families should understand when and how to administer such therapy, as
well as other aspects of seizure first aid (rolling the patient on their side, avoiding
placing objects in the mouth, and when to call emergency medical services).
Finally, patients must be informed of the potential risks of recurrent seizures,
including status epilepticus, aspiration, and sudden unexpected death in
epilepsy (SUDEP).
In deciding whether to initiate a prophylactic antiseizure drug, one must
consider the recurrence risk for further seizures, the seizure severity, and the
potential impact of further seizures on the individual patient and balance this
against potential adverse effects of medication. Patient and family preferences
must be considered. Antiseizure medication is typically started in cases of new-
onset epilepsy but not in most cases of first unprovoked seizure with normal EEG
and imaging.

In adults presenting with a first unprovoked seizure, immediate antiseizure

medication treatment compared with treatment delayed until a second seizure
occurs was found to reduce the absolute risk of recurrence by about 35% for a
subsequent seizure within the next 2 years, but it did not alter quality of life or
improve the chance of obtaining sustained seizure remission over the longer
term.18 In children, a similar consensus was reached; however, few data are
available from studies limited to children.40
CONCLUSION
New-onset seizures are a common presentation to the neurologist. A careful
clinical history is key to excluding seizure mimics and provoked or acute
symptomatic seizures. Accurate classification of epilepsy assists with the choice
of cost-effective investigations, optimal treatment, and accurate prognosis.
Counseling regarding seizure safety and first aid should be addressed in all cases
of new-onset seizures.
USEFUL WEBSITES
EPILEPSY FOUNDATION STATE DRIVING LAWS DATABASE INTERNATIONAL LEAGUE AGAINST EPILEPSY
This is a database of state driving laws related to This website provides an online diagnostic manual
epilepsy. of the epilepsies.
epilepsy.com/driving-laws/2008806 epilepsydiagnosis.org
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Guideline Development Subcommittee of the
Commission. Primer part 1-the building blocks of
American Academy of Neurology and the
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American Epilepsy Society. Neurology 2015;
doi:10.1111/epi.13381
84(16):1705-1713. doi:10.1212/WNL.
0000000000001487 32 Ottman R, Hirose S, Jain S, et al. Genetic testing in
the epilepsies—report of the ILAE Genetics
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subcommittee of the American Academy of 33 Shellhaas RA, Wusthoff CJ, Tsuchida TN, et al.
Neurology, The Child Neurology Society, and The Profile of neonatal epilepsies: characteristics of
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20 Wirrell EC. Prognostic significance of interictal 34 Howell KB, Eggers S, Dalziel K, et al. A population-
epileptiform discharges in newly diagnosed based cost-effectiveness study of early genetic
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21 King MA, Newton MR, Jackson GD, et al. 35 Guerrini R, Dobyns WB. Malformations of cortical
Epileptology of the first-seizure presentation: a development: clinical features and genetic
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36 Ritter DM, Holland K. Genetic testing in epilepsy.
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22 Benbadis SR, Lin K. Errors in EEG interpretation s-0040-1719070
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37 Sánchez Fernández I, Loddenkemper T, Gaínza-
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epilepsy: a meta-analysis and cost-effectiveness
23 Recommendations for neuroimaging of patients study. Neurology 2019;92(5):e418-e428.
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38 Capovilla G, Kaufman KR, Perucca E, et al.
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24 Gaillard WD, Cross JH, Duncan JS, et al. Epilepsy Epilepsy. Epilepsia 2016;57(1):6-12. doi:10.1111/
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wnl.0000033622.27961.b6
260 APRIL 2022

EEG Essentials REVIEW ARTICLE

By William O. Tatum IV, DO, FAAN, FACNS, FAES C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
ABSTRACT 
PURPOSE OF REVIEW: EEG is the best study for evaluating the electrophysiologic VIDEO CONTENT
A V AI L A B L E O N L I N E
function of the brain. The relevance of EEG is based on an accurate
interpretation of the recording. Understanding the neuroscientific basis
for EEG is essential. The basis for recording and interpreting EEG is both
brain site–specific and technique-dependent to detect and represent a
complex series of waveforms. Separating normal from abnormal EEG lies at
the foundation of essential interpretative skills.
CITE AS:
RECENT FINDINGS: Seizures and epilepsy are the primary targets for clinical CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):261–305.
use of EEG in diagnosis, seizure classification, and management. Interictal
epileptiform discharges on EEG support a clinical diagnosis of seizures, Address correspondence to
but only when an electrographic seizure is recorded is the diagnosis Dr William O. Tatum IV, Mayo
Clinic College of Medicine &
confirmed. New variations of normal waveforms, benign variants, and Science, Mangurian Building,
artifacts can mimic epileptiform patterns and are potential pitfalls for Fourth Floor, 4500 San Pablo Rd,
misinterpretation for inexperienced interpreters. A plethora of medical Jacksonville, FL 32224,
tatum.william@mayo.edu.
conditions involve nonepileptiform and epileptiform abnormalities on EEG
along the continuum of people who appear healthy to those who are RELATIONSHIP DISCLOSURE :
critically ill. Emerging trends in long-term EEG monitoring to diagnose, Dr Tatum has received personal
compensation in the range of
classify, quantify, and characterize patients with seizures have unveiled $500 to $4999 for serving as an
epilepsy syndromes in patients and expanded medical and surgical options Editor-in-Chief for Epilepsy &
Behavior Reports and as an
for treatment. Advances in terminology and application of continuous EEG
expert witness for a defense
help unify neurologists in the diagnosis of nonconvulsive seizures and law firm on behalf of a patient
status epilepticus in patients with encephalopathy and prognosticate with epilepsy with funds
donated to the Epilepsy
recovery from serious neurologic injury involving the brain. Foundation of America; has
received personal
SUMMARY: After 100 years, EEG has retained a key role in the neurologist’s compensation in the range of
$10,000 to $49,999 for serving as
toolkit as a safe, widely available, versatile, portable test of neurophysiology, a consultant for BioSerenity,
and it is likely to remain at the forefront for patients with neurologic Holberg EEG AS, Neurelis, Inc,
diseases. Interpreting EEG is based on qualitative review, and therefore, Zimmer Biomet; and has
received publishing royalties
the accuracy of reporting is based on the interpreter’s training, from Demos and Springer
experience, and exposure to many new and older waveforms. Publishers. The institution of
Dr Tatum has received
research support from
Cerevel Therapeutics, Engage
Pharma, Esai Inc, LivaNova PLC,
INTRODUCTION the Mayo Clinic, Medtronic,
I
and Xenon.
nitial concepts and clinical observations were described by Hans Berger in his
work on the “Elektroenkephalogram des Menschen” (the EEG of man) that UNLABELED USE OF
depicted electrical currents produced by the brain represented in graphic PRODUCTS/INVESTIGATIONAL
form.1 EEG can be recorded in the hospital, intensive care unit (ICU), USE DISCLOSURE:
Dr Tatum reports no disclosure.
operating room (OR), and ambulatory setting in patients of all ages. Since the
first description in the 1920s, EEG has remained the most relevant testing
modality to evaluate people with seizures. Approximately 1 in 10 people will have © 2022 American Academy
at least one seizure at some point in their lives, and 1 in 26 Americans will be of Neurology.

EEG AT A GLANCE
FIGURE 2-1
Chewing artifact (ovals) mistaken for frequent and prolonged bursts of polyspike and
waves in a 24-year-old driver involved in a car accident. He did not recall the impact when
he was jettisoned from the vehicle. Although he never experienced a seizure, he was
unnecessarily placed on antiseizure medication “just in case.”
TABLE 2-1 Selected Diagnostic Indications for EEG
High-yield EEG
◆ Seizures and epilepsy
◆ Possible seizures/“spells”
◆ Head injury, stroke, central nervous system infection, and brain tumor
◆ Parasomnias and sleep disorders
◆ Movement disorders
◆ Progressive dementias and encephalopathy
◆ Acute altered mental status and coma
Low-yield EEG
◆ Headache
◆ Pain
◆ Chronic behavioral disorders
◆ Isolated dizziness/vertigo
◆ Regular EEGs in patients who are seizure free
EEG = electroencephalography.
262 APRIL 2022

diagnosed with epilepsy,2 imparting a significant burden of disease. EEG is KEY POINTS
foundational for people with epilepsy, and the clinical utility is well established.3
● Since the first description
EEG abnormalities form the physiologic basis when evaluating patients with in the 1920s, EEG has
paroxysmal neurologic events. Qualitative assessment is the standard method of remained the most relevant
interpreting standard EEG for routine clinical use. However, interpretation of testing modality to evaluate
EEG recordings has only moderate interrater reliability using visual analysis people with seizures.
and is therefore subject to misinterpretation (FIGURE 2-1). When epileptiform
● Signals detected and
features are present on the EEG, the frequency, discharge duration, and spatial ultimately recorded by EEG
distribution are defining characteristics of interictal epileptiform discharges and are generated by dynamic
clinical impact. EEG abnormalities in patients with epilepsies aid diagnosis but extracellular currents
also impact management. EEG in the ICU can identify nonconvulsive seizures in produced by
transmembrane ion flow.
patients with altered mental status. Long-term EEG monitoring can clarify the
interictal–ictal continuum and provide prognostic information.
With its versatility and adaptability, EEG is useful in many conditions
(TABLE 2-1). It is also important for interpreters to understand the limits of EEG,
including the lack of specificity for disease states, insensitivity in some patients to
detect abnormalities, and “interference” by artifacts and the physiologic effects
incurred from medication or prior surgery.4 This article on EEG functions as a
primer and highlights common examples across a broad range of neurologic
disease states focused on the epilepsies as a roadmap to aid competency and as an
introduction to formal curricula dedicated to EEG education.5
NEUROSCIENCE CONCEPTS UNDERLYING EEG

Physicians who treat patients with epilepsy need to understand biophysical
aspects of signal generation and recording to accurately interpret the results of
the clinical EEG.4 Signals detected and ultimately recorded by EEG are generated
by dynamic extracellular currents produced by transmembrane ion flow.
These currents are initiated in the apical dendrites of the pyramidal neurons
located in layers IV and V of the cerebral cortex. Excitatory and inhibitory
postsynaptic potentials are arranged in palisades and summate through passive
current flow. The local field potentials generated are volume conducted through
extracerebral tissues to the recording sensor. Excitatory postsynaptic potentials
have an actively maintained separation of electrical charge and extracellular
negativity at the superficial synapse. This serves as a “sink” to actively attract
sodium ions. Compensatory current flow from the extracellular space at the
opposite end of the neuron becomes relatively positive as a passive “source.”
In contrast, inhibitory postsynaptic potentials have extracellular positivity
due to the active influx of chloride ions or efflux of potassium ions at the source
and extracellular negativity at a passive sink resulting from current flow.
Dendrites in the superficial cortical layers have an anatomical separation
with excitatory inputs at the distal dendritic arborization whereas inhibitory
inputs are closer to the soma, resulting in an electrophysiologic dipole. When
a large pool of neurons is synchronized, excitatory postsynaptic potentials
or inhibitory postsynaptic potentials are summated and amplified and can
be recorded by the EEG electrodes. When numerous dipoles are summated,
currents are generated that are large enough to conduct across the brain
tissue and connect an electrophysiologic generator with a recording electrode.
To record EEG signals (ie, interictal epileptiform discharges), at least
10 cm2 of cortex needs to be activated. Dipoles generating abnormal
electrophysiologic potentials have a specific orientation, with the negative

EEG AT A GLANCE
end lying in the superficial cortical layers and the positive end closer to the
cell body in deeper layers of the cortex. Scalp topographic representation by EEG
is determined by the area of the cortex generating the signal and the orientation
of the negative and positive ends of the dipole that determine the spatial
distribution of the recorded signal.4
RECORDING EEG
The American Clinical Neurophysiology Society has published guidelines
regarding EEG monitoring in addition to minimal standards for recording.6,7
Most standard EEGs are obtained using standard scalp electrodes and acquired in
the interictal period when patients are asymptomatic. Standard EEG is a safe,
noninvasive, routine study that is the most common type of EEG recording
obtained. Ambulatory EEG, video-EEG monitoring, critical care continuous
EEG, quantitative EEG, intracranial EEG, and electrocorticography all record the
same brain signals, differing in technique and site of recording. Standard EEG
recording involves a multichannel microprocessor, high sampling rates of 512 Hz
or higher, 128 gigabytes of internal memory or more, and resolution of at least
16 bits.3 Clinical EEG is recorded by using the international 10-20 system of
electrode placement as a universal standard (FIGURE 2-2). Twenty-five channels
of EEG are recommended for clinical use by the International Federation of
Clinical Neurophysiology, incorporating a single channel of ECG.8 Bipolar
montages (two active electrode sites) use phase reversals, and referential
montages (one active electrode site) use absolute voltage to measure electrical
field maxima. Anterior-posterior longitudinal bipolar montage (also known as
the double banana) is commonly used as a screening montage. Standard parameters
for recording EEG include sensitivity (adult, 7 μV/mm), filter settings of 1 to
70 Hz (notched filter with 60-Hz artifact), and a time base of 30 mm/s.
FIGURE 2-2
Electrode placement for scalp-recorded EEG. The international 10-20 system of electrode
placement (A) uses anatomic landmarks on the skull with sites subdivided by intervals of 10%
and 20% to designate the site where an electrode will be placed. The modified combinatorial
system (B) uses more closely spaced electrodes in a 10-10 system.
264 APRIL 2022

Advantages of altering recording parameters include changing the display speed KEY POINT
(FIGURE 2-3), montage (FIGURE 2-4), sensitivity (FIGURE 2-5), and filter settings to
● Most standard EEGs are
enhance the EEG recording. obtained using standard
Sleep, sleep deprivation, and sedated sleep may be useful to activate scalp electrodes and
interictal epileptiform discharges during standard EEG recording. Therefore, acquired in the interictal
obtaining sleep in every routine EEG recording is desirable. Hyperventilation period when patients are
asymptomatic.
and intermittent photic stimulation are standard activation procedures to
enhance detection of interictal epileptiform discharges. This is especially
applicable in patients with generalized genetic epilepsy, where activation is
most likely to occur. Hyperventilation performed for 3 minutes at a rate of
about 20 breaths/min normally produces a “buildup” (FIGURE 2-6). Nearly
every person with untreated absence seizures has hyperventilation-provoked
3-Hz generalized spike-and-wave discharges. Intermittent photic stimulation,
using a series of stroboscopic photic flashes 20 to 30 cm from the patient’s
eyes, can identify abnormal photosensitivity if a photoparoxysmal response
(FIGURE 2-7) is recorded.9 However, an isolated occurrence may also occur
in people without clinical seizures. If a photoparoxysmal response is
seen during EEG recording, intermittent photic stimulation should be
discontinued to prevent a generalized tonic-clonic seizure. Use of video
cameras may reveal subtle symptomatology (or artifact) during review
that is not reported by patients and increases the interpretative potential over
EEG alone. Real-time remote EEG and wireless network connections with high-
speed data transfer are possible with most modern EEG systems (FIGURE 2-8).
NORMAL EEG
A wide range of background frequencies can be seen in the EEG. Interpreting
abnormal EEG requires understanding when and what studies are normal.10,11
FIGURE 2-3
Continuous EEG demonstrating nonconvulsive status epilepticus in a 45-year-old woman
after left hemicraniectomy for left frontocentral intraparenchymal hemorrhage during
pregnancy. Note the slow display speed of 15 mm/s (oval) that enhances continuous left
hemispheric slowing (rectangles) and F3 ictal fast activity under a breach rhythm (arrows).

EEG AT A GLANCE
FIGURE 2-4
Combined circle and transverse bipolar montage accentuating the alpha rhythm in the
occipital region. Note the lateral rectus spikes (myogenic artifact, arrows) and reactivity with
return of the alpha when the eyes are closed (EC).
A normal EEG is a common result when patients obtain a standard study.

However, a normal result does not exclude the possibility a patient has epilepsy,
and EEG should not be used to make an epilepsy diagnosis independent of the
clinical context of recording.
Interpretation involves the qualitative process of visually extracting a complex
series of brain signals.4 Most clinical EEG interpretations identify frequencies
FIGURE 2-5
EEG with a 2.5-second burst of 3.3-Hz generalized frontally predominant spike and waves
(oval) without clinical signs in N2 sleep. Note the sensitivity of 15 μV/mm, which makes the
background look suppressed, but which allows visualization of the spike phase reversals in
the frontal region.
266 APRIL 2022

KEY POINT
● A normal EEG is a common

result when patients obtain
a standard study. However,
a normal result does not
exclude the possibility that
a patient has epilepsy, and
EEG should not be used to
make an epilepsy diagnosis
independent of the clinical
context of recording.
FIGURE 2-6
A robust but normal buildup with bursts of frontal intermittent rhythmic delta activity (FIRDA)
intermixed with theta and delta during hyperventilation. This 17-year-old girl had migraines
and had last eaten the day before the EEG recording.
FIGURE 2-7
Self-limited photoparoxysmal response (oval) in a patient with idiopathic (presumed genetic)
photosensitive occipital lobe epilepsy. During intermittent photic stimulation, an incremental
series of flashes is delivered for about 4 seconds, with at least 4 seconds in between each
train increasing to 30 Hz.

EEG AT A GLANCE
FIGURE 2-8
Modern EEG systems.
A-D = analog to digital.
between 1 and 35 Hz (also known as the Berger band), including a mixture of

frequencies involving alpha (8 to 13 Hz), beta (13 to 30 Hz), theta (4 to 8 Hz), and
delta (less than 4 Hz). The alpha rhythm (posterior-dominant rhythm) is the
starting point for interpretation (FIGURE 2-9). Each frequency bandwidth can
have normal and abnormal implications depending on the clinical context of
recording (TABLE 2-2).12
A crucial aspect of interpreting EEG lies in differentiating pathologic from
physiologic waveforms (TABLE 2-3). Normal aspects of the EEG (FIGURE 2-9
and FIGURE 2-10), variations of normal (FIGURE 2-11), and benign variants in the
EEG may be epileptiform (FIGURE 2-12) or rhythmic patterns (FIGURE 2-13).
These may look abnormal but are not despite appearing “suspicious” to novice
interpreters.11 Overinterpretation of normal features of the EEG is a common
reason for misinterpretation.11,13 Some normal variations in frequency (eg, left
temporal delta during wakefulness in older adult patients) or morphology (eg,
posterior temporal “apiculate” alpha; FIGURE 2-11) may lead the interpreter to
misinterpret a normal EEG as abnormal and result in incorrect treatment (CASE 2-1).
Artifact occurs from a wide range of sources and is present in essentially
every EEG recording. Artifact is an essential means of identifying normal
levels of wakefulness and sleep, although in electrically hostile environments,
artifacts can completely obscure a tracing (FIGURE 2-15) and interfere with
the ability to interpret underlying electrocerebral activity. Both physiologic
and nonphysiologic sources of artifact may mimic interictal and ictal abnormalities
(FIGURE 2-16). Experienced technologists are invaluable in ensuring optimal EEG
recording and annotation of events.14 In expert hands, interpreting a quality home
video recording has the potential to separate epileptic and nonepileptic events
although it remains only an indirect supplement to seizure diagnosis without the
268 APRIL 2022

KEY POINTS
● Benign variants of
uncertain significance,
normal waveform variations,
and artifacts may be pitfalls
to overinterpreting a normal
record as abnormal leading
to inappropriate treatment
with antiseizure medication.
● Standard EEG is the

diagnostic test of choice to
provide electrophysiologic
information about the
presence of
neurophysiologic
dysfunction.
FIGURE 2-9
Awake EEG. In the first half of the tracing, horizontal and vertical eye blink artifact
is present generating lambda waves (arrows). Note the reactivity and return of alpha after
eye closure (EC). Lambda waves have a “sharp” appearance, are located bilaterally over the
occipital region, and are evoked by scanning eye movements.
definitive means provided by EEG.15 During video-EEG monitoring,

reviewing the video can clarify waveforms when EEG is challenging. For
example, movements identified on video may correlate with a sustained
rhythmic discharge signifying an artifact as opposed to a seizure (VIDEO 2-1).
Wicket spikes are unilateral or bilateral independent benign variants
composed of 7- to 11-Hz bursts of anterior-mid temporal, medium- to
high-voltage, monophasic waveforms (FIGURE 2-12). Bursts of wicket
spikes have a negative polarity, repetitive rhythmic spikey morphology,
and duration of 0.5 to 1 second. They are common in older adults, accentuated
by light sleep, and appear with left temporal predominance. Isolated, sharply
contoured single waveforms may occur over any head region as spikey
“fragments” of a burst. The pattern may be deceiving when it is unilateral and
has a temporal location and can be mistaken for a pathologic interictal
epileptiform discharge.
NONEPILEPTIFORM ABNORMALITIES
Abnormal EEGs include both nonepileptiform and epileptiform activity.
Nonepileptiform abnormalities include diffuse slowing in encephalopathy
and focal slowing with a structural brain lesion involving the white matter
tracts.16 Neither of these abnormalities connotes epilepsy.17 Nonepileptiform
abnormalities are common in hospital and ICU EEGs. Prognosis is relative
to the underlying cause of the slowing. Standard EEG is the diagnostic
test of choice to provide electrophysiologic information about the presence of
neurophysiologic dysfunction.
Diffuse slowing of the background activity is nonspecific and may be
intermittent (FIGURE 2-17) or continuous (FIGURE 2-18). Diffuse slowing is
associated with a toxic-metabolic-systemic etiology but also may be due to a

EEG AT A GLANCE
diffuse or multifocal structural cause, neurodegenerative and posttraumatic

injury, or postictal state. The degree of background slowing reflects the severity
of encephalopathy. A mild to moderate encephalopathy is present when the
normal posterior-dominant rhythm is intermixed with theta and/or delta
activity. When the posterior-dominant rhythm is in the delta range, a moderate
to severe encephalopathy is present. Other features include loss of an anterior-
posterior gradient, cyclical alternating patterns, discontinuous patterns with
background attenuations, and asymmetries in patients with moderate to severe
encephalopathy. The severity of encephalopathy is proportional to the
degree of slowing of the posterior-dominant rhythm, with/without periods of
voltage attenuation (FIGURE 2-19), periods of suppression, and reactivity
of the electrocerebral activity to external stimulation. Burst attenuation,
electrocerebral inactivity, diffuse low-voltage (less than 20 μV) or suppressed
(less than 10 μV) recording (FIGURE 2-20), and coma with a monomorphic
TABLE 2-2 Frequency Analysis and Clinical Correlatesa
Bandwidth Frequency (Hz) Selected conditions

b
Alpha 8-13 Normal: posterior-dominant rhythm, mu rhythm, wicket waves
Abnormal: alpha coma, focal (temporal) seizures
Betab 13-30 Normal: medication (benzodiazepines/barbiturates), drowsiness

Abnormal: drug use and abuse, breach rhythm, focal seizures (extratemporal)
b
Theta >3.5 to < 8 Normal: drowsiness, children, older adults, concentration
Abnormal: nonspecific (mild) encephalopathy, theta coma
Deltab 0.5-3.5 Normal: N3 sleep, hyperventilation, posterior slow waves of youth, focal delta
complexes in older adults
Abnormal: encephalopathy (diffuse), white matter dysfunction (focal)
Infra-slow <0.5 Normal: artifact (eg, sweat, movement, electrode)

Abnormal: focal seizures (invasive EEG)
Gamma 30-80 Normal: volitional movement, learning, memory

Abnormal: focal seizures onset (invasive EEG)
Ripples 80-250 Normal: cognitive processing and memory consolidation; identified in patients
with chronic pain
(high gamma)
Abnormal: high-frequency oscillations, focal seizures (invasive EEG)
Fast ripples 250-500 Normal: undetermined if fast ripples are associated with normal function
Very fast ripples 500-1000 Normal: acquisition of sensory information

EEG = electroencephalography.
a
Modified with permission from Tatum WO, et al, MedLink Neurology. © 2021 MedLink, LLC.12
b
Bandwidths included in the “Berger band.”
270 APRIL 2022

unreactive frequency (eg, alpha, theta coma) usually portend a poor prognosis
when they occur in the appropriate clinical context (eg, hypoxic injury,
subarachnoid hemorrhage) and persist off IV sedation. Loss of reactivity
(FIGURE 2-3) is an unfavorable sign when present.18 Slowing of the background
activity and the absence of reactivity and periodic discharges (FIGURE 2-21)
have prognostic implications.19
Morphologic differences of waveforms occur between recordings and within
the same EEG recording of a single patient. Focal slowing that is irregular or
polymorphic (FIGURE 2-22A) may suggest an underlying structural lesion
involving white matter, although morphology is neither sensitive nor specific for
an underlying etiology and does not suggest the potential to generate seizures
Waveforms That May Be Confused With Interictal Epileptiform Discharges TABLE 2-3
Normal variations in EEG

◆ Normal frequencies (predominantly involving alpha and beta morphology and frequency)
◆ Vertex sharp waves (eg, spiky vertex)
◆ Lambda waves
◆ Mu rhythm
◆ Breach rhythma
◆ Positive occipital sharp transients of sleep
◆ Frontal intermittent rhythmic delta activity (FIRDA) during hyperventilationb
Benign EEG variants
◆ Wicket waves (wicket spikes)
◆ 6-Hz spike-and-wave discharges
◆ 14- and 16-Hz positive bursts
◆ Benign epileptiform transients of sleep
◆ Rhythmic midtemporal theta of drowsiness (sharp form)
◆ Subclinical rhythmic EEG discharges of adults
◆ Frontal midline theta
Artifacts
◆ Over-filtering (eg, fast activity and myogenic artifact)
◆ Single electrode artifact
◆ Myogenic “spikes”
◆ Chewing
◆ Rhythmic patient-generated movements
◆ ECG (eg, confusion with periodic epileptiform discharges)
◆ Ocular flutter/rapid eye blinking
ECG = electrocardiogram; EEG = electroencephalography.

a
Normal for the physiologic conditions of recording in the context of a skull disruption (eg, craniotomy and
skull fracture).
b
Increased intracranial pressure, recent cerebrovascular disease, severe cardiopulmonary disease, recent
surgery, hyperviscosity syndromes, and pregnancy are relative contraindications to hyperventilation.

EEG AT A GLANCE
FIGURE 2-10
EEG demonstrating the contrast between mu (arrows) and alpha (rectangle). The frequency
is the same, but the location (central mu versus occipital alpha) and stimulus for reactivity
(eye-opening with alpha versus contralateral limb movement with mu) differ. In people with a
mu rhythm, asymmetry may appear abnormal. However, both may appear “spiky.”
FIGURE 2-11
EEG with a normal variation of “sharp” alpha (T5) mimicking an abnormal sharp wave (oval ) as
the patient becomes drowsy. This 19-year-old woman was referred for migraine and did not
have a history of seizures. EEG is not indicated for headache diagnosis; if EEG is obtained, it
may serve as a pitfall that leads to overdiagnosis and mismanagement.
272 APRIL 2022

FIGURE 2-12
Normal EEG with a left temporal burst of wicket waves (oval). Note the single complexes of
bitemporal delta (arrows) that are normal during drowsiness in this 68-year-old woman
evaluated for suspected convulsive syncope.
(FIGURE 2-22B). However, the greater the persistence of polymorphic delta, the
greater the likelihood of being associated with a destructive lesion. Intermittent
generalized slowing may also appear rhythmic and may be a normal feature of
the EEG during hyperventilation (FIGURE 2-6) and drowsiness (FIGURE 2-17).
Temporal intermittent rhythmic delta activity (TIRDA) is unlike other forms of
slowing (FIGURE 2-23), including occipital and frontal intermittent rhythmic
delta activity (FIRDA). TIRDA is a unilateral or bilaterally asynchronous EEG
pattern that predicts focal seizures with high likelihood in patients with temporal
FIGURE 2-13
EEG with normal bursts of sharply contoured theta (oval) during transitioning between the
awake and drowsy state. Some bursts may appear “sharp” but are normal. These may be
pronounced and prominent in younger people.

EEG AT A GLANCE
CASE 2-1 A 65-year-old right-handed man with a past history of hypertension,

transient ischemic attack, chronic dizziness, and major depression was
evaluated for recurrent “blackouts.” The patient described a warning of
light-headedness, and coworkers described him as having sudden loss of
consciousness and “shaking all over.” Over the past few months, he
developed an asymmetric tremor, bradykinesia, and falls. He was
diagnosed with parkinsonism due to chronic neuroleptic use, and a
head-up tilt table test was reported as “positive.” Brain MRI had
subcortical microvascular ischemic changes.
An EEG obtained in the office was interpreted as showing “seizure
activity” over the left temporal region (FIGURE 2-12). Levetiracetam was
begun and increased, but the patient became violent. Lamotrigine was
then added, but episodes continued.
The patient then presented for a second neurologic opinion. Video-
EEG monitoring was performed. Interictal EEG was normal, and abundant
wicket waves were present during light sleep (FIGURE 2-14). A spell was
captured during orthostatic blood pressure assessment that was typical
of the patient’s previous events. As a result, he was diagnosed with
syncope/convulsive syncope, and rereview of the outside EEG
demonstrated wicket waves. Antiseizure medication was withdrawn, and
midodrine was begun without recurrence of events.
FIGURE 2-14
Independent left and right rhythmic (5 Hz) temporal theta discharges of drowsiness
(ovals) in a patient referred for evaluation of syncope. Note the sharply contoured
morphology in this patient with a benign EEG variant.
COMMENT Benign variants of uncertain significance as in this case, normal waveform

variations, and artifacts may be pitfalls to overinterpreting a normal record
as abnormal, leading to inappropriate treatment with antiseizure
medication.
274 APRIL 2022

FIGURE 2-15
Diffuse myogenic and instrumental artifact due to loss of the reference electrode. Note the
montage was reformatted into an anterior-posterior longitudinal bipolar array.
FIGURE 2-16
Epochs of EEG during a “seizure” that was suspected during initial interpretation of the
EEG. Note the onset (A, arrow), rhythmic pattern (B), pseudo-evolution (C), and termination
(D, arrow) in the images. The persistent focal distribution without propagation to adjacent
regions, pseudo-evolution in amplitude without change in frequency, and lack of postictal
slowing reflecting a hand tremor during a telephone call that produced artifact on the EEG.

EEG AT A GLANCE
FIGURE 2-17
Brief 4-second burst of frontal intermittent rhythmic delta activity (FIRDA) during drowsiness
(oval). This EEG was obtained in an 81-year-old man after an acute confusional state. FIRDA
during the awake state is abnormal, yet it may be normal during drowsiness and
hyperventilation.
lobe epilepsy.20 Normal EEG waveforms are not perfectly symmetric. In some
cases, attenuation of the waveform amplitude suggests localized gray matter
dysfunction within the ipsilateral hemisphere. Amplitude differences are
considered abnormal asymmetries with greater than 50% side-to-side difference
(FIGURE 2-24). Voltage attenuation of brain signals normally occurs because of
the effect of overriding skull and pericranial tissues limiting propagation of
FIGURE 2-18
EEG with diffuse slowing of the posterior-dominant rhythm to 6 to 7 Hz in a 56-year-old man
evaluated for mild cognitive impairment.
276 APRIL 2022

FIGURE 2-19
Encephalopathy during rewarming from iatrogenic hypothermia with EEG showing diffuse
mixed-frequency irregular background slowing coupled with attenuations (first and last 1 to
2 seconds) in a patient with hypoxic-ischemic encephalopathy and left hemispheric ischemic
infarction after cardiac arrest.
FIGURE 2-20
Low-voltage recording (10 to 15 μV) associated with a subarachnoid hemorrhage in a 56-year-
old man with uncontrolled hypertension.

EEG AT A GLANCE
FIGURE 2-21
Generalized periodic discharges with triphasic morphology. Note the diffusely slow
background activity in addition to the triphasic morphology and anterior-posterior lag (ovals)
that supports a toxic-metabolic-systemic etiology. This was a 46-year-old woman with an
orthotopic liver transplant evaluated for acute mental status changes due to sepsis.
signals to the scalp. A focal area of high-voltage electrocerebral activity (often

beta) is present where the skull is breached (FIGURE 2-25).
INTERICTAL EPILEPTIFORM ACTIVITY

The interictal EEG is useful to differentiate focal from generalized seizures and
epilepsies. Diagnostic criteria (TABLE 2-3) differentiate epileptiform activity from
nonepileptiform transients.21,22 Spikes and sharp waves are interictal
epileptiform discharges and are surrogate biomarkers of epilepsy. Spikes have a
duration of 20 to 70 milliseconds, and sharp waves have a duration of 70 to
200 milliseconds. When EEG is viewed using a display speed of less than 30 mm/s
or lowering the high-frequency filter below 70 Hz, a false “spiky” appearance may
be produced. Therefore, an understanding of the parameters of recording is
essential for accurate interpretation (FIGURE 2-26). An EEG that contains spikes
and sharp waves supports a clinical diagnosis of epilepsy. When EEG records an
electrographic seizure (FIGURE 2-27) in patients with a history of recurrent
unprovoked seizures, this is diagnostic of epilepsy.
The likelihood of an EEG recording interictal epileptiform discharges depends
on the presence of several factors: a lesion, the location, state of arousal, spatial
distribution of interictal epileptiform discharges, and the patient’s clinical course.
Factors that influence the ability to record interictal epileptiform discharges in
the routine EEG include age, location, sleep, use of special electrodes, recording
within 24 hours after a seizure, specific syndromes, antiseizure medication, and
the number and length of EEG recordings.17 Temporal interictal epileptiform
discharges have a strong association with epilepsy. In contrast, central interictal
epileptiform discharges are associated with clinical seizures less than 50% of the
time. An underlying structural basis (eg, cerebral palsy with central spikes) and
an inherited trait independent of seizures (eg, a photoparoxysmal response) are
possible reasons for the difference.
278 APRIL 2022

KEY POINTS
● An EEG that contains

spikes and sharp waves
supports a clinical diagnosis
of epilepsy.
● When EEG records an

electrographic seizure in
patients with a history of
recurrent unprovoked
seizures, this is diagnostic of
epilepsy.
FIGURE 2-22
EEG with focal slowing. A, Abnormal EEG with continuous left anterior temporal slowing
(oval ) in a 60-year-old man with a normal MRI referred for memory loss and possible
seizures. Note the variable hemispheric spatial field of distribution (with hemispheric
involvement [thin arrow]; time of less involvement [thick arrow]). B, Irregular bitemporal
delta (ovals) present in the same patient. Note the midtemporal localization and
appearance of right midtemporal delta slowing at different times during video-EEG
monitoring performed for quantification of subclinical seizures and subtle seizures
without awareness.
The prevalence of interictal epileptiform discharges on EEG is related to

multiple factors. Nevertheless, EEG is persistently “negative” in about 10%
to 15% of people with epilepsy.3 Sleep is the best modulator of interictal
epileptiform discharges and seizures and is activating in about one-third of
patients with epilepsy and preferentially affecting those with genetic generalized
epilepsies.3 However, sleep may alter the frequency, morphology, and location
of interictal epileptiform discharges. In patients with focal epilepsies, bilateral

EEG AT A GLANCE
FIGURE 2-23
Left anterior temporal intermittent rhythmic delta activity (TIRDA) (oval) in the EEG with a
left regional temporal spike (arrow) in second 5. TIRDA is strongly associated with temporal
lobe epilepsy, unlike other forms of intermittent rhythmic delta activity. In this case,
“intermittent” appears continuous during an epoch of a prolonged burst.
FIGURE 2-24
Amplitude asymmetry (rectangles over the left hemisphere) with greater than 50% difference
in the left-right voltage. Diffuse attenuation (arrow in second 6) and background slowing is
also present in a 46-year-old woman with an intraparenchymal hemorrhage after rupture of a
berry aneurysm with a subsequent left hemicraniectomy. Focal asymmetries associated with
focal slowing are abnormal.
280 APRIL 2022

FIGURE 2-25
Left midtemporal breach rhythm in a 26-year-old woman with prior left temporal lobectomy
for drug-resistant temporal lobe epilepsy. She was seizure free for 2 years, and EEG was
obtained to evaluate the risk of antiseizure medication taper. No interictal epileptiform
discharges were present. Note the breach rhythm (arrows) were associated with left
temporal theta and delta slowing.
FIGURE 2-26
EEG in a 21-year-old with juvenile myoclonic epilepsy with 4.5-Hz left greater than right
generalized spike-and-wave (oval) 1-second burst. A “fast” frequency is present at 4.44 Hz
(see inset). Note the written entries made by the technologist on the left-hand side of the
EEG (the annotation viewer) indicating frequent generalized spike and waves. Left
hemispheric predominance can be seen in this discharge but no focal evidence to support
secondary bilateral synchrony.

EEG AT A GLANCE
FIGURE 2-27
Right temporal seizure evolving. Note the obscuration by bitemporal artifact at onset (A,
arrows), right temporal maximum with T8 phase reversal (B, arrow), right hemispheric
predominance (C, arrows) before bilateral rhythmic ictal theta, and abrupt termination and
postictal background attenuation (D, arrow).
discharges may appear, and polyspike formation and slower interspike intervals
may emerge in deeper stages of sleep as interictal epileptiform discharges may
become irregular. Overnight recording with ambulatory EEG may reveal
interictal epileptiform discharges on awakening in patients with genetic
generalized epilepsy (FIGURE 2-28). Patients with genetic generalized epilepsy
treated with valproate may suppress generalized spike and wave on EEG.
Lamotrigine may reduce photosensitivity, and benzodiazepines may reduce
interictal epileptiform discharges acutely. However, in patients with focal
epilepsies, antiseizure medication does not significantly alter the interictal
epileptiform discharge frequency. Electrographic or electroclinical focal seizures
have a characteristic EEG pattern beginning abruptly at onset, evolving in
frequency and spatial distribution, followed by an abrupt offset with postictal
slowing (FIGURE 2-27). With scalp EEG, the location of interictal epileptiform
discharges and focal seizures does not always indicate the same location for the
source of abnormality or epileptogenicity.
Asymptomatic individuals may rarely demonstrate interictal epileptiform
discharges. EEGs with centrotemporal spikes, occipital spikes, and a self-limited
photoparoxysmal response may manifest in people as an inherited trait,
independent of clinical seizures. Congenital blindness (“needle spikes”), cerebral
palsy (central spikes), autism spectrum disorder (temporal spikes), a sibling/
282 APRIL 2022

KEY POINTS
● People who experience a

first seizure are at risk for
recurrence when EEG
demonstrates abnormal
interictal epileptiform
discharges.
● When history and other

imaging modalities are
considered in addition to an
ictal EEG, epilepsy
syndromes can usually be
defined for the purpose of
providing optimal
treatment.
FIGURE 2-28
Ambulatory EEG without video demonstrating a 5-second burst of generalized spike-and-
wave discharges (oval) detected in a patient with sleep-related epilepsy shortly after
awakening with episodes of morning confusion.
family member with epilepsy (generalized spike and wave), and medications
(eg, antipsychotics, lithium, baclofen) (atypical generalized spike and wave)
may demonstrate interictal epileptiform discharges as an epiphenomenon of a
nonepileptic condition.
People who experience a first seizure are at risk for recurrence when EEG
demonstrates abnormal interictal epileptiform discharges (CASE 2-2). Overall,
routine EEG yields interictal epileptiform discharges in approximately one-third
of initial recordings in patients who are referred for evaluation of seizures. For
some patients, the yield increases when performed within 24 hours of a seizure,
after sleep deprivation, or when the recording duration is prolonged.24 Repeating
several EEGs increases the yield even further. When interictal epileptiform
discharges are present on EEG, level A evidence supports the likelihood of
seizure recurrence within the first 2 years.25 An abnormal nonepileptiform EEG
increased the risk of recurrence to 40%, but interictal epileptiform discharges
increased the risk to more than 60% to establish a working diagnosis of
epilepsy,23 prompting discussion with patients regarding antiseizure
medication.25 Reevaluating patients who are seizure free for 2 to 5 years with EEG
is less predictive when antiseizure medication taper is considered.3,25,26
The risk is favorable when interictal epileptiform discharges remit and greater
risk is present when interictal epileptiform discharges persist, especially when
they include generalized polyspike and wave and generalized spike and wave
(FIGURE 2-31).27
ICTAL EEG CLASSIFIES EPILEPSIES

Seizure type(s) and epilepsy syndromes are classified based on event-related
signs and symptoms of an event, supplemented with EEG, MRI/CT, and
laboratory findings.27 When history and other imaging modalities are

EEG AT A GLANCE
considered in addition to an ictal EEG, epilepsy syndromes can usually be

defined for the purpose of providing optimal treatment.28 Focal seizures
are the most common form of human adult epilepsies, and temporal lobe
epilepsy is the most common syndrome.29 In temporal lobe epilepsy, spikes
are located over the anterior temporal regions in more than 90% of patients.
Bitemporal independent interictal epileptiform discharges are present in
more than one-third of cases of temporal lobe epilepsy when recording
is prolonged.
A focal aware seizure (also known as “aura”) will be visible in a standard EEG
in only 30% of cases. Focal impaired awareness seizures associated with temporal
CASE 2-2 A 45-year-old man with a history of hypertension and bipolar disorder
had no risk factors for epilepsy. He attended a social event for his job
where he reportedly drank several alcoholic beverages. He returned
home inebriated and later experienced a spell during sleep. At 2:00 AM,
his wife awoke to a guttural noise. When she turned on the light, she saw
her husband “flailing around in bed.” He was initially unarousable, but
after a minute, she noted blood trickling down the right side of his mouth,
which was caused by a tongue laceration (FIGURE 2-29). She called
emergency medical services, and he was taken by ambulance to the
closest emergency department.
He had partial recall of the
transport but denied loss of
awareness, noting “I just
had a bad dream.” Brain
CT was normal. The patient
was sleepy, but an EEG
was normal. Overnight,
bedside EEG demonstrated
bitemporal spike and
waves (FIGURE 2-30). He was
placed on antiseizure
FIGURE 2-29
medication with seizure Right lateral tongue laceration (arrow) in the patient
precautions and remained in CASE 2-2 after a first nocturnal “spell” suspected
seizure free. to be caused by a generalized tonic-clonic seizure.
COMMENT When encountering a limited historical description for spells, a witnessed

paroxysmal event, congruent symptomatology, occurrence out of sleep,
lateral tongue laceration, partial amnesia for the event, and potential
triggers portend a high risk for seizure recurrence. This establishes a
working diagnosis of epilepsy despite the occurrence of a single seizure
and should prompt discussion with the patient regarding implementation
of antiseizure medication.23 When EEG is repeated or prolonged, the yield
of identifying interictal epileptiform discharges is enhanced (TABLE 2-4). In
this case, the patient was appropriately diagnosed and successfully
treated for epilepsy.
284 APRIL 2022

lobe epilepsy manifest a unilateral temporal rhythmic 5- to 9-Hz ictal theta
discharge (VIDEO 2-2). Lateral (neocortical) temporal lobe epilepsy is more likely
to demonstrate evolving rhythmic ictal delta at seizure onset with a broad
hemispheric field of spatial distribution present. Focal or lateralized postictal
slowing is often present but is less localizing than EEG at seizure onset. Localizing
ictal EEG in patients with extratemporal epilepsies seldom occurs. Diffuse,
nonlocalized seizures are more likely to be seen with various morphologies
present. In frontal lobe epilepsies, interictal EEG is often normal and may appear
hemispheric or bifrontal, diffuse, or as midline interictal epileptiform discharges.
Secondary bilateral synchronous interictal epileptiform discharges appear
FIGURE 2-30
EEG from the patient in CASE 2-2. Bilateral independent anterior temporal spike-and-wave
complexes (arrows) with a regional temporal field of spatial distribution activated by N2
and N3 sleep are seen on overnight video-EEG monitoring. The cross-chains of the
anterior-posterior and transverse bipolar montages intersect, localizing interictal
epileptiform discharges to the temporal region.

EEG AT A GLANCE
“generalized” but reflect focal onset. Focal epilepsies with interictal epileptiform
discharges and secondary bilateral synchrony can be differentiated from
generalized spike and wave in genetic generalized epilepsy30; a lead-in time of
the initial discharge should occur for 2 seconds or more, and the morphology of
the triggering spikes should resemble other focal spikes from the same region.
Also, the morphology of focal interictal epileptiform discharges should differ
from the bisynchronous interictal epileptiform discharges. When not obscured
by artifact, the ictal EEG in frontal lobe epilepsy may demonstrate bilateral
nonlateralized voltage attenuation, slowing, or epileptiform features. Low-
voltage fast activity at seizure onset (eg, gamma activity and high-frequency
oscillations) favorably suggest a dorsolateral frontal localization. Normally it is
attenuated by the skull (or obscured by artifact) until propagated to higher-
amplitude slower frequencies detectable by scalp EEG. Interictal epileptiform
discharges in parietal and occipital lobe epilepsies are infrequent. Like the ictal
EEG of frontal lobe epilepsy, the EEG is poorly localized, bilateral, or even falsely
lateralized to the ipsilateral temporal region and rarely has well-localized seizures
(FIGURE 2-32) and interictal epileptiform discharges.31
In generalized epilepsies, the discharges present in EEG are symmetrical,
synchronous, frontally dominant, generalized spike and wave, and generalized
polyspike and wave recurring at 3 Hz or higher. Interictal epileptiform discharges
on EEG in conjunction with a normal background typically are present in genetic
generalized epilepsy syndromes, yet no generalized interictal epileptiform
discharges are specific for a seizure type or epilepsy syndrome.32 Most seizures
provoked by activation are absences or myoclonic seizures and rarely a
generalized tonic-clonic seizure.33 Interictal features of genetic generalized
epilepsy are nonspecific and may demonstrate generalized spike and wave,
generalized polyspike and waves, or a combination that is associated with one or
a combination of generalized seizures including myoclonus, absence, and
generalized tonic-clonic seizures. Generalized interictal epileptiform discharges
appear bilateral with maximal voltage present in the anterior head regions of the
EEG. Lateralized (FIGURE 2-26) or “fragmented” generalized interictal
epileptiform discharges, like the appearance of lateralized seizure behavior, may
TABLE 2-4 Recommendations to Identify Interictal Epileptiform Discharges
◆ Waveforms differ in duration (frequency) from the surrounding background activity

◆ The amplitude of the waveform stands out from the background, and the waveform disrupts
the ongoing background activity
◆ The waveform has an asymmetric contour with a steep upslope relative to the downstroke
◆ Waveforms may be either diphasic or triphasic with a pointed peak
◆ The waveform is often followed by an aftergoing slow wave
◆ The waveform coexists in the area of abnormality (eg, a sharp wave occurs in the same region
as focal slowing), and the orientation of the dipole corresponds with a source in
the brain
Independently, none of the criteria qualify individually to distinguish an interictal epileptiform discharge or
not.22
286 APRIL 2022

KEY POINT
● Selection of antiseizure
medication may be guided
by EEG when the historical
recount for an observed
manifestation is unable to
classify the seizures or an
epilepsy syndrome.
FIGURE 2-31
Burst of generalized bifrontally dominant 5- to 5.5-Hz polyspike and spike-and-slow-wave
discharges (oval) asymptomatic during drowsiness. This 22-year-old woman reported
generalized tonic-clonic seizures at night beginning at age 12. Video-EEG monitoring
demonstrated absence seizures on awakening and a syndromic diagnosis of juvenile
absence epilepsy.
confuse accurate classification of generalized seizures and incorrectly lead to the

false diagnosis of focal epilepsy. Selection of antiseizure medication may be
guided by EEG when the historical recount for an observed symptomatology is
unable to classify the seizures or an epilepsy syndrome.
Diffuse or multifocal structural brain pathology is present in patients with
epileptic encephalopathies and developmental disorders. Cognitive comorbidity
FIGURE 2-32
Continuous EEG in the intensive care unit with left occipital focal subclinical seizure (arrows).
Occipital seizures are rarely well localized to one hemisphere as in this case. Note the
evolving field and the annotation viewer with more than 40 nonclinical seizures.

EEG AT A GLANCE
is felt to be exacerbated by frequent interictal epileptiform discharges on EEG.34 A

symptomatic etiology is represented by diffusely slow background activity and
focal or multifocal nonepileptiform and epileptiform features. An interictal EEG
demonstrating slow spike and waves (FIGURE 2-33) is the hallmark of Lennox-
Gastaut syndrome, the prototypic epileptic encephalopathy. A diffusely slow
background, multifocal independent spike discharges, and bursts of generalized
paroxysmal fast activity (FIGURE 2-34) are characteristic features. EEG with
generalized paroxysmal fast activity manifest as 10- to 25-Hz frontally dominant
spikes during non–rapid eye movement (REM) sleep correlates with tonic seizures.
LONG-TERM EEG MONITORING

Standard EEG has utility for diagnosis and treatment in patients with epilepsy
(TABLE 2-5). Long-term EEG monitoring encompasses several forms of video-
EEG monitoring including short-term scalp video-EEG, ambulatory EEG
with video, and inpatient continuous EEG with video in the epilepsy monitoring
unit or ICU.35 Ambulatory EEG with video recorded over 24 to 72 hours is a
portable, outpatient strategic alternative to inpatient video-EEG monitoring
when a high diagnostic pretest probability is present (FIGURE 2-28), but inpatient
video-EEG monitoring is required for safe withdrawal of antiseizure medication
to characterize the electroclinical seizure onset zone for epilepsy surgery.
The yield of video-EEG monitoring for nonspecific “spells” is high. A definitive
diagnosis of epilepsy is established when epileptiform activity is present during a
seizure, and a nonepileptic event is supported by the absence of physiologic
changes in the EEG background activity during a paroxysmal neurologic
event where awareness is lost (FIGURE 2-35). When a clinical seizure is
accompanied by an ictal discharge on EEG, an epilepsy diagnosis is confirmed,
and seizure classification (FIGURE 2-36) may be deduced for management.
FIGURE 2-33
Slow spike and waves (rectangle) in a patient with Lennox-Gastaut syndrome. Note the 2-Hz
interspike frequency and diffusely slow background of 5 Hz.
288 APRIL 2022

FIGURE 2-34
Generalized paroxysmal fast activity (oval) with mixed left temporal polysharp and slow
waves followed by a burst of slow spike and waves (thick arrow) and bifrontal sharp waves
(thin arrow).
Utility of EEG in People With Epilepsy TABLE 2-5
Diagnosis
◆ Provide objective support for a clinical diagnosis of epilepsy
◆ Evaluate patients with paroxysmal neurologic events for the presence or absence of
epileptiform activity
◆ Classify focal versus generalized seizure type(s) and epilepsy syndrome(s)
◆ Quantify seizure frequency and burden of epileptiform activity
Treatment
◆ Assess recurrence risk after a first seizure to determine treatment need
◆ Select antiseizure medication based on seizure/epilepsy classification
◆ Estimate risk of seizure relapse when planning antiseizure medication withdrawal
◆ Characterize the electroclinical features of seizures for surgical therapya
◆ Monitor the course of antiseizure medication treatment (eg, during critical care)a
◆ Aid neurosurgeons during brain surgery to identify regions of importancea
a
Continuous EEG is needed.

EEG AT A GLANCE
The cumulative yield of EEG to record interictal epileptiform discharges

during long-term EEG monitoring increases relative to the duration of
recording.
A significant minority of people are self-unaware of experiencing seizures
despite impaired consciousness and overt signs that are visible to other individuals.
Approximately 20% to 30% of patients are never aware of their seizures.36
Nocturnal seizures (FIGURE 2-28), subclinical (electrographic) seizures
(FIGURE 2-37), and focal seizures without self-awareness may be objectively
quantified with long-term EEG monitoring. In patients experiencing frequent
seizures or events, such as those with Lennox-Gastaut syndrome (FIGURE 2-33
and FIGURE 2-34), short-term outpatient EEG may provide information on event
frequency and duration.37 EEG may be modified by antiseizure medication,
which can reduce interictal epileptiform discharges.38 Selected patients with
drug-resistant focal epilepsy who have their source localized on scalp ictal EEG
patterns in noneloquent regions confirmed by long-term EEG monitoring are
favorable candidates for epilepsy surgery, whereas those with a multifocal or
poorly localized seizure onset have a less successful outcome (CASE 2-3).39
Classification of focal versus generalized seizures and epilepsies may at times
be challenging. Juvenile myoclonic epilepsy (JME) is a “great mimicker” and the
most common genetic generalized epilepsy, representing about 10% of all
epilepsies. Fast spike-and-wave runs and prolonged epileptiform bursts of
3 seconds or longer, including photoparoxysmal and hyperventilation-induced
runs, were associated with persistent seizures in JME.40 Seizure onset in
adolescence and myoclonus are the cornerstone of JME, but generalized
tonic-clonic seizures occur in more than 90% of patients and usually prompt
evaluation and management. Standard EEG is often normal, but interictal
epileptiform discharges composed of “fast” (3 to 6 Hz) generalized spike-and-
wave and generalized polyspike-and-wave discharges (FIGURE 2-28) arise mostly
FIGURE 2-35
EEG during a psychogenic nonepileptic attack with unresponsiveness with normal EEG.
During nonepileptic movements, artifact may impair the ability to observe the underlying
cerebral activity. Anterior “slowing” (oval) is caused by eye flutter artifact validated by eye
movement monitors that show “out-of-phase” deflection (arrows).
290 APRIL 2022

KEY POINTS
● A significant minority of
people are self-unaware of
experiencing seizures
despite impaired
consciousness and overt
signs that are visible to other
individuals.
● Video-EEG classifies
focal and diffuse cerebral
dysfunction and can support
an epilepsy syndromic
diagnosis that aids in
medical and surgical
management.
FIGURE 2-36
Prolonged burst of generalized 3- to 4-Hz generalized spike and waves (rectangle) without
response testing. The duration of 7 seconds carries a concern for brief alteration of
awareness. Spike-and-seizure burden can be quantified during long-term EEG monitoring.
from sleep. Ictal EEG in JME demonstrates symmetrical generalized frontally

dominant 10- to 16-Hz polyspike discharges coalescing into continuous myogenic
artifact with tonic stiffening; these are followed by phasic myogenic artifact
during clonic jerking (FIGURE 2-38), terminating with postictal generalized EEG
suppression. Photosensitivity is observed in 30% of patients. Although focal and
generalized epilepsies can coexist, it is quite rare.30
FIGURE 2-37
Subclinical seizure (arrows) due to a left hemispheric intraparenchymal hemorrhage in a
59-year-old comatose man. Evolution was subtle and enhanced by using a 15-mm/s (slow)
display speed.

EEG AT A GLANCE
CRITICAL CARE EEG

Standard EEG is helpful when evaluating hospital and ICU patients with
encephalopathy, changes in cognition and behavior, disorders involving
ischemic brain disease, intermittent and episodic movements, and coma and has
been used as an adjunct in the clinical determination of brain death.41
Continuous EEG monitoring in critically ill patients in the ICU has been
increasingly used to identify and quantify nonconvulsive seizures and status
epilepticus and assist with management decision-making in refractory cases.
Standardized critical care terminology has been validated for clinical use.15
Background abnormalities are common in hospital-based EEG and continuous
EEG recordings. Background slowing of the EEG ranges from mild to severe and
CASE 2-3 A 32-year-old man had seizure onset at 12 years of age, which became
uncontrolled by antiseizure medication resulting in his referral for
presurgical evaluation. When he presented for evaluation after 20 years
of recurrent seizures, they were manifested by a “warning” right before
he would experience a convulsion with a frequency that occurred every
other month. Brain MRI revealed a right temporal lobe lesion consistent
with the radiographic appearance of a meningioma. Phenytoin,
oxcarbazepine, levetiracetam (brief trial limited by side-effects), and
lacosamide in low doses had been ineffective. Standard EEGs were
normal.
During video-EEG monitoring, oxcarbazepine 600 mg orally 2 times a
day and lacosamide 100 mg orally 2 times a day were tapered, and
overnight long-term video-EEG recorded frequent (hourly) bursts of 4- to
4.5-Hz generalized spike-and-wave and generalized polyspike-and-
wave discharges lasting up to 12 seconds. Intermittent photic stimulation
produced a self-limited photoparoxysmal response with subtle upper
body myoclonus reported by the patient to represent his “warning.” On
the morning of day 3 of video-EEG monitoring, a generalized tonic-clonic
seizure of nonfocal origin was captured and preceded by myoclonus.
Drug-resistant juvenile myoclonic epilepsy (JME) was successfully
treated with valproate monotherapy, and surgery was deferred to
neurosurgical follow-up for ongoing surveillance by annual brain MRI with
intervention if growth occurred or the lesion became symptomatic.
COMMENT Warnings are usually associated with focal seizures. In this case, focal
epilepsy was initially suggested in association with a focal structural lesion
on brain MRI. Furthermore, the presence of resistance to more than two
antiseizure medications was redefined as “pseudo–drug resistance”
following confirmation of a genetic generalized epilepsy syndrome by
video-EEG monitoring. By accurately identifying the epilepsy syndrome as
JME, the appropriate antiseizure medication could be instituted. By
defining and classifying a genetic generalized epilepsy, the meningioma
was determined to be asymptomatic, and unnecessary surgery was
therefore avoided.
292 APRIL 2022

FIGURE 2-38
Generalized tonic-clonic seizure in a 19-year-old man with reflex photosensitive epilepsy
triggered during photic stimulation. The red bars at the bottom reflect stimulations. The
stimulator was moved away from the patient to allow the technologist to attend to the
patient. Display speed was 10 mm/s. Note the tonic phase (X) and clonic phase (Y).
includes focal, hemispheric, diffuse, and multifocal slowing; low-voltage EEGs;

burst suppression; and electrocerebral inactivity.42 Postsurgical EEGs may
demonstrate a breach rhythm (FIGURE 2-25) where higher amplitudes and faster
frequencies make normal rhythms appear “spikier,” mimicking a pathologic
interictal epileptiform discharge.
Periodic patterns (a discharge repeating itself for at least six cycles) occurring
in critically ill patients are well established.15 Morphology of the periodic patterns
varies. They may or may not be associated with fast activity (FIGURE 2-39).
FIGURE 2-39
Right central lateralized periodic discharges (LPDs) plus fast activity at 1 Hz (ovals) during
standard EEG. Later, continuous EEG performed in this 55-year-old man with persistent
unexplained altered mental status after operation for a right perirolandic glioblastoma
recorded serial nonconvulsive seizures.

EEG AT A GLANCE
FIGURE 2-40
EEG depicting encephalopathy. A, Diffuse slowing of the posterior-dominant rhythm to 5 Hz
with continuously intermixed delta and triphasic waves in a 78-year-old woman with end-
stage renal disease and a syncopal episode during hemodialysis. Note the triphasic
morphology (circle) and “anterior-posterior lag” of the waveform from the frontal to the
occipital derivations (oval ). B, EEG in a 91-year-old man with generalized periodic discharges
with triphasic morphology (arrows) associated with postinfarction focal epilepsy. He was
admitted for acute mental status changes and urosepsis after he was found on the floor at
home by his daughter. Despite a treatment challenge with benzodiazepine administration, the
patient did not improve. The clinical course ultimately resulted in a fatal outcome.
Lateralized periodic discharges (LPDs) and LPDs plus fast activity (LPD+F) are
strongly associated with seizures and status epilepticus.43 Independent bilateral
LPDs have a periodic pattern; the periods and morphologies arising from each
hemisphere differ and reflect diffuse cortical injury (ie, hypoxia). Lateralized
rhythmic delta activity, like LPDs, is an EEG pattern strongly associated with
seizures43,44 Generalized periodic discharges (GPDs) are bilateral synchronous
symmetrical discharges. GPDs include many morphologies, including GPDs with
294 APRIL 2022

a triphasic morphology (FIGURE 2-40A), that reflect diffuse cerebral gray KEY POINTS
matter dysfunction.
● EEG is the only test in
When nonconvulsive seizures and nonconvulsive status epilepticus occur, critically ill patients with
EEG is the only means of arriving at the diagnosis when no clinical signs are altered mental status that
present. Therefore, continuous EEG is useful in demonstrating ongoing can result in the diagnosis of
electrographic seizures and nonconvulsive status epilepticus to implement or nonconvulsive seizures and
nonconvulsive status
modify treatment.45 Criteria for diagnosing nonconvulsive status epilepticus
epilepticus.
include the presence of at least 25 epileptiform discharges/10-second epoch or
2.5 discharges/s. When discharges are 2.5/s or less or rhythmic delta/theta exceeds ● The goals of therapy for
0.5/s, an additional criterion must be present. This includes clinical and EEG ongoing nonconvulsive
improvement from antiseizure medication administration (FIGURE 2-40B), the seizures and nonconvulsive
status epilepticus aim at
presence of subtle ictal clinical features, or spatiotemporal evolution of achieving seizure
epileptiform activity.46 Quantitative EEG and trend analysis of the ICU EEG suppression on continuous
(FIGURE 2-41) is a useful adjunct to raw continuous EEG when utilized over long EEG and reducing cerebral
periods of time (CASE 2-4).19 metabolic rates by achieving
a burst-suppression pattern.
INTRACRANIAL EEG
During noninvasive presurgical evaluations with scalp EEG (FIGURE 2-45),
attempts to localize the source may fail. Deep-seated and interhemispheric foci,
discordant noninvasive evaluations, and cases of false localization merit
intracranial EEG to lateralize and localize one or more seizure onset zones.49
Intracranial EEG recording methods vary by institution, although depth
electrodes and stereo-EEG, subdural grids and strips, foramen ovale electrodes,
and epidural pegs may be used alone or in combination. Intracranial EEG has a
high signal-to-noise ratio when recording brain signals, and therefore, it is less
subject to artifact but prone to sampling biases. Waveform frequencies are the
same as those on scalp EEG. Interictal epileptiform discharges on intracranial
EEG are more likely to accurately reflect the seizure onset zone when they are
FIGURE 2-41
Intensive care unit EEG and trending. A 45-year-old woman with aphasia and right
hemiparesis underwent a left craniotomy for resection of a high-grade glioma. Standard
EEG showed left frontal lateralized periodic discharges (LPDs). Continuous EEG in the
intensive care unit (raw EEG on the left, trends on the right) detected serial subclinical
seizures with waxing and waning ictal EEG (oval) that persisted after treatment. Here, the fast
Fourier transform and rhythmicity spectrogram (not the seizure probability algorithm) best
reflected ongoing seizures (arrows).

EEG AT A GLANCE
CASE 2-4 A 67-year-old man presented as a stroke alert after awakening with
“garbled speech” and left-sided weakness (last well time 12 hours prior).
He had a history of hypertension, coronary artery disease, and
hyperlipidemia. A prior transient ischemic attack (transient aphasia)
occurred 2 months before admission.
In the emergency department, he was aphasic with right hemiplegia.
Diffusion-perfusion brain MRI showed early signs of a left middle cerebral
artery ischemic infarction. He underwent emergency angiography with
thrombectomy and was transferred to the intensive care unit (ICU) on
thrombolytics. He began to be unresponsive with continuous right face
and head twitching. A stat EEG demonstrated left frontotemporal
lateralized periodic discharges (LPDs) and LPDs plus fast activity (LPD+F)
at 1 Hz. Subsequently, he was administered levetiracetam, and continuous
EEG demonstrated serial nonconvulsive seizures despite treatment with
lorazepam, levetiracetam, and valproate. Ketamine was then begun and
titrated to burst suppression on continuous EEG. The goals of therapy for
ongoing nonconvulsive seizures and nonconvulsive status epilepticus aim
at achieving seizure suppression on continuous EEG and reducing cerebral
metabolic rates by achieving a burst-suppression pattern. However,
despite maintaining burst suppression with administration of anesthetics
and antiseizure medication, seizures were intermittently present
(FIGURE 2-42) as anesthetics were withdrawn. With continued treatment, the
seizures became infrequent, and the patient’s mental status improved
with reduction of anesthetics. He reached the point where he was able to
be stabilized and discharged from the hospital to a rehabilitation facility
for ongoing therapy.
FIGURE 2-42
EEG of the patient in CASE 2-4 who had a left hemispheric focal seizure arising from iatrogenic
burst suppression pattern. This 67-year-old man in a coma had super-refractory status
epilepticus with ongoing electrographic seizures arising from the left parietal region (arrow).
Compressed display speed (10 mm/s) highlights EEG bursts (ovals) in seconds 2 to 3, 15 to 16,
and 32 to 33 before the seizure.
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An EEG demonstrating LPDs usually reflects an acute or subacute injury of COMMENT
the cortex. Infrequently, LPDs reflect a postictal feature or acute
reactivation of an underlying chronic structural lesion. Stroke is the most
commonly encountered structural etiology generating LPDs but probably a
reflection of the prevalence as opposed to specificity. LPDs on EEG are
high-voltage periodic or semiperiodic discharges, often every 1 to
2 seconds, correlated with focal seizures.44 LPD+F on EEG is a high risk for
status epilepticus; their finding on standard EEG should prompt further
investigation with continuous EEG. Continuous EEG monitoring in the ICU
and special care units provides dynamic information about seizures and
brain function.47 Electrographic status epilepticus must be 10 minutes or
longer or a total duration of 20% or more of any 60-minute recording
period.48 Seizures on EEG are 10 seconds or longer but may be briefer when
accompanied by clinical signs. Brief potentially ictal rhythmic discharges
(BIRDs) can be focal or generalized rhythmic activity greater than 4 Hz and
between 0.5 seconds and less than 10 seconds (FIGURE 2-43). Like stimulus-
induced rhythmic periodic ictal discharges (FIGURE 2-44), BIRDs lie on the
ictal-interictal continuum.
FIGURE 2-43
Brief potentially ictal rhythmic discharge (BIRD) (oval). This BIRD was seen multiple times
in a patient with subclinical seizures and symptomatic occipital lobe epilepsy.
CONTINUED ON
PAGE 298

EEG AT A GLANCE
CONTINUED FROM
PAGE 297
FIGURE 2-44
Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) usually accompany other
EEG abnormalities such as lateralized periodic discharges (LPDs) or lateralized rhythmic
delta activity found in patients in the intensive care unit, including subclinical seizures.
Notice the increase in right frontal spiking that occurs after applying a sternal rub.
high amplitude and frequent with a short interspike interval (FIGURE 2-46).
Interictal epileptiform discharges are more frequent on intracranial EEG than
scalp EEG and often extend outside the region of seizure onset. Because
intracranial EEG has greater spatial-temporal resolution than scalp EEG, it is
more likely to detect seizures early. Diffuse attenuation and multiple-electrode
involvement of intracranial EEG at seizure onset suggest a propagated pattern.
FIGURE 2-45
EEG taken from a Wada test by using methohexital where left hemispheric spike and waves
(ovals) were precipitated in a prolonged run after injection in the left internal carotid artery.
298 APRIL 2022

FIGURE 2-46
Subdural intracranial EEG with repetitive sharp waves (single arrow) and seizure termination
(double arrow) during a phase 2 evaluation. A 64-channel grid over the frontoparietal region
and two 1 x 6 strips in the left temporal and inferior parietal region approximated a region of
possible focal cortical dysplasia. This patient had drug-resistant extratemporal focal
epilepsy and recurrent right focal motor seizures.
Intracranial EEG is also used for functional brain mapping by using direct
electrocortical stimulation (FIGURE 2-47) for prognostication before epilepsy
surgery, and via neuromodulation and after localization using thermocoagulation
to provide treatment.3,49 Because of greater sensitivity, intracranial EEG can
identify high-frequency oscillations (brief high-frequency bursts in bandwidths
subserved by gamma, ripples, and fast-ripples bandwidths) that are felt to
represent areas of epileptogenesis. (TABLE 2-2).
ELECTROCORTICOGRAPHY
Electrocorticography may be performed extraoperatively, although it usually
refers to intraoperative EEG associated with direct brain recording. One use of
electrocorticography in epilepsy (or lesional) surgery is mapping areas of the
cortex associated with interictal epileptiform discharges before tailoring
surgical resection or suggesting postresection prognosis.50 Electrocorticography is
also used to monitor for afterdischarges (FIGURE 2-47) during direct electrocortical
stimulation performed for functional brain mapping.51 Language, motor, and
sensory cortices are defined by using direct superficial or deep electrical
stimulation directed by a wand handheld by the neurosurgeon. Compared
with intracranial EEG, intraoperative electrocorticography has brief recording
periods, less sustained discomfort, and lower risk from electrode placement.
However, commercially available electrocorticography has limited sampling
from electrodes (FIGURE 2-48) as well as electrode placement. Resection of high-
frequency oscillations present on electrocorticography (and intracranial EEG)
has shown predictive value in localizing the seizure onset zone in neocortical
epilepsies to forecast a favorable surgical outcome.52

EEG AT A GLANCE
FIGURE 2-47
Direct electrocortical stimulation for 4 seconds at 2 mA during intraoperative
electrocorticography that resulted in a regional afterdischarge (arrows). The insert displays
the location of a 64-channel high-density grid, depth electrode placement that was
evaluated before the use of a customized circular electrode for real-time
electrocorticography during functional brain mapping and surgery.
FIGURE 2-48
High-density 64-channel electrocorticography with 2-mm sensors, spaced 5 mm apart,
recorded focal periodic epileptiform discharges (arrows) in a patient undergoing awake
craniotomy for resection of a high-grade glioma. Note the restricted field of spatial
distribution that is confined to 1 cm.
300 APRIL 2022

OTHER EEG RECORDING TECHNIQUES
EEG, among other neurophysiologic techniques, helps determine brain
function.19 The evidence is good for successful temporal and extratemporal
source localization using EEG source localization/imaging to identify the
“inverse solution” from a scalp EEG–generated location.53,54
Long-term intracranial electrocorticography is now possible on an
outpatient basis with neuromodulation devices (FIGURE 2-49). High-density
EEG augments the standard 10-20 international system of electrode
placement and typically utilizes 64 channels or more to record EEG.
High-density EEG can demonstrate highly focal abnormalities beyond
the resolution of standard EEG.55 Computerization enables high-density
EEG recording with high temporal resolution and good spatial resolution
of subcortical regions in the study of scalp-based brain dynamics.56
Computer-assisted EEG source localization (FIGURE 2-50) of dipolar and
distributed EEG sources and signal analysis localizes the source through
enhanced computational capability seen with digital technology. Research
use of microwires recording from single columns of neuronal activity has
revealed microseizures at the neuronal level.57
CONCLUSION
To interpret abnormal interictal EEG, knowledge of the “gray areas” and boundaries
of normal is essential. Patients with seizures and epilepsy are best suited for
evaluation with EEG with practical implications for diagnosis, management, and
prognosis. Long-term EEG with video provides dynamic information in patients
who need a definitive diagnosis or those with drug-resistant epilepsy evaluated for
surgery. Effective use of continuous EEG has identified nonepileptiform and
epileptiform features in patients with acute and chronic brain disorders and can
quantify nonconvulsive seizures to guide patient management. In the operating
room, like in the epilepsy monitoring unit, electrocorticography may be used for
localizing areas of functional brain via direct electrocortical mapping. Intracranial
EEG has been associated with presurgical evaluation of patients with drug-resistant
epilepsies but is increasingly used outside hospital-based epilepsy monitoring units
with advances in neuromodulation. Whether EEG is performed in the clinical
neurophysiology laboratory, special care units in the hospital, or the home setting, it
provides unique information unparalleled by other testing modalities. The limits of
FIGURE 2-49
Electrocorticogram in a patient with a responsive neurostimulator implanted with recording
and treating bitemporal depth electrodes. Note the initial detection and repetitive electrical
stimulations (arrows) that did not abort this focal impaired awareness seizure.

EEG AT A GLANCE
FIGURE 2-50
EEG source localization. Waveforms presented as raw EEG and modeled as a spherical
source, topographic map, and butterfly chart. The 256-channel high-density EEG obtained
in a 59-year-old woman after right temporal resection revealed source localization in the
residual right lateral temporal neocortex. Note the topographic map with interictal
epileptiform discharges (circle) reflects averaged interictal epileptiform discharges
(thin arrows) on the spherical head model (thick arrow). Blue is the negative end of the
dipolar source measured.
learning EEG from primers lies in visualizing a single “classic” example. With the
myriad of waveform variations involving one example, the permutations of each
waveform are infinite.
VIDEO LEGENDS
VIDEO 2-1 VIDEO 2-2
Right temporal artifact on EEG due to tremor. Focal impaired awareness seizure of right temporal
Video clarifying right temporal artifact on EEG. Note lobe origin. Focal impaired awareness seizure of
that the tremor while the patient is holding the right temporal lobe origin during video-EEG monitoring
telephone over his right ear produces a local for presurgical evaluation. Note the initial stare,
multiple-electrode artifact simulating a right vocalization, and oroalimentary and bimanual
temporal electrographic seizure. automatisms with the ability to retain “ictal speech.”
This symptomatology and ictal EEG support a temporal
© 2022 American Academy of Neurology and nondominant hemispheric origin.
© 2022 American Academy of Neurology
USEFUL WEBSITE
AMERICAN CLINICAL NEUROPHYSIOLOGY SOCIETY
This website provides links to guidelines
pertinent to understanding EEG performance.
acns.org/practice/guidelines
302 APRIL 2022

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REVIEW ARTICLE

Neuroimaging of Epilepsy
C O N T I N UU M A UD I O By Samuel Lapalme-Remis, MDCM, MA, FRCPC;
I NT E R V I E W A V AI L A B L E Dang K. Nguyen, MD, PhD, FRCPC
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of imaging modalities,
important imaging pathologies, and the role each imaging modality can
play in the diagnosis, evaluation, and treatment of epilepsy, including
epilepsy surgery.
RECENT FINDINGS: The Harmonized Neuroimaging of Epilepsy Structural

Sequences (HARNESS-MRI) protocol was proposed to standardize MRI
imaging for all patients with seizures. The role of 7-Tesla MRI in finding
previously occult epileptogenic lesions is under investigation, and the
technique is increasingly used. Developing MRI postprocessing techniques
can increase the sensitivity of MRI. Improvements in functional imaging
techniques such as EEG–functional MRI (fMRI) and magnetic source
imaging provide complementary methods of identifying seizure foci. New
epileptogenic pathologies such as multinodular and vacuolating neuronal
tumors (MVNT) are being discovered, and the importance of others, such
as encephaloceles, is better appreciated.
SUMMARY: Brain imaging is a critical component of the diagnosis and

evaluation of patients with epilepsy. Structural imaging modalities such as
MRI and CT allow for the identification of a wide variety of potentially
epileptogenic lesions. For patients with drug-resistant epilepsy under
consideration for resective surgery, both structural and functional
neuroimaging may be needed for focus identification and surgical planning
for preservation of neurologic function.
CITE AS:
2022;28(2, EPILEPSY):306–338.
INTRODUCTION
E
Address correspondence to
Dr Nguyen, 1000 Saint-Denis,
pilepsy is a paroxysmal disease of the brain that presents diagnostic and
Montreal, Quebec, H2V 2L9, treatment challenges for neurologists. From the beginning of the
Canada, d.nguyen@umontreal.ca. disease course, brain imaging assists neurologists in reaching the
RELATIONSHIP DISCLOSURE: correct diagnosis, selecting initial treatments, and estimating the
Drs Lapalme-Remis and Nguyen prognosis for treatment response. For patients whose disease later
report no disclosures.
demonstrates resistance to pharmacologic treatments, neuroimaging becomes
UNLABELED USE OF even more important when considering epilepsy surgery because multiple
PRODUCTS/INVESTIGATIONAL imaging modalities are often necessary to maximize the likelihood of localizing
USE DISCLOSURE:
Drs Lapalme-Remis and Nguyen
the epileptogenic onset zone, thus optimizing seizure freedom and minimizing
report no disclosures. the risk of neurologic impairment.
Traditionally, epilepsy was diagnosed after a patient had at least two
© 2022 American Academy unprovoked seizures occurring greater than 24 hours apart. A definition
of Neurology. proposed by the International League Against Epilepsy (ILAE) in 2014 allows for
306 APRIL 2022

a new scenario in which the diagnosis of epilepsy can be made before the second KEY POINTS
seizure arises.1 When a patient has a single documented seizure and clinical
● The finding of an
evaluation identifies factors that would represent a greater than 60% risk of epileptogenic lesion on
seizure recurrence, the diagnosis of epilepsy can be made, often leading to brain imaging in a patient
treatment with an antiseizure medication. The most common factors that can with a single seizure may
lead a clinician to reach this conclusion are an epileptiform EEG abnormality or a lead to the diagnosis of
epilepsy if the treating
potentially epileptogenic lesion on structural brain imaging. An evidence-based
neurologist estimates a risk
guideline of the American Academy of Neurology (AAN) and American Epilepsy of seizure recurrence
Society on the management of an unprovoked first seizure in adults identified a greater than 60%.
significant brain imaging abnormality as associated with an increased risk of
seizure recurrence within 2 years (Level B evidence). The hazard ratio for seizure ● In adults with an
unprovoked first seizure,
recurrence in patients with abnormal brain imaging was calculated at 2.44, significant brain imaging
higher even than for patients with an EEG with epileptiform abnormalities abnormalities are associated
(hazard ratio, 2.16).2 with an increased risk of
Furthermore, it can be challenging to confirm that an event was, in fact, a seizure recurrence within
2 years.
seizure when patients are unable to recall the event, especially if it was not
witnessed. In such instances, EEG and brain imaging are helpful in establishing ● Brain imaging assists
an epilepsy diagnosis (CASE 3-1). neurologists in estimating
Beyond assistance with confirming the diagnosis, neuroimaging at an early whether a paroxysmal event
was likely a seizure,
stage may allow the neurologist to better classify the patient’s epilepsy type and
determining whether a
identify appropriate treatments. In the 2017 ILAE classification of the epilepsies, patient has epilepsy,
seizures are stratified into focal, generalized, and unknown types.3 classifying the epilepsy
Distinguishing between a focal and generalized onset may be especially difficult type, selecting treatments,
predicting the prognosis,
when patients present with bilateral tonic-clonic seizures without a clear
and completing a
description of the initial symptomatology and with inconclusive EEG data. An presurgical workup.
epileptogenic lesion on MRI can help support a focal-onset epilepsy, offering
more appropriate therapies early on and promoting early consideration of ● A first seizure associated
surgical treatment if pharmacologic treatments prove ineffective. with a cavernous
malformation is strongly
Following seizure and epilepsy types, the ILAE epilepsy classification associated with recurrent
framework stresses the importance of identifying the etiology of the epilepsy, seizures, with a 5-year risk
divided into structural, genetic, infectious, metabolic, immune, or unknown of 94%. Only about half of
cause. Many of these etiologies are diagnosed principally by neuroimaging, patients achieve seizure
freedom with antiseizure
which will guide any specific treatment of the epilepsy beyond antiseizure medications alone.
medications and help establish the prognosis.
Indeed, from the time of the first seizure, imaging data are needed to establish
the prognosis of a patient’s epilepsy and prepare the patient and their family
and/or caregiver for what may come next. As mentioned earlier, a neuroimaging
abnormality, in general, is associated with a higher risk of seizure recurrence
after a first seizure. Depending on the specific abnormality, more detail can
generally be provided and specific interventions proposed. For example, a first
seizure associated with a cavernous malformation almost assures recurrent
seizures, with a 5-year risk of 94%. When treated with an antiseizure medication,
47% to 60% of patients can achieve seizure freedom, a lower proportion than is
found among patients with all-cause epilepsy. Furthermore, a longer duration
of cavernous malformation–related epilepsy is associated with worse postsurgical
outcomes, so early surgery in such patients has been proposed after the failure of
a single antiseizure medication,4 at least in the case of patients with nondominant
temporal lobe epilepsy. Other etiologies portending a poor prognosis for seizure
control without surgery include mesial temporal sclerosis and periventricular
nodular heterotopia, the former offering a greater likelihood of seizure freedom

NEUROIMAGING OF EPILEPSY
CASE 3-1 A 29-year-old right-handed woman was seen in clinic for an episode of
loss of consciousness that had occurred 3 weeks previously during an
overnight transcontinental flight. She was on a business trip, and no
family or friends traveled with her. She had no memory of the loss of
consciousness, recalling only that she regained consciousness to find
herself lying on the floor of the aisle surrounded by flight personnel. She
was confused for a few minutes but returned to normal quickly. She had
no tongue laceration or incontinence.
The patient had not received any information about the manifestations
of the loss of consciousness from flight personnel or other witnesses and
did not seek medical care when she landed at her destination. After
returning home, she reported the episode to her family physician, who
referred her to an urgent neurology clinic. On questioning, she reported a
similar episode approximately 12 months previously, also while traveling
internationally with disturbance in her sleep schedule. Neurologic
examination was normal.
Although the episodes were
suspicious for bilateral
tonic-clonic seizures, the
patient was hesitant to
accept a diagnosis of epilepsy
or begin treatment, given the
lack of corroborating data.
An EEG obtained the same
day of the clinic visit was
normal. An EEG with sleep
deprivation and MRI were
requested within 1 week.
MRI was performed first and
revealed the presence of
periventricular nodular
heterotopia (FIGURE 3-1).
This MRI finding supported
a diagnosis of epilepsy,
and the patient FIGURE 3-1
began treatment with an MRI from the patient in CASE 3-1 identified the
antiseizure medication presence of a large periventricular nodular
without recurrence. The heterotopia (arrow) adjacent to the right lateral
ventricular atrium, seen here as a solid mass
sleep-deprived EEG was isointense to the cortex on a coronal
canceled. T2-weighted slice.
COMMENT In cases in which a diagnosis of epilepsy is suspected but unconfirmed or a

patient requires objective evidence of epilepsy beyond a clinical history to
accept a diagnosis of epilepsy, imaging revealing epileptogenic lesions
may serve to support the diagnosis. In this case, the MRI findings obviated
the need for a sleep-deprived EEG, which could have placed the patient at
a higher risk of a third seizure.
308 APRIL 2022

after surgical resection than the latter. However, adults who develop epilepsy KEY POINTS
after a stroke generally respond well to treatment5; although data are mixed, one
● In the acute setting, a CT
randomized controlled treatment trial demonstrated seizure freedom in 85% to scan of the head is often
94% of treated patients.6 necessary to ensure that
Neuroimaging is, therefore, an essential step in the evaluation of any patient the seizure was not caused
presenting with one or more possible seizures. In the acute setting, urgent by a threatening intracranial
pathology.
imaging is often necessary to ensure that a seizure was not caused by a
threatening intracranial pathology, such as a stroke, hematoma, vascular ● The International League
malformation, tumor, trauma, or infection, that might require specific and Against Epilepsy
potentially urgent treatment. The urgent imaging of patients with new-onset Neuroimaging Task Force
seizures is not discussed in this article; refer to the October 2016 Continuum issue recommends that MRI be
performed for all patients
on neuroimaging.7 But even in the clinic, at a distance from the event in an presenting with a first
apparently stable and neurologically intact patient, appropriate selection and seizure or newly diagnosed
interpretation of imaging modalities are important facets of the evaluation epilepsy where resources
of epilepsy. allow.
● The Harmonized
STRUCTURAL DIAGNOSTIC IMAGING IN EPILEPSY Neuroimaging of Epilepsy
All patients with seizures or epilepsy should receive head imaging early in their Structural Sequences
disease course as part of their basic diagnostic and prognostic workup. (HARNESS-MRI) protocol is
recommended for all
patients with seizures. It
MRI consists of three mandatory
MRI is the mainstay of epilepsy imaging; it is highly sensitive to many types of sequences and two optional
intracranial pathology and provides a level of structural detail unattainable by sequences, optimized for
3-Tesla (T) scanners but
other forms of imaging. The ILAE Neuroimaging Task Force reviewed the role of
compatible with 1.5T
MRI in epilepsy diagnosis and proposed methods to improve its yield.8 The Task scanners.
Force recommended that, resources allowing, MRI be performed for all patients
presenting with a first seizure or newly diagnosed epilepsy. Neurologists should
not rely on a report of a normal examination; if the MRI was done at another
center where the MRI protocol was suboptimal or the radiologist was not
experienced with neuroimaging of epilepsy, a repeat examination can provide
a higher yield (CASE 3-2).
To ensure that appropriate sequences are obtained and to standardize imaging
practices across different centers, the ILAE Neuroimaging Task Force
recommends using the Harmonized Neuroimaging of Epilepsy Structural
Sequences (HARNESS-MRI) protocol for all patients with seizures. This
protocol, which is optimized for 3-Tesla (T) scanners but remains compatible
with a 1.5T scanner, consists of three mandatory sequences and two optional
sequences. The sequences are summarized in TABLE 3-1. Taken together, these
sequences permit evaluation of the brain’s anatomy and morphology, pathologic
lesions, and the internal structures of the hippocampus. When clinically
indicated, the optional postgadolinium T1-weighted sequence can evaluate
tumors, vascular malformation, or infectious processes, and T2 susceptibility-
weighted imaging (SWI) is sensitive to blood products and calcifications.
CT
When MRI was first used in the early 1980s for patients with epilepsy, studies
immediately demonstrated the superiority of the new technique over CT
scanning, both in sensitivity and specificity, of identifying epileptogenic lesions.9
The importance of CT imaging in epilepsy has since been greatly reduced.
Nevertheless, being faster, cheaper, and more rapidly available, CT is often used

as the initial imaging modality in patients presenting with acute seizures to

exclude major intracranial pathology, and in environments with limited
resources, it may be the only imaging modality available. Furthermore, in the
evaluation of a limited set of pathologies, the images obtained by CT may be
complementary to those of MRI.
In particular, calcified lesions such as neurocysticercosis are well visualized on
CT and well differentiated from hemosiderin deposits, which can be challenging
on MRI. Certain tumors or tubers containing areas of calcification may also
benefit from characterization by CT as a complement to MRI. CT angiography
offers excellent resolution of many vascular abnormalities such as arteriovenous
malformations and arteriovenous fistulas and can assist with their
characterization. Finally, CT offers superior resolution of the bony skull
CASE 3-2 A 27-year-old right-handed woman was seen in the emergency

department for increased seizure frequency in the context of a 15-year
history of drug-resistant focal epilepsy. Seizures were characterized by a
sensation of thoracic pressure associated with anxiety, often followed by
a period of impaired awareness with automatisms. Seizures during sleep
were also common. The patient had recently moved from another
country, where she had been investigated for her epilepsy. A 1.5-Tesla (T)
MRI report from her original country of residence was obtained and
described a normal examination.
The patient underwent a presurgical evaluation including a repeat MRI
using a 3T scanner with the Harmonized Neuroimaging of Epilepsy
Structural Sequences (HARNESS-MRI) protocol (FIGURE 3-2); it revealed
left hippocampal sclerosis. The patient later underwent a successful left
amygdalohippocampectomy and anterior temporal lobectomy.
COMMENT Especially in the evaluation of drug-resistant focal epilepsy, neurologists

should not rely on a report of a normal MRI without examining the source
images themselves to ensure quality and accuracy or without requesting a
repeat MRI using an epilepsy protocol.
310 APRIL 2022

structures. A skull base CT can be helpful in the diagnosis of a suspected
encephalocele, confirming the location of the bone defect through which it
protrudes (FIGURE 3-3).
EPILEPTOGENIC LESIONS ON IMAGING

A great variety of different intracranial pathologies may be epileptogenic in
certain patients, but imaging may also reveal findings with no causal link to a
patient’s symptoms. It is the clinician’s responsibility to determine whether a
lesion is the likely culprit for a patient’s seizures. To do so, it is necessary to have
knowledge of the epileptogenicity of different lesions in general before carefully
reviewing a patient’s relevant clinical data, including history, examination,
seizure symptomatology, EEG, location of the lesion, and laboratory data. Only
FIGURE 3-2
Three-Tesla MRI from the patient in CASE 3-2 shows increased T2 signal of the left hippocampus
(arrows) on axial (A) and coronal (B) fluid-attenuated inversion recovery (FLAIR) sequence and
loss of hippocampal internal architecture on a coronal T2-weighted image (arrow) (C).

then can the neurologist make an educated hypothesis as to the role of the lesion
in causing the patient’s symptoms, and that hypothesis must be subject to
reevaluation as more information becomes available over time.
For example, an arachnoid cyst is usually an incidental finding in the
evaluation of a patient with suspected seizures and can be dismissed as the
epileptogenic lesion if its location is not highly compatible with the patient’s
symptomatology and EEG findings. However, highly epileptogenic lesions such
as mesial temporal sclerosis or cavernous malformations require a far lower
threshold, and a putative diagnosis can be made in the clinic if the history and
seizure symptomatology are compatible with the lesion.
This section reviews different lesion types that are known to cause epilepsy,
focusing on representative pathologies of different etiologic categories, as well as
others that have received recent attention. A detailed description of all potential
epileptogenic lesions seen on imaging is beyond the scope of this review; more
comprehensive lists can be found in the tables. For the purpose of this review,
lesions have been classified into six categories: malformations of cortical
development, vascular lesions, tumors, gliosis and lesions caused by physical
deformation of the brain, autoimmune conditions, and infectious causes.
TABLE 3-1 Harmonized Neuroimaging of Epilepsy Structural Sequences

(HARNESS-MRI) Protocol Mandatory and Optional Sequencesa
Sequence
Sequence name type Focus Clinical scenario
Magnetization-prepared rapid T1-weighted Optimal evaluation of brain anatomy Mandatory for all
gradient echo (MPRAGE)/three- and morphology patients
dimensional spoiled gradient echo/
three-dimensional turbo field echo
Three-dimensional fluid-attenuated T2-weighted Assessment of signal anomalies, in Mandatory for all

inversion recovery (FLAIR) particular, hyperintensities related to patients
gliosis and increased extracellular
space; enhances the visibility of
hyperintense cortical Lesions
High in-plane resolution two- T2-weighted Examination of hippocampal internal Mandatory for all
dimensional coronal (turbo spin echo) structure (images are acquired patients
perpendicular to the long axis of the
hippocampus by using high resolution)
Gadolinium-enhanced T1-weighted Assessment for contrast enhancement Optional; when tumor,

vascular malformation,
or infectious process is
suspected
Susceptibility-weighted imaging (SWI) T2*-weighted Assessment of venous blood, Optional; when tumor,
hemorrhage, iron deposits, and vascular malformation,
calcifications or infectious process is
suspected
a
Data from Bernasconi A, Epilepsia.8
312 APRIL 2022

Malformations of KEY POINTS
Cortical Development
● CT remains useful in the
Malformations of cortical evaluation of potentially
development are a heterogeneous epileptogenic calcifications,
group of mostly congenital brain vascular abnormalities, and
lesions arising from disrupted encephaloceles.
cerebral cortex development
● Malformations of cortical
that can be caused by genetic, development are a
infectious, vascular, or other heterogeneous group of
etiologies.10 The dominant mostly congenital and
classification scheme for potentially epileptogenic
brain lesions arising from
malformations of cortical disrupted cerebral cortex
development separates development that can be
malformation types according to caused by genetic,
the stage of development during infectious, vascular,
or other etiologies.
which it is disrupted, thus
dividing them into malformations ● Focal cortical dysplasia is
due to abnormal neuronal cell a common cause of drug-
proliferation or apoptosis, resistant focal epilepsy that
may escape detection on
abnormal neuronal migration, or
routine MRI.
abnormal cortical organization
(postmigrational development).11
Depending on the nature
and extent of the malformation
of cortical development, a wide
spectrum of impairment is possible.
FIGURE 3-3 Certain malformation types, such
Coronal skull-base protocol CT (A) and three- as some forms of microcephaly or
dimensional skull-base reconstruction (B)
demonstrating inferior bony defect of left middle hemimegalencephaly, are
cranial fossa (A, B, arrows) in a patient with left associated with failure to thrive,
anterior left temporal anteroinferior encephalocele. severe intellectual disability, and
Images courtesy of Lily C. Wong-Kisiel, MD, and Robert J.
drug-resistant epilepsy, often
Witte, MD, Mayo Clinic, Rochester, Minnesota.
from the neonatal period.
However, many malformations of
cortical development are
compatible with normal development and cognitive function, sometimes passing
unnoticed through childhood and adolescence but leading eventually to the
development of focal epilepsy, often intractable to medications. This section
focuses on examples of malformations for which epilepsy can be the primary or
only manifestation. A more complete list is provided in TABLE 3-2.
FOCAL CORTICAL DYSPLASIA. Focal cortical dysplasia is a term encompassing a

variety of focal brain malformations that have in common disordered cortical
lamination, and in some types, abnormal cell types. Focal cortical dysplasias are
thought to be caused by disturbances in neuronal cell proliferation, cortical
organization, or both. Being focal by definition and often subtle in their
expression, focal cortical dysplasias are a common culprit of “MRI-negative”
focal epilepsy; in fact, patients with focal epilepsy and normal MRIs evaluated
at epilepsy centers are generally presumed to have a focal cortical dysplasia
that escapes visualization or was missed by the untrained eye.

Focal cortical dysplasias are classified into three subgroups, each of which has
multiple types.12 Briefly, focal cortical dysplasia type I is characterized on
pathologic inspection by alterations in the cytoarchitecture of neurons and can
affect large or small regions of the cortex. Focal cortical dysplasia type I is often
subtle and often invisible or missed on MRI imaging. When visualized on MRI, it
may appear as regions of hypoplasia or thin cortex, blurring of the gray-white
matter interface, or abnormally shaped or deep sulci.
Focal cortical dysplasia type II is characterized by disruption of the cortical
lamination, accompanied by morphologically abnormal cell types. Focal
cortical dysplasia type IIa contains only dysmorphic neurons, whereas focal
cortical dysplasia type IIb also contains balloon cells. Focal cortical dysplasias
type II are generally easier to detect on MRI than focal cortical dysplasias type I.
Like focal cortical dysplasia type I, focal cortical dysplasia type II may be
characterized by blurring of the gray-white junction or abnormal gyral or sulcal
patterns. However, it may also present additional features, including areas of
thickened cortex, increased T2/fluid-attenuated inversion recovery (FLAIR)
signal in the adjacent subcortical white matter, or the well-described
transmantle sign, seen in cortical dysplasia type IIb, which is a long region of
T2/FLAIR hyperintense signal tapering between the affected region of cortex
and the ventricular wall (FIGURE 3-4). Some focal cortical dysplasias type II are
located at the bottom of sulci, making them a challenge to identify, but when
found, bottom-of-sulcus dysplasia is often highly amenable to successful
surgical treatment.13
Focal cortical dysplasia type III refers to dysplasia that is found in the same
region of the brain as another lesion such as hippocampal sclerosis or a vascular
malformation. The focal cortical dysplasia itself may have imaging characteristics
of focal cortical dysplasias type I or type II or may not be visible at all (CASE 3-3).
An important feature of focal cortical dysplasias to be considered in
pediatric epilepsy is that they can be masked by the maturation of myelination
TABLE 3-2 Malformations of Cortical Development and Other Congenital Structural

Causes of Epilepsy That Can Be Seen on Imaging
◆ Dysgyria
◆ Focal cortical dysplasia
◆ Hemimegalencephaly
◆ Lissencephaly
◆ Megalencephaly
◆ Microcephaly
◆ Periventricular nodular heterotopia
◆ Polymicrogyria
◆ Schizencephaly
◆ Subcortical band heterotopia
◆ Sturge-Weber syndrome (vascular phakomatosis)
◆ Tuberous sclerosis (neurocutaneous syndrome)
314 APRIL 2022

KEY POINTS
● The transmantle sign

denotes a long region of T2/
fluid-attenuated inversion
recovery (FLAIR)
hyperintense signal tapering
between the affected
region of cortex and the
ventricular wall, usually
associated with focal
cortical dysplasia type IIb.
● Because focal cortical

dysplasia can be masked by
the maturation of
myelination in childhood, it
is essential to obtain high-
FIGURE 3-4 quality MRI early in the
MRI showing a left frontal focal cortical dysplasia, probable type IIb. A, Axial fluid- course of epilepsy.
attenuated inversion recovery (FLAIR) image shows a region of cortical thickening with an
extensive ribbon of hyperintensity in the subcortical region underlying the abnormal cortex. ● Periventricular nodular
B, On a coronal T2-weighted image, a blurry tapering region of hyperintensity (arrow) is visible heterotopias are solid
between the affected cortex and the adjacent ventricular wall (transmantle sign). masses of neurons that line
lateral ventricle walls after
aborted migration of
later in childhood.14 It is therefore important to obtain high-quality images neurons destined for the
early in the course of epilepsy to avoid losing the opportunity to visualize a cortex. Seizures can emerge
focal cortical dysplasia, which may become more subtle or invisible with time from one or more nodules,
areas of the overlying
(FIGURE 3-6). cortex, or a complex
network.
Periventricular Nodular Heterotopia
Periventricular nodular heterotopias are solid masses of neurons that line ● Periventricular nodular
heterotopias are
lateral ventricle walls after aborted migration of neurons originally destined conspicuous on MRI or CT as
for the cortex. Patients may have single or multiple nodules. Epilepsy often solid masses isointense/
develops in late adolescence or early adulthood and is frequently drug isodense to gray matter;
resistant. Although the nodules themselves may be epileptogenic, the their location in a region
where pathologic lesions
overlying cortex (to which the neurons were destined) is often abnormal, with rarely occur makes them
areas of subtle focal cortical dysplasia. Seizures can therefore emerge from one easy to miss.
or more nodules, areas of overlying cortex, or a complex network of
interactions between nodules (eg, the overlying cortex and sometimes the
hippocampus).15
On MRI, the periventricular nodular heterotopias appear as solid masses
isointense to gray matter lining the ventricular walls, sometimes with a
ribbonlike morphology, usually in the anterior or posterior regions of the
lateral ventricles; multiple heterotopias may be present in the same patient
(FIGURE 3-7). Careful attention should also be paid to the overlying cortex for
signs of focal cortical dysplasia. Unless it is small, a periventricular nodular
heterotopia is conspicuous on MRI or CT, but its location in a region where
pathologic lesions rarely occur makes it easy to miss when not specifically
looked for.
Vascular Lesions
Many different abnormalities of brain vasculature may cause epilepsy, and many
mechanisms of epileptogenesis can occur across different lesion types. For

example, arteriovenous malformations may cause seizures by acute bleeding,

posthemorrhagic encephalomalacia, the presence of sclerotic brain parenchyma
within capillary beds, or the adjacent development of a focal cortical dysplasia
type III. Arteriovenous fistulas may provoke seizures because of the buildup of
cerebral edema caused by high pressure within the cerebral venous system. In
general, the characterization of vascular lesions benefits from multiple imaging
modalities including MRI, CT angiogram, and, for some lesion types,
conventional angiography.
CAVERNOUS MALFORMATIONS. Cerebral cavernous malformations are vascular

lesions composed of immature endothelium channels without intervening
brain tissue. These often evolve over time and may bleed acutely,
sometimes causing neurologic symptoms. In some patients, cerebral
cavernous malformations are highly epileptogenic, likely due to
hemosiderin deposits that accumulate around the lesion rather than due to
the lesion itself. On imaging, the lesions may appear in any region of the
central nervous system (CNS) and be of highly variable size. Larger
cerebral cavernous malformations may be visible on CT as a hyperdense
lesion with regions of variable calcification. On MRI, cerebral cavernous
malformations may have a classic “popcorn” appearance caused by the
presence of variable blood products contained in different endothelium
CASE 3-3 A 27-year-old man was assessed at an epilepsy center for drug-resistant
focal epilepsy. He experienced bilateral tonic-clonic seizures as a child but
had been successfully weaned off antiseizure medications at age 14. His
seizures recurred at age 22. These were characterized by an onset of
palinopsia and oscillopsia, followed by a rising sensation of heat, nausea,
hypersalivation, alteration of consciousness, and confusion with preserved
language, rarely followed by evolution to a bilateral tonic-clonic seizure.
Brain MRI showed a region of encephalomalacia and hemosiderin in the right
occipital lobe, suggestive of a chronic ruptured vascular lesion (FIGURE 3-5).
Recorded seizures first showed EEG onset in the right posterior temporal
region, then spreading to the anterior temporal region.
Seizure symptomatology and imaging suggested that the primary seizure
focus was in the right parieto-occipital region, with propagation to the
ipsilateral mesial temporal structures. A right occipital lesionectomy was
performed. Surgical pathology showed that the region of encephalomalacia
was caused by an obliterated primitive vascular malformation. In the
adjacent cortex, neuronal lamination was anomalous, consistent with focal
cortical dysplasia type III.
COMMENT Focal cortical dysplasia type III arises in the presence of an adjacent lesion
during development and may explain the epileptogenesis of a static
encephalopathy, in this case a long-ruptured vascular malformation. In this
patient, the focal cortical dysplasia could not be radiologically
distinguished from the patient’s known lesion.
316 APRIL 2022

channels. T2* sequences such as gradient recalled echo (GRE) or SWI
will show areas of hypointensity, as well as the epileptogenic hemosiderin
rim that surrounds the whole structure (FIGURE 3-8). Unlike most other
vascular structures, cerebral cavernous malformations have no feeding
arteries or draining veins, making them radiographically silent
on angiography.
Tumors
All varieties of brain tumors can cause seizures, and seizures are often their
presenting symptom, leading to diagnosis through neuroimaging. Malignant
tumors such as high-grade gliomas and metastases from systemic cancers may
cause seizures, but their treatment is primarily directed at preserving the life and
neurologic function of the patient rather than controlling seizures. Some intra-axial
tumors such as gangliogliomas are benign and almost never expand, but they are
epileptogenic and usually operated for the sole purpose of controlling epilepsy.
Extra-axial tumors such as meningiomas cause epilepsy less frequently, but they
may become epileptogenic as they expand and distort the adjacent cortex, often
requiring surgery by the time they cause symptoms. Low-grade gliomas, discussed
in the following section, hold a middle ground between highly malignant and
benign tumor types. Although they may expand and threaten the patient’s life and
neurologic function, for years or decades the primary difficulty they present may
FIGURE 3-5
MRI from the patient in CASE 3-3 shows a region of encephalomalacia and hemosiderin
deposits (A, B, arrows) in the right occipital region on axial T1 (A) and coronal fluid-
attenuated inversion recovery (FLAIR) image (B). Although pathology of the adjacent
cortex (C) revealed focal cortical dysplasia type IIIc with cortical dyslamination, neuronal
loss most dramatic in cortical layers 2 and 3 (area within the box), and reactive gliosis (area
within the circle), no focal cortical dysplasia was visible on MRI imaging.
GFAP = glial fibrillary acidic protein; NEUN = neuron-specific nuclear protein.
Pathology images courtesy of France Berthelet, MD, and Romain Cayrol, MD, Centre hospitalier
de l'Université de Montréal.

FIGURE 3-6
Images showing the evolution of a focal cortical dysplasia through infancy to adolescence. A,
MRI showing the prominence of a right frontal focal cortical dysplasia (arrow) when imaged
by a dual echo T2-weighted sequence in a patient at the age of 8 months. B, When the patient
was 2 years old, the same focal cortical dysplasia was undetectable on fluid-attenuated
inversion recovery (FLAIR) because of ongoing changes in myelination. C, At the age of
14 years, the focal cortical dysplasia (arrow) became visible again, but it remained subtle
compared with the initial MRI.
Images courtesy of David Dufresne, MD, Université de Sherbrooke.
FIGURE 3-7
MRI showing multiple periventricular nodular heterotopias in one patient. A, Axial T1-weighted
image shows multiple periventricular nodular heterotopias (arrows) lining the occipital horns
of the lateral ventricles. B, Coronal T2-weighted image shows an additional nodule (arrow)
adjacent to the right hippocampus. The nodules represent masses of neurons that have failed
to migrate normally and are therefore isointense to cortex on all sequences.
318 APRIL 2022

FIGURE 3-8
Right hippocampal cavernous malformation causing focal epilepsy. A, On axial noncontrast
CT, the malformation (white arrow) appears as a mostly hyperdense, round mass containing
areas of lesser density. B, On axial T1-weighted image, the mass (black arrow) reveals areas of
various intensities (classic “popcorn” appearance) with a deeply hypointense rim. C, The
same rim of hypointensity (white arrow) is visible on the coronal T2-weighted image. D,
Susceptibility-weighted imaging (SWI) shows the lesion (white arrow) as thoroughly
hypointense, reflecting the chronic deposition of blood products throughout the lesion.
be epilepsy, requiring adjustments in therapy as they evolve over time. A more

complete list of tumors causing epilepsy is provided in TABLE 3-3.
LOW-GRADE GLIOMAS. Low-grade gliomas, which include grade II astrocytomas,

oligodendrogliomas, or oligoastrocytomas, are a common cause of focal seizures.
These infiltrating tumors often cannot be fully resected and are treated with a
variable combination of surgery, radiation therapy, and chemotherapy, growing
slowly and at times progressing to a higher-grade tumor. Epilepsy that was well
controlled for a time may suddenly become more difficult to treat, requiring
repeat neuroimaging to ensure tumor stability.
On MRI, low-grade astrocytomas are hypointense on T1-weighted and
hyperintense on T2-weighted sequences, with a moderate mass effect. When
calcifications are present, these will show blooming on T2* images. They show
neither contrast enhancement nor restricted diffusion. Their imaging
Benign or Slowly Progressive Intracranial Tumors Strongly Associated With TABLE 3-3
Epilepsy That Can Be Seen on Imaging
◆ Dysembryoplastic neuroepithelial tumor (DNET)

◆ Gangliocytoma
◆ Ganglioglioma
◆ Grade II astrocytoma
◆ Hypothalamic hamartoma
◆ Meningioma
◆ Multinodular and vacuolating neuronal tumor (MVNT)
◆ Oligoastrocytoma
◆ Oligodendroglioma

KEY POINTS
● Cerebral cavernous
malformations may have a
classic “popcorn”
appearance on MRI. T2*
sequences such as gradient
recalled echo (GRE) or
susceptibility-weighted
imaging (SWI) show areas of
hypointensity and the
epileptogenic hemosiderin
rim that surrounds the
structure.
● Low-grade gliomas are

infiltrating tumors causing
focal seizures. They are
treated with surgery, FIGURE 3-9
radiation therapy, and Biopsy-confirmed right frontal grade II astrocytoma, stable for several years, in a patient
chemotherapy. Their with focal motor seizures. The patient underwent multiple tumor resections but refused
continued growth may lead radiation therapy. A, Coronal fluid-attenuated inversion recovery (FLAIR) image shows
to a more drug-resistant diffuse subcortical hyperintensity (arrow) with limited mass effect. B, Axial postcontrast
epilepsy. T1-weighted image shows that the area of tumor adjacent to resection cavity (arrow) is
diffusely hypointense but does not enhance.
● Dysembryoplastic
neuroepithelial tumors
(DNETs) are among the most characteristics are often similar to those of oligodendrogliomas, but
common tumors causing oligodendrogliomas generally have more calcification and may show foci of
focal epilepsy. MRI displays contrast enhancement. Oligoastrocytomas combine histologic features of these
a classic “bubbly”
two tumor types and are usually indistinguishable on imaging alone, but they are
appearance, with multiple
lobulated regions of generally more heterogeneous in appearance (FIGURE 3-9).
hyperintensity on T2-
weighted sequences. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS. Dysembryoplastic neuroepithelial
● Multinodular and
tumors (DNETs) are among the most common tumors causing focal epilepsy.
vacuolating neuronal tumors These benign tumors, thought to be congenital, are usually static over decades or
(MVNTs) are recently grow very slowly. They are, however, highly epileptogenic and are a frequent
described epileptogenic target of epilepsy surgery. On imaging, most tumors are located in the temporal
lesions with an MRI
appearance of multiple
or frontal lobes, usually within the cortex. On CT, they appear as a wedge-shaped
discrete ovoid intra-axial hypodense mass and may contain calcifications or cause remodeling of adjacent
nodules found at the bony structures. MRI shows the classic “bubbly” appearance, with multiple
junction of superficial lobulated regions of hyperintensity on T2-weighted sequences. The calcifications
subcortical white matter
seen on CT also appear as a blooming artifact on T2* sequences. DNETs do not
and a deep cortical ribbon,
often surrounding a sulcus. avidly enhance or cause edema (FIGURE 3-10).
MULTINODULAR AND VACUOLATING NEURONAL TUMORS. Multinodular and

vacuolating neuronal tumors (MVNTs) are epileptogenic lesions first reported in
2013.16 Although initially classified as tumors, a 2018 analysis of the genetic and
pathologic features of resected specimens suggests that they may, in fact, be
more analogous to a malformative lesion than a neoplasm.17 Clinically, MVNTs
may be asymptomatic or cause adult-onset focal epilepsy, with seizure
symptomatology dependent on the site of the lesion. Typical MRI findings are of
a collection of multiple discrete ovoid intra-axial nodules, described as “bubbly,”
found at the junction of superficial subcortical white matter and a deep cortical
ribbon, often surrounding a sulcus. They are hypointense on T1-weighted
320 APRIL 2022

FIGURE 3-10
MRI of a patient with right posterior temporal dysembryoplastic neuroepithelial tumor
(DNET) causing focal seizures with impaired awareness. A, Coronal fluid-attenuated inversion
recovery (FLAIR) image shows a small, discrete lesion (arrow) of mixed intensity with areas
isointense to CSF giving the classic “bubbly” appearance. B, Axial postcontrast T1-weighted
image shows the same “bubbly” appearance (arrow) with areas of faint contrast
enhancement.
images and hyperintense on T2/FLAIR, typically nonenhancing, often with

internal nodularity. Little expansion of the brain region is involved and no edema
or mass effect is present (FIGURE 3-11).18 MVNTs do not usually enlarge over
time or recur when resected, even with incomplete resection. Given their
indolent course, MVNTs are usually resected only when the epilepsy is
drug resistant.
FIGURE 3-11
MRI of a patient with left posterior temporal multinodular and vacuolating neuronal
tumors (MVNTs) causing focal seizures with impaired awareness. Coronal (A) and axial (B)
T2-weighted images show multiple discrete small nodules (arrows) at the junction of
superficial subcortical white matter and the cortex surrounding the bottom of a sulcus.
Axial fluid-attenuated inversion recovery (FLAIR) image (C) shows the nodules (arrow)
more clearly as T2 hyperintensities. The lesion is barely visible on axial postcontrast
T1-weighted image (D) as scattered hypointensities (arrow) that were nonenhancing.

CASE 3-4 A 59-year-old right-handed woman presented to an epilepsy center for

evaluation of drug-resistant epilepsy since childhood. Around the age of
12 months, she had experienced several febrile seizures lasting longer
than 60 minutes. Later in childhood, she developed episodes of chest-
and throat-tightening, déjà vu, and intrusive mental images, initially
without frank alterations of consciousness, that were never medically
evaluated. While pregnant at the age of 29, she began having bilateral
tonic-clonic seizures following these symptoms, which persisted
monthly despite treatment with phenytoin prescribed by a neurologist.
At age 52, while under the care of a second neurologist, phenytoin was
replaced by carbamazepine. The bilateral tonic-clonic seizures largely
ceased, but she continued to have frequent episodes of chest- and
throat-tightening, déjà vu, and intrusive mental images, followed by frank
alteration of consciousness and manual automatisms, as well as postictal
disinhibition and confusion. She was referred to the epilepsy center by an
orthopedic surgeon caring for her son after she entered a discussion with
the surgeon about her personal struggle with epilepsy.
On evaluation at the epilepsy center outpatient clinic, EEG showed
right temporal spikes, and MRI showed right mesial temporal sclerosis
(FIGURE 3-12). The patient continued to have focal seizures with impaired
awareness despite replacement of carbamazepine with levetiracetam
and, later, the addition of lacosamide. Inpatient continuous EEG
monitoring confirmed the right temporal origin of her seizures, and after
complete presurgical evaluation, she underwent a right anterior temporal
lobectomy. Pathology confirmed hippocampal sclerosis. The patient
remained seizure free after surgery.
FIGURE 3-12
Coronal MRI shows right hippocampal hyperintensity and atrophy on fluid-attenuated
inversion recovery (FLAIR) image (A, arrow) and loss of internal structure on T2-weighted
image (B, arrow).
COMMENT The diagnosis of epilepsy with mesial temporal sclerosis can be made in
the clinic based on history, EEG, and MRI. Patients with mesial temporal
sclerosis often benefit from surgical treatment of their epilepsy and should
be referred to a comprehensive epilepsy center.
322 APRIL 2022

Gliosis and Lesions Caused by Physical Deformation of the Brain KEY POINTS
Injury to the brain is the most common cause of focal or multifocal epilepsy.
● Mesial temporal sclerosis
Whether caused by trauma, perinatal injury, or stroke in adulthood, is a surgically treatable form
encephalomalacia can be epileptogenic, although knowledge as to why it of drug-resistant epilepsy
becomes so in some patients and not in others is incomplete. Mesial temporal that can be diagnosed in
(hippocampal) sclerosis is another way in which a gliotic process can cause the clinic.
epileptogenicity. Other physical deformations of the brain, such as in
● On MRI, mesial temporal
encephaloceles, can become seizure foci as well and may exhibit signs of gliosis sclerosis is characterized by
on postoperative pathology. hippocampal atrophy, T2/
FLAIR hyperintensity, and
loss of internal architecture.
MESIAL TEMPORAL SCLEROSIS. Mesial temporal lobe epilepsy with hippocampal Supportive imaging findings
sclerosis, whose imaging findings are commonly referred to as mesial temporal include temporal lobe
sclerosis, is a classic, surgically treatable syndrome of often drug-resistant epilepsy atrophy or asymmetry of the
fornix and mammillary
that can be diagnosed in the clinic (CASE 3-4). Pathologically, hippocampal sclerosis bodies.
shows segmental neuronal cell loss with sparing of the CA2 subfield, gliosis, and
depletion of granule cells. In addition to hippocampal sclerosis, patients with mesial ● An encephalocele is a
temporal sclerosis also show changes in adjacent structures such as the anterior region of brain herniation
through a defect of bone
temporal lobe, amygdala, or entorhinal cortex. Mesial temporal sclerosis represents
and dura mater. Anterior
a collection of pathologic changes that may be the cause of seizures, may be caused temporal encephaloceles
by seizures, or both. In many patients, who often have a history of prolonged are a surgically treatable
febrile seizures, mesial temporal sclerosis is the only pathologic change in the cause of temporal lobe
epilepsy, often missed
brain, and its surgical removal carries a high likelihood of seizure freedom. In
during image interpretation.
other patients, seizures arise in different regions of the brain but propagate to a
temporal lobe, which can develop secondary epileptogenesis and eventually
undergoes hippocampal atrophy and becomes another seizure focus. This can
also occur when one temporal lobe with mesial temporal sclerosis leads to the
generation of a second focus of mesial temporal sclerosis in the contralateral lobe.
The imaging findings of mesial temporal sclerosis should be known to every
neurologist who treats patients with epilepsy and specifically looked for when
reviewing images. Hippocampal atrophy is the most specific feature and should
be assessed primarily with multiple coronal slices. The hippocampus loses its
normal oval shape and becomes flattened, and the adjacent temporal horn of the
lateral ventricle appears widened. On T2/FLAIR, the hippocampus may display a
hyperintense signal. On coronal T2-weighted sequences, the internal architecture
of the hippocampus may appear blurred or frankly lost, reflecting the pathologic
changes. Other structures can also be abnormal; supportive imaging findings
include temporal lobe atrophy or asymmetry of the fornix and mammillary
bodies with a reduced volume on the ipsilateral side.
ENCEPHALOCELE. An encephalocele is a region of brain herniation through a defect

of bone and dura mater. Although encephaloceles may develop following
trauma, neurosurgery, or CSF leaks, no cause is identified in many cases. It is
thought that distortions of the brain parenchyma, as it protrudes through the
bone, may be epileptogenic. Although they can cause epilepsy in many regions of
the brain, encephaloceles of the anterior temporal region have recently been
recognized as a relatively common and surgically treatable cause of temporal
lobe epilepsy, which is frequently missed on imaging. In one case series,
temporal encephaloceles were found in nearly 2% of all patients referred to an
epilepsy center for drug-resistant epilepsy.19

On MRI, protrusion of the

brain parenchyma with
surrounding CSF through the
skull defect may be observed, but
it can be subtle in the case of
small encephaloceles (FIGURE 3-13).
Sensitivity can be increased with
the use of a 3T scanner with
particular attention to axial and
sagittal sections using a high-
contrast T2-weighted turbo spin
echo sequence. Associated MRI
signs of idiopathic intracranial
hypertension such as flattening
of the orbital globe or empty sella FIGURE 3-13
turcica are often observed in the Coronal fluid-attenuated inversion recovery
same patients.20 In uncertain (FLAIR) MRI showing an inferior temporal
encephalocele in a patient with right temporal
cases, skull-base CT may identify focal seizures. The encephalocele (arrow) can be
the skull defect through which seen protruding through the skull base. The area
the encephalocele protrudes. of protruding encephalocele is hyperintense,
which may represent gliosis within the brain
parenchyma.
Autoimmune Conditions
A great variety of autoimmune
and inflammatory conditions, both systemic and limited to the CNS, are known to
cause epilepsy, sometimes only in the acute phase and sometimes leaving epilepsy as
a permanent sequela; for more information about this, refer to the article
“Autoimmune-Associated Seizures” by Lisa Gillinder, MBBS, FRACP, and Jeffrey
Britton, MD, FAAN,21 in this issue of Continuum. Imaging findings may be absent or
nonspecific to the causative entity, but some autoimmune conditions can produce
characteristic imaging findings.
RASMUSSEN ENCEPHALITIS. Rasmussen encephalitis is a rare, chronic, progressive

inflammatory disease of the brain of unknown etiology, most frequently seen in
children and causing devastating seizures and neurologic deficits, typically
limited to a single hemisphere. Patients usually present with seizures, often
highly drug-resistant, and neurologic impairment follows progressively. Imaging
is unremarkable at first, but cortical swelling and T2 hyperintensity later develop.
The swelling then resolves, and the cortex begins to atrophy, but T2
hyperintensity remains. Eventually, the hyperintensity resolves, but significant
atrophy remains permanent in the “burnt-out” stage (FIGURE 3-1422).23
AUTOIMMUNE GLIAL FIBRILLARY ACIDIC PROTEIN ASTROCYTOPATHY. Autoimmune

glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described
inflammatory disease of the brain causing meningoencephalitis. Approximately
one-fifth of patients with GFAP astrocytopathy develop seizures, often resistant
to medications.24 It is mentioned here because it presents with a typical imaging
pattern that should not be missed in a patient presenting with encephalopathy and
seizures. In a majority of patients, contrast-enhanced T1-weighted MRI images
show diffuse perivascular enhancement radiating out from the lateral ventricles,
and less frequently, the fourth ventricle into the cerebellum (FIGURE 3-15). Other,
324 APRIL 2022

FIGURE 3-14
Serial MRI findings in a 52-year-old-woman with adult-onset Rasmussen encephalitis.
A, Axial fluid-attenuated inversion recovery (FLAIR) image at 1 year after diagnosis disclosing
no obvious abnormalities (A, top left); axial FLAIR image at the same level at 2 years showing
perisylvian hyperintense signal (A, top right); MRI findings at 3 years during acute focal
status epilepticus with impaired awareness: axial contrast-enhanced T1-weighted image
revealing mild subcortical frontal operculum enhancement (A, bottom left) and axial FLAIR
image showing mild progression of frontal operculum hyperintensity (A, bottom right). Axial
diffusion-weighted images (DWI) demonstrating restricted diffusion throughout the left
cerebral cortex (B) and axial T2-weighted images through cerebellum showing signal
abnormalities in the right cerebellum hemisphere consistent with crossed cerebellar
diaschisis (C) when the patient was in status epilepticus (at the same time as the bottom
images in panel A). D, Follow-up images at 3 months after status epilepticus showing
persistent atrophy and gliosis of the left perisylvian region on coronal FLAIR images.
Modified with permission from Irislimane M, et al, Can J Neurol Sci.22 © 2011 Canadian Neurological
Sciences Federation.

KEY POINTS less specific, MRI findings

include T2 hyperintensities in
● Autoimmune glial
fibrillary acidic protein
white matter and leptomeningeal
(GFAP) astrocytopathy is an enhancement. This entity
inflammatory cause of responds well to corticosteroids.
meningoencephalitis with
seizures. It has a typical
Infectious Causes
imaging pattern of diffuse
perivascular enhancement CNS infections may cause
radiating out from the seizures acutely, during a
lateral ventricles on chronic infection, or through
contrast-enhanced MRI.
sequelae that persist long after
● CT imaging may be the infectious organism is no
necessary as a complement longer living in the CNS. A more
to MRI images for the complete list is provided in
imaging diagnosis of TABLE 3-4.
neurocysticercosis.
NEUROCYSTICERCOSIS.
Neurocysticercosis is a leading
cause of focal epilepsy in many
FIGURE 3-15
low- and middle-income regions
Axial postcontrast T1-weighted MRI of autoimmune and can cause epilepsy
glial fibrillary acidic protein (GFAP) astrocytopathy. throughout the several-year life
Patterns of enhancement include radial cycle of its causative parasite,
periventricular (A), leptomeningeal and punctate
Taenia solium, or long after its
(B), serpiginous (C), and periependymal (D).
Reprinted with permission from Kunchok A, et al, Curr Opin death. The parasite is ingested
Neurol.24 © 2019 The Authors. through fecal-oral contamination
and can release larvae into the
human bloodstream, and from
there, some can reach the brain. The larvae then proceed through four stages of
development, each with unique imaging characteristics (TABLE 3-5).25 When the
parasite dies, it progresses to the nodular calcified stage, remaining within the
brain for the rest of the patient’s life as a fibro-calcified nodule.
On CT imaging, the chronic lesions appear as single or multiple small
nodular hyperdense masses, without perilesional edema or enhancement.
These lesions appear hypointense on T1-weighted and T2-weighted MRI
sequences. T2* sequences reveal a strongly hypointense blooming artifact
(FIGURE 3-16).
IMAGING IN PRESURGICAL EVALUATION

Although most patients with epilepsy can achieve control of seizures with
antiseizure medications alone, a substantial proportion of patients have drug-
resistant epilepsy. Where resources are available, all such patients should be
referred to a comprehensive epilepsy center for a presurgical evaluation; for
more information about this, refer to the article “Surgical Treatments for
Epilepsy” by George W. Culler IV, MD, and Barbara C. Jobst, MD, PhD, FAAN,26
in this issue of Continuum. In simple terms, epilepsy surgery consists of carefully
identifying the seizure focus within the brain and surgically removing it when
safe to do so.
The decision to remove a region of the brain is not taken lightly and requires
an intensive and detailed evaluation of the patient’s seizures. On one hand, the
326 APRIL 2022

Chronic Central Nervous System Infections or Infection Sequelae TABLE 3-4
Associated With Epilepsy That Can Be Seen on Imaging
◆ Cerebral malaria
◆ Cryptococcosis
◆ Herpes simplex virus encephalitis
◆ Neurocysticercosis
◆ Toxoplasmosis
◆ Paragonimiasis
◆ Subacute sclerosing panencephalitis
◆ Syphilis
◆ Tuberculosis
Stages of Neurocysticercosis Evolution and Their Radiologic Findingsa TABLE 3-5
Stage MRI findings CT findings
Stage 1: vesicular (living parasite) A scolex may be seen a within cyst of Cyst appears as a hypodense
approximately 1-2 cm; when visible, the lesion isodense to CSF
scolex may enhance and is best seen on
fluid-attenuated inversion recovery (FLAIR)
images; minimal or absent enhancement of
the cyst wall; cyst fluid isointense to CSF
Stage 2: colloidal vesicular (early Scolex is no longer visualized; a fluid-fluid Cyst appears as a hypodense
degeneration and host inflammatory level may be seen within the cyst, lesion with ring enhancement
response) suggesting internal debris; cyst fluid with contrast
hyperintense on T1-weighted sequences;
gadolinium ring enhancement surrounds the
cyst; T2-weighted sequences may show
perilesional edema; absence of diffusion-
weighted imaging (DWI) restricted diffusion
Stage 3: granular nodular (further Morphology evolved to a smaller nodular Contrast images may show
degeneration) lesion; gadolinium enhancement of lesion enhancement within the lesion
with possible small ring enhancement; or small ring enhancement
T2-weighted sequences may show mild
perilesional edema
Stage 4: nodular calcified (end stage as a Hypodense nodule on T1- and T2-weighted Hyperdense nodule;
nonviable calcified granulomatous lesion sequences; usually no edema or nonenhancing
without host inflammatory response) enhancement
CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging.

a
Data from Lerner A, et al, Neuroimaging Clin N Am.25

FIGURE 3-16
Imaging from a patient with anterior temporal neurocysticercosis causing left temporal onset
seizures. Two other lesions were seen in other regions of the brain (not shown). On axial
T1-weighted (A) and fluid-attenuated inversion recovery (FLAIR) (B) images, the lesion
(arrows) was seen as a small nodular hypointensity, with prominent hypointense “blooming”
artifact (arrow) on axial susceptibility-weighted imaging (SWI) (C). MRI could not distinguish
whether the lesion represented calcification or hemosiderin deposit, so CT was performed
(D), confirming highly dense calcifications (arrow) and the diagnosis of chronic
neurocysticercosis lesions.
seizure focus must be established with maximal confidence. On the other hand,
the function of any region of cortex under consideration for removal must be
established to avoid a permanent disabling functional deficit from the surgery.
The presurgical evaluation is therefore highly individualized, and imaging data
are essential to focus both identification and surgical planning for preservation of
neurologic function.
Focus Identification
Identifying the seizure focus for resection is a simple endeavor in some
patients but highly complex in others. A general principle of focus
identification is to collect different types of data, which may include the
details of seizure symptomatology, neuropsychological profile, interictal EEG,
video-EEG recordings of seizures, structural imaging, and, when necessary,
different methods of functional imaging or intracranial EEG data, each of
which may suggest a particular seizure focus. When these different methods
of evaluation are concordant, the seizure focus can be predicted with higher
confidence, and the likelihood of surgical success is increased. When they are
inconclusive or discordant, surgical planning becomes more challenging.
In the evaluation of a patient with focal epilepsy, the presence or absence of an
epileptogenic lesion that can be visualized on structural imaging is usually the
most important factor predicting the eventual success of surgery. For many
lesion types such as mesial temporal sclerosis, DNETs, or cavernous
malformations, rates of seizure freedom after surgery can exceed 70%.27 Simply
put, a lesion that can be seen can more easily be identified and removed. This
concept is so basic that focal epilepsy was traditionally divided as “lesional” or
“nonlesional,” referring to whether patients have a visible lesion on MRI. Without
a visible lesion, intracranial EEG monitoring is often necessary before focus
resection. The lower rates of postoperative seizure freedom attest to the difficulty
of correctly identifying the seizure focus in patients with so-called
“nonlesional” epilepsies.28
328 APRIL 2022

In fact, however, it is understood that all focal epilepsy must be “lesional,” KEY POINTS
given that a lesion of some type must be responsible for the seizures, even if not
● In the course of a
visible on MRI. Therefore, the term MRI-negative is now preferred to describe the presurgical evaluation for
situation previously referred to as nonlesional. With improvements in MRI drug-resistant epilepsy,
scanners, imaging protocols, and special techniques, lesions are now found that imaging results are essential
in the past would have gone unnoticed, converting MRI-negative patients to for seizure focus
identification and surgical
MRI-positive patients.
planning for the
Functional imaging technologies can assist with focus identification, preservation of neurologic
particularly when structural imaging is negative. Functional imaging takes function.
advantage of different physiologic characteristics of epileptogenic brain regions,
such as altered glucose metabolism, to identify the region of abnormal function. ● In the presurgical
evaluation of a patient with
Although lacking the anatomic precision and etiologic detail of structural imaging, focal epilepsy, the presence
when successful, functional imaging can help lateralize or even localize the seizure or absence of an
focus. When concordant with other types of data, the images obtained assist with epileptogenic lesion on
the formation of a hypothesis for the putative seizure focus, which may guide structural imaging has a
major impact on surgical
intracranial EEG investigation or, in some cases, direct resective surgery. planning and seizure-free
outcomes.
STRUCTURAL IMAGING. Structural neuroimaging allows neurologists to visualize
the anatomy of the brain and adjacent structures, as well as pathologic lesions
that can be responsible for seizures.
3-TESLA MRI AND POSTPROCESSING TECHNIQUES. As discussed in previous sections,

MRI provides unparalleled anatomic detail for identifying and characterizing
potentially epileptogenic lesions. An important task for the neurologist and
neuroradiologist is to ensure that any potential lesion is not missed. Often,
this requires reexamination of the images as more clinical detail is obtained; for
example, if the region of seizure onset is confirmed during EEG monitoring in an
apparently MRI-negative patient, that region should be carefully reviewed to look
for subtle abnormalities that might have passed unnoticed on previous screening
examinations. A major focus of research in this area is the use of postprocessing
techniques that can visually accentuate potentially epileptogenic lesions.
Techniques highlighted by the ILAE Neuroimaging Task Force include volumetry
of mesiotemporal lobe structures, hippocampal T2 relaxometry, and texture
analysis.
Volumetry of mesiotemporal lobe structures. Atrophy of mesiotemporal structures

is an important imaging correlate of mesial temporal epilepsy, but it may be
subtle and escape routine visual inspection. Either through the use of manual
volumetry or automated algorithms, evaluation with T1-weighted MRI of the size
of structures associated with the mesiotemporal lobe, including the hippocampus,
amygdala, entorhinal cortex, and temporal pole, either in comparison with
normal controls or the patient’s contralateral mesiotemporal structures, can
help lateralize the seizure focus and implicate the temporal lobe in epilepsy
patients.
Hippocampal T2 relaxometry. In addition to atrophy, T2/FLAIR hyperintensity of

the hippocampus is an important finding in the visual inspection of mesial
temporal sclerosis, but various technical difficulties are involved in trying to
identify a subtle abnormality or asymmetry of signal intensity on a computer
screen. T2 relaxometry offers a quantitative estimate of the intensity of the T2

signal, which increases the sensitivity of MRI for identifying mesiotemporal

gliosis, in particular when hippocampal volumes are normal.
Texture analysis. Focal cortical dysplasia is a common cause of MRI-negative

epilepsy and may be extremely subtle or frankly undetectable with standard MRI
sequences. Various methods of automated texture analysis may be used to
quantitatively evaluate and visually enhance the MRI correlates of focal cortical
dysplasia, such as blurring of the gray-white matter or alterations in the intensity
of gray matter signal. Depending on the sensitivity of the algorithm, multiple
areas of potential abnormality can be expressed visually and correlated with the
patient’s other clinical data to evaluate potential targets of intracranial EEG
evaluation (FIGURE 3-17).
FIGURE 3-17
Imaging from a patient with nocturnal seizures. Axial 3-Tesla MRI shows an area of focal
atrophy in the left orbitofrontal region (purple cursor in all images) in axial (top row),
sagittal (middle row), and coronal (bottom row) images (note that, contrary to the usual
orientation, the patient’s left side is shown on the left in the axial and coronal images).
The sulcogyral pattern is abnormal and includes many small gyri. On T1-weighted (first
column) and fluid-attenuated inversion recovery (FLAIR) (second column) images, a blurring
of the gray-white matter junction can be seen. The FLAIR signal is also increased. These
anomalies were confirmed by image processing (third and fourth columns) with texture
analysis showing hyperintensity and decrease of gradient, with a large darkened area.
This anomaly is suggestive of focal cortical dysplasia type IIa.
Image courtesy of Andrea Bernasconi, MD, Montreal Neurological Hospital.
330 APRIL 2022

7-TESLA MRI. Compared with 3T MRI, 7T MRI offers a higher field strength, KEY POINTS
which can be translated to superior image quality and susceptibility contrast,
● MRI postprocessing
as well as a greater spatial resolution. The introduction of 7T MRI into techniques such as
epilepsy clinical practice offers the hope of translating these advantages to a volumetry of mesiotemporal
higher sensitivity for epileptogenic lesions in patients for whom no lesion was lobe structures,
detected on MRI with lower magnetic field strength. Research has shown it to hippocampal T2
relaxometry, and automated
be more sensitive in detecting malformations of cortical development including
texture analysis may be
focal cortical dysplasia, hippocampal sclerosis, and vascular malformations.29 helpful in identifying lesions
Other potential uses include better characterization and delineation of known that were not detectable on
lesions, more precise planning of electrode positioning for intracranial EEG simple visual inspection.
monitoring, and better mapping of eloquent regions of the brain before
● Functional imaging
resection.29 However, 7T MRI presents several technical and logistic challenges, evaluates physiologic
as well, and its high cost has limited its adoption in many epilepsy centers. characteristics of
epileptogenic brain regions
FUNCTIONAL IMAGING. Especially when structural imaging fails to identify a clear to identify regions of
abnormal function, helping
epileptogenic lesion or when investigations reveal multiple potential epileptic to lateralize or localize the
foci, functional imaging may assist in restricting the areas of the brain under seizure focus.
investigation, often in the context of planning a subsequent intracranial EEG
study. Different types of functional imaging take advantage of the fact that
epileptogenic brain tissue has different metabolic and electrophysiologic
characteristics from normal tissue. These regions of difference are then
expressed visually and projected onto existing structural images, usually
MRI. The resulting images, when concordant with other data, allow neurologists to
lateralize or localize the seizure focus, therefore assisting with surgical planning.
POSITRON EMISSION TOMOGRAPHY. The epileptic focus and the region surrounding it
may have reduced metabolism during the interictal period. This region with
interictal hypometabolism consumes differentially less fludeoxyglucose (FDG)
than regions of healthy tissue, a phenomenon that can be detected and expressed
with FDG–positron emission tomography (PET) imaging. A glucose analogue
radiotracer (18F-FDG) is injected into the patient. Brain cells, which rely primarily
on glucose for energy, avidly take in the tracer, where it remains trapped
unmetabolized. The patient is scanned no less than 30 minutes later, and the PET
images display the regions of the brain that contain relatively more or less of the
radiotracer. Areas that light up less than expected, either through visual
inspection in comparison with the contralateral side or by using quantitative
algorithms, can be considered hypometabolic. PET images can also be exported to
existing MRI images of the same patient, adding anatomic detail to the regions of
altered metabolism.
In temporal lobe epilepsy, unilateral temporal hypometabolism is correlated
with the side of seizure focus, allowing lateralization in such cases. Even in
MRI-negative epilepsy, patients with temporal hypometabolism on FDG-PET
have more favorable postsurgical outcomes. It should be noted, however, that the
region of hypometabolism often extends well beyond the true epileptic focus,
such that PET imaging cannot be used to guide delineation during surgical
planning (CASE 3-5). Recent research suggests that for patients with mesial
temporal epilepsy, a more widespread region of hypometabolism portends a
lesser likelihood of postsurgical seizure freedom, especially when extending into
extratemporal or contralateral regions, with the best outcomes found when the
hypometabolism is restricted to the anteromesial region.31 Although FDG-PET

can also be used to detect extratemporal epileptic foci, the reported sensitivity in
such patients is much lower.
Compared with many other functional imaging techniques, the logistic
barriers to obtaining PET imaging are significantly fewer because this technique
can be obtained routinely on an outpatient basis. As a result, it can sometimes be
used as an adjunctive technique in the diagnosis and classification of epilepsy,
even in patients who are not presently candidates for epilepsy surgery.
SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY. Like FDG-PET imaging, single-

photon emission computed tomography (SPECT) detects altered metabolism in
epileptic brain tissues; however, these techniques have two fundamental differences
between them. The first is that the surrogate for metabolism is not glucose
CASE 3-5 A 14-year-old boy presented with left

temporal seizures that were refractory
to antiseizure medications. Seizures
were characterized by alteration of
consciousness accompanied by
swallowing and left-arm automatisms.
EEG showed left temporal spikes and
seizures originating from the left
anterior temporal head region. MRI
showed a left temporal anteroinferior
encephalocele with an adjacent skull
defect on skull-base CT (FIGURE 3-3).
FDG-PET coregistered with MRI
showed an area of hypometabolism
in the left temporal lobe, extending FIGURE 3-18
well posterior to the encephalocele Axial fludeoxyglucose positron
emission tomography (FDG-PET) MRI
(FIGURE 3-18). After resection of showing both the left temporal
the encephalocele and anteroinferior encephalocele (arrow)
temporal pole, seizure frequency was and region of hypometabolism,
reduced by more than 90%.30 indicated by the blue-shaded area of
the left temporal lobe, much larger
than on the right. Note that the blue-
shaded region extends well posterior
of the encephalocele.
Image courtesy of Lily C. Wong-Kisiel, MD, and
Robert J. Witte, MD, Mayo Clinic, Rochester,
Minnesota.
COMMENT The FDG-PET shows a region of hypometabolism that extends well beyond
the epileptogenic lesion. In such cases, the region of hypometabolism
should not be used to delineate the surgical margins, as this phenomenon
is well described. The larger region of hypometabolism does suggest a
lesser probability of postsurgical freedom from seizures, even when the
presumptive seizure focus is fully resected, but should not be a
contraindication to surgery.
332 APRIL 2022

consumption but rather altered blood flow. The second is that, in common clinical
practice, SPECT seeks evidence of increased metabolism at the time of a seizure,
rather than decreased metabolism in the interictal period. Seizures are, by
definition, transient events of excessive or synchronous neuronal activity in the
brain, which by their nature require increased metabolism if an energy crisis is to be
avoided. The brain vasculature, therefore, diverts blood flow toward seizing tissue.
SPECT exploits this change in blood flow by the injection, at the moment of a
seizure, of a radiotracer such as technetium 99m–hexamethylpropyleneamine
oxime (99mTc-HMPAO) that is rapidly taken up within the brain and then
remains for several hours, providing an image of cerebral blood flow at the
moment of injection when the patient is scanned within 4 hours of the seizure.
The images obtained are then compared with images taken after an injection in
the same patient during an interictal period, allowing a statistical analysis of the
differences in regional blood flow between the ictal and interictal periods.
Regions of hyperperfusion during the ictal period compared with the interictal
period are considered candidate regions of seizure focus. By using statistical
parametric analysis, the data can also be normalized and compared with a control
group, and the result can be coregistered to MRI to allow visualization of the
areas of ictal hyperperfusion on the patient’s anatomy for hypothesis building or
surgical planning (FIGURE 3-19).
The logistic challenges to obtaining an ictal SPECT are significant. In practice,
SPECT is almost always obtained during an inpatient epilepsy monitoring unit
admission. While the patient is being monitored continuously by EEG and watched
carefully by medical personnel, antiseizure medications are frequently reduced to
provoke seizures. The radiotracer must be continuously replenished at the bedside
given its short half-life, and it is usually unavailable outside of normal work hours.
Immediately on the onset of a seizure, as identified by patient notification, EEG
changes, or clinical symptoms, a nurse or EEG technician near the bedside must
inject the radiotracer as quickly as possible. Given the tendency of focal seizures to
spread to adjacent regions or to become bilateral tonic-clonic seizures, a late
injection may indicate the region of spread rather than the initial focus. Therefore,
the sooner the tracer is injected after seizure onset, the better the yield.
FIGURE 3-19
Ictal-interictal subtracted single-photon emission computed tomography (SPECT)
coregistered to axial MRI showing activation centered on the right mesial temporal
structures during seizure onset, suggesting a right temporal seizure focus.

FIGURE 3-20
EEG–functional MRI (fMRI) showing activation clusters superimposed on axial (A), sagittal (B),
and coronal (C) T1-weighted fMRI correlated with interictal spikes and slow waves diffusely
maximal over the right temporal and parietal head regions on EEG. These discharges were
correlated with maximal activation of the right supramarginal and angular gyri.
FIGURE 3-21
Magnetic source imaging showing the location of magnetoencephalography dipoles
coregistered to MRI, superimposed on coronal (A), sagittal (B), and axial (C) T1-weighted
images. The images show that the biggest clusters of magnetic dipoles are located in the
left opercular and anterior insular regions. Note that, contrary to the usual orientation, the
patient’s left side is shown on the left in the coronal and axial images.
334 APRIL 2022

Despite these hurdles, SPECT is a well-established technique for identifying a KEY POINTS
temporal or extratemporal seizure focus in patients with MRI-negative focal
● Fludeoxyglucose positron
epilepsy. In MRI-negative extratemporal cases, SPECT is an important test that emission tomography (FDG-
can establish a putative surgical target for intracranial EEG monitoring and is PET) imaging identifies
predictive of seizure-free outcomes.32 regions of interictal glucose
hypometabolism. In
temporal lobe epilepsy,
EEG–FUNCTIONAL MRI. EEG–functional MRI (fMRI) is a functional imaging
unilateral temporal
technique focused on correlating changes in focal oxygen levels with interictal hypometabolism is
EEG discharges, allowing more precise localization of the discharges within the correlated with the side of
brain. Interictal scalp-surface EEG spikes are often generated at the seizure seizure focus. FDG-PET is
less sensitive in
focus, but for various technical and theoretical reasons, it is not possible to
extratemporal epilepsy.
precisely extrapolate their location inside the skull. fMRI allows the visualization
of changes in blood oxygen levels within the brain (see the later section on ● Single-photon emission
other uses of fMRI). When EEG discharges are seen to be correlated in time computed tomography
with a focal change in blood oxygen levels, the region of metabolic change (SPECT) uses a radiotracer to
detect increased blood flow
can be delineated as the generator of the discharges (FIGURE 3-20). The during the ictal period to
information obtained can be correlated with other clinical data in the identify the seizure focus.
planning of epilepsy surgery in patients with complex epilepsy who have The tracer must be injected
interictal discharges.33 immediately on seizure
onset, creating logistic
challenges.
MAGNETIC SOURCE IMAGING. Similar to EEG-fMRI, magnetic source imaging (MSI)
is a method used to detect the source of interictal discharges within the brain to ● Functional MRI (fMRI) and
identify a potential seizure focus. Instead of correlating them with brain oxygen diffusion tensor imaging
(DTI) are imaging modalities
levels, however, magnetic source imaging records magnetic fields that are
that can help identify the
generated by neuronal currents at the moment of interictal spikes, recording them location of critical brain
at the surface of the head (magnetoencephalography). Unlike EEG electric tissue and assist with the
potentials, which are distorted by the tissues of the brain, skull, and scalp, safe resection of the
magnetic fields are not altered by these structures, allowing for more effective seizure focus.
modeling of the spike sources. The magnetoencephalographic data are then

coregistered with MRI data to display the posited location of the magnetic dipoles
within the patient’s brain anatomy, providing another method to localize the
seizure focus in MRI-negative
patients (FIGURE 3-21).34
Surgical Planning
Once the seizure focus has been identified, it must be removed or destroyed
surgically to achieve seizure freedom. Patients are often surprised to learn that a
piece of the brain can be taken out without causing serious neurologic injury. But
given the specialization of different regions of the brain, it is essential to ensure
that the region to be removed is not responsible for some critical function such as
speech or motor activity. Knowledge of brain anatomy is essential but not
sufficient to avoid neurologic impairment, given the variability in functional
topography among patients, especially in regions affected by a lesion that may
have been present since birth and influenced brain development from a young
age. fMRI and diffusion tensor imaging (DTI) are imaging methods that can
predict the location of critical brain tissue.
FUNCTIONAL MRI. fMRI is an imaging modality primarily used to identify the

regions within the brain associated with different neurologic functions. The
technique detects changes in blood oxygen levels that indicate which regions of

the brain are more active when a patient performs a specific standardized task
using the function under review compared with a rest or control condition.
Although fMRI can be used to evaluate the localization of sensory or motor
function, it is most frequently used in epilepsy surgery planning to lateralize
and localize language areas. Different language functions (eg, naming,
comprehension) can be tested individually by using protocols and mapped onto
the patient’s brain anatomy. This information can be used to estimate the risk
of language impairment after surgical resection, especially when considering a
left temporal lobectomy, or to help define surgical margins. Being less invasive,
this technique has partially replaced the Wada test for language lateralization
(FIGURE 3-22). When a surgery is considered high risk for loss of function,
however, intracranial cortical stimulation mapping may be necessary
before resection.
DIFFUSION TENSOR IMAGING. Whereas fMRI examines cortical function, DTI is

primarily used to map critical white matter tracts, damage to which might leave
FIGURE 3-22
Functional MRI (fMRI) used to evaluate lateralization of language function in a right-handed
patient with left mesial temporal sclerosis and drug-resistant epilepsy before lobectomy.
A, Statistical representation of changes in blood oxygen level–dependent (BOLD) activation
on a normalized brain during a language completion task to evaluate expressive speech;
darker areas show greater activation. The patient read an incomplete written sentence and
spoke out the missing words. This task showed bilateral activation in the frontal regions,
near the Broca area, left greater than right. B, Areas of higher BOLD activation (yellow) are
superimposed onto left sagittal, coronal, and axial T1-weighted MRI images of the patient’s
brain. Bilateral occipital activation was also seen due to the visual nature of the task. Note
that, contrary to the usual orientation, the patient’s left side is shown on the left in the axial
and coronal images. C, Areas of higher BOLD activation (see the yellow-red scale) are
superimposed onto a three-dimensional reconstruction of the patient’s brain MRI, shown
from different perspectives. Other language tasks (not shown) also mostly showed bilateral
activation, suggesting bilateral language function. A left temporal amygdalohippocampectomy
and anterior temporal lobectomy was performed without impact on the patient’s language
function.
336 APRIL 2022

the patient with permanent
neurologic impairment. DTI is a
magnetic resonance technique
that measures the random
movements of water molecules
in three dimensions within the
brain tissue, which have
different characteristics
according to the nature of
the tissue within which the
water is contained. Modeling
of the information obtained
allows the graphic
representation of white
matter tracts such as the FIGURE 3-23
corticospinal tract or Meyer Diffusion-tensor imaging (DTI) coregistered to
coronal T1-weighted MRI showing the locations of
loop, allowing prediction of a the corticospinal tract (blue) relative to a large left
postsurgical deficit risk or frontal oligodendroma (red mass) causing seizures
assisting in surgical planning before a partial resection.
(FIGURE 3-23).
CONCLUSION
It is the neurologist’s task to understand each patient’s epilepsy well enough to better
explain and treat their disease. In this endeavor, the importance of neuroimaging
cannot be underestimated, especially for more challenging cases. For neurologists
who treat patients with epilepsy, understanding the advantages and limitations of
each modality is essential and will lead directly to better care and a higher likelihood of
seizure freedom in their patients. As imaging technology improves, the judicious
selection and interpretation of imaging modalities will become all the more critical.
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338 APRIL 2022

Genetic Epilepsy REVIEW ARTICLE

Syndromes CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Kenneth A. Myers, MD, PhD, FRCPC, CSCN(EEG)
ABSTRACT
PURPOSE OF REVIEW: This article reviews the clinical features, typical EEG
findings, treatment, prognosis, and underlying molecular etiologies of the
more common genetic epilepsy syndromes. Genetic generalized epilepsy,
self-limited focal epilepsy of childhood, self-limited neonatal and infantile
epilepsy, select developmental and epileptic encephalopathies,
progressive myoclonus epilepsies, sleep-related hypermotor epilepsy,
photosensitive occipital lobe epilepsy, and focal epilepsy with auditory
features are discussed. Also reviewed are two familial epilepsy
syndromes: genetic epilepsy with febrile seizures plus and familial focal
epilepsy with variable foci. CITE AS:
2022;28(2, EPILEPSY):339–362.
Recent years have seen considerable advances in our
RECENT FINDINGS:
understanding of the genetic factors underlying genetic epilepsy Address correspondence to
syndromes. New therapies are emerging for some of these conditions; in Dr Kenneth A. Myers, Montreal
Children's Hospital, 1001 Décarie
some cases, these precision medicine approaches may dramatically
Blvd, Montreal, Quebec,
improve the prognosis. H4A 3J1, Canada,
kenneth.myers@mcgill.ca.
SUMMARY: Many recognizable genetic epilepsy syndromes exist, the
RELATIONSHIP DISCLOSURE :
identification of which is a crucial skill for neurologists, particularly those Dr Myers has received personal
who work with children. Proper diagnosis of the electroclinical syndrome compensation in the range of
$500 to $4999 for serving as an
allows for appropriate treatment choices and counseling regarding academic writer with Springer
prognosis and possible comorbidities. Publishing Company. The
institution of Dr Myers has
received research support
from Dravet Canada, Fonds
de recherche du Québec,
INTRODUCTION Koolen-de Vries Syndrome
A
lthough epilepsy is an etiologically heterogeneous condition, the Foundation, The Liam
Foundation, and the Savoy
importance of genetic factors has been acknowledged for many Foundation.
decades.1 This is perhaps clearest in the case of generalized epilepsy,
where the risk in first-degree relatives is 5- to 10-fold greater than UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
the general population.2-4 In twin studies, the concordance rate is USE DISCLOSURE :
significantly higher for monozygotic compared with dizygotic twins.5-8 Epilepsy Dr Myers discusses the
unlabeled/investigational use of
inheritance can follow a Mendelian pattern (ie, autosomal dominant, autosomal
clobazam for the treatment of
recessive, or X-linked); however, in many cases the pattern appears more forms of epilepsy other than
complex, likely involving polygenic inheritance and epigenetic factors.1,9 Lennox-Gastaut syndrome and
quinidine for the treatment of
In many epilepsy syndromes, the underlying cause is known or assumed to be epilepsy due to KCNT1
genetic. These conditions include both self-limited (formerly termed benign) pathogenic variants.
phenotypes and more severe conditions, such as developmental and epileptic
encephalopathies. This article reviews the clinical and electrographic aspects of © 2022 American Academy
these syndromes, as well as what is known about the underlying molecular factors. of Neurology.

GENETIC EPILEPSY SYNDROMES
GENETIC GENERALIZED EPILEPSIES

Also known as idiopathic generalized epilepsies, the genetic generalized epilepsy
syndromes comprise a group of disorders that share some common clinical and
electrophysiologic factors (TABLE 4-1). In the 2017 International League Against
Epilepsy (ILAE) epilepsy classification, genetic generalized epilepsy was described
as the more accurate nomenclature; however, idiopathic generalized epilepsy is
also considered acceptable.10 Overall, the genetic generalized epilepsy
syndromes are characterized by normal background activity and interictal
generalized epileptiform discharges on EEG; brain imaging is also almost always
TABLE 4-1 Genetic Generalized Epilepsy Syndromes
Typical
age of
onset, Seizure Brain Genetic
Syndrome years type(s) Treatment Prognosis EEG imaging causes
Childhood 4-10 Typical Ethosuximide or Majority have Normal Normal Complex
absence absences, valproic acid as spontaneous background; inheritance in
epilepsy rarely first-line remission, interictal vast majoritya;
generalized usually before generalized glucose
tonic-clonic or during spike-wave transporter
adolescence; fragments; type 1 (GLUT1)
minority evolve 3-Hz generalized deficiency
into juvenile spike-wave should be
myoclonic during considered if
epilepsy or absences onset is at
other syndrome <4 years or
other atypical
features are
present
Juvenile 12-18 Myoclonic Valproic acid Majority are Normal Normal Complex
myoclonic and usually first-line; controlled on background; inheritance in
epilepsy generalized in female medication, but interictal vast majoritya;
tonic-clonic; patients, other only a small generalized GABRA1 is rare
absences are options should be minority are spike-wave autosomal
less common considered first; able to wean off and polyspike- dominant
avoid of treatment wave cause
carbamazepine fragments;
and high-amplitude
oxcarbazepine spike-wave/
polyspike-
wave bursts
with myoclonic
seizures
340 APRIL 2022

normal. Genetic testing is usually negative, as the vast majority of cases are
thought to occur through complex inheritance.11 The individual syndromes are
differentiated largely by seizure type(s), EEG findings, age of onset, and clinical
course (ie, likelihood of spontaneous remission).
Childhood Absence Epilepsy

Childhood absence epilepsy is a relatively common epilepsy syndrome, having an
estimated cumulative incidence of approximately 1 in 1000 people.12,13 Seizure
onset is typically between 4 and 10 years of age; children with onset before
Typical
age of
onset, Seizure Brain Genetic
Syndrome years type(s) Treatment Prognosis EEG imaging causes
Juvenile 12-18 Typical Many options Less than half Normal Normal Complex
absence absences are seizure free background; inheritance in
epilepsy and on medication; interictal vast majoritya
generalized usually require generalized
tonic-clonic lifelong spike-wave
treatment and polyspike-
wave
fragments; 4-
to 5-Hz
generalized
spike-wave
during
absences
Epilepsy 5-40 Generalized Many options Variable; Normal Normal Complex

with tonic-clonic Patients with background; inheritance in
generalized childhood- interictal vast majoritya
tonic-clonic onset have a generalized
seizures better spike-wave
alone prognosis fragments
Epilepsy 1-16 Eyelid Many options Drug resistance Normal Normal Complex
with eyelid myoclonia, in 80% background; 3- inheritance in
myoclonia absences, to 6-Hz vast majoritya;
generalized generalized pathogenic
tonic-clonic spike-wave/ variants in
polyspike- CHD2,
wave; fixation- SYNGAP1, and
off sensitivity KCNB1 can
produce
similar
phenotype
but usually
with more
severe
intellectual
disability
a
If the syndrome occurs in the context of a family with genetic epilepsy with febrile seizures plus, genetic testing should be considered.

4 years of age can be considered to have early-onset absence epilepsy.14 For

reasons that are unclear, childhood absence epilepsy may have a higher incidence
in girls than boys.15
In childhood absence epilepsy, the defining seizure type is a typical absence
seizure, involving a sudden, brief loss of awareness (usually 4 to 30 seconds)
followed by an almost immediate return to baseline (ie, no significant postictal
state).16 Patients typically stare blankly and may have subtle automatisms, most
commonly oral.16 Typical absence seizures are often subtle, and children are
often having hundreds per day at the time of diagnosis. Affected children may be
misdiagnosed with attention deficit disorder or daydreaming before diagnosis.
Typical absence seizures can often be provoked by hyperventilation; asking the
patient to hyperventilate for at least 3 minutes provides a useful method to
evaluate seizure control in the clinic. During seizures, EEG shows an abrupt
onset of generalized rhythmic spike-wave discharges at approximately 3 Hz
(FIGURE 4-1).16 Interictal EEG often shows normal background activity with
generalized spike-wave fragments in up to 92% of patients.17
Initial treatment of childhood absence epilepsy is usually with either
ethosuximide or valproic acid; efficacy of the two agents is similar although
ethosuximide may be better tolerated overall.18 The long-term prognosis is good
with the majority of patients having spontaneous remission. In one study of
patients with childhood absence epilepsy, followed for at least 12 years, only 7%
still had seizures.19 Generalized tonic-clonic seizures occur in approximately 12%
of patients with childhood absence epilepsy, usually at least several years after
the onset of absences.20 This finding can signal an evolution of phenotype from
childhood absence epilepsy into a different epilepsy syndrome such as juvenile
myoclonic epilepsy (JME).
In the vast majority of patients with childhood absence epilepsy, brain
imaging is normal and the underlying genetic inheritance is thought to be
complex, so investigations beyond routine EEG are of little utility. However,
genetic testing should be considered in patients with atypical courses,
FIGURE 4-1
Typical absence seizure. EEG of a 12-second typical absence seizure in a 4-year-old girl
with childhood absence epilepsy. Three-Hz generalized spike wave is seen, with abrupt
onset and offset.
342 APRIL 2022

particularly early-onset absence epilepsy because 10% of these patients have KEY POINTS
pathogenic variants in SLC2A1, the gene encoding glucose transporter type 1
● Genetic epilepsy
(GLUT1).21 Children with GLUT1 deficiency may have other neurologic features, syndromes may follow
such as paroxysmal dyskinesias, and require different management, including Mendelian patterns or may
the ketogenic diet.22 Brain imaging should be considered in patients who are exhibit complex inheritance,
drug-resistant, as focal lesions can rarely mimic childhood absence epilepsy. likely related to both
polygenic and epigenetic
factors.
Juvenile Myoclonic Epilepsy
JME is another relatively common form of epilepsy, with a point prevalence in ● Overall, the genetic
generalized epilepsy
adults of approximately 0.4 in 1000.23 Age of onset is typically between 12 and syndromes are
18 years.24 The prototypic seizure type is myoclonic jerks that are most characterized by normal
prominent in the mornings, although patients may also experience generalized background activity and
tonic-clonic or absence seizures. Seizures are often provoked by sleep interictal generalized
epileptiform discharges on
deprivation, flashing lights, or alcohol intake.24 Avoiding these inciting factors is
EEG; brain imaging is also
often challenging for young people of normal intelligence and can limit quality of almost always normal.
life.25 Interictal EEG typically shows normal background activity with Genetic testing is usually
generalized 4- to 6-Hz spike-wave and polyspike-wave fragments.24 negative, as the vast
majority of cases are
Photosensitivity is often seen, and patients may have myoclonic seizures with
thought to occur through
high-amplitude spike-wave or polyspike-wave bursts (FIGURE 4-2).24 complex inheritance.
Valproic acid appears to have the greatest efficacy in controlling seizures in
JME; however, many clinicians avoid use in female patients because of the ● In childhood absence
teratogenic and neurodevelopmental risk to the fetus in pregnancy; other agents epilepsy, the defining
seizure type is a typical
such as levetiracetam or lamotrigine can be used instead.24,26,27 However, as well absence seizure, involving
as with other sodium channel antagonists such as carbamazepine and a sudden, brief loss of
oxcarbazepine, lamotrigine risks exacerbating myoclonic seizures and even awareness (usually 4 to
provoking myoclonic status epilepticus.26 Although the majority of patients with 30 seconds) followed by an
almost immediate return to
JME have seizures controlled with medication, the rate of long-term epilepsy baseline (ie, no significant
remission is very low; in one study, 80% of patients with JME who attempted postictal state). Patients
medication weaning had seizure recurrence.28 typically stare blankly and
may have subtle
automatisms, most
commonly oral.
● Typical absence seizures

can often be provoked by
hyperventilation; asking the
patient to hyperventilate for
at least 3 minutes provides a
useful method to evaluate
seizure control in the clinic.
During seizures, EEG shows
an abrupt onset of
generalized rhythmic spike-
wave discharges at
approximately 3 Hz.
FIGURE 4-2
Myoclonic seizure. EEG of a myoclonic seizure during 18-Hz photic stimulation in a 13-year-
old girl with juvenile myoclonic epilepsy. High-amplitude generalized polyspike-wave
discharges are seen, correlating with the patient’s clinical jerks.

For patients with JME, the diagnosis is clinical, and further investigations are
rarely indicated beyond routine EEG. Most clinicians would not perform genetic
testing, even though there may be some rare genes exhibiting Mendelian
inheritance, namely GABRA1.29 However, for patients who exhibit significant
developmental impairment, neuropsychiatric decline, or other atypical features,
alternative diagnoses, including progressive myoclonus epilepsy (discussed later
in this article), should be considered and investigated thoroughly.
Juvenile Absence Epilepsy

Juvenile absence epilepsy bears many similarities to JME, with one of the main
differentiating factors being the lack of myoclonic seizures.30 Typical absence
seizures are the most prominent seizure type; however, unlike in childhood
absence epilepsy, most patients with juvenile absence epilepsy have, at most, a
few seizures per day, and loss of awareness may be less complete.31 As well, the
ictal EEG during absences shows a faster rhythmic spike-wave signature of 4 to
5 Hz. Interictal EEG shows a normal background with generalized spike-wave
and polyspike-wave fragments. Roughly 50% to 80% of patients with juvenile
absence epilepsy will also experience generalized tonic-clonic seizures.30,31
The long-term prognosis may be slightly worse with juvenile absence epilepsy
than JME; in one study, only 39% of patients had been seizure free on
medications for at least 2 years, and 100% of patients who attempted medication
withdrawal had seizure relapse.28 As with JME, the diagnosis is primarily clinical,
and further investigations are not usually indicated if the patient is of normal
intelligence and has no atypical features.
Epilepsy with Generalized Tonic-Clonic Seizures Alone

As the name suggests, epilepsy with generalized tonic-clonic seizures alone is a
genetic generalized epilepsy in which generalized tonic-clonic seizures are the
only seizure type. Age of onset has been reported to vary from 5 to 41 years, but
some have argued that childhood-onset epilepsy with generalized tonic-clonic
seizures alone should be considered a distinct entity from patients who have
onset in adolescence or later.32,33 A subset of patients have seizures exclusively on
awakening, leading some to classify those patients separately from those with a
“random” seizure pattern.33
Interictal EEG typically shows a normal background with interictal
generalized spike-wave fragments.33 Valproic acid has classically been the first-
line therapy, with approximately two-thirds of patients becoming seizure free.33
Prognosis may be better overall in those with onset in childhood, with all
remaining seizure free after weaning of antiseizure medication in one study.32
As with the other genetic generalized epilepsy syndromes, genetic testing and
neuroimaging have limited utility, particularly if the patient has normal
intelligence.
Epilepsy With Eyelid Myoclonias

Epilepsy with eyelid myoclonias (also known as Jeavons syndrome) is a childhood-
onset genetic generalized epilepsy classically involving a triad of (1) characteristic
brief eye-fluttering seizures (eyelid myoclonia), (2) eye closure–induced seizures/
epileptiform abnormalities on EEG, and (3) photosensitivity.34,35 These eyelid
myoclonias usually occur hundreds of times per day and can often be triggered by
voluntary eye closure. Patients may also have other seizure types, the most
344 APRIL 2022

common being generalized tonic-clonic (70% to 75%) or typical absences (100% KEY POINTS
in one study).34,36 Age of seizure onset is variable, from 1 to 16 years.34,36
● Children with absence
Seizures are drug resistant in 80% of patients.36 Mild to moderate intellectual seizures starting before the
disability is reported in 23% to 35% of patients.34,36 Genetic testing is usually age of 4 years are
negative in patients with a classic phenotype. De novo pathogenic variants in considered to have early-
CHD2, SYNGAP1, and KCNB1 have been associated with epilepsy with eyelid onset absence epilepsy; 10%
of these patients have
myoclonia–like phenotypes; however, these patients usually have more severe glucose transporter type 1
cognitive impairment and sometimes have phenotypes more in keeping with (GLUT1) deficiency due to
developmental and epileptic encephalopathies.37-39 pathogenic SLC2A1 variants.
● Age of onset of juvenile

SELF-LIMITED FOCAL EPILEPSIES OF CHILDHOOD
myoclonic epilepsy is
The self-limited (formerly called benign) focal epilepsies of childhood are a group typically between 12 and 18
of sometimes overlapping epilepsy syndromes that share several common years. The prototypic
features (TABLE 4-2). The term benign was replaced by self-limited and seizure type is myoclonic
pharmacoresponsive in the 2017 ILAE epilepsy classification.10 Children with jerks that are most
prominent in the mornings,
self-limited focal epilepsies of childhood typically have normal or near-normal although patients may also
development and normal neuroimaging, and seizures usually spontaneously experience generalized
resolve before or during adolescence. tonic-clonic or absence
seizures. Seizures are often
provoked by sleep
Childhood Epilepsy With Centrotemporal Spikes deprivation, flashing lights,
Childhood epilepsy with centrotemporal spikes has previously been referred to or alcohol intake.
as benign epilepsy of childhood with centrotemporal spikes” and benign Rolandic
epilepsy. Children first present with seizures typically between 7 and 10 years of ● Interictal EEG of JME
typically shows normal
age (range, 1 to 14 years), often from sleep.40 The seizure symptomatology is
background activity with
focal aware or focal impaired awareness, involving prominent hemifacial jerking generalized 4- to 6-Hz
or dystonia, facial paresthesia, drooling, and mumbling, and occasionally spike-wave and polyspike-
progressing to bilateral tonic-clonic convulsions.40 EEG shows focal wave fragments.
monomorphic medium-high amplitude spikes and spike-wave discharges over
● Although the majority of
one or both centrotemporal regions, having a characteristic morphology and patients with JME have
horizontal dipole (FIGURE 4-3). The discharges may be sparse in wakefulness but seizures controlled with
are markedly potentiated in sleep. medication, the rate of long-
Seizures typically respond well to antiseizure medication; most agents would term epilepsy remission is
very low.
likely be effective, with carbamazepine and valproic acid being popular choices
in published studies.41 However, as many children will have only several ● Sodium channel inhibitors
seizures in their life, clinical practice varies as to whether to initiate treatment at should be avoided in
all. The overall practice tends to be to recommend antiseizure medication41; patients with juvenile
myoclonic epilepsy, if
however, it is reasonable to make this decision in consideration of several factors,
possible, as there is the
including the number of seizures the child has experienced, time interval potential to exacerbate
between seizures, seizure duration, whether seizures have progressed to bilateral myoclonic seizures.
tonic-clonic, and parent/caregiver preference.
Although originally termed a “benign” disorder, neuropsychological ● Juvenile absence epilepsy
bears many similarities to
evaluation of cohorts of children with childhood epilepsy with centrotemporal JME, with one of the main
spikes finds an elevated risk for mild developmental impairment, particularly differentiating factors being
involving language function.42-45 Childhood epilepsy with centrotemporal spikes the lack of myoclonic
is considered to be at the mild end of the epilepsy-aphasia spectrum of disorders, seizures.
which also includes atypical childhood epilepsy with centrotemporal spikes, ● The ictal EEG of juvenile
Landau-Kleffner syndrome, and epileptic encephalopathy with continuous spike absence epilepsy during
wave in sleep.46 For isolated, typical childhood epilepsy with centrotemporal absences shows a faster
spikes, genetic testing has little utility at this time, although this is not the case for rhythmic spike-wave
signature of 4 to 5 Hz.
other epilepsy aphasia spectrum disorders.47 Neuroimaging is not necessary for

patients with typical presentations and well-controlled seizures, particularly if

the EEG shows independent bilateral epileptiform discharges; however, brain
MRI should be performed to rule out an intracranial lesion for any patients not
following the expected clinical course.
Atypical Childhood Epilepsy With Centrotemporal Spikes

The original clinical description of atypical childhood epilepsy with
centrotemporal spikes by Aicardi and Chevrie48 described patients with the same
TABLE 4-2 Self-Limited Focal Epilepsy Syndromes of Childhood
Typical
age of Brain Genetic
Syndrome onset, years Seizure type(s) Treatment Prognosis EEG imaging causes
Childhood 7-10 Focal aware May not need Majority have Normal Normal Complex
epilepsy with seizures/focal to initiate <10 seizures; background; inheritance
centrotemporal impaired medication; spontaneous interictal focal in vast
spikes awareness most agents remission spikes and majoritya
seizures, effective within 2-4 years spike-wave
hemifacial discharges
sensorimotor independently
(hemiface over right and/
clonic/ or left
dystonic, centrotemporal
drooling, regions,
vocalization, markedly
facial potentiated in
paresthesia); sleep
may have
focal-to-
bilateral tonic-
clonic seizures
Atypical 2-6 Focal aware Most agents May have Normal Normal Complex
childhood seizures/focal can be drug-resistant background; inheritance
epilepsy with impaired effective; seizures interictal focal in most;
centrotemporal awareness carbamazepine initially, but spikes and GRIN2A
spikes seizures (as in and spontaneous spike-wave pathogenic
childhood oxcarbazepine remission discharges variants in
epilepsy with can exacerbate usually occurs independently some
centrotemporal seizures by adolescence over right and/ patients;
spikes), negative or left single
myoclonus, centrotemporal reports of
atypical regions, de novo
absences markedly pathogenic/
potentiated in likely
sleep pathogenic
variants in
GRIN2B,
CAMK2A,
and
CACNG2
346 APRIL 2022

focal seizures and EEG signature as childhood epilepsy with centrotemporal
spikes, but additional ictal symptomatologies, including atypical absences and
myoclonic or atonic seizures. With time, negative myoclonus has come to be
recognized as the classic feature of atypical childhood epilepsy with
centrotemporal spikes, and the presence of this or other seizure types should be
the primary consideration when considering the diagnosis of atypical childhood
epilepsy with centrotemporal spikes. Some authors have used the term atypical
childhood epilepsy with centrotemporal spikes to describe cases of typical childhood
Typical
age of Brain Genetic
Syndrome onset, years Seizure type(s) Treatment Prognosis EEG imaging causes
Panayiotopoulos 3-6 Focal aware May not need Few seizures Normal Normal Complex
syndrome seizures/focal to initiate (1/3 have background; inheritance
impaired medication; only one); interictal focal in vast
awareness most agents spontaneous spikes and majoritya
seizures with effective remission spike-wave
prominent within discharges
autonomic 2-4 years independently
features (eg, over right and/
vomiting, pallor) or left occipital
regions
Gastaut 7-10 Focal aware Most agents Seizures may Normal Normal Complex
syndrome seizures/focal can be be frequent; background inheritance
impaired effective majority have interictal focal in vast
awareness spontaneous spikes and majoritya
seizures with remission in spike-wave
visual 2-4 years discharges
hallucinations; independently
ictal blindness over right and/
and headache or left occipital
may occur regions;
fixation-off
sensitivity may
occur
a
If the syndrome occurs in the context of a family with genetic epilepsy with febrile seizures plus, genetic testing should be considered.

KEY POINTS
● Roughly 50% to 80% of

patients with juvenile
absence epilepsy will also
experience generalized
tonic-clonic seizures.
● The seizure control

prognosis is poor in juvenile
absence epilepsy, with less
than half of patients seizure
free on medications after
2 years and nearly all having
seizure recurrence if
medication weaning is
attempted.
FIGURE 4-3
● Epilepsy with generalized Centrotemporal spikes. EEG of interictal centrotemporal spikes in a 9-year-old boy
tonic-clonic seizures alone with childhood epilepsy with centrotemporal spikes. Independent monomorphic focal
is a genetic generalized spike-wave discharges are seen over both the right and left centrotemporal regions (arrows).
epilepsy in which
generalized tonic-clonic
seizures are the only seizure
epilepsy with centrotemporal spikes in which seizures are more frequent and
type.
difficult to control or in which neuropsychological dysfunction is more
● Epilepsy with eyelid profound49; however, these patients are better considered to have unusual forms
myoclonias is a childhood- of typical childhood epilepsy with centrotemporal spikes, rather than a separate
onset genetic generalized electroclinical syndrome.
epilepsy classically
involving a triad of (1)
Age of seizure onset tends to be earlier than childhood epilepsy with
characteristic brief eye- centrotemporal spikes, usually between 2 and 6 years.48,50 Although seizures are
fluttering seizures (eyelid more difficult to control, patients will still usually have spontaneous resolution
myoclonia), (2) eye closure– before or during adolescence.50 Most antiseizure medications can be used;
induced seizures/
epileptiform abnormalities
however, there is the potential for seizure exacerbation with carbamazepine and
on EEG, and (3) other sodium channel antagonists.51 The likelihood of significant cognitive
photosensitivity. dysfunction is much greater than in childhood epilepsy with centrotemporal
spikes, more than 50% in some studies.50 Inheritance is probably still complex in
the majority of cases; however, pathogenic variants in GRIN2A and several other
genes have been associated, so genetic testing should be considered, especially if
family history is consistent with autosomal dominant inheritance.52-54
Panayiotopoulos Syndrome
In Panayiotopoulos syndrome, seizure onset is usually between 3 and 6 years
of age (range, 1 to 14 years).55 Seizures may be focal aware or focal impaired
awareness, usually occurring from sleep, with the most notable feature being
prominent autonomic symptoms. Vomiting, pallor, flushing, mydriasis/miosis,
and temperature changes are among the autonomic signs that may be seen.55
Lateral head and eye deviation may occur late in seizures, and progression to
bilateral tonic-clonic seizures is possible.55 Seizures are often prolonged, lasting
more than 30 minutes in nearly 44% of patients.55 Interictal EEG shows focal
spikes and spike-wave discharges, which are often abundant, over one or both
occipital regions (CASE 4-1).55 Children have cognitive function in the normal
range; however, full-scale IQ is significantly lower than in controls.56,57
Patients with Panayiotopoulos syndrome have spontaneous remission by
adolescence and usually few seizures; approximately one-third of children will
348 APRIL 2022

A 4-year-old girl presented to the emergency department with a prolonged CASE 4-1
seizure. Over the past 3 months, she had four episodes of unexplained
vomiting. The events had occurred soon after falling asleep and had been
associated with pallor, sweating, and dilated pupils. The duration was
estimated at 1 to 2 minutes, after which she went back to sleep. During the
events, she maintained at least partial awareness. However, with the event
on the day of presentation, she developed right-eye deviation and became
unresponsive. The event continued for 25 minutes and was aborted when
emergency medical personnel administered midazolam. She had no fever,
infectious symptoms, or recent trauma.
Her background history was mostly unremarkable. She was born after an
uncomplicated pregnancy and delivery at term. She had no medical issues,
and her developmental milestones had all been normal. Her family history
was significant only for a first cousin with childhood epilepsy with
centrotemporal spikes. Her EEG showed normal background activity, but
abundant high-amplitude focal monomorphic spike-wave discharges were
seen over the left occipital region (FIGURE 4-4).
She was diagnosed with Panayiotopoulos syndrome, and her parents were
counseled regarding seizure safety precautions. The treating neurologist
elected not to order brain imaging or genetic testing. The patient was
prescribed daily clobazam, as well as home intranasal midazolam to be
administered by the parents for any seizure lasting longer than 5 minutes. She
did not have any further seizures and was weaned off clobazam 2 years later.
FIGURE 4-4
EEG of interictal epileptiform discharges in the patient in CASE 4-1 with Panayiotopoulos
syndrome. Abundant monomorphic focal spike-wave discharges are seen over the left
occipital region (arrows).
This case illustrates that neuroimaging may not be necessary if the clinical COMMENT
and EEG findings are classic for a self-limited focal epilepsy of childhood.
In this case, the girl avoided exposure to a general anesthetic, which would
have been necessary to perform a brain MRI given her young age.

have only one event.55 Thus, as with childhood epilepsy with centrotemporal
spikes, it is reasonable to reserve treatment at the time of diagnosis and prescribe
medications only for those with frequent seizures. Inheritance is almost always
complex, so genetic testing is generally not indicated in isolated cases without a
relevant family history.
Gastaut Syndrome
Gastaut syndrome (not to be confused with Lennox-Gastaut syndrome) is an
occipital epilepsy syndrome with electrographic features essentially
indistinguishable from Panayiotopoulos syndrome, but it has a very different
clinical presentation. Seizure onset is slightly later on average, most commonly
7 to 10 years of age (range, 3 to 16 years).58 Patients have focal aware seizures,
although awareness may become impaired late in events. The symptomatology
mostly involves visual hallucinations usually lasting 1 to 3 minutes. These are
most typically elementary visual phenomena such as multicolored circles, but
about 10% of patients can have complex hallucinations, such as faces or figures.58
Ictal blindness lasting several minutes is also commonly reported. Patients may
also have headache during or after seizures.58 EEG shows focal occipital spikes
and spike-wave discharges as in Panayiotopoulos syndrome, and fixation-off
sensitivity (the appearance of epileptiform abnormalities with removal of visual
fixation, often by eye closure) often occurs.58
Diagnosis may be delayed as patients can be mistakenly thought to have either
migraines or a psychiatric condition. Unlike Panayiotopoulos syndrome, no clear
difference in IQ is seen when comparing children with Gastaut syndrome and
healthy controls.57 Seizures are usually sufficiently frequent that antiseizure
medication should be prescribed. Few data are available for long-term prognosis,
but the majority likely have spontaneous seizure resolution in 2 to 4 years.58
SELF-LIMITED FAMILIAL NEONATAL AND INFANTILE EPILEPSY

Spontaneously resolving seizures may occur in the first 1 to 2 years of life. The
two most common syndromes fitting this description are self-limited neonatal
epilepsy and self-limited infantile epilepsy.
Self-Limited Neonatal Epilepsy

In self-limited familial neonatal epilepsy, seizures begin in the neonatal period,
usually on the second or third day of life.59,60 Seizures may involve any or all of
tonic posturing, apnea, vocalization, eye deviation, change in skin color, and
unilateral or bilateral clonic movements.59 Duration is typically brief, usually less
than 30 seconds.59 EEG is usually normal in the interictal period, although
focal interictal epileptiform abnormalities are reported in 25% of patients.59,61
Affected children have spontaneous resolution of seizures, occurring by 6 weeks
in two-thirds of cases and by 6 months in 94% of cases.59,61 Neurologic
examination is normal, as is development. If present, family history is consistent
with autosomal dominant inheritance. Genetic testing identifies a cause in more
than 90% of familial cases; the most common cause is pathogenic variants in
KCNQ2, but KCNQ3 and SCN2A are also associated.61
Self-Limited Infantile Epilepsy

Self-limited infantile epilepsy is usually defined as seizures occurring in
otherwise healthy and typically developing children, usually between the ages of
350 APRIL 2022

3 and 20 months.62 Family history is often positive, following an autosomal KEY POINTS
dominant pattern. In some familial cases, patients may have younger onset, and
● Children with childhood
an overlap syndrome termed self-limited familial neonatal-infantile seizures has epilepsy with centrotemporal
been proposed in the past.63 Patients have focal impaired awareness seizure, spikes first present with
often with hemiclonic movements, head and eye deviation, or facial/limb seizures typically between 7
automatisms. Seizures usually occur in clusters of up to 8 to 10 per day over 1 to and 10 years of age (range, 1 to
14 years), often from sleep.
3 days.62 Interictal EEG is usually normal, as is brain MRI.62
The seizure symptomatology
In familial cases, PRRT2 pathogenic variants are identified in more than 80% is focal aware or focal
of patients.64,65 Other associated genes include SCN2A, KCNQ2, and KCNQ3, impaired awareness, involving
although these are often the earlier-onset self-limited familial neonatal-infantile prominent hemifacial jerking
or dystonia, facial
seizure phenotype.63,66 Despite the self-limited course, patients are usually
paresthesia, drooling, and
treated with antiseizure medication because of the high seizure frequency during mumbling, and occasionally
clusters; most antiseizure agents should be effective.62 Seizures usually resolve progressing to bilateral tonic-
within 1 year of onset. clonic convulsions. EEG
shows focal monomorphic
medium-high amplitude
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES spikes and spike-wave
The 2017 ILAE epilepsy classification introduced the term developmental and discharges over one or both
epileptic encephalopathy to describe patients who have both epilepsy and centrotemporal regions,
developmental impairment, in whom the epileptic activity contributes to the having a characteristic
morphology and horizontal
degree of developmental impairment.10 In most cases, patients with dipole.
developmental and epileptic encephalopathy will have experienced
developmental regression at some point, often at the time of seizure onset or ● Decisions on whether to
worsening. Although many developmental and epileptic encephalopathies are initiate antiseizure
medication in childhood
genetic, most of the developmental and epileptic encephalopathy syndromes
epilepsy with
may occur as a result of other factors, including after brain injury early in life. centrotemporal spikes
Here, only the developmental and epileptic encephalopathy syndromes that should be made on a child-
occur solely due to genetic factors are discussed. Other developmental and by-child basis, taking into
consideration frequency
epileptic encephalopathies that are more etiologically heterogeneous such as
and duration of seizures, if
West syndrome and Lennox-Gastaut syndrome are discussed elsewhere; refer to seizures have progressed to
the articles “Evaluation of First Seizure and Newly Diagnosed Epilepsy” by bilateral tonic-clonic, as
Elaine Wirrell, MD, FRCP(C), FAAN,67 and “Seizures and Epilepsy in well as parent/caregiver
Childhood” by Maria Gogou, MD, PhD, and Judith Helen Cross, MBChB, PhD,68 concerns.
in this issue of Continuum. Also, many genes may produce a nonspecific ● In Panayiotopoulos
developmental and epileptic encephalopathy phenotype, but they are also not syndrome, seizure onset is
discussed here. usually between 3 and
6 years of age (range, 1 to
14 years). Seizures may be
Dravet Syndrome focal aware or focal
Dravet syndrome (previously known as severe myoclonic epilepsy of infancy) first impaired awareness, usually
presents around 6 months of age, usually with febrile seizures that are often occurring from sleep, with
hemiclonic and prolonged.69 Patients subsequently develop afebrile seizure types the most notable feature
being prominent autonomic
that most commonly include any or all of generalized tonic-clonic, focal impaired
symptoms. Vomiting, pallor,
awareness, atypical absences, and myoclonic seizures.69 Seizures are almost flushing, mydriasis/miosis,
always drug resistant, with the most effective treatments being clobazam, and temperature changes
valproic acid, topiramate, and stiripentol.69,70 More recent data support the use are among the autonomic
signs that may be seen.
of cannabidiol and fenfluramine.71,72 EEG is initially normal but eventually
Lateral head and eye
shows generalized or multifocal epileptiform abnormalities and background deviation may occur late in
slowing.69 Brain imaging is typically normal. seizures, and progression to
The underlying cause in 80% to 90% of cases of Dravet syndrome is a bilateral tonic-clonic
pathogenic variant in SCN1A; however, it is crucial to remember that other seizures is possible.
epilepsy phenotypes may be associated with SCN1A.73,74 Dravet syndrome is a

clinical diagnosis and is not made by a positive SCN1A result. Development is

initially normal, with regression or plateau most commonly occurring in the
second year of life.69 The long-term developmental prognosis is highly variable;
all patients have some degree of intellectual disability, but this can range from
mild to profound. Dravet syndrome has a high rate of early mortality. The rate of
sudden unexpected death in epilepsy (SUDEP) is much higher than in other
forms of epilepsy, but individuals can also die by drowning or as a result of
massive cerebral edema developing after prolonged seizures.75,76
Myoclonic-Atonic Epilepsy
Myoclonic-atonic epilepsy (previously known as epilepsy with myoclonic-astatic
seizures and Doose syndrome) is considered a developmental and epileptic
encephalopathy, although the developmental course can be quite variable.77
Patients initially present with afebrile seizures and are between 1 and 6 years of
age, although a minority of patients have a preceding history of febrile
seizures.77,78 Myoclonic-atonic seizures are essential for diagnosis, although
patients may also have myoclonic, atonic, atypical absence, tonic, and
generalized tonic-clonic seizures.77,78 Nonconvulsive status epilepticus occurs in
a minority of patients.77,78 Many patients experience a “stormy phase” during
which the frequency of seizures is increased, development may deteriorate, and
EEG may show background slowing.77,78 Family history may be positive for
febrile seizures or other genetic epilepsy with febrile seizures plus (GEFS+)
phenotypes (discussed later in this article).
Genetic testing is negative in the majority of patients with myoclonic-atonic
epilepsy, and inheritance is probably complex in most. Even in monogenic cases,
the syndrome appears to be highly genetically heterogeneous, with pathogenic
variants in many genes reported to be causative. Some of the more commonly
reported include SLC6A1, SCN1A, and SLC2A1 (the gene for GLUT1 deficiency,
discussed earlier).79-82 Valproic acid and clobazam are the most commonly used
first-line antiseizure medications, but the ketogenic diet should be considered
early if patients do not respond to initial medical therapy.77,78 Seizures remit in at
least half of patients, generally within 5 years of onset.77,78 Of those with
complete remission, more than half are developmentally normal; the remainder
of patients typically have mild to moderate developmental impairment.77
Epilepsy of Infancy With Migrating Focal Seizures

Epilepsy of infancy with migrating focal seizures has a very characteristic seizure
symptomatology involving focal seizures with interhemispheric migration that
can be diagnosed either by clinical observation or EEG or both (FIGURE 4-5).
Seizure onset ranges from the first day of life to 6 months; in addition to the
migrating focal seizures, children may have epileptic spasms or tonic seizures, as
well.83 Interictal EEG may show focal/multifocal epileptiform discharges,
hypsarhythmia, or burst suppression.83 Although most patients have severe to
profound intellectual disability, milder phenotypes involving even normal
development can rarely occur.83
Genetic testing will be positive in the majority, although the condition is quite
genetically heterogeneous. Pathogenic variants in KCNT1 account for
approximately one-quarter of cases, followed by SCN2A in about 7%; however,
many other genes are associated, as well.83 Mortality is high, with at least one-
third of patients dying during childhood.83 Optimal treatment may depend on
352 APRIL 2022

KEY POINTS
● Status epilepticus is
common in Panayiotopoulos
syndrome, with nearly half
of patients having seizures
lasting longer than
30 minutes.
● Interictal EEG in patients

with Panayiotopoulos
syndrome shows focal
spikes and spike-wave
discharges, which are often
abundant, over one or both
occipital regions.
● Patients with Gastaut

syndrome have focal aware
FIGURE 4-5 seizures, although
Migrating focal seizure. EEG demonstrating migrating focal seizure in an 8-day-old girl with awareness may become
epilepsy of infancy with migrating focal seizures. The seizure starts in the right frontal region impaired late in events. The
and then migrates to the left frontal region. Note that the time scale is compressed. symptomatology mostly
involves visual
hallucinations usually lasting
the underlying genetic cause; those with SCN2A variants presenting before 1 to 3 minutes. These are
3 months of age will typically respond very well to sodium channel antagonists most typically elementary
visual phenomena such as
(eg, carbamazepine, oxcarbazepine, and lacosamide).84-86 Patients with KCNT1 multicolored circles, but
pathogenic variants may respond to quinidine; however, this is not universal, about 10% of patients can
and children should be carefully monitored for cardiac arrhythmias when the have complex
medication is initiated.87-90 hallucinations, such as faces
or figures. Ictal blindness
lasting several minutes is
PROGRESSIVE MYOCLONUS EPILEPSIES also commonly reported.
The progressive myoclonus epilepsies are a clinically and genetically
● EEG in patients with
heterogeneous group of disorders that share the common features of myoclonic Gastaut syndrome shows
seizures and progressive neurologic decline.91 Age of onset is typically in focal occipital spikes and
childhood or adolescence, and patients may have additional seizure types spike-wave discharges as in
including focal, atypical absence, atonic, and generalized tonic-clonic. Panayiotopoulos syndrome,
and fixation-off sensitivity
Photosensitive seizures, which may be noted on EEG, are a common feature in (the appearance of
several of the forms.91 epileptiform abnormalities
Depending on the underlying cause, patients may have other neurologic with removal of visual
features, including ataxia, dysarthria, vision loss, hearing loss, neuropathy, and fixation, often by eye
closure) often occurs.
myopathy. Historically, ophthalmologic examination (to identify cherry-red
spot) and skin biopsy were universally indicated as part of the diagnostic ● Children with Gastaut
workup; however, a gene panel is now often sufficient to determine the syndrome may be
molecular cause. In most cases, the underlying genetic cause occurs via misdiagnosed with migraines
or psychiatric disorders as
autosomal recessive inheritance; however, mitochondrial and autosomal
they present with visual
dominant forms exist.91,92 TABLE 4-3 summarizes the more studied forms of hallucinations, sometimes
genetic progressive myoclonus epilepsies. with associated headache.
SLEEP-RELATED HYPERMOTOR EPILEPSY

Sleep-related hypermotor epilepsy (previously known as nocturnal frontal lobe
epilepsy) is a form of focal epilepsy involving seizures that usually occur
exclusively from sleep. Seizures usually arise from the frontal lobe; however,

TABLE 4-3 Progressive Myoclonus Epilepsy
Other seizure
types that may Additional features
Disease Gene(s) Inheritance Age of onset occur that may be seen Prognosis
Lafora body EPM2A, Autosomal 14-16 years Generalized Dysarthria, ataxia, Death usually
disease NHLRC1 recessive (range, tonic-clonic, spasticity within
8-19 years) atypical 10 years of
absences, onset
atonic, focal
impaired
awareness
seizure
(transient
blindness or
visual
hallucinations)
Unverricht- CSTB Autosomal 6-15 years Generalized Ataxia Life

Lundborg recessive tonic-clonic expectancy
disease decreased,
but patients
usually live to
at least
40 years
Myoclonic MT-TK in Mitochondrial Childhood to Atonic, focal Myopathy, migrainous Variable

epilepsy with >90%; adulthood clonic, headaches, hearing
ragged red others: generalized loss, peripheral
fibers (MERRF) MT-TF, tonic-clonic, neuropathy, psychiatric
MT-TH, myoclonic- illness
MT-TI, atonic,
MT-TL1, absences,
MT-TP, myoclonic-
MT-TS1, absences
MT-TS2
Neuronal PPT1, TPP1, Autosomal Variable Generalized Retinopathy (may have Variable
ceroid DNAJC5, recessive tonic-clonic, cherry-red spot), vision
lipofuscinoses MFSD8, (rarely focal impaired loss, ataxia
CTSD, autosomal awareness
GRN, dominant) seizure
ATP13A2,
CTSF,
KCTD7
354 APRIL 2022

Other seizure
types that may Additional features
Disease Gene(s) Inheritance Age of onset occur that may be seen Prognosis
Action SCARB2 Autosomal Late Generalized Tremor, peripheral Variable

myoclonus- recessive adolescence clonic-tonic- neuropathy, dysarthria,
renal failure to adulthood clonic ataxia, sensorineural
syndrome hearing loss,
proteinuria/nephrotic
syndrome/renal failure
Myoclonus KCNC1 Autosomal 3-15 years Generalized Ataxia, clinical Mild

epilepsy and dominant tonic-clonic improvement with fever cognitive
ataxia due to decline in
potassium 50%
mutation
Sialidosis type I NEU1 Autosomal Infancy to Focal, bilateral Retinopathy (cherry-red Variable
and type II recessive third decade tonic-clonic spot), vision loss, ataxia,
of life coarse features,
hepatosplenomegaly,
dysostosis multiplex,
hearing loss, hernias
Gaucher GBA Autosomal Childhood to Generalized Ophthalmoplegia, Death often

disease, type III recessive adolescence tonic-clonic ataxia, spasticity, within
neuronopathic dementia, growth several years
retardation, delayed of onset
puberty,
hepatosplenomegaly,
bone abnormalities
Dentatorubral- ATN1 Autosomal <12 months to Generalized Ataxia Progressive

pallidoluysian dominant 19 years tonic-clonic, decline
atrophy (CAG repeat tonic, atonic,
expansion) clonic
North Sea GOSR2 Autosomal 2-8 years Generalized Ataxia (precedes Cognitive
progressive recessive tonic-clonic, myoclonus), dysarthria, function
myoclonus absences areflexia, scoliosis relatively
epilepsy spared;
assistance
required with
activities of
daily living

extrafrontal onset with spread to the frontal regions can produce the same
phenotype.93 The seizure symptomatology typically involves hypermotor
behaviors such as violent thrashing and writhing, often with vocalization and
emotional facial expression.93 Tonic and dystonic features are often seen, as well.
Seizures are usually frequent, often occurring several times per night. A clear
ictal rhythm is rarely seen on EEG, which may show only artifacts from muscle
and movement.93 Interictal EEG is usually normal, and the clinical presentation
can be easily confused with parasomnias or nonepileptic seizures, so inpatient
video-EEG recording is often essential to confirming the diagnosis. Treatment
with most standard antiseizure medications is appropriate, although patients are
often drug resistant.
A family history suggestive of autosomal dominant inheritance is present in
some patients with sleep-related hypermotor epilepsy. Pathogenic variants in
acetylcholine receptor subunit genes (CHRNA4, CHRNB2, CHRNA2) are
the most common identified causes of autosomal dominant sleep-related
hypermotor epilepsy.94-96 Pathogenic variants in KCNT1 can also produce
autosomal dominant sleep-related hypermotor epilepsy, but these are often de
novo, and patients usually have more severe comorbid neuropsychiatric
disturbance.97 Lastly, some evidence has been shown that pathogenic variants
in CRH are causative in some families.98
Pathogenic variants in mammalian target of rapamycin (mTOR) regulatory
genes (ie, DEPDC5, NPRL2, NPRL3) may also cause sleep-related hypermotor
epilepsy; however, these families more commonly have familial focal epilepsy
with variable foci (discussed later in this article) in which a variety of phenotypes
that may or may not include sleep-related hypermotor epilepsy are seen. For
patients in this group who are drug resistant or those with negative genetic
testing, a thorough workup should be undertaken to investigate if they have a
surgically remediable lesion such as a focal cortical dysplasia.
PHOTOSENSITIVE OCCIPITAL LOBE EPILEPSY

Photosensitive occipital lobe epilepsy (formerly known as idiopathic
photosensitive occipital epilepsy) is an epilepsy syndrome in which photosensitivity
is a hallmark feature. The classic seizures involve simple, colorful visual auras
that often progress to conscious tonic lateral head and eye version.99 Seizure
onset can be from childhood to adolescence (range, 5 to 17 years of age).99 EEG
shows occipital spikes or spike wave, although centrotemporal spikes may also
occur.99 Intelligence is usually in the normal range. The clinical features of
photosensitive occipital lobe epilepsy may overlap with other epilepsy
syndromes, including JME, epilepsy with eyelid myoclonias, and Gastaut
syndrome.99-101 Presently, no genes are clearly associated with the classical
phenotype, and inheritance is presumed to be complex in most cases.
FOCAL EPILEPSY WITH AUDITORY FEATURES

Epilepsy with auditory features is an epilepsy syndrome characterized by focal
aware seizures localized to the lateral temporal region. Patients experience
seizures involving simple or complex auditory hallucinations, and 86% of
patients have focal-to-bilateral tonic-clonic seizures.102 Patients may report that
loud sounds or noise can provoke seizures. Some patients may also experience an
aura of receptive or global aphasia. Seizure onset is usually in adolescence, but a
range from 0.5 to 57 years has been reported.102 At least one-third of patients are
356 APRIL 2022

drug resistant, and although seizures can eventually remit, this may not occur KEY POINTS
until decades after onset.102 Intelligence is usually normal. Interictal EEG is
● In self-limited familial
normal in two-thirds of patients, and ictal EEG may not show abnormalities with neonatal epilepsy, seizures
the auditory phenomena alone.102 The differential diagnosis includes migraine begin in the neonatal period,
variants and psychiatric disorders, so inpatient video-EEG monitoring may be usually on the second or
necessary to confirm the diagnosis. third day of life. Seizures
may involve any or all of
Family history may suggest autosomal dominant inheritance, although genetic
tonic posturing, apnea,
testing is positive in only 5% and 15% of sporadic and familial cases, vocalization, eye deviation,
respectively.103 Pathogenic variants in LGI1, RELN, MICAL1, SCN1A, and change in skin color, and
DEPDC5 have all been associated.104-108 unilateral or bilateral clonic
movements. Duration is
typically brief, usually less
FAMILIAL SYNDROMES WITH VARIABLE PHENOTYPES than 30 seconds.
When obtaining a family history, it is not uncommon to identify other
individuals who may have experienced seizures, but with apparently different ● Affected children with
phenotypes from the proband the neurologist is seeing. This history may still be self-limited neonatal
epilepsy have spontaneous
very relevant because in two main familial epilepsy syndromes affected family resolution of seizures,
members may have a range of epilepsy syndromic phenotypes. occurring by 6 weeks in two-
thirds of cases and by
Genetic Epilepsy With Febrile Seizures Plus 6 months in 94% of cases.
GEFS+ (previously known as generalized epilepsy with febrile seizures plus) is a
● Self-limited infantile
familial syndrome in which autosomal dominant or complex inheritance patterns epilepsy is usually defined
are most commonly seen.109,110 The most frequent epilepsy phenotypes are as seizures occurring in
febrile seizures and febrile seizures plus111; the latter refers to patients with otherwise healthy and
typically developing
febrile and afebrile generalized tonic-clonic seizures or in whom febrile seizures
children, usually between
continue outside the usual age range (ie, after 6 years).109 However, many other the ages of 3 and 20 months.
epilepsy phenotypes may occur within families, most commonly including
genetic generalized epilepsies, focal epilepsy without preceding febrile seizures, ● Patients with self-limited
and the developmental and epileptic encephalopathies, Dravet syndrome, and infantile epilepsy have focal
impaired awareness seizure,
myoclonic-atonic epilepsy.111 often with hemiclonic
A family with GEFS+ has been defined as having two or more individuals with movements, head and eye
a GEFS+ spectrum phenotype, at least one of which is febrile seizures plus, or, if deviation, or facial/limb
no individuals have febrile seizures plus, at least three individuals have other automatisms. Seizures
usually occur in clusters of
classic GEFS+ phenotypes (eg, febrile seizures or myoclonic-atonic epilepsy).111 up to 8 to 10 per day over 1 to
An example pedigree is shown in FIGURE 4-6A. Notably, a family in which the only 3 days.
phenotype seen is febrile seizures would not be considered GEFS+ but instead
classified as familial febrile seizures.111 Although complex inheritance likely ● Dravet syndrome first
presents around 6 months of
accounts for the majority of families with GEFS+, a monogenic cause (usually
age, usually with febrile
autosomal dominant) is identified in up to one-third.111 The most commonly seizures that are often
associated genes are SCN1A, SCN1B, SCN2A, SCN9A, GABRG2, and STX1B.111 hemiclonic and prolonged.
Patients subsequently
Familial Focal Epilepsy With Variable Foci develop afebrile seizure
types that most commonly
Familial focal epilepsy with variable foci is an autosomal dominant familial include any or all of
syndrome in which all affected members have focal epilepsy but with different generalized tonic-clonic,
seizure types.112 For example, a woman with temporal lobe epilepsy might give focal impaired awareness,
birth to two children, one of whom has sleep-related hypermotor epilepsy and atypical absences, and
myoclonic seizures.
the other occipital epilepsy. An example pedigree is shown in FIGURE 4-6B.
Affected patients may have normal brain MRI or may show signs of
malformations, namely focal cortical dysplasia.
The underlying genetics have thus far all involved genes related to the mTOR
pathway. Pathogenic variants in DEPDC5, NPRL2, and NPRL3 have all been

FIGURE 4-6
Pedigrees for familial epilepsy syndromes. Example pedigrees for genetic epilepsy with
febrile seizures plus (A) and familial focal epilepsy with variable foci (B).
CAE = childhood absence epilepsy; FS = febrile seizures; FS + = febrile seizures plus; MAE = myoclonic-
atonic epilepsy; SHE = sleep-related hypermotor epilepsy; TLE = temporal lobe epilepsy.
associated.113-115 These genes encode subunits of the GATOR1 complex, an

inhibitor of mTOR.116
CONCLUSION
Many genetic epilepsy syndromes have been identified for individuals, as well as
two main familial syndromes. A neurologist’s ability to recognize these
syndromes is crucial to allow for appropriate investigation, including the need
for neuroimaging and molecular genetic testing. Regarding the latter, the yield of
genetic testing will be much higher in certain syndromes (eg, severe early-onset
developmental and epileptic encephalopathies such as Dravet syndrome)
compared with others (eg, self-limited focal epilepsy of childhood and genetic
generalized epilepsy). Accurate identification of genetic epilepsy syndromes also
allows for proper counseling of patients and their families regarding prognosis
and risk for comorbidities such as developmental impairment and SUDEP.
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362 APRIL 2022

Autoimmune-Associated REVIEW ARTICLE

Seizures CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Lisa Gillinder, MBBS, FRACP; Jeffrey Britton, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article focuses on the seizure manifestations and
presentations of autoimmune-associated epilepsy and acute symptomatic
seizures in autoimmune encephalitis. It discusses the specificity of the various
central nervous system autoantibodies and clarifies when their presence
can be considered indicative of an immune etiology. Finally, current
recommendations regarding patient selection for autoimmune antibody
evaluation are reviewed, and an approach to immunotherapy is provided.
RECENT FINDINGS: Although autoimmune seizures are caused by a

heterogeneous group of autoantibodies, key features reported in the
literature should alert clinicians to the possible diagnosis. In particular,
seizure characteristics including frequency, timing, duration, and CITE AS:
symptomatology can provide vital clues to help differentiate autoimmune- CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):363–398.
associated seizures from other causes of epilepsy. Diagnostic certainty also
requires an understanding and integration of the spectrum of clinical and
paraclinical presentations, and several scoring systems have been developed Dr Lisa Gillinder, Mater Advanced
that may be useful to aid the identification of autoimmune seizures. Epilepsy Unit, Level 8 Salmon
Building, Raymond Terr, South
Brisbane, QLD 4101, Australia,
SUMMARY: Seizures due to autoimmune etiology are increasingly lisa.gillinder@mater.org.au.
encountered in clinical practice. It is critical that clinicians recognize
immune seizure etiologies early in their course given they are often Dr Gillinder reports no
responsive to immunotherapy but are usually resistant to antiseizure disclosure. Dr Britton has
medications. Currently, however, it is unfortunately not uncommon for received personal
autoimmune-associated seizure disorders to remain undiagnosed, $0 to $499 for serving as an
resulting in missed opportunities to administer effective therapies. Efforts online course instructor for the
American Clinical
to better understand autoimmune seizure manifestations and treatment Neurophysiology Society.
strategies are ongoing.
UNLABELED USE OF
USE DISCLOSURE :
Drs Gillinder and Britton
INTRODUCTION discuss the unlabeled/
S
eizures due to autoimmune etiology are increasingly encountered in investigational use of
azathioprine,
clinical practice. This was formally acknowledged by the International
cyclophosphamide, IVIg,
League Against Epilepsy (ILAE) in 2017, with the addition of “immune” methylprednisolone,
as an etiology in the ILAE’s Classification of the Epilepsies.1 Although mycophenolate mofetil,
prednisone, and rituximab for
seizures due to immune causes represent less than 20% of patients the treatment of autoimmune
encountered in an epilepsy clinic, it is critical that immune seizure etiologies be encephalitis.
identified early in their course given they are responsive to immunotherapy and are
usually resistant to antiseizure medications. This is especially true since improved © 2022 American Academy
outcomes are associated with earlier use of immunotherapy. of Neurology.

AUTOIMMUNE-ASSOCIATED SEIZURES
In current practice, it is unfortunately not uncommon for autoimmune-

associated seizure disorders to remain undiagnosed for weeks to months.
Such delays may result in missing a window of opportunity to effectively treat
the underlying etiology in these cases. This article focuses on the seizure
manifestations and presentations of autoimmune-associated epilepsy and
acute symptomatic seizures in autoimmune encephalitis. It discusses the
specificity of the various central nervous system (CNS) autoantibodies and
clarifies when their presence can be considered indicative of an immune etiology.
Finally, current recommendations regarding patient selection for autoimmune
antibody evaluation are reviewed, and an approach to immunotherapy
is provided.
DEFINITIONS
Seizures and epilepsy may both result from autoimmune disorders affecting the
CNS, but these terms should not be considered interchangeable. The term
autoimmune epilepsy has been used in recent years in reference to any seizures
occurring in the context of autoimmune disorders. However, when reflecting on
the concepts and meanings of seizure and epilepsy as laid out by the ILAE, the
term autoimmune epilepsy has not held up as the most appropriate one for use in
these conditions. One reason for this is that seizures are a common clinical
feature in autoimmune encephalitis but are typically not the only clinical feature.
Also, after resolution of the active phase of encephalitis, seizures may resolve,
thus not meeting the definition of epilepsy, which implies an ongoing
predisposition to seizures. Therefore, the term recommended for use in reference
to seizures occurring in the setting of active autoimmune encephalitis is acute
symptomatic seizures secondary to autoimmune encephalitis.2
However, some patients with autoimmune encephalitis continue to have
seizures after resolution of acute encephalitis. In addition, some patients with
chronic epilepsy may be discovered to have findings suggesting an immune
etiology despite a long history of seizures and the absence of a clear prior episode
of acute encephalitis. Finally, ongoing drug-resistant seizures are a hallmark of
Rasmussen encephalitis, an immune-mediated disorder stemming from chronic
encephalitis and its structural cerebral aftermath, leading to an enduring
predisposition to unprovoked seizures. In these cases, the concept of “epilepsy” is
appropriate, given the presence of an ongoing potential for seizures. Hence,
autoimmune-associated epilepsy has been proposed as the most appropriate term
for those situations.2
PATHOPHYSIOLOGY AND DIAGNOSIS

Autoimmune seizure disorders may result from antibody-, cytokine-, and T-cell–
mediated immune mechanisms. Certain autoantibodies targeting particular
neural cell surface antigens have been demonstrated to be directly pathogenic,
leading to seizures, as well as affecting other behavioral functions.3 Several
antibodies targeting intracellular neural antigens have also been identified in
patients with acute symptomatic seizures and chronic epilepsy. In these cases,
the direct pathogenicity of these antibodies has been called into question, and
their significance has been interpreted to be that of a nonspecific marker of past
or present immune cell-mediated processes. Finally, it is increasingly realized
that humoral mediators of inflammation, such as cytokines, interleukins, and
interferons, may play a role in the pathogenesis of seizures and epilepsy and that
364 APRIL 2022

a clearer understanding of these may allow discovery of innovative and unique KEY POINTS
antiseizure and antiepileptic treatment options in the future.4-6
● Immune seizure etiologies
A disruption in the normal homeostatic balance of neuronal excitation and are often responsive to
inhibition caused by immune pathophysiologic processes is hypothesized to immunotherapy but are
underly the occurrence of seizure generation in patients with autoimmune- usually resistant to
associated seizures.7 Indeed, the demonstration of direct effects of antibodies antiseizure medications.
targeting specific cell surface antigens in experimental models (eg, leucine-rich
● The term autoimmune-
glioma inactivated protein 1 [LGI1],8,9 N-methyl-D-aspartate [NMDA] associated epilepsy is now
receptor3,10) supports a pathogenic role for these CNS autoantibodies. Currently, proposed to describe a
autoantibodies targeting neuronal structures are the most commonly used clinical presentation with an
biomarker for diagnosing acute symptomatic seizures secondary to autoimmune enduring predisposition to
unprovoked seizures with
encephalitis and autoimmune-associated epilepsy. Neuronal cell surface evidence of an immune
antibodies that have been clearly linked to limbic encephalitis, in particular, are etiology, whereas acute
considered specific for the presence of an underlying autoimmune etiology, symptomatic seizures
provided the clinical picture is consistent.11-13 secondary to autoimmune
encephalitis is
However, the significance of other neuronal antibodies is less clear.7 For recommended for seizures
example, recent studies have called into question the pathogenic significance of that occur as a symptom of
antibodies such as low-titer (less than 20 nmol/L or less than 1000 U/mL) active autoimmune
glutamic acid decarboxylase 65 (GAD65) antibodies and voltage-gated potassium encephalitis.
channel antibodies that do not have LGI1 or contactin-associated proteinlike
● Not all neural antibodies
2 (CASPR2) affinity.14,15 Therefore, clinicians must have a clear understanding are considered definitively
of the pathogenic significance of each antibody type to ensure appropriate pathogenic, so clinicians
diagnosis and treatment decisions (TABLE 5-1). must have an understanding
of the pathogenic
Although antibodies serve an important role as a biomarker for autoimmune-
significance of each
mediated seizure disorders, in occasional cases, immunity is suspected based on antibody to ensure accurate
clinical, imaging, and CSF results, but antibodies are absent.16 In these cases, the diagnostic and treatment
possible presence of pathogenic autoantibodies that are not yet detectable by decisions are made.
current techniques has been suggested by reports of such patients undergoing
● Seizures in adults with
successful treatment with rituximab,17 a medication that prevents differentiation autoimmune encephalitis
of mature B cells into antibody-producing plasma cells.18 Seronegative cases such are reported to occur at a
as these provide evidence suggesting a broader role of immunity in clinical higher frequency and with
epilepsy and highlight the need to identify additional biomarkers to facilitate shorter duration than
seizures due to other
diagnosis. etiologies.
ACUTE SYMPTOMATIC SEIZURES SECONDARY TO AUTOIMMUNE

ENCEPHALITIS
Autoimmune encephalitis classically presents with a cluster of symptoms,
including cognitive and memory impairment, personality and psychiatric
changes, movement disorders, and seizures. Seizures are common and often the
presenting symptom in antibody-mediated autoimmune encephalitis. It is crucial
that neurologists recognize the types of seizures that can indicate the presence of
neuronal cell surface antibody–mediated autoimmune encephalitis. A discussion
of seizure manifestations and paraclinical findings that may be encountered in
patients with seizures due to autoimmune encephalitis follows.
Seizure and Clinical Characteristics

The most common seizure types in autoimmune encephalitis at presentation are
focal seizures. In studies evaluating the clinical features of seizures associated
with autoimmune encephalitis, they tend to occur without impaired awareness
or postictal confusion.19 In a study comparing seizures associated with

hippocampal sclerosis and seizures secondary to autoimmune encephalitis, those

associated with autoimmune encephalitis were significantly shorter in duration,
lasting seconds as opposed to 1 to 3 minutes.19 In this study, it was also noted
that bilateral tonic-clinic seizures, especially nocturnal, were more common in
acute symptomatic seizures secondary to autoimmune encephalitis than in
epilepsy caused by hippocampal sclerosis.
Seizure frequency in autoimmune encephalitis is also unusually high
compared with seizures in most patients with focal epilepsy due to other causes,
often occurring daily, and in some many times per day.19,20 In addition, a
preceding febrile illness and a history of systemic autoimmunity or malignancy
should also raise suspicion of an immune etiology.
The clinical seizure symptomatology is often the first information obtained in
seizure evaluation and can be helpful in identifying seizures of autoimmune
etiology. Autoimmune encephalitis often affects the limbic structures, especially the
mesial temporal, insula, and perisylvian networks, so it is not unexpected that this is
reflected in the seizure symptoms. Clinical features of seizures that have been
reported in cases of autoimmune encephalitis are summarized in TABLE 5-2.21-25
Anti–Leucine-Rich Glioma Inactivated Protein 1 Antibody Encephalitis

Anti-LGI1 encephalitis most commonly presents with focal seizures. Patients are
typically between the ages of 40 and 80 years (median, 65 years). It is somewhat
TABLE 5-1 Neural Autoantibodies With Definite and Uncertain Association With
Autoimmune Encephalitis
Antibodies with definite association with autoimmune encephalitis

◆ Antineuronal nuclear antibody type 1 (ANNA-1)
◆ α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor
◆ Contactin-associated proteinlike 2 (CASPR2)
◆ Dipeptidyl-peptidase–like protein 6 (DPPX)
◆ High-titer glutamic acid decarboxylase 65 (GAD65)
◆ γ-Aminobutyric acid A (GABAA)
◆ γ-Aminobutyric acid B (GABAB)
◆ Leucine-rich glioma inactivated protein 1 (LGI1)
◆ Ma/Ta
◆ Metabotropic glutamate receptor 5 (mGluR5)
◆ N-methyl-D-aspartate (NMDA) receptor
Antibodies with uncertain association with autoimmune encephalitis
◆ Ganglionic nicotinic acetylcholine receptor
◆ Low-titer CASPR2
◆ Low-titer GAD65
◆ Voltage-gated calcium channel
◆ Voltage-gated potassium channel (without reactivity to LGI1 or CASPR2)
366 APRIL 2022

Seizure Clinical Features Reported in Autoimmune Encephalitis TABLE 5-2
Experiential and perceptive

◆ Déjà vu
◆ Jamais vu
◆ Autoscopy
◆ Psychic sensations (fear)
◆ Sense of levitation
◆ Dizziness (nonvertiginous)
Somatosensory
◆ Paresthesia
◆ Pain
◆ Thermal sensations (warm or cold waves)
◆ Numbness
Viscerosensitive
◆ Pharyngeal sensation and throat-clearing
◆ Taste
◆ Epigastric sensations
◆ Hiccups
Auditory
◆ Musical aura
◆ Musicogenic seizures
Language
◆ Vocalizations
◆ Dysarthria
Autonomic
◆ Tachycardia
◆ Flushing
◆ Salivation
◆ Piloerection
◆ Shuddering
Motor
◆ Posturing
◆ Dystonia
◆ Automatisms (orofacial or bimanual)
◆ Clonic
◆ Twitching
Visual
◆ Not defined

more common in men than women (66%). Hyponatremia is relatively

common.26,27 Faciobrachial dystonic seizures are the most characteristic seizure
type in this disorder, although they are absent in more than half of cases.
Faciobrachial dystonic seizures are brief, lasting seconds, occur multiple times
per day, and typically present with simultaneous contraction of the upper limb
muscles and ipsilateral facial and neck muscles. Within a single seizure, they
often remain unilateral but can quickly be followed by a similar attack affecting
the other side. In some cases, one side is affected exclusively; however, bilateral
independent attacks can also occur. Sometimes the lower extremities can be
involved, and sometimes they involve the face or upper extremity alone. These
seizures usually precede the onset of other features suggestive of encephalitis.
A wide range of other clinical features has been described in seizures
associated with anti-LGI1 encephalitis. These include autonomic symptoms such
as piloerection; sensations of alteration of temperature, referred to as thermal
seizures; somatosensory changes, especially paresthesia or pain; a sensation that
can only be characterized as a “wave”; body-shuddering; and paroxysmal
nonvertiginous dizziness.21,25 Additional manifestations that can also occur
include automatisms, vocalizations, blinking, clonus, dystonia, and posturing
(CASE 5-1).
It is important to realize that EEG may show no ictal findings even during
focal seizures in anti-LGI1 encephalitis. This is presumed to be because of either
(1) localization of seizures involving deeper structures such as the insula, and in
the case of faciobrachial dystonic seizures, potentially the basal ganglia; or (2)
perhaps the size of the seizure onset zone falling below that necessary to allow
scalp EEG detection. When EEG correlate is present, the ictal and interictal
abnormalities are most commonly localized to the temporal and frontal regions.
They can also be multifocal. Both slowing and epileptiform discharges may be
present; however, it is important to note that the EEG may be completely
normal.21 Although faciobrachial dystonic seizures are typically not associated
with EEG abnormalities during an attack, use of specialized ultralow-frequency
filtering can demonstrate a contralateral slow wave potential before clinical
seizure onset.29
MRI may be negative but may show abnormalities in the mesial temporal
structures, basal ganglia, and insula and, less commonly, in the extratemporal
regions.30-33 A unique finding in anti-LGI1 encephalitis with faciobrachial
dystonic seizures is the presence of T1, fluid-attenuated inversion recovery
(FLAIR), and T2 hyperintensities in the basal ganglia. Fludeoxyglucose positron
emission tomography (FDG-PET) may show hypometabolism or
hypermetabolism involving the basal ganglia and mesial temporal structures.20,34
CSF may show mild to moderate inflammatory changes with mild pleocytosis
(6 to 11 cells/mm3) and mild protein elevation (63 to 110 mg/dL), but in 50% of
cases CSF is normal.20,26 LGI1 antibodies are absent in spinal fluid in up to 50%
of patients even in clear cases of anti-LGI1 encephalitis, especially when using
cell-based assays, so clinicians should take care not to exclude LGI1 as a cause of
seizures or encephalitis based on a negative CSF antibody result.27,35
Anti–N-methyl-D-aspartate Receptor Encephalitis

Anti–NDMA receptor encephalitis most commonly occurs in women in the third
decade of life but can affect the very young, older adults, and males as well.
Seizures are common in anti–NMDA receptor encephalitis, occurring in 70% of
368 APRIL 2022

patients; however, they are the presenting symptom in less than 50% of adult KEY POINTS
cases.36 Seizures occur more commonly in the early phase of disease in children
● Anti-LGI1 encephalitis
and young men. Later in the course, status epilepticus may occur in most commonly presents
approximately one-quarter of cases.37 Neurobehavioral abnormalities are with focal seizures. Patients
typically the most prominent presenting feature and include psychosis, speech are typically between the
disorder, catatonia, personality changes, impaired cognition, and memory ages of 40 and 80 years. It is
somewhat more common in
disturbance.
men than women.
The seizure types present in anti–NMDA receptor encephalitis include focal Hyponatremia is relatively
aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures, common. Faciobrachial
which occur in almost 80% of cases.22 Specific clinical features of seizures in dystonic seizures are the
most characteristic seizure
anti–NMDA receptor encephalitis include autonomic symptoms such as
type in this disorder,
piloerection and palpitations or, less commonly, sensory changes.19,22,38 Motor although they are absent in
manifestations occur in 50% of patients with seizures,22 and multiple seizure more than half of cases.
types can occur in the same patient.39 Movement disorder manifestations are also
a common feature and may cause diagnostic uncertainty as some findings, such ● EEG may show no ictal
findings even during focal
as orofacial dyskinesias, can resemble seizure-related oral automatisms. seizures in anti-LGI1
The first EEG after presentation may show a normal background rhythm or encephalitis.
only mild slowing, which correlates with a better prognosis.40 However, the EEG
usually becomes abnormal, typically showing prominent slowing initially. As the ● Certain seizure
manifestations can provide
encephalopathy progresses, generalized rhythmic delta activity is commonly
clues about an autoimmune
present (FIGURE 5-3A).41 A characteristic EEG finding in anti–NMDA receptor etiology.
encephalitis is the “extreme delta brush” pattern, present in up to 30% of
cases. This consists of generalized rhythmic delta activity with superimposed ● Although seizures are
1- to 2-second bursts of high-frequency low-amplitude beta or gamma activity common in anti–N-methyl-
D-aspartate (NMDA)
(FIGURE 5-3B).42 Focal seizures are the most common seizure type seen on EEG, receptor encephalitis,
and they can be multifocal. Prolonged EEG monitoring or serial EEG recordings affecting approximately 70%
are useful in clarifying the epileptic nature of clinical symptoms, monitoring of cases, it is less common
progression of the encephalopathy, quantifying seizure frequency, and for them to be the
presenting symptom in
determining efficacy of treatment. adults. Seizures are most
Structural MRI is normal in up to 70% of anti–NMDA receptor encephalitis common in children and
cases.36 However, several findings have been reported, especially cortical young men.
hyperintensity on FLAIR or T2-weighted images. These findings most commonly
● EEG changes in anti–
involve the temporal lobe and, in particular, the hippocampus; however, other
NMDA receptor encephalitis
regions may be affected, including the frontal lobe, insula, cingulate gyrus, and typically progress in parallel
subcortical structures such as the thalamus and basal ganglia.43,44 FDG-PET may with the severity of the
show alterations in brain metabolism throughout the course of the disease. In the clinical illness, and a higher
degree of abnormality on
acute phase, cortical hypometabolism may occur, especially in the occipital
EEG can correlate with a
cortex.45 Often, mild hypermetabolism can also be seen in the frontal regions, poorer prognosis.
including the basal ganglia.46,47 Importantly, these findings have been found to
correlate with the severity of clinical symptoms and prognosis. ● A characteristic EEG
CSF is abnormal in the majority of anti–NMDA receptor encephalitis cases, finding in anti–NMDA
receptor encephalitis
showing mononuclear pleocytosis and mild to moderate protein elevation, is the “extreme delta
especially in the acute phase of the illness.36,48 CSF anti–NMDA receptor brush” pattern, present in
antibody testing is important because in some cases NMDA receptor antibodies up to 30% of cases.
are found only in CSF and not in serum.
Seizure Manifestations in Other Antibody-Mediated Encephalitides

Other encephalitides associated with neuronal cell surface antibodies that may
present with seizures include those with antibodies targeting γ-aminobutyric
acid B (GABAB) receptor, γ-aminobutyric acid A (GABAA) receptor,

CASE 5-1 A 46-year-old man was self-referred for recent onset of confusion and
seizures. Eight weeks before presentation to clinic, he began
experiencing “out of body” episodes, and 3 weeks later, he experienced
an acute confusional episode. EEG recorded a right temporal seizure.
Levetiracetam was initiated, then valproate and low-dose
oxcarbazepine, but he continued experiencing 30 focal aware seizures
daily, manifested by the sensation of “a wave.”
He presented to clinic continuing to experience the above episodes
multiple times per day. Neurologic examination was unremarkable,
including mental status testing. Head MRI showed subtle right
hippocampal enlargement (FIGURE 5-1). He was admitted to the hospital,
where EEG monitoring captured 100 “wave” seizures in the first 2 days,
most accompanied by right or left temporal seizure discharges (FIGURE 5-2)
but some without correlate. IV methylprednisolone 1 g/d was initiated on
admission. By day 3, seizures declined to four daily. Serum leucine-rich
glioma inactivated protein 1 (LGI1) antibody positivity was reported on day
3; CSF showed mildly elevated protein (65 mg/dL [normal range, 15 to
35 mg/dL]).
Oral prednisone 60 mg/d resulted in seizure freedom for 6 weeks. The
seizures recurred, and the patient was re-treated with 1000 mg/d IV
methylprednisolone for 3 days without benefit. Intravenous
immunoglobulin (IVIg) was initiated at 0.4 g/kg/d for 3 days and then
weekly for 5 weeks, leading to an initial 1 month of seizure freedom; then
seizures recurred during treatment. Mycophenolate mofetil 1000 mg
2 times a day was initiated, and oxcarbazepine was increased to 450 mg
2 times a day, resulting in
sustained seizure freedom.
Three months later,
levetiracetam was tapered.
Prednisone was discontinued
after 16 months of treatment.
Nine months after prednisone
discontinuation, he developed
a recurrence of pilomotor
seizures, which resolved
following an oxcarbazepine
dose increase to 750 mg
2 times a day. Oxcarbazepine
was tapered successfully
56 months after illness onset,
and mycophenolate mofetil
was discontinued 5 years after FIGURE 5-1
illness onset. He continued to Coronal fluid-attenuated inversion recovery (FLAIR)
MRI of the patient in CASE 5-1 who had anti–leucine-
work, but experienced rich glioma inactivated protein 1 (LGI1) encephalitis
occasional name and word- showing subtle hyperintensity and enlargement of
finding errors. the right hippocampus (arrow).
370 APRIL 2022

FIGURE 5-2
EEG in the patient in CASE 5-1 with anti–leucine-rich glioma inactivated protein 1 (LGI1)
encephalitis showing a left temporal predominant (A, arrow) and a right temporal onset
(B, arrow) seizure during initial admission, each manifested by the feeling of a “wave.”
CONTINUED ON
PAGE 372

CONTINUED FROM
PAGE 371
COMMENT This patient had acute symptomatic seizures secondary to anti-LGI1

antibody encephalitis presenting with frequent focal aware seizures with
autonomic and sensory symptomatology. The ultrahigh seizure frequency
provided the first clinical clue suggesting autoimmune encephalitis.20
Regarding symptomatology, it is important to note that, although
faciobrachial dystonic seizures are characteristic of LGI1 antibody
encephalitis, this seizure type is present in only one-third of patients, and
other seizure types may be present.21,25 Early immunotherapy is associated
with the greatest chance for a favorable outcome, which justifies initiation
of treatment before laboratory confirmation in select cases. Of note, MRI
was not specific in this patient for the diagnosis of limbic encephalitis,
which contributed to delay in diagnosis.20 EEG confirmed the presence of
seizures in this case, but EEG can be unremarkable in this disease, even
when focal seizures without impaired awareness occur during the
recording.21
This patient responded to immunotherapy, but a sustained response did
not occur immediately, and several adjustments were necessary, with
definitive control finally occurring after initiation of mycophenolate mofetil
and an increase in the oxcarbazepine dose. This complexity of response is
not always made clear in retrospective case series of autoimmune
encephalitis. Although the management focus in these patients
understandably pivots to immunotherapy after diagnosis, antiseizure
medication can achieve seizure control in 15% and can play a contributing
role in management.22,28
anti–α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor,

dipeptidyl-peptidase–like protein 6 (DPPX), and metabotropic glutamate
receptor 5 (mGluR5). The clinical and paraclinical features are summarized
in TABLE 5-3.
Anti-GABAB receptor encephalitis most commonly presents with seizures
and, in many cases, status epilepticus.49 The seizures can be either focal or
bilateral tonic-clonic in nature. The condition most commonly occurs in men
between the ages of 40 and 80 years. Additional neurologic symptoms at
presentation include memory deficit, confusion, delirium, hallucinations, and
behavioral changes including aggression; however, seizures are the only
symptom in some cases. Extralimbic symptoms can also occur, including
cerebellar ataxia, opsoclonus-myoclonus, and progressive encephalomyelopathy.
EEG and MRI may be normal and do not provide information specific enough to
allow clinical diagnosis. The presence of anti-GABAB receptor antibodies in
serum should be confirmed in the CSF.50 Mortality rates are higher than in
anti-LGI1 or anti–NMDA receptor encephalitis. Poor prognosis is associated with
older age at presentation, presence of malignancy (especially small cell lung
cancer), and medical complications during hospital admission.50
Anti–GABAA receptor encephalitis commonly presents with drug-resistant
seizures, may present with epilepsia partialis continua or status epilepticus in
372 APRIL 2022

KEY POINT
● Although anti–leucine-
rich glioma inactivated
protein 1 (LGI1) and anti–
NMDA receptor encephalitis
are most commonly
associated with seizures,
many other autoimmune
encephalitides can also
cause seizures.
FIGURE 5-3
EEGs in anti–N-methyl-D-aspartate (NMDA) receptor encephalitis. A, Generalized rhythmic
delta activity in a minimally responsive 27-year-old woman. Diffuse alpha is also present.
B, Extreme delta brush in a 24-year-old woman. EEG background contains generalized
rhythmic delta activity with triphasic morphology and superimposed diffuse, maximal
anterior bursts of high-frequency activity located on crests of delta waves.
addition to encephalopathy, and has no clear age or sex preference.51 Unlike anti–
GABAB receptor encephalitis, often clear MRI abnormalities are present and are
most apparent on T2-weighted sequences, affecting both gray and white matter.
These lesions are often multifocal, non–diffusion-restricting, nonenhancing, and
of a medium to large size.52 Therefore, anti–GABAA receptor encephalitis should
also be considered in the differential diagnosis of fulminant multiple sclerosis and
acute disseminated encephalomyelitis (ADEM). Similar to GABAB receptor
antibodies, the presence of GABAA receptor antibodies in serum should be
confirmed in the CSF.
Anti–AMPA receptor encephalitis typically presents as limbic encephalitis,
often with prominent psychiatric symptoms and hyponatremia. Although
seizures are associated with this condition, they are uncommonly a presenting or
prominent feature. Anti–AMPA receptor antibodies are often paraneoplastic,
seen in association with cancer of the lung and breast, thymoma, and ovarian

TABLE 5-3 Summary of Clinical and Paraclinical Features Associated With Specific
Neural Autoantibodies
Main presenting FDG-PET Cancer

Antibody targets symptom Seizure types MRI findings findings association
Antibodies targeting neuronal cell surface antigens associated with encephalitis and seizures
N-methyl-D- Psychiatric Focal aware Normal or transient Increased Ovarian teratoma,

aspartate (adults), seizures seizures, focal non–region- frontal and others (in patients
(NMDA) receptor (pediatric) impaired awareness specific T2 temporal FDG older than
seizures, hyperintensities uptake; 40 years)
generalized tonic- decreased
clonic seizures, occipital
autonomic update
symptoms
(piloerection and
palpitations),
sensory changes,
motor
manifestations
(orofacial and
manual
automatisms,
twitching)
Leucine-rich Seizures, memory Faciobrachial Hyperintense T2 Basal ganglia Rare: thymoma,

glioma impairment dystonic seizures, signal, subtle and temporal small cell lung
inactivated autonomic enlargement increased cancer,
protein 1 (LGI1) symptoms (acutely) in mesial uptake adenocarcinoma
(piloerection, temporal lobes, (breast, prostate)
sensations of insula, and basal
alteration of ganglia;
temperature hippocampal
[“thermal” atrophy (chronic)
seizures]),
somatosensory
changes
(paresthesia or pain),
a sensation of a
“wave,” body-
shuddering,
paroxysmal
nonvertiginous
dizziness,
automatisms,
vocalizations,
blinking, clonus,
dystonia, and
posturing
γ-Aminobutyric Seizures Focal or focal to Normal or Increased Small cell lung

acid B (GABAB) bilateral tonic-clonic hyperintense T2 uptake in cancer
receptor seizures, status signal in mesial temporal lobes
epilepticus temporal lobes
374 APRIL 2022

Main
Main presenting
presenting FDG-PET
FDG-PET Cancer
Cancer
Antibody
Antibody targets
targets symptom
symptom Seizure types
Seizure types MRI
MRI findings
findings findings
findings association
association
γ-Aminobutyric Encephalopathy Focal seizures, Hyperintense signal May show Thymoma
acid A (GABAA) and seizures epilepsia partialis in multiple cortical increased
receptor continua, or status and subcortical uptake in the
epilepticus areas region of MRI
abnormalities
α-Amino-3- Psychiatric, Focal seizures, Bilateral mesial Increased Thymoma, small

hydroxy-5- hyponatremia symptomatology temporal T2 temporal cell lung cancer,
methylisoxazole- not clarified in the hyperintensities uptake breast
4-propionic acid literature adenocarcinoma
(AMPA) receptor
Dipeptidyl- Diarrhea, weight Focal seizures as Normal or non– No specific B-cell lymphoma,
peptidase–like loss, part of central region-specific reports in the leukemia
protein 6 (DPPX) parkinsonism nervous system changes literature
hyperexcitability
(can also result in
hyperekplexia,
tremor, or
myoclonus)
Metabotropic Psychiatric Focal, secondary Normal or Normal or Hodgkin

glutamate generalized hyperintense signal decreased lymphoma
receptor 5 seizures, status in various brain uptake in
(mGluR5) epilepticus (more regions various regions
common in children)
Antibodies targeting intracellular antigens that can be associated with encephalitis and seizures
Glutamic acid Stiff person Focal aware Normal, T2 Normal or Rare; thymoma,
decarboxylase syndrome seizures; hyperintensities increased or adenocarcinoma
65 (GAD65) musicogenic and enlargement of decreased (lung, breast,
seizures; the amygdalae and uptake mesial colon)
experiential hippocampi; late temporal
phenomena hippocampal regions
(especially déjà vu, atrophy
but also anxiety,
déjà vécu,
derealization, and
autoscopy); auditory
(especially musical),
olfactory,
somatosensory, and
visual auras;
ascending epigastric
sensations and
nausea; motor
manifestations
(manual or orofacial
automatisms,
dystonic limb
posturing)

Main presenting FDG-PET Cancer

Antibody targets symptom Seizure types MRI findings findings association
Antineuronal Seizures, memory Focal aware seizures Normal or T2 Increased Strongly
nuclear antibody disturbance, and focal impaired hyperintense non- uptake of associated with
type 1 (ANNA-1) sensory awareness seizures enhancing focal affected small cell lung
neuropathy (often described as lesions (can be in regions in cancer
temporal lobe the sensorimotor acute setting
seizures), epilepsia cortex in patients
partialis continua with epilepsia
(especially affecting partialis continua)
the face or arm),
status epilepticus
Ma/Ta Encephalitis Focal impaired Brainstem FLAIR Normal or Testicular, non–

(including awareness seizures hyperintensity or decreased small cell lung
brainstem), generalized tonic- mesial temporal uptake of cancer, breast
parkinsonism clonic seizures FLAIR various regions
hyperintensity
FDG-PET = fludeoxyglucose positron emission tomography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.
teratoma. One-third of cases are associated with the presence of additional

neuronal cell surface antibodies, which can influence the presenting phenotype.53
MRI is often abnormal and most commonly demonstrates increased FLAIR and
T2 signal hyperintensities in both mesial temporal regions. EEG is abnormal in
almost half of patients, but the findings are often nonspecific and, most
commonly, generalized slowing is seen.54
Anti-DPPX encephalitis differs from other encephalitides in that patients
often present after a subacute or chronic course with symptoms of weight loss
and gastrointestinal symptoms, especially diarrhea, owing to the prominent
expression of DPPX in the myenteric plexus. The most common presentation
consists of a triad of (1) gastrointestinal symptoms/weight loss; (2) limbic
symptoms (cognitive or mental); and (3) CNS hyperexcitability. Seizures form
part of the expression of CNS hyperexcitability, but this can also take the form of
myoclonus, hyperekplexia, or tremor.55 EEG can either be normal or demonstrate
nonspecific findings, and it is less common to see epileptiform discharges or
seizures. Similarly, MRI may be normal or demonstrate nonspecific T2/FLAIR
hyperintensities, and CSF can be normal or reveal a mild to moderate pleocytosis.
An association with lymphoma has been reported, so clinicians should take care
to exclude this in these patients.
Anti-mGluR5 encephalitis most often presents with psychiatric symptoms,
but seizures are common. In children, generalized seizures and status epilepticus
are much more common. The median age at presentation is 29 (range, 6 to
75 years), and no clear sex preference exists. Malignancy is present in just more
than half of cases.56 MRI abnormalities are present in about half of cases and are
not restricted to the mesial temporal structures, often involving extratemporal
cortical regions, the thalamus, and even the cerebellum and pons.56 CSF
376 APRIL 2022

pleocytosis is common in reported cases, and more than half of patients will have KEY POINTS
an abnormal EEG, usually comprising focal or generalized slowing. Epileptiform
● Autoimmune encephalitis
abnormalities are uncommon. can occur in the absence of
Anti-GAD65 antibody acute limbic encephalitis is relatively uncommon. This detectable neural
antibody is more commonly associated with chronic focal epilepsy of temporal autoantibodies, and if the
lobe origin, which is discussed later in this article. Importantly, a diagnosis of pretest probability is high,
then the diagnosis of
anti-GAD65 encephalitis should not be made unless concomitant behavioral
seronegative autoimmune
change or cognitive or memory impairment is present, and these features should limbic encephalitis should
help clinicians differentiate the phenotypes of encephalitis and epilepsy. be considered.
Seronegative Autoimmune Limbic Encephalitis ● Examples of autoimmune-

associated epilepsy include
Symptoms of limbic encephalitis can also occur in the absence of CNS the persistence of seizures
autoantibodies. In such cases, provided other secondary causes of encephalitis after resolution of the active
are reasonably excluded, the diagnosis of seronegative autoimmune limbic phase of encephalitis;
encephalitis can be made.57 Seronegative autoimmune limbic encephalitis chronic unresolving
encephalitis including
(SNALE) accounts for approximately 7% of cases of limbic encephalitis, and it Rasmussen encephalitis;
typically affects older men (median age, 62 years; age range, 40 to 79 years).58 and in patients with epilepsy
Clinicians should note that this can occur as a paraneoplastic condition even in with compelling evidence of
the absence of paraneoplastic antibodies. In half of cases, patients may have a a CNS autoimmune
condition where no
prodrome of viral symptoms and memory difficulties lasting up to weeks before alternative etiology for the
the onset of encephalitis. epilepsy is identified.
The predominant presenting symptom is short-term memory difficulties, and
in one-third of cases, this may be the only symptom. In other cases, patients may
experience disorientation and confusion, whereas more florid behavioral and
neuropsychiatric symptoms are uncommon.58 Seizures are reported in only 8% of
cases; however, not all reported cases are evaluated with prolonged EEG
monitoring, so the frequency of seizures might be underreported. When seizures
do occur, they may not be the predominant presenting symptom. The EEG is
often abnormal but with nonspecific slowing, and epileptiform discharges may
be absent. MRI changes with T2/FLAIR hyperintensities in both hippocampi are
required to make the diagnosis, and involvement of the insula, orbitofrontal
cortex, or basal ganglia is also common.58 CSF pleocytosis occurs in almost 60% of
cases; however, it is often mild when present (median, 13 cells/mm3; range, 9 to
25 cells/mm3).
SEIZURE AND CLINICAL CHARACTERISTICS IN AUTOIMMUNE-

ASSOCIATED EPILEPSY
The term autoimmune-associated epilepsy denotes a condition characterized by an
enduring predisposition to unprovoked seizures in which evidence of an immune
etiology is present. This can occur in several contexts, including persistence of
seizures after resolution of the active phase of encephalitis, in the setting of
chronic unresolving encephalitis, and in patients with epilepsy with compelling
evidence of a CNS autoimmune condition and where no alternative etiology for
the epilepsy is identified.
Postencephalitic Epilepsy
Although seizures eventually resolve in the majority of patients after timely
treatment of the active phase of autoimmune encephalitis with immunotherapy,
a subset of patients will continue to experience seizures or experience a
recurrence after initial resolution of the active phase. Persistent seizures occur in

up to 37% of cases of autoimmune encephalitis, and additional immunotherapy

does not always result in seizure freedom.59 Postencephalitic epilepsy typically
emerges 3 to 6 months after initial presentation. Initially, this may be difficult to
distinguish from autoimmune encephalitis relapse, but it is characterized by a
predominant presentation with seizures in the absence of other symptoms of
encephalitis.59,60 Clinicians should be vigilant, however, to monitor for
additional features of encephalitis, which can occur in 11% of cases. At the time of
seizure recurrence, it is advisable to reassess the entire clinical picture and
consider rechecking antibody titer, neuroimaging, and CSF to determine if
additional immunotherapy is warranted.59
An important risk factor for the development of postencephalitic epilepsy is
delayed initiation of immunotherapy.60 Other risk factors include a history of
status epilepticus, interictal epileptiform discharges, and high CSF protein
level.59,60 Antibody type is also important to determine the likelihood of seizure
recurrence. For example, anti–NDMA receptor antibody–mediated disease
rarely results in postencephalitic epilepsy.44,59 However, persistent seizures may
be present after resolution of encephalitis associated with anti-LGI1 antibodies in
up to 47% of cases and GABAB antibodies in up to 64% of cases.59 Seizure
outcome is not thought to be affected by early or late withdrawal of antiseizure
medications, so antiseizure medication discontinuation can be considered after a
significant period of seizure freedom without concern that doing so will
influence the ultimate development of epilepsy.60
Anti–Glutamic Acid Decarboxylase 65 Antibody–Associated Epilepsy

Despite their discovery more than 30 years ago, the role of anti-GAD65
antibodies in CNS diseases is uncertain and controversial. Anti-GAD65
antibodies are unique among other neural antibodies discussed in the context of
autoimmune-associated seizure disorders in that they are more commonly seen
in association with chronic epilepsy than the neuronal cell surface antibodies
summarized previously. The pathogenicity of anti-GAD65 antibodies is heavily
debated on the basis that GAD65 is an intracellular antigen, and the ability of the
antibody to pass intracellularly is not fully established.15,61,62 Anti-GAD65
antibodies are also associated with other neurologic presentations, including
cerebellar ataxia and stiff person syndrome.63
Anti-GAD65 antibodies were initially described in association with chronic
temporal lobe epilepsy, and this finding has been confirmed in several
studies.64-67 They have also been described in new-onset epilepsy, epilepsy of
unknown cause, drug-resistant epilepsy, pediatric epilepsy, and in association
with systemic autoimmunity.12,68-70 Anti-GAD65 antibody–associated epilepsy is
most common in women (70% to 80%) in the third decade of life (median age,
26 years), and up to 40% will have comorbid autoimmune conditions, especially
type 1 diabetes mellitus or thyroid disease.
The seizure types in anti-GAD65 antibody–associated epilepsy vary;
however, certain characteristics can serve as clinical clues for the diagnosis.
The seizures are relatively frequent. Focal aware seizures are common; however,
focal seizures with impaired awareness and focal to bilateral tonic-clonic
seizures can also occur.24 The symptomatology is often reflective of temporal-
perisylvian seizure involvement. One unique clinical characteristic that should
raise suspicion for the diagnosis of anti-GAD65 antibody–associated epilepsy is
the presence of musical auras and musicogenic seizures.23 Other clinical features
378 APRIL 2022

that can occur are varied and include experiential phenomena (especially
déjà vu, anxiety, déjà vécu, derealization, and autoscopy); olfactory,
somatosensory, and visual auras; ascending epigastric sensations; and
nausea.24,71,72 Motor manifestations can also occur during focal seizures,
including manual or orofacial automatisms and dystonic limb posturing
(CASE 5-2).
A 35-year-old right-handed woman presented for epilepsy management CASE 5-2

recommendations. Her seizures began at the age of 4 years and were
currently manifested as focal impaired awareness seizures that were
often provoked by music. She had type 1 diabetes mellitus but no history
of head injury, perinatal difficulties, febrile convulsions, or family history
of epilepsy. Her focal seizures were reported as daily and focal to
bilateral tonic-clonic seizures once per month. She had previously tried
seven antiseizure medications, all of which failed; her current regimen
included cannabidiol, gabapentin, and levetiracetam. Brain MRI showed
left hippocampal atrophy but was otherwise unremarkable.
EEG monitoring showed four left and two right temporal-onset
seizures. Given her history of type 1 diabetes mellitus and observations
that her seizure frequency was very high, a serum neuroimmunology
panel was ordered; it showed a high anti–glutamic acid decarboxylase 65
(GAD65) antibody titer (1482 nmol/L [normal, less than 0.02 nmol/L]). CSF
showed one nucleated cell, a protein level of 17 mg/dL, five oligoclonal
bands, and elevated CSF anti-GAD65 antibody titer of 53.7 nmol/L
(normal, less than 0.02 nmol/L). Given the bilateral seizure localization
and probable autoimmune etiology, resective surgery was excluded.
Immunotherapy with IVIg was offered but declined. Neuromodulation
was considered.
This patient has epilepsy as defined as an enduring predisposition to COMMENT

seizures. The high serum anti-GAD65 antibody titer and its presence in CSF
suggest a possible autoimmune etiology. Anti-GAD65 antibodies are
suspected to be a marker of autoimmunity, but they are not considered
directly pathogenic given that GAD65 is located intracellularly. Several
studies have shown these patients generally have a poor response to
immunotherapy.73,74 Immunotherapy was presented to the patient as an
option, along with a transparent discussion about the limited reported
efficacy, and she declined.
The clinical cues that prompted anti-GAD65 antibody evaluation were
the high seizure frequency,20 presence of a musicogenic trigger,23 and type
1 diabetes mellitus. Musicogenic seizures may be a characteristic
manifestation in patients with GAD65 antibody–associated seizures.
Although anti-GAD65 antibodies are found in more than 50% of patients
with type 1 diabetes mellitus, the titers are generally much lower than that
found in this patient.75 Titers less than 20 nmol/L are generally considered
nonspecific in the evaluation of neuroimmunologic disorders.

No EEG findings are specific to anti-GAD65 antibody–associated epilepsy. The

EEG may be normal, but temporal slowing and epileptiform discharges are
common and often have a bilateral distribution.73 Rarely, status epilepticus
including epilepsia partialis continua may occur. Where intracranial EEG has
been used, an unusually high frequency of subclinical seizures has been reported,
occurring up to hundreds of times daily.76 MRI changes vary over the course of
the illness and early in the presentation may demonstrate T2 or FLAIR
hyperintensities and enlargement of the amygdalae and hippocampi.77,78 Later in
the disease, hippocampal atrophy may develop. FDG-PET may demonstrate
mesial temporal hypermetabolism.79 CSF in chronic anti-GAD65 antibody–
associated epilepsy is typically noninflammatory, although occasionally mild
pleocytosis or CSF protein elevation may be present. Oligoclonal bands may also
be present. Anti-GAD65 antibody testing in CSF is generally recommended in
suspected cases to help assess the significance of serum anti-GAD65 antibody
positivity. As outlined earlier, only high titer results should be considered
potentially etiologically relevant. Results are considered potentially significant in
quantitative tests (radioimmunoassays or enzyme-linked immunosorbent assays
[ELISAs]) when the titer is greater than 20 nmol/L or greater than 1000 U/mL
or if confirmatory testing with qualitative methods (immunohistochemistry,
cell-based assays, or line-blot assays) is positive.63
Rasmussen Encephalitis
Chronic encephalitis can also result in an enduring predisposition to seizures, of
which Rasmussen encephalitis is the classic example. Rasmussen encephalitis is a
rare neuroinflammatory disorder resulting in chronic focal seizures, emanating
from one hemisphere, progressive hemiparesis, other lateralized cortical deficits,
and cognitive impairment. Unlike the other conditions discussed earlier,
Rasmussen encephalitis is thought to be mediated predominantly by T-cell
inflammatory processes.80 Several antibodies have been described in association
with Rasmussen encephalitis, including those targeting the GluN2 subunit of the
NMDA receptor, the GluA3 (or GluR3) subunit of the AMPA receptor, and
other neuronal antigens. However, these antibodies have also been found in up to
40% to 60% of epilepsy cases without Rasmussen encephalitis, so their specific
significance referable to Rasmussen encephalitis is generally disputed at
this time.74
Rasmussen encephalitis most commonly presents in children (median age,
6 years) but can occur in young adults. Three phases of disease have been
described.81 In stage 1, the patient may present with a prodrome of mild
hemiparesis and infrequent focal seizures up to years before the acute phase.
Stage 2 is heralded by a more acute presentation with frequent unilateral motor
seizures that evolve into treatment-refractory epilepsia partialis continua in 50%
of cases.81 As the disease progresses, other seizure types can occur, including
focal nonmotor seizures with or without impaired awareness and focal to
bilateral tonic-clonic seizures, suggestive of ongoing neuroinflammatory activity
in this stage.82 Loss of cortical function typically develops, resulting in varying
degrees of unilateral hemiplegia, hemianopia, cognitive decline, and dysphasia
over time.80 Neuroimaging characteristically shows contralateral hemiatrophy,
which is progressive over time, and FDG-PET typically demonstrates
hemispheric hypometabolism.83 Stage 3 represents a relative stagnation of
progression and underlying active inflammation. This is sometimes accompanied
380 APRIL 2022

by a reduction in seizures, although focal seizures often persist to a degree for KEY POINTS
several years. Unfortunately, despite the inflammatory etiology, Rasmussen
● Rasmussen encephalitis is
encephalitis is inconsistently responsive to immunotherapy, even in the active a rare neuroinflammatory
stage. Surgery, specifically hemispheric disconnection, is often necessary to gain disorder resulting in chronic
seizure control in very young children with Rasmussen encephalitis and high focal seizures, emanating
seizure burden. This procedure, which risks cortical neurologic deficits, from one hemisphere,
progressive hemiparesis,
nonetheless can result in seizure freedom in 60% to 85% of patients.84
other lateralized cortical
deficits, and cognitive
NEURAL AUTOANTIBODY PRESENCE IN EPILEPSY AND GUIDES TO impairment.
SELECT PATIENTS FOR TESTING
Among patients with epilepsy, the relative increased prevalence of CNS ● Immunotherapy can lead
to seizure freedom when
autoantibody positivity outside of the context of encephalitis has been reported due to autoimmune
for many years. Although the clinical relevance of some autoantibodies in the etiologies; consideration of
epilepsy clinic setting continues to be debated, some cases with pathogenic these disorders should be
autoantibodies have been reported where immunotherapy resulted in improved given in the setting of drug-
resistant seizures, especially
seizure outcome and even seizure freedom. Therefore, the diagnosis of those of recent onset and
autoimmune-associated epilepsy warrants consideration in the epilepsy intractability from inception.
outpatient setting, especially when treatment with standard antiseizure
medications has been unsuccessful. The literature in this area continues to ● Diagnostic accuracy
requires an understanding
evolve, but certain features should raise suspicion for a potential diagnosis.
and integration of the
Potentially pathogenic CNS autoantibodies have been more commonly spectrum of clinical and
reported in focal epilepsy of unknown cause,12,13,85 where structural, genetic, and paraclinical presentations,
metabolic causes have been excluded. CNS autoantibodies have also been and several scoring systems
have been developed that
reported in cases of temporal lobe epilepsy with and without hippocampal
may be useful in aiding the
sclerosis,13,65-67,86 drug-resistant epilepsy,87,88 new-onset focal epilepsy,85,89 identification of
epilepsy in female patients,90 and pediatric epilepsy.68,91,92 Importantly, these autoimmune seizures.
patients do not always present with acute encephalitic features. The frequency of
autoantibodies reported in patients with epilepsy varies greatly. The highest
frequencies reported are 15% to 25% of patients69,85,86,93; however, other studies
have reported a rate of 0%.94-97 The most commonly identified antibodies in
these series are anti-GAD65 (3.94%), with high-titer anti-GAD65 comprising
2.16%. Other antibodies that have been reported include anti–glycine receptor
(2.36%), anti–NMDA receptor (2.15%), anti-CASPR2 (1.37%), and anti-LGI1
(1.37%) antibodies.
Patient Selection for Immune Etiology Evaluation

In the outpatient setting, seizure manifestations and other clinical features can be
used to help identify patients who are most appropriate for autoantibody testing.
The presence of faciobrachial dystonic seizures should clearly prompt neural
autoantibody testing, which includes anti-LGI1 antibody. Clinicians should also
consider antibody screening in new-onset focal epilepsy of unknown cause,12
especially in patients with a high daily seizure burden98 and in the presence of
perisylvian99-101 or autonomic symptomatology.102 For example, ictal
piloerection, which is a common finding in the autoimmune encephalitides, has
been found to be a predictive clinical feature for autoantibody positivity.21,103,104
The EEG is often abnormal in autoimmune-associated epilepsy; however, the
findings are rarely specific enough to trigger consideration of an autoimmune
etiology, and the EEG may be normal.
Neuroimaging is also of varying clinical utility in identification of patients
with autoimmune-associated epilepsy. Brain MRI findings may demonstrate

FLAIR or T2 signal abnormalities in the mesial temporal lobe but may be

normal.105 Therefore, MRI might be suggestive of an autoimmune etiology, but a
normal study does not exclude the diagnosis.
CSF evaluation should be performed if autoimmune-associated epilepsy is
suspected. It is important to remember that the sensitivity for certain CNS
autoantibodies, particularly anti–NMDA receptor antibody, may be higher in
CSF than serum.42,106 CSF testing should also include nucleated cell count,
protein level, IgG index, and evaluation for the presence of oligoclonal bands.
However, the absence of inflammatory CSF findings in the setting of possible
autoimmune-associated epilepsy does not completely exclude the diagnosis.
Diagnostic Criteria and Scoring Systems

Diagnostic criteria have been developed to assist in the identification of
patients with autoimmune encephalitis. The criteria developed by Graus and
colleagues57 for possible and definite autoimmune encephalitis are shown in
TABLE 5-4. These criteria are highly specific for patients with clear limbic
encephalitis; however, they may not identify those with more subtle
encephalitis presentations and are often not confirmatory in patients with
autoimmune-associated epilepsy.
TABLE 5-4 Diagnostic Criteria for Possible and Definite Autoimmune Encephalitisa
Diagnosis of possible autoimmune encephalitis can be made when all three of the following
criteria have been met:
1 Subacute onset (rapid progression of less than 3 months) of working memory deficits
(short-term memory loss), altered mental status, and/or psychiatric symptoms
2 At least one of the following:
◇ New focal central nervous system findings
◇ Seizures not explained by a previously known seizure disorder
◇ CSF pleocytosis (white blood cell count of more than 5 cells/mm3)
◇ MRI features suggestive of encephalitis
3 Reasonable exclusion of alternative causes
Diagnosis of definite autoimmune encephalitis can be made when all four of the following
criteria have been met:
1 Subacute onset (rapid progression of less than 3 months) of working memory deficits,
seizures, and/or psychiatric symptoms suggesting involvement of the limbic system
2 Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the mesial
temporal lobes
3 At least one of the following:
◇ CSF pleocytosis (white blood cell count of more than 5 cells/mm3)
◇ EEG with epileptic or slow-wave activity involving the temporal lobes
4 Reasonable exclusion of alternative causes
CSF = cerebrospinal fluid; EEG = electroencephalogram; FLAIR = fluid-attenuated inversion recovery;

MRI = magnetic resonance imaging.
a
Modified with permission from Graus F, et al, Lancet Neurol.57 © 2016 Elsevier Ltd.
382 APRIL 2022

Scoring systems have also been developed to aid in the identification of an
autoimmune etiology in patients presenting with seizures. These scales typically
include elements that are weighted toward the identification of acute or subacute
encephalitis phenotypes. Thus, they may miss patients with more subtle
encephalitis presentations and those with chronic autoimmune-associated
epilepsy, but they are helpful in identifying patients with a high pretest
probability of autoantibody positivity.107-109 One such scoring system is the
Antibody Prevalence in Epilepsy (APE) and the related Antibody Prevalence in
Epilepsy and Encephalopathy (APE2) score (TABLE 5-5). A score of 4 or greater on
the APE scale showed 82.6% sensitivity and 82% specificity for the detection of
serum CNS autoantibodies in a mixed cohort of inpatients and outpatients whose
serum was sent for neuroimmunology evaluation.85 Although APE and APE2
scales will not help diagnose patients with seronegative autoimmune encephalitis
and autoimmune-associated epilepsy, their use can help avoid the detection of
neural antibodies with a less clear pathogenicity, such as non-LGI1/non-CASPR2
voltage-gated potassium channel antibodies and low-titer anti-GAD65
antibodies, and those rare neural antibodies that sometimes are present in control
populations as an expression of natural immunity.
Another scale developed to aid in determining the clinical relevance of
seropositive results is the Neuronal Autoantibody Confidence Scale.110 Although
many of the autoantibodies with intracellular targets are well characterized and
associated with specific clinical phenotypes, some of the surface neuronal
autoantibodies are less so. This is especially true of voltage-gated calcium channel
antibodies, voltage-gated potassium channel without immunoreactivity to LGI1
or CASPR2, and ganglionic nicotinic acetylcholine receptor antibodies, which are
all thought to have limited clinical relevance in the setting of seizures and
epilepsy. Therefore, this scale is particularly useful as a tool to increase the
confidence in the clinical relevance of these less specific antibodies. Clinicians
should be careful, however, to always correlate the clinical presentation to the
antibody detected and question the clinical relevance of the result if clinical-
serologic discordance is present.110
To further address the question of clinical phenotype in antibody-positive
epilepsy, another scoring model was recently published by McGinty and
colleagues.104 This scoring model was based on clinical features found in patients
presenting to an epilepsy clinic who were subsequently found to be antibody
positive. This model and scoring are shown in TABLE 5-5. In this study, the
authors distinguished patients with epilepsy from those with autoimmune
encephalitis through application of the criteria from Graus and colleagues57 and
found that a proportion of patients presenting to an outpatient epilepsy clinic
actually had mild, but clinically evident, symptoms of autoimmune encephalitis.
Ictal piloerection, low mood, age older than 54 years, and MRI abnormalities in
limbic regions were predictive of CNS autoantibody positivity in this cohort,
whereas poor attention on cognitive assessment and the presence of customary
epilepsy risk factors (eg, history of traumatic brain injury and epilepsy family
history) predicted seronegativity. This scoring model can be used in concert with
the APE2 score to identify patients with “mild encephalitis” who might benefit
from neural autoantibody testing.
Finally, another scoring system called the Antibodies Contributing to Focal
Epilepsy Signs and Symptoms (ACES) score, published in 2021, helps identify
patients presenting with seizures due to an autoimmune etiology.111 The score

TABLE 5-5 Scoring Systems to Aid Identification of Autoimmune Encephalitis and

Autoimmune Associated Epilepsy
Antibodies
Contributing to
Antibody Prevalence in Neuronal Focal Epilepsy
Epilepsy and Antibody Criteria from Signs and
Encephalopathy (APE2) Confidence McGinty and Symptoms (ACES)
scale Score (NAC) scale Score colleagues104 Score scale Score
New-onset, rapidly 1 Antibody 1 Age older than 1 Cognitive 1
progressive mental status against 54 years symptoms
changes that developed intracellular
over 1-6 weeks or new- antigen (or high
onset seizure activity clinical
(within 1 year of evaluation) relevance
surface
antibody)
Neuropsychiatric changes; 1 Movement 1 Self-reported 1 Behavioral 1

agitation, aggressiveness, disorder and/or mood changes
emotional lability stiff person disturbance
syndrome
Autonomic dysfunction 1 Cancer and/or 1 Limbic system 2 Autonomic 1

(sustained atrial smoking history lesions on MRI symptoms
tachycardia or bradycardia,
orthostatic hypotension
[≥20 mm Hg fall in systolic
pressure or ≥10 mm Hg fall
in diastolic pressure within
3 minutes of quiet
standing], hyperhidrosis,
persistently labile blood
pressure, ventricular
tachycardia, cardiac
asystole, or gastrointestinal
dysmotility)
Viral prodrome (rhinorrhea, 2 Inflammatory 1 Ictal piloerection 2.5 Speech problems 1

sore throat, low-grade CSF (either high
fever) to be scored in the cell count, IgG
absence of underlying index and/or
systemic malignancy within positive
5 years of neurologic oligoclonal
symptom onset bands)
Faciobrachial dystonic 3 Serum 1 Addenbrooke’s -1.5 History of other 1

seizures hyponatremia Cognitive autoimmune
Examination disease
attention
score ≥ 16
Facial dyskinesias, to be 2 Chronic course -1 Epilepsy risk -1.5 Temporal MRI 1

scored in the absence of (>3 months) factors hyperintensities
faciobrachial dystonic
seizures
384 APRIL 2022

Antibodies
Contributing to
Antibody Prevalence in Neuronal Focal Epilepsy
Epilepsy and Antibody Criteria from Signs and
Encephalopathy (APE2) Confidence McGinty and Symptoms (ACES)
scale Score (NAC) scale Score colleagues104 Score scale Score
Seizure refractory to at 2
least two antiseizure
medications
CSF findings consistent 2

with inflammation
(elevated CSF protein
>50 mg/dL and/or
lymphocytic pleocytosis >5
cells/mm3, if the total
number of CSF red blood
cells is <1000 cells/mm3)
Brain MRI suggesting 2

encephalitis (T2/FLAIR
hyperintensity restricted to
one or both mesial
temporal lobes, or
multifocal in gray matter,
white matter, or both,
compatible with
demyelination or
inflammation)
Systemic cancer diagnosed 2

within 5 years of neurologic
symptom onset (excluding
cutaneous squamous cell
carcinoma, basal cell
carcinoma, brain tumor,
cancer with brain
metastasis)
Maximum score 18 5 6.5 6
Cutoff score predicting ≥4 a

≥2 b
≥0 c
≥2d
antibody positivity or
autoimmune etiology
CSF = cerebrospinal fluid; FLAIR = fluid-attenuated inversion recovery; IgG = immunoglobulin G; MRI = magnetic resonance imaging.
a
Sensitivity = 82.6% and specificity = 82%.
b
Sensitivity = 77% and specificity = 94%.
c
Sensitivity = 66.7% and specificity = 84.9%.
d
Sensitivity = 100% and specificity = 84.9%.

was based on antibody assessment performed in patients referred for evaluation

of epilepsy of unknown cause who had a low clinical suspicion for an
autoimmune etiology. The 6-point ACES scoring system derived by this study
gives 1 point each for the following features: cognitive symptoms, behavioral
changes, autonomic symptoms, speech problems, autoimmune diseases, and
mesial temporal lobe MRI hyperintensities. In this study, which was validated in
an additional cohort, the sensitivity of an ACES score of 2 or greater was 100%,
and specificity 84.9%, for the presence of neuronal cell surface antibodies or
high-titer anti-GAD65 antibodies.
TREATMENT IN ANTIBODY-MEDIATED AUTOIMMUNE ENCEPHALITIS

AND AUTOIMMUNE-ASSOCIATED EPILEPSY
Treatment in autoimmune encephalitis and autoimmune-associated epilepsy is
primarily focused on addressing the underlying etiology with immunotherapy
and can be considered in alignment with the phases of illness. The potential
benefit of adjunct use of antiseizure medications should also be evaluated,
especially during the acute phase.
Antiseizure Medication Therapy in Acute Symptomatic Seizures Secondary

to Autoimmune Encephalitis
Seizure control is infrequently achieved with antiseizure medication therapy
alone in patients with seizures secondary to autoimmune encephalitis.28,112 In
studies evaluating the efficacy of antiseizure medication therapy in this setting,
seizure control with antiseizure medication alone occurred in 15%.22,28
Importantly, some antiseizure medications appear to be more effective than
others. Higher responder rates have been reported with sodium channel
blockers, particularly carbamazepine and lacosamide compared with
levetiracetam, for example.28 Although the reasons for this difference in efficacy
are unclear, it is interesting that certain antiseizure medications, including
carbamazepine, have immunosuppressive effects.113 If carbamazepine or like
agents are used in this setting, however, it should be noted that the rate of
hypersensitivity reactions is greater in patients with autoimmune encephalitis
than in the general population. In addition, hyponatremia, which is a relatively
common adverse effect of carbamazepine and oxcarbazepine, is also common in
autoimmune encephalitis, so sodium concentrations must be watched carefully if
these agents are used in this setting.
The risk of ongoing seizures after recovery from the acute phase of the
encephalitic illness is reported to be higher in older patients, those with severe
seizures and status epilepticus, the presence of cortically based lesions on
neuroimaging, and patients with focal neurologic deficits.114 Seizure control
often occurs after immunotherapy in patients with neuronal cell surface
antibodies, in which case the question of antiseizure medication discontinuation
often arises.114 In this setting, it is important to take the specific neural
autoantibody into account when deciding on the necessity of long-term
antiseizure medication therapy. For example, seizures usually resolve after
resolution of anti–NDMA receptor encephalitis, eventually allowing successful
antiseizure medication discontinuation. However, the rate of persistent seizures
and postencephalitic epilepsy after acute anti–GABAB receptor encephalitis
appears higher. Recurrent seizures and the need for long-term antiseizure
medication administration are also more likely in patients initially presenting
386 APRIL 2022

with status epilepticus regardless of the autoantibody present.115 Therefore, an KEY POINTS
individualized approach to the timing of antiseizure medication discontinuation
● If used alone, antiseizure
needs to be applied in these patients as in epilepsy due to other etiologies. medications are rarely
Long-term antiseizure medication administration is not always necessary in effective in the setting of
many patients after resolution of acute encephalitis, and discontinuation can be symptomatic seizures
considered after 6 months or a greater period of seizure cessation. secondary to autoimmune
encephalitis. They also may
not be required after
Immunotherapy resolution of the acute
Immunotherapy plays a central role in the management of seizure due to illness, so cessation should
autoimmune etiology, particularly in acute symptomatic seizures secondary to be considered after
6 months or a greater period
autoimmune encephalitis. Seizure freedom occurs in 62% to 89% of patients
of sustained seizure
affected by seizures, and the median time to seizure freedom after initiation of freedom.
immunotherapy is 28 days.116 In addition, the benefits are not limited to seizure
cessation; they extend to cognitive and functional outcomes. When the use of ● Immunotherapy is the
immunotherapy is uncertain, the Response to Immunotherapy in Epilepsy mainstay of treatment for
autoimmune seizure
(RITE) score (TABLE 5-6) can be used to help select patients for treatment. In this etiologies and should be
scoring system, a score of 7 or greater is predictive of a positive response.85 administered early in the
Treatment options are listed in TABLE 5-7.117 It is important to note that none of course of the illness. Eighty
these treatment strategies have been subject to placebo-controlled clinical trials, percent to 90% of patients
may achieve seizure
except for a single-center study comparing IVIg to placebo in anti-LGI1 antibody freedom depending on the
encephalitis.118 Also, no prospective head-to-head studies have been done to specific etiology, and it may
allow for comparison of efficacy. Treatment is generally conceptualized as initial lead to improvements in
induction therapy with first-line treatments that include IV corticosteroids, IVIg, cognitive and functional
outcomes.
or plasma exchange, used individually or in combination. Second-line agents,
usually rituximab or cyclophosphamide, are typically initiated if the response to
first-line therapy is inadequate; however, these may also be used if a protracted
course is expected, such as in anti–NMDA receptor antibody encephalitis.
Induction therapy is followed by a maintenance phase, where administration of
first-line therapy or therapies continues weekly to every other week with
gradually increasing intervals between treatments. Initiation of maintenance
immunosuppressive medication may be used if a patient has a significant
response to induction therapy, establishing immunotherapy responsiveness. One
reason for the use of maintenance immunosuppressive therapies is to facilitate
eventual cessation of first-line treatment. Another rationale is to prevent relapse
of encephalitis, which can occur in up to 35% of cases.27
Acute Treatment Strategy

Once an autoimmune diagnosis is considered likely, treatment should ideally be
commenced in consultation with an autoimmune neurology specialist. The most
common approach to first-line therapy for patients in the inpatient setting
involves the use of a combination of agents, typically methylprednisolone and
IVIg.110 In anti-LGI1 encephalitis, high-dose steroids alone are often effective,
and oral (as opposed to IV) administration is often successful. A favorable seizure
response in anti-LGI1 encephalitis may be noted within a few days. IVIg was
shown to be more effective than placebo in anti-LGI1 antibody encephalitis in
one single-center study,118 so it can be tried in patients with a contraindication to
steroid therapy and when the response to corticosteroids is inadequate. If a
patient has no response to corticosteroids or IVIg, plasma exchange is commonly
recommended as an option. Corticosteroids and IVIg are often continued after
the resolution of the induction period if the response was favorable, and they are

continued over the ensuing 6 to 12 months depending on the clinical course on a

gradual tapering schedule.
Second-line immunosuppressant therapy may be administered empirically
during the induction phase in acute inpatient situations.38,119 This is the typical
approach in hospitalized patients with severe anti–NDMA receptor, anti–GABAA
receptor, anti–GABAB receptor, and anti–AMPA receptor encephalitis in
which it is a priority to suppress the inflammatory response and eliminate
circulating neural autoantibodies as quickly as possible. The second-line
immunosuppressant most commonly used is rituximab. When it is decided
that rituximab is necessary, it is usually instituted early because the reduction
in antibody production achieved is usually delayed for 2 to 4 weeks from
administration.110 Rituximab needs to be readministered every 6 months if
TABLE 5-6 Response to Immunotherapy in Epilepsy Scorea
Score
New-onset, rapidly progressive mental status changes that developed over 1-6 weeks or new-onset seizure activity 1
(within 1 year of evaluation)
Neuropsychiatric changes: agitation, aggressiveness, emotional lability 1
Autonomic dysfunction (sustained atrial tachycardia or bradycardia, orthostatic hypotension [≥20 mm Hg fall in 1
systolic pressure or ≥10 mm Hg fall in diastolic pressure within 3 minutes of quiet standing], hyperhidrosis, persistently
labile blood pressure, ventricular tachycardia, cardiac asystole, or gastrointestinal dysmotility)
Viral prodrome (rhinorrhea, sore throat, low-grade fever), only to be scored in the absence of underlying malignancy 2
Faciobrachial dystonic seizures 3
Facial dyskinesias, to be scored in the absence of faciobrachial dystonic seizures 2
Seizure refractory to at least to two antiseizure medications 2
CSF findings consistent with inflammation (elevated CSF protein >50 mg/dL and/or lymphocytic pleocytosis 2
>5 cells/mm3, if the total number of CSF red blood cells is <1000 cells/mm3)
Brain MRI suggesting encephalitis (T2/FLAIR hyperintensity restricted to one or both mesial temporal lobes, or 2
multifocal in gray matter, white matter, or both compatible with demyelination or inflammation)
Systemic cancer diagnosed within 5 years of neurologic symptom onset (excluding cutaneous squamous cell 2
carcinoma, basal cell carcinoma, brain tumor, cancer with brain metastasis)
Initiation of immunotherapy within 6 months of symptom onset 2
Neural plasma membrane autoantibody detected (N-methyl-D-aspartate [NMDA] receptor antibody, γ-aminobutyric acid A 2
[GABAA] receptor antibody, γ-aminobutyric acid B [GABAB] receptor antibody, α-amino-3-hydroxy-5-methylisoxazole-
4-propionic acid [AMPA] receptor antibody, dipeptidyl-peptidase–like protein 6 [DPPX], metabotropic glutamate
receptor 5 [mGlur1], mGluR2, mGluR5, leucine-rich glioma inactivated protein 1 [LGI1] antibody, IgLON5, contactin-
associated proteinlike 2 [CASPR2] antibody or myelin oligodendrocyte glycoprotein [MOG])
Maximum score 22
Cutoff score predicting favorable seizure outcome ≥7b
CSF = cerebrospinal fluid; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.
a
Modified with permission from Dubey D, et al, Epilepsia.85 © 2017 International League Against Epilepsy.
b
Sensitivity = 87.5% and specificity = 83.8%.
388 APRIL 2022

effective because the CD20-expressing lymphocytes targeted by the medication
begin to recover after that timeframe. Cyclophosphamide can be used as an
alternative to rituximab; however, it has risks of infertility, hemorrhagic cystitis,
and malignancy, so it is typically reserved for cases refractory to rituximab.
Maintenance
Corticosteroids are typically continued after the induction phase if a response has
occurred. This may continue to be administered as a 1-g IV methylprednisolone
infusion every 7 to 14 days with gradually increasing intervals as allowed by the
clinical course. Daily oral prednisone may also be used if IV preparations are not
easily accessible. Treatment is typically continued for 6 to 12 months, and oral
dosages are reduced gradually every few weeks. If IVIg was used in induction and
was deemed effective, it can be continued with gradually increasing interdose
intervals while response is monitored, most commonly monthly over the
following 6 to 12 months.
If rituximab was used at induction, and a response was determined to have
been achieved, it usually needs to be readministered every 6 months to prevent
relapse, given that B cells will regenerate eventually and antibody production will
resume. During this time, CD20 levels can be monitored to assess for B-cell
recovery. If cyclophosphamide was used during the initial treatment phase, it is
typically continued as part of the maintenance therapy for 6 months.
Mycophenolate mofetil and azathioprine are sometimes used, if a response to
induction therapy was achieved, to maintain remission and facilitate eventual
discontinuation of first-line therapies. They are also used to prevent relapses,
which can occur in 35% of patients with autoimmune encephalitis. They have also
been used to augment induction therapy in some cases. The use of these
medications has not been established for any of these indications in prospective
trials to date. The duration of treatment is also unclear. It is best to seek advice
through an autoimmune neurologist to determine if these agents are warranted
and clarify duration of treatment.
Monitoring
It is essential to monitor for response and relapse after initial treatment. Seizure
frequency should be recorded and evaluation of treatment response made
6 weeks after commencing induction therapy. A complete response is clearly
desired when immunotherapy is used; however, a 50% reduction in seizure
frequency after initiation of treatment is typically considered a sign of
immunotherapy responsivity. If no improvement in seizure control is seen but a
high degree of suspicion for an autoimmune etiology remains, administration of
another agent or second-line therapy should be considered. Clinicians should also
be mindful that recovery may be slow, such as in anti–NDMA receptor
encephalitis, which may take months.
Precautions and Additional Considerations

Clinicians should have a good understanding of the clinical relevance of
autoantibody test results. For example, voltage-gated potassium channel
antibodies without LGI1 or CASPR2 immunoreactivity and low-titer anti-GAD65
antibodies generally do not justify the use of immunotherapy. Also, the
likelihood of a favorable response to immunotherapy is low with certain
antibodies, such as onconeural antibodies and even high-titer anti-GAD65

TABLE 5-7 Immunotherapy for Symptomatic Seizures Secondary to Autoimmune

Encephalitisa
Drug Dose Duration Precaution Potential side effects

First-line therapies
IV methylprednisolone 1000 mg daily 3-5 days, then Monitor for Infection, avascular
weekly for hyperglycemia if the necrosis hip, peptic ulcer,
5 weeks, then patient has diabetes or insomnia, psychosis,
every 7-14 days is at risk; consider depression, hypertension,
for 6 weeks baseline bone density edema
(12 weeks total) scan at inception
Oral prednisone (if IV 1250 mg daily 3-5 days, then

preparation is not 60 mg daily for
available) 3 months
IVIg 0.4 g/kg/d 3-5 days, then Measure IgA because Headache, aseptic
weekly for deficiency has a risk of meningitis, renal failure,
5 weeks, then anaphylaxis (or use myocardial infarct
every 7-14 days non-IgA formulation); (avoid in at-risk
for 6 weeks consider non–sucrose- patients), venous
(12 weeks total) containing formulations thromboembolism
in renal impairment
Plasma exchange 1 body volume 5 to 7 May need to Anemia, muscle

exchange with treatments discontinue or cramps, electrolyte
albumin every other substitute angiotensin- abnormalities,
replacement day converting enzyme complications of
inhibitors, consult central line insertion
internist for options; (thrombosis, infection)
monitor blood counts
and electrolytes
Second-line therapies 1000 mg IV for 2 Repeat every Exclude tuberculosis, Infusion reactions,
doses 2 weeks apart 6 months or at hepatitis B and hepatitis hypogammaglobulinemia
Rituximab
recovery of C infection before resulting in chronic
OR CD20 count initiation; monthly sinopulmonary infections
blood counts; (can be treated with IVIg),
375 mg/m2 weekly pregnancy test before other infections including
for 4 weeks commencement rare risk of progressive
multifocal
leukoencephalopathy
390 APRIL 2022


Cyclophosphamide Oral: 1-2 mg/kg/d 6 months Suggest consultation Teratogenicity, infection,
with an oncologist, malignancy (lymphoma,
OR rheumatologist to assist skin cancers, and others),
with dosing; encourage hemorrhagic cystitis,
IV: 500 mg/m2 to liberal hydration and infertility, alopecia, and
1000 mg/m2 consider mesna use for nausea/vomiting
monthly IV to prevent
hemorrhagic cystitis;
baseline urinalysis,
complete blood cell
count, creatinine and
liver function
performed weekly for
1 month and every
2 weeks for 2 months
and monthly thereafter
for IV; adjust dose
based on results;
pregnancy test before
commencement
Maintenance therapies
IV methylprednisolone 1000 mg weekly After Monitor for metabolic Infection, osteoporosis,

induction, complications peptic ulcer, cushingoid
gradually appearance, skin thinning,
increase easy bruising, insomnia,
intervals over depression, cataracts,
ensuing hypertension, weight gain,
6-12 months edema; caution when
discontinuing to avoid
Oral prednisone 1 mg/kg/d (adult, After 3 months, addisonian crisis
60 mg daily gradually
maximum) reduce the
dose over
ensuing
6-12 months
IVIg 0.4 g/kg once After Measure IgA because Headache, aseptic
weekly induction, deficiency has a risk of meningitis, renal failure,
gradually anaphylaxis (or use myocardial infarct (avoid
increase non-IgA formulation); in at-risk patients), venous
intervals over consider non–sucrose- thromboembolism
ensuing containing formulations
6-12 months in renal impairment

Oral mycophenolate After establishment 3-5 years Blood cell counts, renal Teratogenicity, infection,
mofetil of response to and liver function tests malignancy (lymphoma,
induction therapy: at baseline, weekly for skin cancers, and others),
500 mg 2 times a day 1 month, every other diarrhea, hypertension,
by mouth for 2 weeks week for 2 months hepatitis,
then 1000 mg 2 times then monthly; myelosuppression,
a day mycophenolate mofetil renal failure, bleeding of
serum levels; pregnancy gastric ulcer
test, ensure
contraception; avoid
antacids containing
magnesium or
aluminum; pregnancy
test before
commencement
Oral azathioprine 2-3 mg/kg/d once 3-5 years Measure thiopurine Infection, malignancy
daily or in divided S-methyltransferase (lymphoma, skin cancers,
doses enzyme activity before and others), nausea,
initiation; blood cell macrocytic anemia,
counts, renal function skin rash, hypersensitivity
and liver function at reaction, pancreatitis and
baseline then weekly for elevated liver function
1 month, every other tests
week for 2 months, and
monthly thereafter;
consider monitoring
mean corpuscular
volume (MCV) as
increases of >5 points
may correlate with
improved efficacy;
pregnancy test before
commencement
IgA = immunoglobulin A; IV = intravenous; IVIg = intravenous immunoglobulin.

a
Modified with permission from Britton JW, et al, John Wiley & Sons.117 © 2021 John Wiley & Sons.
antibodies. In such settings, patient and family expectations may need to be

tempered. In addition, the absence of a neural antibody does not necessarily
exclude the diagnosis of autoimmune encephalitis, and up to 50% of such
patients may be seizure free after immunotherapy.120 Seronegative disease
should, therefore, be considered in the context of an appropriate clinical
syndrome, especially in the presence of status epilepticus or cryptogenic seizures
where paraclinical markers support the presence of CNS inflammation.
Careful consideration of the differential diagnosis is also prudent to ensure
other causes of encephalitis are excluded. This is especially the case for infectious
etiologies because immunosuppression is contraindicated in this context.
Similarly, metabolic and structural causes of seizures also warrant exclusion.
Paraneoplastic causes should be considered and a search for underlying
malignancies pursued, particularly with certain autoantibodies. Importantly,
392 APRIL 2022

treatment of the underlying neoplasm in these cases can result in clinical
improvement, especially in the case of anti–NMDA receptor encephalitis where
resection of an ovarian teratoma can result in improvement.
Before immunosuppression, clinicians should ensure chronic and latent
infections have also been excluded or treated adequately. Screening should be
performed to exclude occult disease including Mycobacterium tuberculosis, viral
hepatitis, and human immunodeficiency virus (HIV) infection. Vaccinations should
also be up to date. Prophylaxis for Pneumocystis jirovecii with sulfamethoxazole/
trimethoprim or dapsone is recommended. Similarly, it is prudent to be mindful
of corticosteroid-related complications, and prophylaxis for osteoporosis with
vitamin D and calcium and for gastritis and ulcers with proton pump inhibitors
or histamine receptor 2 (H2) antagonists is advisable. This is especially important
in cases where these are preexisting conditions, and care should also be taken
with other medical comorbidities, particularly diabetes mellitus.
CONCLUSION
Seizures due to an autoimmune etiology are increasingly encountered in clinical
practice and can take the form of autoimmune-associated epilepsy or acute
symptomatic seizures due to autoimmune encephalitis. Seizures of an immune
etiology are often resistant to antiseizure medications but are usually responsive
to immunotherapy. It is critical that clinicians recognize immune etiologies early
in their course because treatment delays can result in poorer outcomes, and
currently, it is not uncommon for autoimmune-associated seizure disorders to
remain undiagnosed, resulting in missed opportunities to administer effective
therapies. Although autoimmune seizures are caused by a heterogeneous group
of autoantibodies, key features should raise suspicion for the possible diagnosis.
Diagnostic accuracy requires an understanding and integration of the
spectrum of clinical and paraclinical presentations. Clinicians should also become
familiar with the specificity of the various CNS autoantibodies to determine
whether their presence can be considered indicative of an immune etiology and if
antibody positivity might justify the use of immunotherapy. Several scoring
systems have been developed that may be useful in identifying autoimmune
seizures and can be applied in clinical practice to improve the certainty of
diagnostic and therapeutic decision making. Current recommendations
regarding patient selection for autoimmune antibody evaluation and the
approach to immunotherapy are largely based on data derived from autoimmune
encephalitis, and efforts to better understand autoimmune seizure
manifestations and treatment strategies are ongoing.
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features and long-term outcomes of a historical for immunotherapies and future research
cohort not treated with immunotherapy. questions. Seizure 2016;41:26-41. doi:10.1016/
Epilepsia 2016;57(5):823-831. doi:10.1111/epi.13356 j.seizure.2016.07.002

106 Gresa-Arribas N, Titulaer MJ, Torrents A, et al. 114 Huang Q, Ma M, Wei X, et al. Characteristics of
Antibody titres at diagnosis and during follow-up seizure and antiepileptic drug utilization in
of anti-NMDA receptor encephalitis: a outpatients with autoimmune encephalitis. Front
retrospective study. Lancet Neurol 2014;13(2): Neurol 2018;9:1136. doi:10.3389/fneur.2018.01136
167-177. doi:10.1016/S1474-4422(13)70282-5
115 Gaspard N, Foreman BP, Alvarez V, et al. New-
107 Irani SR, Bien CG, Lang B. Autoimmune epilepsies. onset refractory status epilepticus: etiology,
Curr Opin Neurol 2011;24(2):146-153. doi:10.1097/ clinical features, and outcome. Neurology 2015;
WCO.0b013e3283446f05 85(18):1604-1613. doi:10.1212/WNL.
0000000000001940
108 McKeon A. Antibody prevalence in epilepsy
(APE) score-evolution in autoimmune epilepsy 116 Ilyas-Feldmann M, Prüß H, Holtkamp M. Long-
practice. JAMA Neurol 2017;74(4):384-385. term seizure outcome and antiseizure
doi:10.1001/jamaneurol.2016.5479 medication use in autoimmune encephalitis.
Seizure 2021;86:138-143. doi:10.1016/j.seizure.
109 Zuliani L, Graus F, Giometto B, et al. Central
2021.02.010
nervous system neuronal surface antibody
associated syndromes: review and guidelines for 117 Britton JW, Flanagan EP, McKeon A, Pittock SJ.
recognition. J Neurol Neurosurg Psychiatry 2012; Autoimmune epilepsy disorders. In: Cascino GD,
83(6):638-645. doi:10.1136/jnnp-2011-301237 Sirven JI, Tatum WO. Epilepsy. 2nd ed. John Wiley
& Sons; 2021:249-274.
110 Abboud H, Probasco J, Irani SR, et al.
Autoimmune encephalitis: proposed 118 Dubey D, Britton J, McKeon A, et al. Randomized
recommendations for symptomatic and long- placebo-controlled trial of intravenous
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Psychiatry 2021;92(8):897-907. doi:10.1136/ epilepsy. Ann Neurol 2020;87(2):313-323.
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111 de Bruijn MAAM, Bastiaansen AEM, Mojzisova H, 119 Toledano M, Britton JW, McKeon A, et al. Utility of
et al. Antibodies Contributing to Focal Epilepsy an immunotherapy trial in evaluating patients
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ane.12575
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398 APRIL 2022

Women’s Issues in REVIEW ARTICLE
Epilepsy

C O N T I N U UM A U D I O
ONLINE
By Esther Bui, MD, FRCP(C)
ABSTRACT
PURPOSE OF REVIEW: Issues
pertaining to women with epilepsy have advanced
with a better understanding of multidirectional influences among
hormones, seizures, and antiseizure medications, as well as pregnancy-
related concerns around fertility, seizure destabilization, and antiseizure
medication–associated teratogenicity. This article highlights important
developments in this field and reviews best practices in the management
of women with epilepsy.
RECENT FINDINGS: Important external hormonal influences may impact

women with epilepsy particularly in the context of gender-affirming
medications, hormonal replacement therapy, and fertility therapies.
Fertility for women with epilepsy is influenced by multiple variables;
however, in the absence of preexisting fertility issues, epilepsy per se is
not associated with significantly impaired fertility. Once women with
epilepsy are pregnant, the majority have a stable course. Antiseizure
medication use in pregnancy is associated with major congenital
malformations 2 to 5 times that of the general population and is highest
with high-dose (≥1500 mg or greater total daily) valproate. Carefully
considered changes in drug choice and dose may mitigate these risks.
Therapeutic drug monitoring plays an important role in pregnancy care, CITE AS:
and under expert supervision, women with epilepsy in pregnancy have CONTINUUM (MINNEAP MINN)
similar seizure risks as women with epilepsy who are not pregnant. As 2022;28(2, EPILEPSY):399–427.
women with epilepsy age, bone health and menopause may further be
impacted by seizures and antiseizure medications. Dr Esther Bui, Toronto Western
Hospital, 399 Bathurst St, Room
445, 5 West Wing, Toronto,
SUMMARY: The care of women with epilepsy is a multifaceted discipline
Ontario, Canada M5T2S8,
that recognizes the life-long impact of sex and gender influences on Esther.Bui@uhn.ca.
epilepsy care.
Dr Bui reports no disclosure.
UNLABELED USE OF
USE DISCLOSURE :
INTRODUCTION
Dr Bui discusses the unlabeled/
W
orldwide, epilepsy affects men and women nearly equally,1 yet investigational use of
issues pertaining to women with epilepsy are unique and acetazolamide, clobazam, and
hormonal therapies for the
magnified especially during adolescence, pregnancy, and treatment of catamenial
menopause. At these times, an understanding of the epilepsy.
multidirectional and interconnected relationship among
hormones, antiseizure medications, and seizures is paramount for women with © 2022 American Academy
epilepsy, especially during pregnancy. Globally, approximately 15 million women of Neurology.

WOMEN’S ISSUES IN EPILEPSY
with epilepsy are of reproductive age, with approximately 1.3 million of these
women in the United States.2
Distinguishing Sex and Gender

It is important to distinguish between sex and gender. Sex (male and female) is
defined by biological and physiologic factors such as chromosomes and
reproductive organs.3 Most preclinical research has focused on sex differences. In
contrast, gender is a psychosocial construct (women and men) unique to
different cultures and social norms. This distinction is important particularly
pertaining to biopsychosocial issues such as sexual dysfunction, as well as to
transgender women with epilepsy who face issues with stigma and gender-
affirming medications.4 This article highlights important sex and gender aspects
in the care of women with epilepsy.
NEUROBIOLOGY OF SEX HORMONES AND EPILEPSY

Estrogen and progesterone, with estradiol and allopregnanolone being the
respective bioactive forms, are two key sex steroid hormones impacting women
with epilepsy. In animal studies, estrogen has proconvulsant effects by
facilitating and accelerating kindling, as well as decreasing seizure threshold
mainly through glutamate receptors. In contrast, progesterone has
anticonvulsant effects mediated through positive allosteric modulation of
γ-aminobutyric acid (GABA) conductance.5 This simplified relationship is likely
more complex because studies have identified both stabilizing effects of
estrogen as well as destabilizing effects of progesterone receptor agonists.6
Estrogen and progesterone are tertiary products of the hypothalamic-
pituitary-gonadal system with direct, reciprocal connectivity to temporolimbic
pathways as shown in FIGURE 6-1.5 This connectivity may explain how epileptic
activity can disrupt cyclical hormones. Two observed disruptions include
postictal prolactin increase, distinguishing epileptic bilateral convulsive seizures
from nonepileptic events, and altered luteinizing hormone pulsatility in women
with epilepsy.7,8 Real-world observations have identified a higher prevalence
of polycystic ovarian syndrome, amenorrhea, menstrual irregularities, and
premature menopause in women with epilepsy.9 Although hormonal
dysregulation can occur in the absence of antiseizure medications, antiseizure
medications also impact hormones. Enzyme-inducing antiseizure medications
decrease available free sex steroid hormones by inducing hepatic metabolism of
these sex hormones, as well as increasing production of sex-hormone–binding
globulin.5 Valproate, an enzyme inhibitor, is associated with polycystic ovarian
syndrome possibly because of inhibition of testosterone breakdown, valproate-
induced weight gain with subsequent insulin resistance, or direct antiprogestin
effects of valproate due to progesterone receptor blockade.9
CATAMENIAL EPILEPSY
One real-world example of hormonal influences in epilepsy is catamenial
epilepsy, which affects one-third of women with epilepsy and is defined as the
doubling of seizures or seizures occurring almost exclusively during specific
times of the menstrual cycle.10 Menstrual seizure exacerbation, while not
catamenial per se, is reported in 70% or more of women with epilepsy.11 On
average, a menstrual cycle lasts 28 days, with day 1 marking the first day of
menstruation. Ovulation is calculated most reliably 14 days before day 1.
400 APRIL 2022

FIGURE 6-1
Hypothalamic-pituitary-gonadal axis in women.
FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone
Reprinted with permission from Harden CL and Pennell PB, Lancet Neurol.5 © 2013 Elsevier Ltd.
Throughout the cycle, changes in the estrogen-to-progesterone ratio occur to

facilitate (1) ovarian follicular development (follicular stage), (2) ovulation and
endometrial thickening (luteal stage), and (3) sloughing of the endometrial lining
(menstruation). During menstruation (C1 pattern) and ovulation (C2 pattern),
the estrogen-to-progesterone ratio is at its highest, favoring a proconvulsant
state. Women who experience anovulatory cycles may also have menstrual-
related seizures, albeit more subtle to recognize with seizures occurring
throughout the ovulatory, luteal, and menstrual phases (C3 pattern).10 FIGURE 6-2
shows these cyclic changes.
Treatment of Catamenial Epilepsy

Currently, no therapy for catamenial epilepsy is approved by the US Food and
Drug Administration (FDA), although studies have explored potential therapies.
The Progesterone Treatment Trial (n = 294) was a randomized, double-blind,
placebo-controlled trial of natural progesterone supplements for catamenial
epilepsy.12 This trial did not identify a statistically significant reduction in
seizures with progesterone; however, post hoc prespecified subgroup analysis
identified women (n = 63) with the C1 pattern with at least a tripling of their
seizures perimenstrually who experienced statistically significant seizure
reduction.12 In contrast, synthetic progestins, such as IM medroxyprogesterone,

FIGURE 6-2
Types of catamenial epilepsy. Day 1 is the first day of menstrual flow; day -14 is ovulation. A,
The C1 pattern represents perimenstrual seizure exacerbation, and the C2 pattern represents
periovulatory seizure exacerbation. B, The C3 pattern represents catamenial epilepsy in
anovulatory cycles.
F = follicular phase; L = luteal phase; M = perimenstrual; O = periovulatory phase.
Reprinted with permission from Herzog AG, et al, Epilepsia.10 © 2013 The International League Against
Epilepsy.
are not metabolized to allopregnanolone but may reduce seizures through

complete suppression of the menstrual cycle.13 Less robust evidence is available
for other therapies. One small study investigating clobazam (n = 18) in a double-
blind crossover study with doses of 20 mg/d to 30 mg/d compared with placebo
for 10 days during peak seizure-risk time periods reported that 14 of 18 women
found clobazam to be superior to placebo in improving seizure control with
well-tolerated side effects.14 Another study, a retrospective telephone
questionnaire of 20 women with catamenial epilepsy treated with acetazolamide
(majority on polytherapy), identified 40% reporting a decrease in seizure
frequency with doses ranging from 125 mg daily to 750 mg daily; the authors
402 APRIL 2022

recommended a starting total daily dose of 4 mg/kg/d up to a maximum total KEY POINT
daily dose of 1 g/d.15 Finally, anticipatory increases in antiseizure medications
● Gender-affirming
could be considered but should be avoided in drugs associated with toxicity when medications may interact
small increases are made, such as phenytoin. FIGURE 6-3 summarizes therapeutic with antiseizure
options for catamenial epilepsy.16,17 medications, and antiseizure
medications may have
unwanted esthetic side
TRANSGENDER WOMEN WITH EPILEPSY
effects and significant drug-
Hormonal factors are also important for transgender teens and women with drug interactions.
epilepsy. Worldwide, up to 450,000 transgender people have epilepsy.4
Transgender women may experience discrimination, stigma, and reluctance to
discuss gender identity with health care providers.4 This may impact epilepsy
care, including choice of antiseizure medication, access to social work, and
patient advocacy. Drugs such as valproate may be associated with unwanted
esthetic side effects such as alopecia, hirsutism, and weight gain. Although such
esthetic side effects are unwanted in general, transgender women have unique
psychological and medical implications. Esthetic side effects associated with
masculinization may impact transgender women’s mental health as well as
choice and dosing of gender-affirming medications. Furthermore, gender-
affirming medications may interact with antiseizure medications. For example,
oral 17beta-estradiol may lower lamotrigine levels, and conversely, enzyme-
inducing antiseizure medications may lower drug levels of gender-affirming
drugs including gonadotropin-releasing hormone analogue,
medroxyprogesterone, 17beta-estradiol, spironolactone, and transdermal
estrogen.4 Transgender medicine is an emerging topic, and more work needs to
be done to ensure the needs of transgender women with epilepsy are met.
FIGURE 6-3
Approach to the treatment of catamenial epilepsy.
IM = intramuscular; TID = 3 times a day.
a
Avoid with drugs prone to toxicity like phenytoin.
Data from Navis A and Harden C, Curr Treat Options Neurol16 and Vélez-Ruiz NJ and Pennet PB, Neurol Clin.17

SEXUAL DYSFUNCTION AND FERTILITY

Sexual dysfunction among women with epilepsy has been linked to multiple
factors such as poorly controlled, disabling seizures; comorbid mood disorders;
and drug-related decreased libido and sexual dysfunction.18 Specifically,
topiramate, valproate, pregabalin, and gabapentin have been associated with
sexual dysfunction, whereas lamotrigine, levetiracetam, and oxcarbazepine
less so.19
Like sexual dysfunction, fertility issues have also been difficult to isolate to a
singular cause because stigma, employment status, and marital status may also
play a role in whether women with epilepsy have children. Equally important,
women with epilepsy may choose not to have children. In one UK survey, 1 in
3 women with epilepsy chose not to conceive because of epilepsy.20 Infertility is
defined as unprotected sex without achieving pregnancy by 1 year for women
who are 35 years old and younger and by 6 months for women who are older than
35 years. In a web-based study, women with epilepsy self-reported an infertility
rate of 9.2% (95% confidence interval [CI], 6.7% to 12.4%) compared with the
observed 6% infertility rate among married women in the general population.21,22
Identified risk factors for infertility include childhood-onset epilepsy, associated
disability, epilepsy of structural or metabolic cause, drug-resistant or severe
seizures, polytherapy, older age, and lower education.23,24 However, such studies
are limited by their retrospective nature and inherent challenges of disentangling
biopsychosocial factors.
A 2018 prospective observational cohort group study aimed to clarify whether
epilepsy in and of itself affects fertility in women with epilepsy.22 The study
recruited women with epilepsy as well as a control group of women without
epilepsy (all aged 18 to 40 years) seeking pregnancy; the mean age was 31.9 years
for women with epilepsy and 31.1 years for the control group. Women with a
preexisting history of infertility or disorders impacting fertility were excluded.
This study did not identify any difference between time to pregnancy (6 months
for women with epilepsy, 9 months for controls), sexual activity, ovulatory rates,
pregnancy rates (approximately 60% in both groups), and live birth rates
(approximately 81.5% in both groups). Miscarriage rates were not statistically
different (14.8% in women with epilepsy, 18.5% in the control group). It is
notable that only a minority (10%) of women with epilepsy were on polytherapy.
This study provides encouraging data for women with epilepsy who do not have
preexisting risks for infertility that their chances of conceiving are similar to
age-matched controls.
FERTILITY TREATMENT
For women struggling with fertility, assisted reproductive technology is an
option but may have associated risks from exogenous hormones that heighten
the estrogen-to-progesterone ratio or can interact with antiseizure medication,
particularly lamotrigine, and subsequently lower seizure threshold. For example,
gonadotropin therapy used commonly for ovarian stimulation, as well as
exogenous estrogen for menstrual synchronization and endometrial preparation,
both increase systemic estrogen. A 2018 case report described two women who
experienced seizure exacerbation in the context of well-controlled epilepsy
and recent fertility therapy; seizure recurrence was attributed to either a
documented rise in estrogen levels or a concomitant fall in lamotrigine levels
observed during fertility therapy.25
404 APRIL 2022

Reassuringly, women with epilepsy appear to have similar chances as women KEY POINTS
without epilepsy of conceiving through assisted reproductive technology. In a
● Women with epilepsy
Danish observational cohort, a health registry study identified all embryo without preexisting
transfers from 2006 to 2017.26 In Denmark, the tax-supported health service infertility have as good of a
provides free access to assisted reproductive technology, including three in vitro chance for conceiving as do
fertilization cycles and unlimited frozen embryo transfers for infertile couples women without epilepsy.
and single women aged 41 years or younger. The study compared 730 assisted
● Seizure exacerbation may
reproductive technology treatments in 264 women with epilepsy with 128,387 occur with hormonal
assisted reproductive technology treatments in 42,938 women without epilepsy. therapies used in assisted
The adjusted live birth rate for women with epilepsy after embryo transfer was reproductive technology;
24.7%, similar to the control group’s rate of 23.9% (odds ratio, 1.06; 95% CI, however, women with
epilepsy have a similar
0.88 to 1.28). Antiseizure medication use did not appear to impact assisted chance at successful
reproductive technology success rates. Women with epilepsy on antiseizure assisted reproductive
medications had similar embryo transfer success rates (26.8%) compared with technology treatment as
women with epilepsy who had recently discontinued antiseizure medications women without epilepsy
irrespective of concurrent
(22.3%) with an adjusted odds ratio of 1.22 (95% CI, 0.77 to 1.92). This large antiseizure medication use.
retrospective registry study provides the best evidence to date of outcomes for
women with epilepsy undergoing assisted reproductive technology treatment.
CASE 6-1 presents a woman with epilepsy undergoing fertility treatment.
CONTRACEPTION
Contraceptive counseling should be offered to all women with epilepsy of
childbearing age beginning at menarche. Contraceptive counseling is particularly
important for women with epilepsy because in utero exposure to antiseizure
medications is associated with structural teratogenicity, as well as cognitive and
behavioral adverse outcomes in children. Despite these risks, approximately 50%
of pregnancies among women with epilepsy are unplanned. This is a similar rate
seen in the general population.27,28 Furthermore, women with epilepsy become
first aware of their pregnancy on average at 6.5 weeks of gestation when fetal
development is well underway, with the neural tube having closed at 4 weeks of
gestation.27,28 Neurologists can significantly influence the use of reliable
contraceptives. When specifically counseled on contraceptive options by their
neurologist, one retrospective chart review found a higher rate of intrauterine
device (IUD) use among women with epilepsy.29 FIGURE 6-4 highlights an
approach to contraceptive counseling for women with epilepsy.30-32 As
contraceptive options expand, neurologists need to be informed and involved in
contraceptive counseling for women with epilepsy. TABLE 6-1 summarizes
contraceptive options for women with epilepsy.31,33-35
While ensuring women with epilepsy have their best chance at a planned
pregnancy, contraceptives may inadvertently destabilize epilepsy in women.
Real-world, self-reported data on contraceptive use come from the Epilepsy
Birth Control Registry, a Web-based survey with self-enrollment by women with
epilepsy (n = 1144 women of reproductive age) recruited through social media
and Web-based platforms. The Epilepsy Birth Control Registry study reported
that women with epilepsy on hormonal birth control reported a 6.75 times risk
of increased seizures compared with women with epilepsy using the barrier
method ( P<.0001).36 Seizure exacerbation may occur due to interactions
between hormonal oral contraception and antiseizure medications.
Ethinylestradiol, the main estrogen component of combined oral contraceptive
pills, induces enzymes in the glucuronidation metabolic pathway by up to 50%.

This pathway is important to the metabolism of lamotrigine and, to a lesser

extent, valproate and oxcarbazepine.30 An equally important bidirectional
interaction is induction of combined oral contraceptive pill metabolism by
enzyme-inducing antiseizure medications via the cytochrome P450 3A4
(CYP3A4) enzyme pathway resulting in potential contraceptive failure. Women
should monitor for midcycle breakthrough bleeding as a potential indicator of
combined oral contraceptive failure, especially if hormonal levels are not readily
available. Birth control methods not affected by enzyme-inducing antiseizure
medications include depot medroxyprogesterone acetate injection and IUDs
(both levonorgestrel and copper) because of their localized rather than systemic
contraceptive effects. TABLE 6-2 summarizes key drug-drug interactions of
antiseizure medications and hormonal oral contraceptives.33,37-39
PRECONCEPTION COUNSELING
For women with epilepsy who hope to conceive, many worry about how
seizures, epilepsy treatment, and their developing fetus will impact one another.
Preconception counseling, in addition to addressing women’s concerns, has been
prospectively observed to lower antiseizure medication burden, improve folic
acid use, and reduce seizure burden.40 The value of preconception counseling is
CASE 6-1 A 41-year-old woman with drug-resistant left temporal lobe epilepsy and
left mesial temporal sclerosis underwent a successful left temporal
lobectomy at age 35 with postoperative seizure freedom. Subsequent
lowering of antiseizure medications led to seizure recurrence. As a result,
she resumed carbamazepine 100 mg 3 times a day, lamotrigine 100 mg 2
times a day, and folic acid 1 mg daily and remained seizure free. After
6 years of infertility, at age 41, she sought assisted reproductive therapy.
During her first in vitro fertilization therapy, she experienced a prolonged
convulsive seizure. Her lamotrigine serum level before fertility therapy
was in the midtherapeutic range but subtherapeutic at the time of
seizure. Carbamazepine levels remained stable. In response, clobazam
10 mg daily was added with the next three in vitro fertilization cycles.
Seizure-free, she underwent a successful embryo transfer. During
pregnancy, carbamazepine levels remained stable, but lamotrigine serum
levels fell, dramatically prompting incremental upward dose adjustments
to ultimately 200% of her preconception dose.
She delivered a healthy baby girl via elective cesarean delivery. One
month postpartum, she developed double vision and balance difficulties.
Her postpartum lamotrigine level was in the toxic range, and lamotrigine
was titrated down over 1 week from 200 mg 2 times a day to 125 mg
2 times a day. This resulted in resolution of her symptoms.
406 APRIL 2022

reinforced by its role in ensuring informed consent when choosing
epilepsy therapies.
Risk of Seizure Exacerbation Due to Pregnancy

Pregnancy is associated with several physiologic changes, including increased blood
volumes, alterations in serum albumin, increased renal blood flow, and induction
of hepatic metabolism resulting in an overall reduction of both free and protein-
bound antiseizure medication serum levels. Decreases in drug levels may be further
aggravated by hyperemesis gravidarum, nonadherence, or if women with epilepsy
are instructed to reduce or withdraw antiseizure medications. FIGURE 6-5 shows
physiologic changes during pregnancy that impact women with epilepsy.41
Reassuringly, most women with epilepsy have either stable or improved
seizure frequency during pregnancy. The European Registry of Antiepileptic
Drugs and Pregnancy (EURAP), a prospective pregnancy registry consisting
of 3806 pregnancies of 3451 women with epilepsy, showed that 66.6% of the
women remained seizure free in pregnancy. Of those with seizures, generalized
tonic-clonic seizures were seen in only a minority (15.2%) of pregnancies.
Women with generalized epilepsy of presumed genetic origin were more likely to
remain seizure free (73.6% versus 59.5%, P<.0001) compared with women with
This case demonstrates several important concepts in fertility and COMMENT

pregnancy for women with epilepsy. In the absence of preexisting
infertility, women with epilepsy have a similar chance of conceiving
compared with women without epilepsy. Nonetheless, with advancing age,
assisted reproductive technology is available for women experiencing
infertility, including women with epilepsy. Reassuringly women with
epilepsy, whether on antiseizure medications or not, have similar
pregnancy success rates with assisted reproductive technology as women
without epilepsy. Reports of seizure exacerbation during assisted
reproductive technology have raised concerns about hormone-based
fertility therapies because of possible direct proconvulsant effects or
drug-drug interactions, particularly with lamotrigine. Once pregnant, under
expert care, women with epilepsy have similar rates of seizures as
nonpregnant women with epilepsy but may require more frequent dose
adjustments, especially if serum drug levels fall more than 35% from
preconception levels. This is particularly seen with levetiracetam and
lamotrigine, requiring incremental adjustments resulting in doses as high as
200% to 300% of prepregnancy dosing. Intrapartum dose changes need to
be reevaluated postpartum, especially with lamotrigine, where levels rise
as early as 1 to 2 weeks postpartum. Tapering from pregnancy peak dosing
to approximately 125% of the prepregnancy dose can mitigate drug toxicity.
Maintaining the dose at 125% for the first few months may provide added
antiseizure effects during a period of anticipated sleep deprivation and
stress, both potential seizure triggers. At the 3- to 6-month follow-up,
women should be reassessed as to whether drug doses can be further
lowered back to prepregnancy doses.

KEY POINTS
● The intrauterine device,

either hormonal based or
copper based, continues to
be the top-recommended
contraceptive choice for
women with epilepsy taking
enzyme-inducing antiseizure
medications or lamotrigine.
● Up to two-thirds of
women with epilepsy remain
seizure free in pregnancy.
The best predictor of
seizure frequency during
pregnancy is the 9 to
12 months of seizure
frequency before
conceiving.
FIGURE 6-4
Approach to contraceptive options for women with epilepsy on antiseizure medications.
Data from Davis AR, et al, Springer30; Woodhams EJ and Gilliam M, Anne Intern Med31; and Thomas SV, Ann
Indian Acad Neurol.32
focal epilepsy. Women with epilepsy on lamotrigine monotherapy (compared

with carbamazepine, phenobarbital, or valproate monotherapy) were less likely
to remain seizure free (58.2%, P<.001) possibly because of the low observed
rate of lamotrigine dose adjustments, seen in only 26% of pregnancies.42 It is now
recognized that antiseizure medications such as lamotrigine and levetiracetam
have significant decreases in serum levels due to pregnancy-related
physiologic changes.43
Predictive factors for seizures in pregnancy include decreases in antiseizure
medication serum levels, focal epilepsy, and polytherapy, with the best predictor
being the frequency of seizures 9 to 12 months before conception.44-46 In
contrast, women with catamenial epilepsy may experience seizure improvement
during pregnancy.47
More recent data from the Maternal Outcomes and Neurodevelopmental
Effects of Antiepileptic Drugs (MONEAD) study provide reassurance for women
with epilepsy. Under specialized epilepsy care, the risk of seizures for women
with epilepsy during pregnancy is similar to that for women with epilepsy who
are not pregnant. This prospective, observational, parallel-cohort, multicenter
study compared pregnant women with epilepsy (n = 351) with nonpregnant
women with epilepsy (n = 109). Between the groups, no differences in the
incidence of seizures with impaired awareness were observed. Pregnant women
with epilepsy had similar rates (19.8%) as nonpregnant women with epilepsy (17.
2%) during a comparable time frame (odds ratio, 0.93; 95% CI, 0.54 to 1.60). As
well, the majority of pregnant women with epilepsy in this study reported either
stability or improvement of all seizure types (71.2%), with even higher
percentages of stability or improvement seen specifically for seizures with
impaired awareness (80.2%) and convulsive seizures (85.8%). Pregnant women
with epilepsy in this study, however, had a higher rate of antiseizure medication
408 APRIL 2022

Contraceptive Options for Women With Epilepsy TABLE 6-1
Rate of unplanned
pregnancy in first year Contraceptive Issues relevant to women with
Contraceptive type33 of use, real-world use31 mechanism31,34 epilepsy31,34
Hormonal
Combined oral contraceptive 7% Ethinylestradiol, Avoid with enzyme-inducing

pill progestin antiseizure medications
If unable to discontinue combined oral
contraceptive, adding second
contraceptive method (barrier, intrauterine
device [IUD]) should be considered
Can lower lamotrigine serum levels
Combined dermal patch 7% Ethinylestradiol, Can lower lamotrigine serum levels

progestin
Combined vaginal ring 7% Ethinylestradiol, Can lower lamotrigine serum levels

progestin
Progestin-only pills 7% Progestin Efficacy reduced by enzyme-inducing

antiseizure medications, to a lesser
extent by lamotrigine and perampanel
Progestin-only implants 0.1% Progestin Efficacy may be reduced by enzyme-

inducing antiseizure medications
Progestin-only depot 4% Progestin May reduce seizures in some patients if

medroxyprogesterone amenorrhea achieved
acetate injections
Associated with loss of bone mineral density
Progesterone-only 0.1% Progestin May eliminate menstrual bleeding

intrauterine device
Does not impact antiseizure
medications and antiseizure
medications do not impact IUD efficacy
Nonhormonal
Coitus interruptus 20% Withdrawal High failure rate
Male condoms 13% Barrier method High failure rate, relies on partner compliance
Female condoms 21% Barrier method High failure rate
Diaphragm 17% Barrier method Requires fitting by a physician
Cervical caps 16-32% Barrier method High failure rate
Copper or steel IUD 0.8% Creates a sterile May have issues with MRI compatibility,
inflammatory especially a steel IUD35
environment
Vasectomy 0.15% Surgical Permanent, relies on sexual partner’s

sterilization health decision
Tubal ligation 0.5% Surgical Permanent, no impact on epilepsy

sterilization
MRI = magnetic resonance imaging.

dose adjustments with 74% having dose adjustments compared to 34% of

controls (nonpregnant women with epilepsy).46
Risk of Maternal Seizures to the Fetus

Convulsive seizures, especially if prolonged, pose risks to the mother and can be
associated with fetal hypoxia and lactic acidosis, whereas fetal decelerations or
distress have been described with focal seizures.48,49 A Taiwanese population-
based study of pregnant women with epilepsy (n = 1016) compared with age-
matched pregnant women with chronic disease (n = 8128) identified a 1.37-fold
risk of small for gestational age (95% CI, 1.09 to 1.7), 1.63-fold risk for preterm
delivery (95% CI, 1.21 to 2.19), and 1.36-fold risk for low birth weight (95% CI,
1.01 to 1.88) associated with maternal seizures requiring hospitalization or
emergency medical attention.50 This study was limited in that seizure subtypes
(convulsive or nonconvulsive) were not specified nor were milder seizures not
requiring emergent medical attention included. To date, no evidence suggests that
seizures in and of themselves are associated with major congenital malformations.
Risks of Antiseizure Medications to the Fetus

Although maternal seizures have not been associated with fetal major congenital
malformations, in utero exposure to antiseizure medications is associated with
TABLE 6-2 Drug-Drug Interactions of Antiseizure Medications and Hormonal Oral

Contraceptivesa,b
Enzyme inducers Decrease in ethinylestradiol Decrease in progestin
Carbamazepine Yes Yes
Felbamate Yes Yes
Lamotriginec No Yes
d
Oxcarbazepine Yes Yes
Eslicarbazepine acetate Yes Yes
Phenobarbital Yes Yes
Phenytoin Yes Yes

d
Topiramate Yes No
Perampaneld No Yes
Rufinamide Yes Yes
Clobazam Yes Yes
Primidone Yes Yes
a
Data from Reimers A, et al, Seizure33; Reimers A, Open Access J Contracept37; Dutton C, et al,
Contraception in Neurologic and Psychiatric Disorders38; and Stockis A, et al, Epilepsia.39
b
Valproate is an enzyme inhibitor. Clonazepam, brivaracetam, ethosuximide, gabapentin, levetiracetam,
tiagabine, vigabatrin, zonisamide, and lacosamide have no effect on hormonal contraceptives. It is unknown
if pregabalin and stiripentol have an effect on hormonal contraceptives.
c
Antiseizure drug levels decreased by a combined oral contraceptive pill.
d
Enzyme-induction effect is dose dependent (eg, topiramate at doses of ≥200 mg total daily,
oxcarbazepine at doses ≥1200 mg total daily, perampanel at doses ≥12 mg total daily).
410 APRIL 2022

KEY POINT
● Under specialized
epilepsy care, women with
epilepsy in pregnancy have
similar rates of seizures as
women with epilepsy who
are not pregnant, but
women with epilepsy in
pregnancy require higher
rates of antiseizure
medication dose
adjustments.
FIGURE 6-5
Changes in antiseizure medication levels in pregnancy for women with epilepsy.
Modified with permission from Stephen LJ, et al, Lancet Neurol.41 © 2019 Elsevier Ltd.
teratogenicity, recognized across multiple, prospective, observational pregnancy

registries including the Australian Pregnancy Register (APR), the EURAP, the
North American Antiepileptic Drug Pregnancy Registry (NAAPR), and the UK
and Ireland Epilepsy Pregnancy Register.2 Neural tube, cardiac, urogenital, and
craniofacial congenital malformations are observed with in utero antiseizure
medication exposure with the highest rate consistently associated with valproate.
EURAP, the largest multinational registry, has observed a 10.3% major congenital
malformation rate with valproate (95% CI, 6.6 to 12.9). Currently, the FDA warns
that the use of valproate should be avoided in women of childbearing age unless
other medications have failed or are deemed unacceptable. Intermediate-risk
drugs include phenobarbital with a major congenital malformation rate of 6.5%
(95% CI, 2.8 to 12.2), phenytoin with a major congenital malformation rate of
6.4% (95% CI, 2.8 to 12.2), carbamazepine with a major congenital malformation
rate of 5.5% (95% CI, 4.5 to 6.6), and topiramate with a major congenital
malformation rate of 3.9% (95% CI, 1.5 to 8.4). Drugs with the lowest risk of
major congenital malformations are levetiracetam with a major congenital
malformation rate of 2.8% (95% CI, 1.7 to 4.5), lamotrigine with a major
congenital malformation rate of 2.9% (95% CI, 2.3 to 3.7), and oxcarbazepine
with a major congenital malformation rate of 3.0% (95% CI, 1.4 to 5.4).51
51
FIGURE 6-6 shows the findings across three international pregnancy registries.
The risk of teratogenicity is also likely dose related. Lower doses of antiseizure
medications are associated with lower rates of major congenital malformations. In
the EURAP registry, lower-dose lamotrigine (≤325 mg total daily) had the lowest
rate of major congenital malformation (prevalence 2.5%; 95% CI, 1.8 to
3.3%), with increasing odds of major congenital malformation comparatively
seen in high-dose, higher-risk drugs such as valproate. With decreasing valproate
doses (<650 mg total daily), the major congenital malformation rate is near
comparable to higher-dose carbamazepine.51 FIGURE 6-7 shows the observed
major congenital malformation rates associated with different antiseizure
medication doses.

FIGURE 6-6
Prevalence of major congenital malformations of eight antiseizure medication
monotherapies from three prospective pregnancy registries.
CI = confidence interval; EURAP = European Registry of Antiepileptic Drugs and Pregnancy.
Reprinted with permission from Tomson T, et al, Curr Opin Neurol.51 © 2019 Wolters Kluwer Health, Inc.
FIGURE 6-7
Prevalence of major congenital malformations of antiseizure medication compared with
lamotrigine ≤325 mg/d.
CBZ = carbamazepine; CI = confidence interval; LEV = levetiracetam; LTG = lamotrigine;
OXC = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; Ref = reference; TPM = topiramate;
VPA = valproate.
Reprinted with permission from Tomson T, et al, Curr Opin Neurol.51 © 2019 Wolters Kluwer Health, Inc.
412 APRIL 2022

In addition to dose-related risks, individual antiseizure medications have
variable malformation profiles that can guide physicians toward specific
assessments such as a fetal echocardiogram or urogenital assessment. Notably,
the most common malformation associated with barbiturates (eg, phenobarbital),
carbamazepine, and lamotrigine is cardiac, whereas topiramate is linked with cleft
palate/lip, and valproate with neural tube, cardiac, and urogenital malformations
at near equal distribution. FIGURE 6-8 shows the variability of major congenital
malformations among different antiseizure medications.52
Less is known about the newer antiseizure medications. A recent review of a
global database for perampanel identified 96 pregnancies in 90 women, the
majority of whom were on polytherapy (71.1%). Of the 96 pregnancies, 43
reached full term; the remaining were lost to follow-up, did not complete the
pregnancy, or had an ongoing pregnancy. Among the 43 completed pregnancies,
low Apgar scores (n = 2), neonatal aspiration (n = 1), cystic fibrosis and
congenital deafness (n = 1), and poor suckling reflex and shallow breathing
(n = 1) were reported, with only the last finding possibly attributed to
perampanel although clonazepam was a concomitant antiseizure medication.53
Data from the eslicarbazepine acetate global safety database identified 91
pregnancies, 30 of which reached term without major congenital malformations,
5 births were reported to have congenital anomalies, and the remaining
pregnancies were aborted, ongoing, or unknown (ie, no available data). These
anomalies included de novo unbalanced chromosomal 18, conjoined twins,
congenital knee dislocation, talipes, and cytogenic abnormality with most
deemed unlikely related to eslicarbazepine exposure.54 Lacosamide has three
published exposures in pregnancy and no major congenital malformations
FIGURE 6-8
Common major congenital malformations associated with in utero monotherapy exposure.
Total number of exposed fetuses or infants are shown in parentheses with the number of
those with specific malformations shown on top of the bars.
Reprinted with permission from Tomson T, et al, Lancet Neurol.52 © 2016 Elsevier Ltd.

observed in offspring,55 whereas brivaracetam has three published exposures

(two on polypharmacy) with no observed major congenital malformation,
although minor malformations were described, including congenital dermal
melanocytosis, ankyloglossia (n = 1), and hemangioma on the thumb and back
(n = 1).56 The available data on newer antiseizure medications are currently
insufficient to draw conclusions. Encouraging all eligible women to enroll in a
pregnancy registry ensures the best chance of collecting these data.
Polytherapy that specifically includes valproate or topiramate is associated
with a higher major congenital malformation risk. The NAAPR prospectively
followed 6857 women on antiseizure medications and identified that children
exposed to carbamazepine combined with valproate polytherapy had a 15.4%
major congenital malformation risk (odds ratio, 6.2; 95% CI, 2.0 to 16.50)
compared with carbamazepine combined with any other antiseizure medication
where a 2.5% major congenital malformation risk was observed.57 More recently,
the Kerala, India, registry prospectively followed 1688 pregnancies, and among
women with epilepsy on polytherapy (n = 368), the highest risk was observed
when polytherapy included topiramate (relative risk, 14.62; 95% CI, 1.88 to
113.83) or valproate (relative risk, 5.43; 95% CI, 0.72 to 40.81). This study was
limited by the small numbers as reflected in the wide confidence intervals.58
These variables are further nuanced in that a low-dose polytherapy regimen
may be safer than a high-dose, high-risk monotherapy regimen. In the EURAP
registry, low- to moderate-dose valproate plus another antiseizure medication
had a lower observed major congenital malformation rate than high-dose
valproate monotherapy. The major congenital malformation rate observed in
women taking low-dose valproate (<700 mg/d) combined with other antiseizure
medications was 5.4% (95% CI, 1.9 to 14.9); it was 11.2% (95% CI, 6.4 to 12.0)
in women taking intermediate-dose valproate (≥700 mg/d to <1500 mg/d)
combined with other antiseizure medications and 24% (95% CI, 16.8 to 33.1) in
women taking high-dose valproate monotherapy (≥1500 mg/d). Again, much
like subgroup analyses in other registries, these observations should be
interpreted with caution because of the small numbers. CASE 6-2 discusses
these therapeutic challenges with valproate choice, dosing, and polytherapy.
The presence of a positive family history with a major congenital
malformation in either parent increases the risk of major congenital
malformation by 2.95-fold (95% CI, 1.52 to 5.87; P=.0023) as observed in the
EURAP registry.59 In addition, the UK and Ireland registry reported women, who
after having a child with a major congenital malformation, had a 16.8% major
congenital malformation recurrence risk, whereas after two children with a
major congenital malformation they had a 50% recurrence risk.60 Taken as a
whole, these observations suggest a genetic contribution to major congenital
malformation risk.
Beyond structural malformations, impaired cognitive and behavioral
outcomes have been observed at a significantly higher rate with valproate
exposure. In the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD)
study, children exposed to valproate and assessed at the ages of 3 and 6 years
were identified to have lower IQ (6 to 9 points lower) compared with those
exposed to carbamazepine, lamotrigine, and phenytoin, with a dose-dependent
relationship.61 As well, an increased risk for developmental delay in cognition,
psychomotor, and language skills; attention deficit hyperactivity disorder; and
lower performance in the Children’s Memory Scale were observed.61,62
414 APRIL 2022

Independently, a Danish population-based study identified a 4.15% (95% CI, KEY POINTS
2.2% to 7.81%) absolute risk of autism spectrum disorder among children born
● The risk of major
to women with epilepsy on valproate with an adjusted hazard ratio of congenital malformations is
1.7 (95% CI, 0.9 to 3.2).63 drug and dose dependent.
When these factors are
Risks of Valproate Withdrawal in Generalized Epilepsies for Women combined, some risks may
be near comparable, for
With Epilepsy
example, high-dose
Results of the pregnancy registries have changed prescribing patterns for women carbamazepine (>700 mg
with epilepsy around the world. The North American data from the MONEADS total daily) and low-dose
study (n = 351) reported 73.8% of pregnant women with epilepsy were on valproate (≤650 mg total
daily).
monotherapy, in order of decreasing prevalence: lamotrigine (42.1%),
levetiracetam (37.5%), carbamazepine (5.4%), zonisamide (5.0%), ● Different antiseizure
oxcarbazepine (4.6%), and topiramate (3.1%).64 Not surprisingly, the EURAP medications are associated
registry has observed major congenital malformation rates decline by 27%.2 A with different malformation
dramatic decrease in the use of valproate as a therapeutic option for women with types, and fetal assessment
as well as neonatal
epilepsy has resulted in a call for a more balanced, tailored approach, particularly examination should be
for women who experience generalized tonic-clonic seizures and myoclonic tailored to these risks.
seizures. A recent retrospective review of outcomes among 190 women with
epilepsy diagnosed with generalized epilepsy of presumed genetic origin ● Data on major congenital
malformation risk of newer
explored prescription habits, rates of switching from valproate to another
antiseizure medications
antiseizure medication, and the likelihood of seizure remission.65 Seizure continue to be insufficient
remission rates in juvenile myoclonic epilepsy were observed to be highest because of the limited
among women on valproate ( P<.001). Of the 51 women who subsequently numbers of reported
exposure, with most on
switched from valproate to another antiseizure medication, 70.5% experienced
polytherapy.
seizure recurrence.65 EURAP also observed an increased risk of generalized tonic
seizures among women who had a withdrawal (33%) or a switch from valproate ● Polytherapy that includes
to another antiseizure medication (29%) in the first trimester compared with either valproate or
women who remained on valproate (16%).66 Superior seizure control by topiramate as a component
infers the highest risk of
valproate versus other antiseizure medications has not been uniformly observed. major congenital
CASE 6-2 highlights a clinical scenario of a woman with epilepsy on valproate. An malformations among
open-label active-controlled 26-week trial with a two-parallel-group design different polytherapy
investigating levetiracetam versus valproate for men and women with combinations.
generalized topic-clonic seizures or myoclonic seizures did not identify any
● The risk of major
differences in time to first seizure as well as the seizure-freedom rate.67 Although congenital malformations
this was a prospective study, it was limited by the lack of blinding and with antiseizure medication
randomization. The decision to avoid valproate is a decision that requires exposure is highest with
high-dose (≥1500 mg total
balancing multiple factors, including the risk of seizure recurrence, potential
daily) valproate. The risks
physical and psychosocial harm specific to the patient’s seizure type(s), her may be lowered with low-
likelihood of pregnancy, and her individual health values. FIGURE 6-9 shows an dose valproate combined
approach to valproate use in women with epilepsy. with another antiseizure
medication.
Periconceptional Folic Acid ● Genetic factors are

Periconceptional folic acid is recommended for all women with epilepsy of important additional
reproductive age.51,68 Folic acid decreases major congenital malformation risk in influences for the risk of
the general population; the US Department of Health recommends 0.4 mg major congenital
malformations. A paternal
preconception folic acid and up to 4 mg for women at high risk (ie, prior history and maternal history should
of pregnancy and major congenital malformation).69 However, high-quality data be acquired to fully
specific to women with epilepsy are lacking. A Norwegian observational, characterize the risks.
population-based study of 328 children of women with epilepsy reported those
exposed to folic acid during pregnancy (n = 260) versus those unexposed (n = 68)

had a 5 to 8 times lower risk of autistic traits at 18 and 36 months of age.70 The
NEAD study identified children of women with epilepsy exposed to folic acid
had a higher IQ (mean, 108; 95% CI, 106 to 111) compared with unexposed
children (mean, 101; 95% CI, 98 to 104, P=.009), although this was not seen on
subsequent analyses.71,72 Larger cohorts such as the EURAP and UK and Ireland
pregnancy registries to date have failed to show a decreased risk of major
congenital malformations with folic acid use; however, neither registry was
predefined to assess the impact of periconceptional folic acid.59,73 Less is known
on the optimal dose of folic acid. Recent data raise concerns about
supratherapeutic folic acid. A multicenter prospective cohort study identified in
a multivariate analysis that the offspring of women taking >5 mg folic acid
daily had lower psychomotor scale scores than those exposed to ≤5 mg daily
(difference of -4.35 points; 95% CI, -8.34 to -0.36).73 This was a general
population study and excluded women taking antiseizure medications. As well,
CASE 6-2 A 25-year-old woman had been seizure free since initiating valproate
750 mg 2 times a day when she was first diagnosed with juvenile
myoclonic epilepsy at age 12. At age 20, valproate was switched to
levetiracetam as part of preconception counseling and planning, but
breakthrough myoclonic and generalized tonic-clonic seizures occurred
at 1000 mg of levetiracetam 2 times a day, and higher doses were poorly
tolerated. Lamotrigine was then trialed but stopped because of severe
drug rash. Over the next few years, topiramate, clobazam, clonazepam,
lacosamide, brivaracetam, and perampanel were subsequently trialed
but were either poorly tolerated or ineffective. At age 24, she requested
to resume valproate 750 mg 2 times a day. She was counseled on
valproate’s associated risk for fetal major congenital malformations and
behavioral-cognitive impairment with in utero exposure, considered
highest among all antiseizure medications studied. She was also
counseled on reliable contraceptive options. After careful consideration,
she opted to resume valproate 750 mg 2 times a day with folic acid 5 mg
daily and remained seizure free. During subsequent follow-up visits,
preconception and contraceptive counseling remained part of her regular
epilepsy care. Six months later, she had an unexpected pregnancy,
discovered at 7 weeks of gestation. An early ultrasound at 16 weeks
identified a severe neural tube defect, and she opted to abort the pregnancy.
At age 25 she expressed a desire to try to conceive again. Her valproate
total and free serum levels were in the upper therapeutic range. A review
of her records determined lower doses of valproate had never been
trialed. Over 6 months, valproate was lowered to 250 mg 2 times a day, and
she experienced a recurrent generalized tonic-clonic seizure. With
valproate maintained at 250 mg 2 times a day, levetiracetam 500 mg
2 times a day was added and well tolerated. She was counseled again on
the risks of major congenital malformations and cognitive-behavioral
outcomes with valproate. After 9 months of seizure freedom, she naturally
conceived and with close monitoring delivered a healthy, full-term
baby boy.
416 APRIL 2022

the study did not adjust for maternal IQ, an established major predictor of a
child’s IQ, nor were reasons reported why women were taking ≥5 mg of folic
acid, raising concerns for potential bias.74,75 Current guidelines for women with
epilepsy suggest 0.4 mg to 5 mg folic acid daily starting at least 3 months before
conceiving, with higher doses preferred for highest-risk groups including high-
dose valproate, polytherapy with valproate or topiramate, and women
with a personal or family history or prior pregnancy with a major congenital
malformation.2,68
Safety of Vagus Nerve Stimulation and Ketogenic Diet in Pregnancy

Very little is known about the safety of vagus nerve stimulation in pregnancy,
although to date, the data have been reassuring with 44 pregnancies in 38 patients
reported worldwide.76 Of these pregnancies, only two pregnancies (4.5%) ended
in miscarriage (lower than the 10% miscarriage risk in the general population),
This case highlights the challenges of managing women with epilepsy, COMMENT
especially those who have the best seizure control on valproate. Valproate
should be avoided in all women of childbearing potential if possible.
However, a small proportion of women, especially women with generalized
epilepsy of presumed genetic origin, also known as idiopathic generalized
epilepsy, may achieve optimal seizure control only with valproate. If
attempts at monotherapy with alternate medications fail or the patient
declines changes after detailed preconception counseling, revisiting
valproate at the lowest effective dose should be considered with serum
drug levels as guidance. The lowest effective dose must be individualized
and reevaluated longitudinally. The discovery of an unintended pregnancy
long after neural tube closure is not surprising since 50% of women or more
with epilepsy have unplanned pregnancies, many with delayed discovery.
When trials of monotherapy fail, polytherapy with low-dose valproate may
infer a lower risk than high-dose valproate monotherapy. This patient’s
specific major congenital malformation risk is further increased because of
her prior pregnancy history. Coprescribing high-dose folic acid combined
with early fetal assessment best ensured her desired pregnancy outcome.

FIGURE 6-9
Approach to valproate use in women with epilepsy.
Modified with permission from Tomson T, et al, Lancet Neurol.52 © 2016 Elsevier Ltd.
and two pregnancies resulted in major congenital malformations (4.8%). Both

pregnancies with major congenital malformations had concurrent polytherapy
(three or more antiseizure medications), and as such, the observed major
congenital malformation rate may have been attributed to antiseizure
medication exposure.76
Ketogenic diet is currently not recommended for women with epilepsy in
pregnancy because of the animal data identifying alterations in mice embryo
organogenesis, including brain and heart development.77 To date, two cases of
ketogenic diet during pregnancy in women with epilepsy have been published,
with one healthy infant at 12 months and one infant with bilateral external ear
deformities of unclear significance.78
MANAGEMENT OF WOMEN WITH EPILEPSY DURING PREGNANCY

The management of women with epilepsy during pregnancy focuses on ensuring
women continue to maintain their best chance of seizure freedom balanced by
minimizing in utero drug exposure to the fetus. Therapeutic drug monitoring is
an important tool to help guide drug-dose optimization during pregnancy.
Therapeutic Drug Monitoring

Women with epilepsy should be on the lowest, most effective, tolerated dose of
the appropriately chosen drug for their seizure type, at their specific life stage,
with at least one documented preconception drug level.2,68 Once pregnant,
women’s antiseizure medication serum levels can fall, particularly lamotrigine,
levetiracetam, oxcarbazepine, topiramate, and zonisamide, whereas other drugs
remain stable or show minor decreases, such as carbamazepine, carbamazepine-
10,11-epoxide, and lacosamide.44,79-82 TABLE 6-3 summarizes observed
antiseizure medication changes in pregnancy and recommendations for
therapeutic drug monitoring.51
418 APRIL 2022

Specific times during pregnancy are associated with more dramatic changes in
clearance rates. For example, levetiracetam and lamotrigine changes are greatest
in the first trimester, whereas for oxcarbazepine and topiramate they are the
greatest in the second trimester.80 Decreases in antiseizure medication serum
levels may result in seizure exacerbation. A single-center, retrospective analysis
of 115 pregnancies in 95 women with epilepsy identified that a decrease >35% from
preconception antiseizure medication serum levels was associated with worsening
seizures.44 This observation was later confirmed in a single-center, prospective
study of 44 pregnancies in women on monotherapy of antiseizure medications
including levetiracetam, oxcarbazepine, topiramate, valproate, and phenytoin.80
The changes in serum level of antiseizure medications are attributed to the
physiologic changes in pregnancy, and individual differences reflect variances in
pharmacokinetics, genetic polymorphisms, and possibly sex of the fetus. Drugs such
as levetiracetam and topiramate are excreted via renal clearance and are impacted
by the ≥50% increased renal clearance seen in pregnancy whereas glucuronidation,
a key clearance mechanism for lamotrigine and to a lesser extent valproate and
oxcarbazepine, is enhanced by estrogen. Genetic polymorphisms of enzymes in the
glucuronidation pathway, as well as female sex of the fetus, may further
contribute to enhanced lamotrigine clearance.83 If drug serum levels decrease,
especially ≥35% from preconception levels, dose adjustments should be considered.
Summary of Antiseizure Medication Changes in Serum Levels Observed in TABLE 6-3

Pregnancy (If No Dose Changes Are Made)a
Recommendations to perform
Decrease in serum free therapeutic drug monitoring,
Antiseizure medication Decrease in serum concentration (unbound) concentration if available
Phenobarbital Up to 55% Up to 50% Yes
Phenytoin 60-70% 20-40% Yes, free concentration
Carbamazepine 0-12% None Optional
Valproate Up to 23% None Optional free concentration if

done
Oxcarbazepine 36-62% Not applicable (NA) Yes

monohydroxy-
derivative
Lamotrigine 77% of the population: 69% NA Yes

decrease; 23% of the population:
17% decrease
Gabapentin Insufficient data NA Yes
Topiramate Up to 30% NA Yes
Levetiracetam 40-60%, with maximal decrease NA Yes

reached in first trimester
Zonisamide Up to 35% but little data available NA Yes
a
Reprinted from Tomson T, et al, Epileptic Disord.2 © 2019 John Wiley & Sons, Inc.

In contrast, the need to increase the valproate dose during pregnancy may
pose concerns. Reassuringly, despite decreases in total valproate levels in
pregnancy, a 2018 observational study identified an unpredictable increase of
free serum levels, emphasizing the need for both total and free levels to inform
any decision entailing a valproate dose increase in pregnancy.84
If therapeutic drug monitoring is not available, a dose increase of 30% to 50%
should be considered after the first trimester if a woman with epilepsy (1) is
taking an antiseizure medication with a known pregnancy-associated drop in
serum levels, (2) is already taking the lowest, effective antiseizure medication
dose at the start of pregnancy, (3) has prior severe or injurious seizures, or (4)
has prior breakthrough seizures with missed doses.2 CASE 6-1 discusses a scenario
that incorporates therapeutic drug monitoring.
Maternal Mortality and Morbidity

Increased mortality has been observed among women with epilepsy during labor
and delivery compared with women without epilepsy. A US retrospective
cohort study of inpatient hospital records from 2007 to 2011 (n = 69,385 women
with epilepsy, n = 20,449,532 women without epilepsy) observed women with
epilepsy had 11.46 times (95% CI, 8.64 to 15.19) increased risk of death during
delivery compared with women without epilepsy, even after controlling for
obstetric causes such as hemorrhage and preeclampsia.85 The absolute number
of deaths, however, is low (80 deaths per 100,000 pregnancies for women
with epilepsy and 6 deaths per 100,000 pregnancies for women without
epilepsy).85 Beyond labor and delivery, a subsequent Danish matched case-
control study identified a 5.57-fold increase in mortality rate during pregnancy
and up to 42 days postpartum for women with epilepsy (95% CI, 2.23 to 13.9;
P<.001) compared to women without epilepsy.86 Causes of maternal death
included natural death (66.7%), accidental (16.9%), suicide (8.2%), unknown
(6.8%), and violent death (1.4%), with sudden unexpected death in epilepsy
(SUDEP) a potentially important contributing factor.87 In addition to increased
mortality, increased obstetric-related complications have also been observed
in different retrospective registries, including cesarean delivery rates, induction
of labor, placental abruption, premature rupture of membranes, and
preterm birth.41
POSTPARTUM CARE
The postpartum period marks an important transition for women, including a
return to prepregnancy physiology and metabolism, as well as safety
considerations for both the mother and newborn.
Postpartum Drug Dose Adjustments

Postpartum, many antiseizure medication serum levels may increase, and
anticipatory dose readjustments should be considered. Drugs metabolized
through glucuronidation, such as lamotrigine, may increase precipitously, and
tapering should begin as early as postpartum day 3 with a scheduled return to
near prepregnancy doses by 10 to 21 days postpartum.88,89 Drugs metabolized
through renal clearance pathways such as levetiracetam may normalize within
2 to 3 weeks postpartum. Drugs metabolized through the cytochrome P450
pathways such as carbamazepine may be slower to return to prepregnancy states,
taking 4 to 8 weeks to normalize.88 It is reasonable to maintain a slightly increased
420 APRIL 2022

dose (ie, 125% of the prepregnancy dose) to account for anticipated postpartum KEY POINTS
sleep deprivation.2 Monitoring for drug side effects including mood changes and
● Decisions to withdraw or
sedation should be done on an ongoing basis as a part of postpartum clinical care. avoid valproate should be
specific to the individual
Breastfeeding woman, her seizure type,
Benefits of breastfeeding for infants include better neurodevelopmental and physical as well as
psychosocial impact of
outcomes and decreased rates of obesity, allergies, infections, blood cancers, and
potential seizure
sudden infant death syndrome. Maternal health benefits include decreased recurrence.
postpartum bleeding, involution of the uterus, weight loss, delayed ovulation,
and reduced risk of breast and ovarian cancer.90 For women with epilepsy, these ● Preconception folic acid
benefits are moderated by the concern of antiseizure medication transmission via 0.4 mg to 5 mg daily is
recommended for women
breast milk. Breast milk transmission has been observed with primidone, with epilepsy of
levetiracetam, gabapentin, lamotrigine, and topiramate, whereas valproate, reproductive potential,
phenobarbital, carbamazepine, and phenytoin do not significantly accumulate in although some recent
breast milk.91 Women with epilepsy, particularly those taking benzodiazepines concerns have been raised
about supratherapeutic
or barbiturates, should be counseled to monitor their babies for sedation. A (>5 mg daily) folic acid
European study of breastfed children of women with epilepsy taking antiseizure supplementation.
medications did not demonstrate any adverse effects on motor or social skills,
language development, or behavior.92 The NEAD study also did not identify any ● Antiseizure medication
clearance and metabolism
adverse effects on IQ, verbal/nonverbal memory, or executive function in
are differentially impacted
breastfed children of women with epilepsy taking antiseizure medications, at specific stages in
finding potential positive cognitive outcomes at age 6 of adjusted IQ scores of pregnancy. When these
4 points higher in breastfed children.93 More recently, the MONEAD study serum drug levels decrease
by more than 35% of
prospectively measured infant-to-mother serum drug concentrations in
preconception levels,
breastfed infants of women with epilepsy taking antiseizure medications. Of seizures may recur.
164 matching infant-mother concentration pairs, 49% of all antiseizure
medication concentrations found in the serum of nursing infants were below the ● Regular therapeutic drug
lower limit of quantification. Among the measurable concentrations, the median monitoring should be
considered in pregnancy,
infant-to-mother concentration for antiseizure medications was as low as 0.3% when available, especially
(range, 0.2% to 0.9%) seen with oxcarbazepine and as high as 44.2% (range, with drugs recognized to
35.2% to 125.3%) seen with zonisamide. Overall, breastfed infants’ serum drug have pregnancy-related
concentrations were low compared with maternal serum drug concentrations for altered pharmacokinetics
such as lamotrigine,
carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, topiramate, valproic levetiracetam,
acid, and zonisamide.94 Combined, the evidence to date provides women with oxcarbazepine, topiramate,
epilepsy reassurance on the relative safety of breastfeeding while taking and zonisamide.
antiseizure medications.
● Maternal mortality is
elevated 5 to 11 times for
Postpartum Safety women with epilepsy
Postpartum safety counseling involves monitoring sleep and stress levels by compared with the general
ensuring sufficient supports are in place. When possible, supporting women with population, although in
epilepsy to achieve at least 6 to 8 hours of consolidated, restful sleep can provide absolute numbers, these
occurrences remain rare.
families with a tangible goal. Maternal safety counseling includes encouraging
showers, and not baths, to avoid drowning injuries, keeping the bathroom door ● If dose increases have
unlocked in case help is needed, and turning down the hot water temperature to been made during
avoid scalding injuries. Women alone with young children may prefer a pregnancy, tapering
antiseizure medication
smartwatch-enabled SOS or panic-button option that can enable women to call doses should be planned
for help quickly. Families with older children may practice “seizure drills,” within the first few weeks
including how to call for emergency assistance. Safety-oriented behavior postpartum, especially with
includes changing the baby on a surface low to the ground, feeding the baby lamotrigine.
while seated on a padded surface low to the ground, avoiding bathing the baby

alone, avoiding cosleeping in the event of nocturnal seizures, establishing

multiple areas in the home for changing the baby, and utilizing a small stroller to
maneuver the baby throughout the house.95,96 Women should be monitored for
mood changes because postpartum depression rates are higher in women with
epilepsy who are multiparous or receiving antiseizure medication polytherapy.97
AGING
Aging is one of the least studied aspects of women’s health and epilepsy but
should include a focus on bone health and menopause.
Bone Health
Antiseizure medication use is associated with accelerated bone loss for both men
and women. However, osteoporosis is four times more common in women
because of lower overall achieved bone density, younger age of onset, and faster
rates of bone loss.98 Significant bone loss has been observed in young women
after only 1 year of phenytoin monotherapy.99 The mechanism of bone loss with
phenytoin may, in part, be attributed to cytochrome P450 enzyme induction and
subsequent acceleration of vitamin D metabolism, also seen with phenobarbital,
primidone, oxcarbazepine, and, to a lesser extent, carbamazepine.100 However,
non–enzyme-inducing drugs such as gabapentin and topiramate, as well as
valproate, an enzyme inhibitor, have also been associated with increased fracture
rate or bone loss.101 Although the mechanisms are poorly understood, reduction
of osteoblast proliferation from valproate-induced carnitine deficiency, altered
collagen synthesis, increased bone turnover, decreased calcium absorption, and
altered parathyroid hormone receptivity have been proposed.102,103
Vitamin D, calcium, and phosphate levels should be acquired, as well as a
baseline bone mineral density, especially with chronic antiseizure medication use.
Women with epilepsy should be counseled on preventive measures including
exercise, nutrition, and calcium and vitamin D supplementation to match at least
the current recommended vitamin D intake of 600 IU daily, although women
with epilepsy likely need higher doses.102 In one randomized control trial of
72 adults with epilepsy comparing low-dose (400 IU/d) versus high-dose
(4000 IU/d) vitamin D supplementation, only high-dose vitamin D was
associated with significant increases in bone mineral density at all skeletal sites.104
Menopause
Menopause is defined by the permanent cessation of menses due to loss of ovarian
follicular function and is confirmed after 12 months of consistent amenorrhea.105
Women with epilepsy may experience early menopause. Women with epilepsy
from a single center, aged 45 years or older (n = 68), were interviewed to
determine the age of last menses before menopause. The mean age of menopause
in this group was 47.8 years (standard deviation [SD], ±4.1 years; range, 37 to
59 years) among women with epilepsy compared with 51.4 years of age in the
general population.106 Women with epilepsy with a higher seizure burden had
a statistically significant ( P=.042) younger age of menopause onset.
Perimenopause is the transitional time before established menopause, lasting a
median of 4 years, and marks a time of greater hormonal fluctuations. For most
women with epilepsy, perimenopause does not significantly alter seizure
frequency. For women with catamenial epilepsy, these fluctuations may be
associated with seizure exacerbation, and with menopause, women may
422 APRIL 2022

experience seizure improvement.107 To date, no clear signal has been identified KEY POINTS
with respect to perimenopausal hormonal fluctuations and antiseizure
● Breastfeeding is generally
medication serum levels, particularly with lamotrigine. safe and beneficial for
Finally, hormone replacement therapy used for perimenopausal symptoms women with epilepsy who
may worsen seizures. In one small (n = 21) randomized, double-blind controlled are taking antiseizure
study exploring hormone replacement therapy in women with epilepsy, 71% medications and for their
babies.
(5 of 7 women) taking double-dose conjugated equine estrogens plus 2.5 mg
medroxyprogesterone acetate, 50% (4 of 8 women) taking single-dose ● Antiseizure medications
conjugated equine estrogens/medroxyprogesterone acetate, and 17% (1 of are associated with
6 women) on placebo had seizures that worsened ( P=.05).108 osteoporosis. Vitamin D and
Medroxyprogesterone acetate, a synthetic progestin, is not metabolized to calcium supplementation
and a baseline bone mineral
allopregnanolone and thus lacks any neuroinhibitory effect. A 2011 review density are recommended
suggested that women with epilepsy who have intolerable perimenopausal especially with chronic
symptoms consider non–estrogen-based therapies such as clonidine, selective antiseizure medication use.
serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake
● Hormonal replacement
inhibitors (SNRIs), and vaginal lubricants for symptomatic treatment. If therapy may exacerbate
hormonal therapy is required, a simplified estrogen such as 17beta-estradiol with seizures in a dose-
natural progesterone could be trialed.109 dependent way. If
necessary, simplified
estrogen with natural
progesterone could be
CONCLUSION considered.
The management of women with epilepsy spans the near entirety of a woman’s
life from adolescence to older age, with most current-day research focused on
reproductive health. In the past few years, significant advancements have been
made in the understanding of fertility for women with epilepsy, seizure control
during pregnancy, and multifactor influences on antiseizure medication–
associated teratogenicity. Although more work needs to be done in reproductive
health research, especially in understanding longer-term effects of in utero
exposure to antiseizure medications, teratogenicity risks of newer antiseizure
medications, optimal folic acid dosing, and risks of fertility treatments, the need
to better understand the issues for women with epilepsy beyond reproductive
health is equal if not more pressing.
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10.1007/s00404-011-1936-4

REVIEW ARTICLE

Seizures and Epilepsy in
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Childhood
By Maria Gogou, MD, PhD; Judith Helen Cross, MBChB, PhD
ABSTRACT
PURPOSE OF REVIEW: This article highlights basic concepts of seizures and
epilepsy in pediatric patients, as well as basic treatment principles for this
age group.
CITE AS:
2022;28(2, EPILEPSY):428–456.
RECENT FINDINGS: Epilepsy is the most common neurologic disorder in
childhood. Accurate diagnosis is key; in older children, epileptic seizures
Prof J. Helen Cross,
need to be differentiated from various paroxysmal nonepileptic events,
Developmental Neurosciences, whereas in neonates, the majority of seizures are subclinical
UCL Great Ormond Street (electroencephalographic). Antiseizure medications remain the first-line
Institute of Child Health, 30
Guilford St, London, WC1N 1EH,
treatment, but ketogenic diet and epilepsy surgery have also shown
United Kingdom, positive outcomes and can decrease drug burden. Genetic causes account
h.cross@ucl.ac.uk. for approximately 30% of cases, and the recognition of electroclinical
RELATIONSHIP DISCLOSURE: syndromes is being replaced by the concept of genetic spectrums.
Dr Gogou reports no disclosure. Precision medicine therapies are promising, but wide application in daily
Dr Cross holds an endowed
practice still has a long way to go. Early access to specialist centers and
chair at the University College
London Great Ormond Street optimal treatments positively affects prognosis and future
Institute of Child Health. The neurodevelopment.
institution of Dr Cross has
received support from
Biocodex, the Engineering and SUMMARY: Although novel findings from all fields of research are being
Physical Sciences Research incorporated into everyday clinical practice, a better quality of life for
Council, Epilepsy Research UK,
Great Ormond Street Hospital children with seizures and epilepsy and their families is the ultimate
Charity, GW Pharmaceuticals priority.
plc, Marinius Pharmaceuticals,
Inc, the National Institute of
Health Research Great Ormond
Street Hospital Biomedical
Research Centre, Nutricia,
Vitaflo (International) Limited, INTRODUCTION
T
the Waterloo Foundation, and
Zogenix.
he tremendous progress in diagnostic testing has transformed our
understanding of epilepsy. According to the current concept, epilepsy
UNLABELED USE OF is not a single condition but represents a common symptom of many
USE DISCLOSURE: different entities. Therefore, this article might refer to epilepsies
Drs Gogou and Cross discuss because they have various different underlying causes and
the unlabeled/investigational use
consequently differing underlying pathophysiologies.1
of memantine for the treatment
of GRIN2A-related epilepsies, It is estimated that epilepsy affects 0.5% to 1% of children, representing the
quinidine for the treatment of most frequently occurring chronic neurologic condition in childhood, with the
KCNT1-related epilepsies, and
radiprodil for the treatment of
highest prevalence during infancy. According to the data from a nationwide child
GRIN2B-related epilepsies. cohort in Norway, the incidence rate of epilepsy was 144 per 100,000 person-
years in infancy and 58 per 100,000 for ages 1 to 10 years with a cumulative
© 2022 American Academy incidence of 0.66% at age 10 years.2 The long-term cognitive and socioeconomic
of Neurology. consequences of childhood-onset epilepsy are of utmost importance and promise
428 APRIL 2022

to drive fast-evolving research in this field to more clinically meaningful KEY POINTS
treatment outcomes.
● Epilepsy affects 0.5% to
The high prevalence in childhood alongside the crucial impact on global 1% of children, and its
functioning makes it essential for clinicians of different specialties (eg, child prevalence is highest during
neurology, general pediatricians, adult neurology) to be familiar with infancy.
management of this entity. This article reviews specific diagnostic and
● Seizures need to be
therapeutic aspects to pediatric epilepsy, highlights special issues in this age group,
differentiated from several
comments on future challenges for clinicians, and discusses relevant cases, thus paroxysmal nonepileptic
providing a framework for understanding basic concepts of childhood epilepsy for events (eg, seizure mimics in
clinicians working in the whole spectrum of pediatric and adult neurology services. infancy, paroxysmal
nonepileptic seizures in
older children). Parental
DIAGNOSTIC APPROACH mobile videos and video-
Differential diagnosis of a seizure from a number of paroxysmal nonepileptic EEG records are useful
events and appropriate description and characterization of seizure types screening tools.
represent principal steps of the diagnostic approach of a child with seizures,
whereas identification of an underlying etiology has now been included as an
essential part of the epilepsy definition. This applies to diagnosis at any age
including neonates (FIGURE 7-1).
Differential Diagnosis
A significant number of paroxysmal nonepileptic events of childhood can be
misinterpreted as seizures. The majority are associated with normal brain activity
and represent physiologic movements, but electrical changes may be present in
few cases as a result of the event rather than the cause (eg, slowing of EEG
activity during prolonged cardiac arrhythmia, syncope of other cardiac origin, or
prolonged breath-holding attacks). Rates of misdiagnosis of epilepsy are high,
reaching up to 39%.3 Prompt diagnosis is essential to prevent unnecessary
investigations, medication use, and family stress.3,4 The most common of those
events are classified per age in TABLE 7-1, along with clues for their differential
diagnosis. Video-EEG recordings are a very sensitive and specific method to
distinguish between seizures and seizure mimics in challenging cases, especially
in the neonatal period and in critically ill or sedated infants.5 CASE 7-1 illustrates
where recurrent paroxysmal motor events in an infant, who was nonresponsive
to antiseizure medications, were later proven to be nonepileptic in origin.
An interesting clinical finding that should be highlighted is that autism
spectrum disorder seems to be a common comorbidity among children with
nonepileptic seizures, and the underlying cause may be associated with
misinterpretation of somatosensory input or aberrant interoceptive processing.
Similarly, literature shows that staring episodes among children with autism do
not represent absences or focal dyscognitive seizures. The aforementioned
findings, alongside the relatively high occurrence of nonspecific (ie, epileptiform
or nonepileptiform) EEG findings in children with autism, suggest that EEG
might be undertaken rather judiciously when evaluating children with autism
and seizurelike episodes.6
An additional type of nonepileptic event that needs to be discussed is
psychogenic nonepileptic events. This type of event is rarely seen in children
younger than the age of 8 years and occurs equally among boys and girls before
puberty. Psychogenic nonepileptic events reflect an underlying neuropsychiatric
condition that causes a temporary change in the level of consciousness and
self-control. They represent an expression of emotional distress and are often

SEIZURES AND EPILEPSY IN CHILDHOOD
FIGURE 7-1
An integrated epilepsy classification.
EEG = electroencephalogram.
a
Auras: somatosensory, auditory, olfactory, abdominal, visual, gustatory, psychic; special seizures: astatic,
akinetic, aphasic, atonic, hypomotor, negative myoclonic.
Data from Fisher RS, et al, Epilepsia9 and Rosenow F, et al, Seizure.10
triggered by overwhelming situations (especially family stressors), and school

bullying victimization has also been recognized as a risk factor.7 Alterations in
functional cortical neuronal networks and increased activity of the autonomic
nervous system and the hypothalamic-pituitary-adrenal axis are considered the
principal pathophysiologic mechanisms. Dialeptic (an episode characterized by
lack of awareness or responsiveness) symptomatology is the most frequent
symptomatology, but motor symptoms and nonepileptic aura may also appear.
Misdiagnosis of psychogenic nonepileptic events as epilepsy is common, and
430 APRIL 2022

Common Nonepileptic Paroxysmal Events Classified by Age and Some TABLE 7-1
Clues for Their Differential Diagnosis
Event Age of onset Clues for differential diagnosis
Jitteriness 0-7 days Stimulus sensitive, more pronounced during vigorous crying
Hyperekplexia Neonatal to puberty Stimulus sensitive, fear and shrinkage in the face, excessive
startle
Benign sleep myoclonus 0-3 months Only during sleep, settled with arousal, bilateral and repetitive,
face not included; otherwise healthy infant
Breath-holding spells 6 months to 5 years Triggered by frustration/excessive crying (cyanotic) or by pain,

(cyanotic, pallid) fever, minor trauma (pallid), apnea in expiration phase, blue or
pale ± unconscious ± floppy or stiff; hypoxia may induce a
seizure
Shuddering attacks 4-6 months Head-trunk-shoulders involved, 1-2 seconds, up to 100/day,

triggered by eating, drinking, urination, nursing (stimulus
overflow)
Self-gratification behavior Infancy to toddlerhood Stereotypic movements of self-gratification behavior while

appearing withdrawn
Spasmus nutans Infancy to early childhood Paroxysmal episodes of nodding, nystagmus, and torticollis
Benign paroxysmal torticollis Infancy to early childhood Episodes may last for 1-2 hours or for days; the head is kept
turned to one direction; vomiting and paleness may
accompany
Sandifer syndrome Infancy to childhood Related to meals, opisthotonic posture, and crying (often
confused with infantile spasms)
Benign paroxysmal tonic 1 month to 2 years Upward deviation of the eyes with a constant or variable
upward gaze period, spontaneous resolution in 1-2 years; if neurologic
findings present, it may not be resolved
Benign paroxysmal vertigo 1-6 years Lasting a few minutes, prominent nausea, vomiting, paleness;
child is awake, panicked as if frightened, and reluctant to move
and has an unbalanced gait
Sleep disorders Early childhood to Parasomnias (night terrors, confusional arousal, sleepwalking,
adolescence rapid eye movement [REM] sleep disorder)
Stereotypies/tics Any age Complex movements, recurrent, usually face to upper limbs,
triggered by stress, can be stopped voluntarily or with
distraction
Syncope Childhood to adulthood Vasovagal: prodromal symptoms present, usually specific

triggers
Cardiac: no prodromal symptoms, related to physical exercise,
palpitations preceded, abnormal ECG
Psychogenic crises Adolescence to Prolonged, no physical injury, eyes usually closed

adulthood
Complicated migraine Childhood to adulthood Normal consciousness level at the end of the episode
Alternating hemiplegia of 3 months to adulthood Initial eye movement abnormality, hemiplegic attacks from
childhood 12 months

almost 50% of pediatric patients with this disorder have been treated with
antiseizure medications, according to some cohorts.8 The essential step in
management is a comprehensive approach to those children and adolescents
with psychogenic nonepileptic events and an explanation of diagnosis in a
nonjudgmental way. However, the fact that some pediatric patients with
nonepileptic events may also have epilepsy should also be considered in
clinical practice.
Seizure Types
After the epileptic nature of an event has been determined, the next step is
classification of the seizure type. Seizures are classified according to their
characteristics, which serves to standardize communication in the context of
clinical care, teaching, and research and provide an anatomic-functional
perspective. Regarding the mode of seizure onset, generalized epileptic seizures
are conceptualized as originating within, and rapidly engaging, bilaterally
distributed networks (cortical or subcortical), not necessarily including the
entire cortex; focal seizures originate within networks limited to one hemisphere
(cortical or subcortical) and can be discretely localized or more widely
distributed. If the onset of a seizure is unwitnessed, the event is classified as an
CASE 7-1 A 2-year-old boy presented for assessment of recurrent paroxysmal

motor events.
He was born of consanguineous parents. The first episode happened
when he was 2 weeks old; it involved vocalization, cessation of breathing,
cyanosis, generalized limb stiffening, and shaking. These occurred in a
frequency of up to two per day. EEG and MRI at presentation were
reported as normal. The episodes continued despite trials of sodium
valproate and carbamazepine. When he was 6 months old, the events
continued; episodes were described from sleep and wake states. His
developmental progress was normal, and further interictal EEG was
normal.
When he was 15 months old, topiramate was initiated. As he started
walking, his parents became concerned about recurrent falls, described
as sudden stiffening that caused a fall to the ground. His development
remained normal. A video-EEG recorded episodes in response to sudden
sound; movement artifact was recorded with no primary change in the
EEG. His parents also reported he was startled by unexpected touch or
sound. He was diagnosed with hyperekplexia and treated with
clonazepam.
COMMENT This case exemplifies how challenging the differential diagnosis of seizures
from nonepileptic paroxysmal events may be and how much this can affect
appropriate management. Hyperekplexia is a genetic disorder
characterized by pronounced startle responses to tactile or acoustic
stimuli and hypertonia. It is the result of mutations in genes involved in the
neurotransmission of glycine, an inhibitory neurotransmitter.
432 APRIL 2022

unknown onset. Focal seizures can spread bilaterally and affect both hemispheres KEY POINTS
(evolution to bilateral tonic-clonic) (FIGURE 7-1).9 Although the distinction
● Seizures can be classified
between simple and complex focal seizures is eliminated, it is important to according to their onset or
recognize the impairment of consciousness/awareness. Furthermore, localization, their ictal symptomatology.
as well as progression of ictal events, can be of paramount importance in the
evaluation of patients for specific purposes (eg, presurgical workup).10 ● Etiology has been
included as an essential part
Seizures can be further classified clinically into motor (tonic-clonic, tonic,
of the operational definition
clonic, atonic, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, epileptic of epilepsy. An underlying
spasms), nonmotor (autonomic, cognitive, sensory, absences [typical, atypical, cause can be identified in
with special features]), and asymptomatic EEG seizures (FIGURE 7-1).9 Infantile two-thirds of children with
spasms are a very specific type of seizure, with the most common age of epilepsy (genetic in one-
third, structural in one-
presentation at 3 to 8 months, and typically happen in clusters and at times of third).
alteration of sleep state. A spasm includes a sudden, rapid, tonic contraction of
the trunk and limb musculature that gradually relaxes over 1 to 2 seconds. Spasms
can be flexor, extensor, or both; symmetrical; asymmetrical; or even unilateral
(TABLE 7-211). In some cases, autonomic disturbance, impaired consciousness, or
even abnormal eye movements can be the dominant initial clinical presentation,
and it is often quite challenging to differentiate from a series of benign
nonepileptic paroxysmal events happening in the same age group (TABLE 7-1).
Spasms persisting beyond infancy or appearing at older ages are described as
epileptic spasms.9
Additional classification systems and subcategories may be implemented and
used by groups with specific interests (eg, epidemiologists, medical educators,
insurance payers, regulatory agencies, advocacy groups) to provide an essential
communication framework.9
Etiology
An operational consensus about the definition of epilepsy in all age groups has
been available since 2014. However, with the 2017 epilepsy framework, etiology
is increasingly recognized as integral to classification (FIGURE 7-1).12 An
underlying cause of epilepsy is identified in approximately two-thirds of
pediatric patients. This makes the need for accurate diagnosis and certainty
crucial in management because etiology can be a major determinant of treatment
and final prognosis. The leading etiologies are genetic in about one-third
(confirmed or presumed) and structural in about one-third of cases.13 “Epilepsy
genes” usually encode for ion channels/G protein, synaptic molecules,
(co-)enzymes of metabolic pathways, cell growth, and proliferation factors. The
genes most frequently implicated in patients younger than 3 years old (greater
than 50% of diagnoses) are PRRT2, SCN1A, KCNQ2, SLC2A1, CDKL5, PCDH19,
and SLC6A1. Structural causes usually include malformations of cortical and
brain development, hypothalamic hamartomas, tuberous sclerosis, vascular
malformations, trauma, perinatal insult, stroke, and glioneuronal tumors. Inborn
errors of metabolism and infections (eg, meningitis, encephalitis, congenital
infection) represent much rarer causes. However, recognition of metabolic
causes in patients younger than 3 years old has been significantly increasing over
the past years.13,14 Autoimmune epilepsy is also being increasingly recognized as
a contributor to the etiology of epilepsy in childhood either within or even
beyond the spectrum of known autoimmune disorders. Several neuronal
autoantibodies (eg, γ-aminobutyric acid B [GABAB] receptor, contactin-
associated protein 2, glycine receptor, leucine-rich glioma inactivated,

TABLE 7-2 Description of the Main Age-Related Epilepsy Syndromes of Childhooda
Electroclinical Age Seizure EEG Other clinical

syndrome onset Etiology types findings features Prognosis Treatment
Neonatal Neonatal Hypoxic- Clinical only: Sharp waves, Varying (from Varying according Phenobarbital,
seizures ischemic motor (tonic, spikes, sharp none or subtle to etiology levetiracetam,
encephalopathy, clonic, and slow to severe phenytoin
infectious, myoclonic, waves, spike encephalopathy)
Start treatment
vascular, spasms, and slow
if:
metabolic, automatisms), waves (full-
genetic, brain nonmotor term), Electro(clinical):
malformations (behavioral rhythmic events lasting
arrest, delta activity ≥1 min or ≥3/h
autonomic), (preterm) at
sequential, the onset of Electrographic:
unclassified; the event seizure burden
>1 min/h
Electroclinical
Electrographic
only
Self-limited Days 1-7 If familial: Subtle; tonic Interictal: Not applicable Excellent, mild Phenobarbital,
neonatal autosomal or clonic normal or developmental benzodiazepines
epilepsy dominant, asynchronous delay in 50%
KCNQ2, KCNQ3 theta
Ictal: focal
sharp, spikes
and slow
waves
Early myoclonic Neonatal Structural, inborn Myoclonic Suppression- Severe Very poor Benzodiazepines,
encephalopathy errors of (segmental or burst pattern developmental neurologic outcome valproate,
metabolism, generalized), delay vigabatrin,
genetic (ERBB4) may evolve to steroids,
infantile spasms topiramate,
zonisamide,
ketogenic diet
Early infantile Neonatal Structural, Mainly tonic, Suppression- Severe Very poor Benzodiazepines,
developmental genetic (eg, ARX, also atonic, burst pattern developmental neurologic outcome valproate,
and epileptic CDKL5, myoclonic, delay vigabatrin,
encephalopathy SLC25A22, hemiconvulsions, steroids,
(previously STXBP1) generalized topiramate,
known as early tonic-clonic zonisamide,
myoclonic seizures ketogenic diet
encephalopathy
and Ohtahara
syndrome)
434 APRIL 2022


Dravet First year Usually SCN1A First seizure: with Generalized Varying No complete Valproate,
syndrome of life mutations fever and may spike-and- developmental seizure control, benzodiazepines,
be a tonic-clonic wave delay, higher rate of stiripentol,
seizure or a complexes, developmental sudden unexpected fenfluramine,
seizure involving focal and arrest after death in epilepsy cannabidiol,
clonic (jerking) multifocal first year and (SUDEP) ketogenic diet,
movements on spikes regression, vagus nerve
one side of the autism stimulation
Atypical
body; later:
absences: The following
atypical
generalized may worsen
absences, tonic-
2- to 3.5-Hz symptoms:
clonic,
spike waves lamotrigine and
myoclonic,
carbamazepine
focal, atonic,
nonconvulsive
status epilepticus
Infantile spasms First year Structural, inborn Brief (1-2 seconds) Hypsarhythmia Varying Treating seizures First-line:
syndrome (West of life errors of tonic or clonic developmental early: maximizing steroids plus
syndrome: (peak at 4- metabolism, seizures, delay child’s vigabatrin11;
infantile spasms 9 months) genetic (eg, typically in developmental steroids for
plus trisomy 21, TSC2, clusters, many potential; even if 2 weeks and
hypsarhythmia ARX, STXBP1, times daily the infantile spasms weaning over
plus CDKL5) (usually on stop, most children 4 weeks;
developmental arousal) develop other kinds vigabatrin: for at
delay) of epilepsy (eg, least 3 months
Lennox-Gastaut in responders
syndrome)
In patients with
infantile spasms
associated with
TSC2: vigabatrin
might be used
alone as very
effective
Second-line
treatments:
valproate,
topiramate,
zonisamide,
vitamin B6,
ketogenic diet
Epilepsy with Infancy to Presumed Multiple types: Initially normal Developmental Two-thirds outgrow Valproate,
myoclonic- early genetic (SCN1A, myoclonic, (or background delay may be epilepsy, one-third lamotrigine,
atonic seizures childhood SCN1B, SCN2A, astatic, theta), then present have persisting topiramate,
SLC2A1, CHD2, myoclonic- generalized seizures, zonisamide,
SYNGAP1, astatic, polyspike- development levetiracetam,
NEXMIF) absences, and-wave depends on seizure rufinamide,
generalized epileptiform control clobazam,
tonic-clonic activity ketogenic diet,
seizures, drop vagus nerve
attacks, often stimulation
status epilepticus
The following may
and
worsen seizures:
nonconvulsive
carbamazepine,
status epilepticus
oxcarbazepine,
phenytoin,
vigabatrin


Self-limited 3-13 years No specific Nocturnal Interictal None or mild Excellent, seizures May not be
epilepsy with (peak at (presumed unilateral tongue, unilateral or learning and remit by puberty needed; if so,
centrotemporal 7-9 years) genetic) lips, cheeks, bilateral behavioral levetiracetam,
spikes pharynx, larynx; centrotemporal difficulties oxcarbazepine,
preserved spikes, carbamazepine
consciousness; prominent in
may be sleep
generalized;
sensory aura
may be present
Self-limited 1-13 years Not specific Long (30+ Multifocal spike No other Self-limiting, Usually not
epilepsy with (peak at (presumed minutes), mainly and wave, clinical features seizures stop needed, but if
autonomic 3-6 years) genetic) autonomic occipital 2-3 years after first so:
seizures seizures predominance episode, no risk of oxcarbazepine,
(headache, epilepsy later in life carbamazepine,
paleness, levetiracetam
vomiting,
flushing,
incontinence,
hypersalivation),
often from
sleep, focal
seizures also
present
Lennox-Gastaut <8 years Structural, Tonic seizures Not Developmental Poor seizure Valproate,
syndrome (peak at acquired brain mainly in sleep: pathognomonic delay (usually control, poor lamotrigine,
3-6 years) injury, congenital very characteristic (most patients present before neurologic clobazam,
infections, (not present at already on seizure onset), outcome rufinamide,
genetic (SCN1A, onset), atypical antiseizure intellectual topiramate,
SCN2A, DNM1, absences, medication) disability, autism steroids,
CHD2, FOXG1), tonic, atonic, cannabidiol,
Wake:
inborn errors of myoclonic, ketogenic diet,
diffuse
metabolism; may generalized vagus nerve
or widespread
evolve from West tonic-clonic stimulation,
background
syndrome or seizures corpus
slowing
early infantile callosotomy
(1-2.5 Hz) and
developmental
slow spike-
and epileptic
wave bursts
encephalopathy
Sleep:
generalized
paroxysmal
fast activity
>10 Hz
436 APRIL 2022


Childhood School Presumed Multiple 3- to 4-Hz Normal previous 60-70%: Valproate,
absence age (6- genetic episodes per generalized neurologic improvement with lamotrigine,
epilepsy 7 years) day, lasting (poly)spike history, learning first antiseizure ethosuximide,
5-15 seconds, and wave difficulties medication levetiracetam
also motor appear
40-50%:
manifestations
generalized tonic-
(myoclonic, tonic,
clonic seizures
atonic) and
automatisms; 15%: juvenile
hyperventilation myoclonic seizures
induces seizures
30%: mild
intellectual
disability
Juvenile 7-16 years Presumed Absences, 2.5- to 4.5-Hz Normal previous Usually lifelong Valproate,
absence (peak at genetic generalized generalized neurologic disorder, but lamotrigine,
epilepsy 10-12 years) tonic-clonic (poly)spike history, learning absences less ethosuximide,
seizures and wave difficulties appear severe with time levetiracetam
(awakening),
myoclonic jerks
Juvenile 12-16 years Presumed Bilateral 3- to 6-Hz Normal Lifelong condition, Valproate,
myoclonic genetic myoclonic generalized previous milder in the third lamotrigine,
epilepsy (Janz seizures (single or (poly)spike neurologic and fourth levetiracetam,
syndrome) multiple) usually and wave, history, mild decades, but topiramate,
on awakening; photosensitivity learning antiseizure zonisamide,
also generalized difficulties medication benzodiazepines,
tonic-clonic appear withdrawal leads to ketogenic diet,
seizures (90%) recurrence
The following
and absences
may worsen
(10-30%)
myoclonic
seizures:
carbamazepine,
oxcarbazepine,
vigabatrin,
phenytoin
Developmental 2-12 years Presumed Before Electrical Cognitive and Spontaneous Steroids,
and epileptic (peak at genetic (GRIN2A regression: status behavioral improvement of benzodiazepines,
encephalopathy 5-7 years) gene); multiple focal motor epilepticus in problems, seizures and EEG valproate,
with spike seizure types seizures; after sleep (non– regression in before puberty, ethosuximide,
activation in sleep may evolve to regression: rapid eye skills, aphasia severe residual levetiracetam
continuous spike also atypical movement (slow or sudden neuropsychological
and wave during absences, [REM] sleep); loss of receptive deficit
slow-wave sleep generalized more focal or/and expressive
tonic-clonic during speech typically
seizures wakefulness seen in a child
and REM previously
sleep; bilateral developing
centrotemporal, appropriately),
posterior attention deficit
temporal, hyperactivity
parietal- disorder, anxiety
occipital spikes,
especially non-
REM sleep
a
Epilepsy surgery may also be considered as a treatment option if some criteria are fulfilled.

N-methyl-D-aspartate [NMDA] receptor, GABAA receptor) have been identified

in the serum of children with epilepsies of unknown etiology, but the precise
frequencies are still not well defined. In almost one-third of cases, no specific
underlying etiology can be found.15
The impact of noncommunicable diseases is growing in low-income countries
where the burden of epilepsy has been significantly increased. The etiology of
seizures and epilepsy in childhood in these areas follows a different pattern
where acquired causes (eg, perinatal and neonatal adverse events, infections)
represent the principal causes.16
Neonatal Seizures
In contrast to seizures at older ages, neonatal seizures are relatively common (2 to
3 per 1000 births, depending on gestational age), they are mainly symptomatic,
and in 50% to 70% of cases, they can be subclinical (electroencephalographic
only). Hypoxic-ischemic encephalopathy represents the most frequent
underlying etiology (35% to 45%); additional causes include ischemic and
hemorrhagic vascular episodes (20% to 30%), brain malformations (5% to 10%),
infections (5% to 20%), metabolic disorders (7% to 20%), and genetic causes (6%
to 10%). Seizures are considered focal at onset, and a division into focal and
generalized is unnecessary. Therefore, typical classification systems used in older
children cannot be applied in this age group.17 According to the International
League Against Epilepsy (ILAE) Task Force on Neonatal Seizures,17 EEG plays a
principal role in diagnosis and needs to be undertaken both in neonates with
clinical events and in neonates at high risk for seizures; clinical events without an
electroencephalographic correlate are not included in the classification.
Furthermore, seizure type is determined by the predominant clinical feature: (1)
motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), (2) nonmotor
(autonomic, behavioral arrest), (3) sequential, and (4) unclassified. Apart from
that, seizure type in neonatal age is closely related to the underlying etiology (eg,
electroencephalographic-only is the predominant seizure type in neonates with
hypoxic-ischemic encephalopathy, infectious etiology, and prematurity, and
clonic events occur frequently in neonates with underlying vascular etiology,
whereas tonic seizures may characterize neonatal seizures of genetic etiology)17
(TABLE 7-2).
REQUIREMENTS FOR THE DIAGNOSIS OF EPILEPSY

A diagnosis of epilepsy is clinical; medical history and description of the events
remain the principal screening tools. The basic tools for an appropriate clinical
approach include a thorough medical history (ie, age of onset, duration, triggers,
state of consciousness, changes during the event, motor-mental developmental
progress, past medical history, family history, exposures, psychosocial aspects),
careful physical and neurologic examination, and witness reports, as well as
observation of captured events on parental videos if available.6 Video-enabled
smartphones are now commonplace in most homes, and videos captured by
parents have been found to have significant predictive and additive value for
differentiating seizures from nonepileptic events.18 The EEG may contribute,
specifically to the syndrome diagnosis. Among otherwise healthy children, 5% to
8% may exhibit nonspecific epileptiform discharges; the EEG result must
therefore be reviewed alongside the clinical information. In children with a clear
phenotype of a specific epilepsy syndrome (eg, childhood absence epilepsy,
438 APRIL 2022

juvenile absence epilepsy, juvenile myoclonic epilepsy, self-limited childhood KEY POINTS
epilepsy with centrotemporal spikes), no other investigations are needed.
● Neonatal seizures affect 2
However, MRI of the brain is recommended in patients with known nonlesional to 3 per 1000 births, and they
syndromes when atypical features are associated (eg, abnormal neurologic/ are mainly subclinical
intellectual development, resistance to treatment, atypical course of epilepsy).19 (electroencephalographic-
Genetic testing (eg, single-gene sequencing, targeted gene panels, whole- only); hypoxic-ischemic
encephalopathy is the most
exome sequencing, microarray) is generally recommended in early-onset
frequent cause.
epilepsies, epilepsy with intellectual disability and neurodevelopmental
disorders, progressive myoclonic epilepsies, nonlesional focal epilepsies in ● A diagnosis of epilepsy is
specific familial syndromes, and nonlesional focal therapy-resistant epilepsies clinical with a medical
in presurgical workup, as well as in epilepsy in the setting of focal history and description of
the event being the principal
malformations of cortical development. Next-generation sequencing diagnostic tools.
techniques have become the new first-tier diagnostic tests in the epilepsies,
reducing diagnostic latency times and the total cost. The exact type of genetic
testing depends on the clinical situation (eg, family history of an epileptic
syndrome, coexisting intellectual disability). The combined diagnostic yield
of targeted gene panels and whole-exome sequencing is 20% to 40%,
significantly decreasing with age of onset. A source of conflicting
interpretations is the significant number of missense variants classified as
likely pathogenic, likely benign, or of uncertain significance. In patients with
unidentified etiology, intronic variants, mosaicism, alternative transcripts,
and the effect of epigenetics need to be considered, and it is essential that
unsolved cases be reevaluated and rediscussed in light of continuous progress
in the field of molecular genetics.20
Although inborn errors of metabolism do not represent a common cause of
seizures, their early identification is of utmost importance because therapeutic
measures beyond that of common antiseizure medications may be justified. Red
flags for an underlying metabolic disease include developmental regression,
fluctuating course, deterioration with fasting, organomegaly, dysmorphic
features, progressive myoclonic epilepsy phenotype, family history, and
parental consanguinity.21
FEBRILE SEIZURES AND SEIZURES WITH FEVER

Seizures associated with fever are a common pediatric problem. Febrile seizures
(simple or complex) represent the most frequent seizure disorder and are
defined as occurring in children between the ages of 6 and 60 months who do not
have an intracranial infection, metabolic disturbance, or history of afebrile
seizures. Their prevalence is estimated to range between 3% and 8%, while a
family history of febrile seizures (25%) or epilepsy (4%) can be present.22
Mutations in sodium channel and GABAA receptor genes have been identified in
several cases, but a polygenic pattern seems to be a more usual inheritance mode.
In the vast majority of cases, febrile seizures are benign with normal cognitive
outcomes. Although recurrence may happen in one-third of cases, the risk of
developing epilepsy is low; risk factors for the development of epilepsy include
complex febrile seizures, family history of epilepsy, and preexisting neurologic
abnormalities. A highly discussed topic is whether febrile seizures can predispose
to development of mesial temporal sclerosis and temporal lobe epilepsy.
Although animal studies suggest a relationship of complex febrile seizures to the
subsequent development of mesial temporal sclerosis, large population studies
have failed to show any significant association.23

No special investigations are usually required, but lumbar puncture is

recommended if signs/symptoms suggestive of meningitis are present and in
complex febrile seizures, toddlers younger than 18 months, and children
previously treated with oral antibiotics. Febrile status epilepticus (prolonged
febrile seizures lasting longer than 30 minutes) is very rare (4 per 100,000
person-years) and is treated as status epilepticus of different etiologies.
Prognosis of febrile seizures is generally favorable and self-limiting, but
almost one-third of children experience a recurrence. Approximately 75% of
recurrences are within 12 months and 90% within 2 years. Risk factors for
recurrence include age of onset younger than 18 months, relatively lower
temperature at the time of the first febrile seizure, shorter interval (less than
1 hour) between the onset of fever and the initial seizure, epilepsy in a first-
degree relative, and frequent febrile illnesses. Cohort studies have also shown
that children with a history of febrile seizures have an increased but still low rate
of epilepsy with a history of complex febrile seizure(s), age older than 3 years at
the time of the first febrile seizure, family history of epilepsy, fever duration less
than 1 hour before seizure onset, and underlying neurodevelopmental disorder.
The total risk of developing epilepsy is 2% after a previous simple febrile seizure,
FIGURE 7-2
The relationship between seizures and fever. Each open arrow leads to additional information
about the entities on the left side of the figure.
FIRES = febrile infection related epilepsy syndrome; GEFS+ = genetic epilepsy with febrile seizures plus;
GTCS = generalized tonic-clonic seizures; HHE = hemiconvulsion-hemiplegia-epilepsy syndrome;
SE = status epilepticus.
Modified with permission from Sadleir LG and Scheffer IE, BMJ.22 © 2007 BMJ Publishing Group Ltd.
440 APRIL 2022

but it increases in children with risk factors with a positive correlation between KEY POINT
the total risk and the number of risk factors. No current literature evidence
● Although several well-
supports the use of prophylactic antiseizure treatment for recurrent febrile known epilepsy syndromes
seizures.24 The term afebrile febrile seizures has also been introduced to describe have been associated with
children who present with seizures, lacking objective evidence of fever at the seizures in the setting of
seizure onset, but with definitive symptoms and signs of minor infection (eg, fever, the majority of febrile
seizures (simple or complex)
gastroenteritis, mild respiratory illness).
have a favorable and self-
At the same time, the relationship between epilepsy and seizures with fever limiting course, but
seems to be more complex, and several well-known epilepsy syndromes are recurrences are frequent.
frequently associated with seizures in the setting of fever (FIGURE 7-2): (1) The total risk of epilepsy
after a previous simple
seizures with fever persist beyond the age of 5 years and/or afebrile seizures also
febrile seizure is 2%.
occur (genetic epilepsy with febrile seizures plus [GEFS+], Dravet syndrome,
PCDH19, hemiconvulsion-hemiplegia-epilepsy syndrome, febrile infection-
related epilepsy syndrome [FIRES]), (2) a period of freedom from seizures
follows febrile seizures before the development of epilepsy, and (3) a child has a
history of afebrile seizures/epilepsy and then subsequently presents with seizures
with fever.25
AGE-RELATED EPILEPSY SYNDROMES

The recognition of a specific electroclinical syndrome (a complex of signs and
symptoms that define a unique epileptic condition: seizure type, age at onset,
etiology, comorbidities, diurnal variation, association with sleep, family history)
is feasible in approximately one-third of pediatric patients with epilepsy. Most
are age related in their development (FIGURE 7-3).13 The Nosology and
Definitions ILAE Task Force has proposed syndrome definitions at various ages
and summarizes diagnostic electroclinical criteria, expected results of
investigations (eg, imaging, genetics), comorbidities, and natural history.26
Infantile spasm syndrome, self-limited epilepsy with centrotemporal spikes,
self-limited epilepsy with autonomic seizures, childhood and juvenile absence
epilepsies, and juvenile myoclonic epilepsy represent the most common
syndromes; more rare syndromes are also outlined in TABLE 7-2. Epilepsy
syndromes encompass a large group of entities due to both genetic and
nongenetic causes. A great number of epilepsy syndromes of childhood are self-
limited and have a good prognosis (CASE 7-2). Nevertheless, several epilepsy
syndromes can be associated with permanent neurologic impairment and
devastating consequences for the developing brain (FIGURE 7-3).
However, not all patients fulfill criteria to be classified into an epilepsy
syndrome; they often exhibit intermediate phenotypes, overlapping features, or
varying degrees of neuropsychological impairment and prognosis. Therefore,
electroclinical epilepsy syndromes might not be considered as purely distinctive
entities but as parts of different spectrums (broad or narrow).
An interesting example can be derived from the continuum of epilepsies
characterized by epileptic discharges precipitated by sleep, which includes self-
limited epilepsy with centrotemporal spikes, and developmental and epileptic
encephalopathy or epileptic encephalopathy with spike-wave activation in sleep.
More specifically, patients with self-limited epilepsy with centrotemporal spikes
will outgrow the tendency to have seizures by puberty and usually do not have
learning difficulties. Similarly, in patients with developmental and epileptic
encephalopathy/epileptic encephalopathy with spike-wave activation in sleep,
an improvement in seizure frequency is usually seen in early teenage years, and

KEY POINT
● Although well-described
electroclinical syndromes
with age-related expression
are known, they still
represent parts of different
spectrums and can also
share underlying genetic
mechanisms.
FIGURE 7-3
A timeline of electroclinical epilepsy (electroclinical) syndromes of childhood. Some
epilepsy syndromes are usually complex (gray boxes) and some are usually not complex
(white boxes)
DEE = developmental and epileptic encephalopathy.
EEG patterns may also return to normal during slow-wave sleep, but learning
and behavioral disorders may persist. Finally, children with developmental and
epileptic encephalopathy/epileptic encephalopathy with spike-wave activation
in sleep often become seizure free but are left with permanent
cognitive impairment.
At the same time, the emergence of novel genetic findings has radically
changed the way epilepsy in childhood is viewed. Although the classic construct
of electroclinical syndromes is being replaced by the concept of genetic
spectrums, sodium channelopathies best illustrate this shift. Several epilepsy
syndromes with seizures in the setting of fever are examples of phenotypic
heterogeneity due to underlying mutations of the sodium channel voltage-gated,
type I, α subunit (Nav1.1), a protein encoded by the SCN1A gene. Mild missense
mutations are associated with benign febrile seizures, and moderate or severe
missense mutations give genesis to the GEFS+ phenotype, whereas Dravet
syndrome is usually the clinical expression of truncating loss-of-function
mutations. Similarly, although children may present with well-described
electroclinical epilepsy syndromes (eg, Lennox-Gastaut syndrome, infantile
spasm syndrome, epilepsy of infancy with migrating focal seizures, epilepsy with
myoclonic-atonic seizures) and associated autism, intellectual disability, or
movement disorders, it is clear that each may be the result of several different
genetic variants. However, it is now becoming clear that pathogenic variants in
442 APRIL 2022

the SCN2A gene (encoding for the voltage-gated sodium channel Nav1.2) are
associated with a variety of neurodevelopmental phenotypes; some missense,
gain-of-function variants tend to present in early infancy with epilepsy, whereas
other missense or truncating, loss-of-function variants present with later-onset
epilepsies or intellectual disability only.27
In this way, phenotypic spectrums are further expanded toward shared and
overlapping genetic mechanisms for a wide range of epilepsy types, severities,
and neurodevelopmental disorders. As will be highlighted in the following
section, knowledge of both mutation type and functional consequences is
essential for appropriate treatment choice.
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY

The need to explore all the underlying pathophysiologic mechanisms associated
with brain dysfunction in children with epilepsy and the need to promote the fact
that the cause of neurodevelopmental compromise goes beyond the epilepsy but
is likely to have major contribution from the underlying cause led to the
introduction of the term developmental and epileptic encephalopathy by the ILAE
in 2017.12
A 6-year-old girl presented with status epilepticus requiring intensive CASE 7-2
care admission. She was reported as having been using a tablet when she
went to her father complaining of nausea. She was able to walk to the
bathroom; her head and eyes then turned to the left, she vomited, and
she became unresponsive. She remained like this with head and eye
deviation and was taken to the hospital where she continued to be
unresponsive. She did not respond to initial benzodiazepines; she was
intubated, ventilated, and transferred to the pediatric intensive care unit
where she was treated for 24 hours, recovered, and was discharged the
following day.
Her father recalled there had been a previous episode 18 months
before when she had been on vacation; she was visiting an arcade when
she was noted to have a change of facial expression, vomited, and lost
tone. She was taken to the emergency department where she completely
recovered. The episode was attributed to dehydration.
Neurodevelopmentally, no previous concerns were noted.
An initial interictal EEG recording following the event was normal. A
subsequent EEG showed occasional sharp and slow waves seen over the
occipital electrodes; on eye closure, brief bursts of posterior
predominant spike-wave discharges were seen consistent with fixation
off sensitivity. A diagnosis of self-limited epilepsy with autonomic
seizures was made, and a regular medication was not initiated.
Twelve months after the second episode, she remained well on no
regular medication.
This case is suggestive of a well-described epilepsy syndrome of COMMENT

childhood with a favorable, self-limited course.

An epileptic encephalopathy is characterized by the presumption that the

epileptic activity contributes to the neurodevelopmental compromise beyond
what might be expected from the underlying pathology alone; it may occur on a
background of normal development or preexisting developmental delay.
Although frequent (often interictal) epileptiform activity is well described as
leading to severe impairment in certain syndromes (eg, infantile spasms
syndrome), the contribution of the underlying pathology responsible for the
epilepsy cannot be ignored. An increasing number of genetic causes have been
identified in those patients and found to independently impact normal
neurodevelopment (beyond what might be expected from the underlying
epileptiform activity alone). In this way, addressing the epilepsy alone will not
resolve the developmental impairment.28,29
SPECIAL CONSIDERATIONS IN THIS AGE GROUP

A major difference between children and adults with epilepsy is the potential
effect on the developing brain, the potential for plasticity, and the need to
preserve a series of functions (eg, language, cognition, social competence,
behavioral skills), which will determine the level of global functioning as
individuals move through childhood and adolescence. The disruptive and
interruptive nature of epilepsy interferes with normal cognitive development
and the general well-being of children and their families.30
FIGURE 7-4
Aspects of the deleterious effect of epilepsy on neurodevelopment.
444 APRIL 2022

At the same time, children with epilepsy, even those with self-limiting KEY POINTS
epilepsy types (eg, self-limited epilepsy with centrotemporal spikes), can exhibit
● The term developmental
a wide range of neurobehavioral problems, which may sometimes be more and epileptic
problematic than seizures themselves. According to results from the Rare encephalopathy was first
Epilepsy Network, the most frequent comorbidities are learning and introduced in 2017 and
developmental disability, memory dysfunction, autism spectrum disorder, highlights the fact that the
epileptic activity
mental health issues, sleep disorders, bone/joint issues, hypertonia/hypotonia,
contributes to the
and eye/vision disorders.31 The prevalence of those comorbidities is highest neurodevelopmental
among children diagnosed with epilepsy in the first year of life.31 All these compromise beyond what
comorbidities can share a common underlying etiologic background with might be expected from the
underlying pathology alone
the epilepsy itself or represent alterations in neuronal network function,
but also that the underlying
while the deleterious effect of epilepsy on neurodevelopment is multifaceted cause independently
(FIGURE 7-4).32 Children and adolescents with epilepsy should be impacts neurodevelopment
systematically screened for comorbidities, and multidisciplinary involvement beyond what might be
is encouraged.33 expected from the epilepsy.
In parallel, with advances in pediatric care, it is becoming increasingly ● Children with epilepsy
common for children with early-onset epilepsy (even with developmental and (even those with self-limited
epileptic encephalopathy) to survive into adulthood. Indeed, the process of types) exhibit a wide range
transition to adult epilepsy services might be quite challenging; several studies of comorbidities, which are
often more deleterious than
have shown that many parents are worried when the clinical management of the seizures themselves.
child needs to be moved from the pediatric neurologist to the adult neurologist,
whereas the physicians generally agree that the contribution of psychologists and
social workers is helpful. The challenge is greater for adolescents with epilepsy
because they face unique challenges at a crucial developmental stage, where the
need to conform to peer standards can indirectly lead to a deterioration in seizure
control. Although adequate communication and coordination among health care
professionals are essential, the active involvement of families and adolescents
themselves can provide important feedback and simplify many stages of the
procedure of transition.34
SOCIAL CONDITIONS AND EPILEPSY CARE ACROSS THE WORLD

Apart from medical aspects of clinical management of epilepsy in children, social
issues also need to be considered, as they may significantly impact treatment
outcomes. As has already been commented, acquired and preventable causes
are the major contributors to epilepsy etiology among children in low- and
middle-income countries, a fact that radically changes the diagnostic approach
and the prioritization. In parallel, although a diagnosis of epilepsy may be
straightforward in a significant number of patients, it might prove to be complex
and challenging in other cases, often being missed in settings with limited
resources.35
According to nationwide studies (data from the United States, Canada, and
English-speaking parts of the Caribbean), social and demographic differences
can affect the access to expert health care and antiseizure medication
prescriptions in children with epilepsy.35 More specifically, children with
epilepsy residing in large cities, as opposed to children living in smaller cities and
rural areas, generally have better access to specialist child neurologists, and this
also has an effect on the type of antiseizure medication prescribed.
Socioeconomic status is related to adherence to treatment. Factors such as
insufficient health insurance and less access to neuropediatricians predispose
individuals to poor adherence.36 Regarding epilepsy surgery, it may be

underutilized even in high-income countries, and remarkable intercenter and

interregional variability can be seen in the availability of epilepsy surgery
services and in the type of surgical procedures that can be offered.37
Stigma and quality of life for children and adolescents with epilepsy also seem
to be impacted by social conditions. Data from low-income countries show that
the prevalence of perceived stigma is still considerable (almost in one-third of
cases) among children with epilepsy, and the most significant risk factors include
injuries or deformities caused by epilepsy (ie, patients with untreated or
undertreated disease), long use of antiseizure medications, and a lack of
appropriate education.38
Consequently, a variety of factors related to social and financial
conditions may interfere with the diagnostic and therapeutic approach to
pediatric epilepsy and the well-being of those patients.35,39 Despite the
aforementioned findings, studies with comparative data are generally
lacking, and studies with more systematic methodologic approaches are
needed to identify causes of disparities in pediatric epilepsy health care and
explore policies to address those inequalities, especially those that are
preventable and/or modifiable.
PROGNOSIS AND OUTCOMES

It has already been commented that a significant number of epilepsy syndromes
with childhood onset have a very good prognosis.14 However, early-life epilepsies
carry a remarkable risk of poor outcome, which is evident shortly after epilepsy
diagnosis. Onset in infancy and developmental delay are significant risk factors,
regardless of epilepsy type. A 2019 study focusing on a large cohort of 775
children with epilepsy onset within the first 3 years of age revealed that, after
6 months of follow-up, 35% developed drug-resistant seizures, 15% of infants
with nonsyndromic epilepsy developed infantile spasms, and 23% of those with
initially typical development or only mild delay at seizure onset had clear
developmental deterioration in the future.40
Several epilepsy syndromes evolve into adolescence and adulthood and
require differing treatments. Seizures may increase or decrease depending on the
etiology, and comorbidities may emerge after adolescence, despite not being
prominent in childhood. Finally, some specific disorders have different clinical
features depending on the age of onset. In general, five different patterns of
evolution can be recognized among children with childhood-onset epilepsy: (1)
epilepsy persisting in adolescence and adulthood (eg, inborn errors of
metabolism), (2) changing phenotype/problems in adolescence and adulthood
(eg, tuberous sclerosis complex, Rett syndrome, Dravet syndrome), (3)
epilepsies changing with age (eg, childhood absence epilepsy, juvenile myoclonic
epilepsy, West syndrome, Lennox-Gastaut syndrome), (4) epilepsies with
varying symptoms and severity according to age (eg, autoimmune encephalitis),
and (5) epilepsies with an unchanged phenotype (eg, those due to
structural causes).40
When prognosis is discussed, the most devastating complication among
children with epilepsy is sudden unexpected death in epilepsy (SUDEP).
SUDEP is a significant cause of death in pediatric epilepsy (almost one-third of
causes of death in the age group of birth to 15 years) and a source of stress and
concerns for patients and their families.40 Although the incidence of SUDEP in
childhood epilepsy populations has been previously thought to be low, 2017
446 APRIL 2022

population-based data suggest the incidence is similar in children and adults.41 KEY POINTS
Studies have consistently identified nocturnal generalized tonic-clonic seizures
● Several epilepsy
as a significant risk factor42; other factors associated with SUDEP among syndromes with childhood
children and adolescents include severe disease (eg, early age of onset, high onset have a very good
seizure frequency), intellectual impairment and developmental delay, prognosis, but early-life
multiple–antiseizure medication therapy, and structural abnormalities as onset epilepsies usually
have poor outcomes.
a cause.11
Respiratory dysfunction and cardiac arrhythmias are considered to be ● Sudden unexpected
involved in the underlying pathophysiology of SUDEP, and hippocampal death in epilepsy (SUDEP) is
alterations (eg, “hippocampal formation maldevelopment”) have also been a significant cause of death
identified in several patients and reflect a common finding in cases of sudden in pediatric epilepsy;
incidence is similar in
unexpected death in childhood due to other causes. At the same time, children children and adults.
with variants in several heart and brain genes may be at higher risk, such as
voltage-gated sodium channels (eg, SCN1A), potassium channels (KCNA1,
KCNQ1, KCNH2), or the PRRT2 gene. This combination of hippocampal
abnormalities with specific genetic variants underlying epilepsy and cardiac
arrhythmias may imply that sudden death could be the result of aberrant
excitability in either the brain or heart.
The best current clinical practice to reduce risk of SUDEP is optimization of
treatment and awareness of families. Although it is generally advised that the risk
of SUDEP be disclosed as part of a comprehensive epilepsy consultation, studies
reveal that child neurologists often face emotional difficulties when dealing with
this issue.43
THERAPEUTIC APPROACHES
Individualization of treatment approach is now prioritized in children with
epilepsy, and emerging precision medicine therapies promise to modify disease
course. In the meantime, antiseizure medications remain the first-line treatment,
although ketogenic diet and epilepsy surgery now have their own place in the
management of these patients.
Antiseizure Medications
Treatment with antiseizure medications can lead to seizure freedom in almost
two-thirds of cases. The choice of an antiseizure agent depends on seizure
type(s), efficacy of the drug for the seizure type or the epilepsy syndrome, and
the side effect profile of the drug(s) relative to comorbidities in the individual.
However, initiation of antiseizure medication is usually postponed until a second
seizure occurs and a confirmed diagnosis of epilepsy is made. It may further be
avoided in cases of self-limited childhood focal epilepsies. With regard to
infantile spasms, the first-line treatments include hormonal therapy (ie, steroids
or adrenocorticotropic hormone [ACTH]) and vigabatrin, according to the
International Collaborative Infantile Spasms Study protocol.44 Their
combination is significantly more effective at stopping infantile spasms than
hormonal therapy alone.11 Phenobarbital is the first-line option for neonatal
seizures, whereas levetiracetam and phenytoin represent second-line options for
this age group.45
Considerable interest has been expressed in the use of cannabinoids
particularly for the complex epilepsies. A pharmaceutical-grade formulation of
purified cannabidiol has now been approved as an adjunctive therapy for the
treatment of seizures associated with Dravet syndrome, Lennox-Gastaut

syndrome, and tuberous sclerosis complex. However, the precise mechanism(s)

of its antiseizure activity, as well as its pharmacokinetic profile, need
further investigation.46
In childhood, pharmacokinetics of antiseizure medications can be influenced
by important age-related factors (eg, different body composition, immature
metabolic patterns, reduced renal activity). Therefore, the use of extended-
release drug formulations can be used to optimize therapeutic outcomes. Special
attention needs to be paid in cases of drug polytherapy because drug-drug
interactions may critically affect metabolism and subsequent efficacy of
treatment; serum concentrations of antiseizure medications may be increased by
enzyme inhibitors or decreased by other mechanisms (ie, induction, reduced
absorption, or excretion).47
Furthermore, appropriate adherence is a key factor for successful treatment
and depends on both patients and their family/caregivers, but it might be quite
challenging. According to a recent meta-analysis based on observational studies
exploring factors affecting adherence to treatment (ie, questionnaires, self-
report, electronic monitoring, medication serum level), family support, smaller
family size, support from health care providers, and higher family socioeconomic
status are usually associated with better medication adherence.48 A wide range of
adverse events have been reported in children receiving antiseizure medications
(eg, slow thinking, drowsiness, attention deficit, memory problems, fatigue,
poor school performance, hypersensitivity reactions) and can interfere with
adherence and affect outcomes. The prevalence of adverse events is significantly
lower in monotherapy regimens.49 However, the underlying pathophysiology of
neurodevelopmental problems in patients with epilepsy is complex and not
clearly elucidated, and, apart from antiseizure medications, additional aspects
(ie, genetic diagnosis, aberrant neuronal networks) need to be considered.50
If seizure freedom has been achieved for a period of at least 2 years, slow
weaning could be attempted over the span of 6 to 8 weeks or longer. It is
estimated that approximately two-thirds of patients remain seizure free, and of
those who experience recurrence, the majority achieve seizure control again
when restarting an antiseizure medication.51 On the basis of available data, it can
be concluded that the most consistent factors predisposing to seizure relapse
during or after weaning include an abnormal EEG at the onset of weaning, age at
onset younger than 2 years or older than 10 years, defined etiology (ie, epilepsy of
structural or metabolic cause), underlying mental retardation, and a seizure-free
period of less than 2 years. Most of these factors are probably related to the
underlying syndrome diagnosis and the likelihood of long-term remission. When
treatment with two or more antiseizure medications fails, alternative treatment
options (eg, ketogenic diet, epilepsy surgery) should be explored. In neonates
with acutely provoked seizures (eg, infection, stroke, hypoxic-ischemic
encephalopathy) successfully treated, antiseizure medications could be
discontinued before discharge because no data exist that continuing treatment
decreases the risk of subsequent epilepsy or improves neurodevelopmental
outcomes.45
Ketogenic Diet
The efficacy of the ketogenic diet in childhood was documented in 13
randomized controlled trials in a 2020 meta-analysis, and it is considered as
effective as conventional therapies (eg, antiseizure medications) among children
448 APRIL 2022

and adolescents with drug-resistant epilepsy, although clear data of superiority
are not available.52 In parallel, the limited number of randomized trials and small
sample sizes impact the accuracy of findings and decrease the level of evidence.
However, for children with drug-resistant epilepsy or those who are unsuitable
for surgical intervention, ketogenic diet represents a valid therapeutic option.52
For several specific conditions (eg, glucose transporter 1 [GLUT1] deficiency
syndrome, pyruvate dehydrogenase deficiency, epilepsy with myoclonic-atonic
seizures, infantile spasms, tuberous sclerosis complex, children with gastrostomy
tubes, Dravet syndrome), the evidence is strong that ketogenic diet should be
considered very early in the course of treatment. Freedom from antiseizure
medication can also be feasible among children undergoing ketogenic diet
treatment, especially in younger ages, children with fewer antiseizure
medications at diet onset, and those with a diagnosis of GLUT1 deficiency or
epilepsy with myoclonic-atonic seizures. Ketogenic diet has also been found to be
safe, well-tolerated, and effective in younger ages, as well (ie, infants, toddlers).
It is noteworthy that in this age group (ie, those younger than 1.5 years) seizure
freedom is more often achieved and maintained with diet introduction.53
Epilepsy Surgery
Children with continuing presumed focal-onset seizures from a localized
pathology are potential resective surgical candidates and warrant further
multidisciplinary evaluation in a specialist center. Epilepsy surgery has an
acceptable safety profile at all ages, when conducted in a specialist pediatric
center. Although various complications have been reported after epilepsy
surgery, the majority represent minor medical complications, and they tend to
improve/resolve with time.54 The efficacy of several surgical techniques (eg,
hemispherectomy, multilobar or sublobar resection, lesionectomy) has now been
well established for a series of anatomic disorders, according to lesion size:
hemimegalencephaly, hemidysplasia and Rasmussen syndrome, focal cortical
dysplasia, tuberous sclerosis, Sturge-Weber syndrome, developmental tumors,
polymicrogyria, and hippocampal sclerosis.55 Minimally invasive surgical
methods (eg, radiosurgery, stereotactic thermoablation, and laser ablation) are
emerging as efficient and safe alternative options in many patients with specific
underlying conditions. It is also worth mentioning that epilepsy surgery could be
an option in children with well-defined lesions in noneloquent areas, even if
seizure control is good, especially if associated with excellent rates of postsurgical
seizure freedom but rare spontaneous seizure remission.56
When resective/ablative surgical procedures have failed to achieve seizure
control, when resective surgery is contraindicated, or when a patient prefers a
minimally invasive procedure, neuromodulatory methods can also be used. The
three most commonly used neuromodulatory techniques with evidence of safety
and efficacy are vagus nerve stimulation, responsive neurostimulation, and deep
brain stimulation (thalamic), considered after full presurgical evaluation in
specialist centers.57
ILAE has developed criteria for Level 1 and Level 2 pediatric epilepsy surgery
centers, according to facilities and competencies. Level 1 centers provide care for
children 9 years old or older with discrete lesions including hippocampal sclerosis
who are undergoing lobectomy or lesionectomy not close to eloquent cortex. The
team includes a pediatric epileptologist, pediatric neurosurgeon, and pediatric
neuroradiologist, and access to video-EEG and 1.5-Tesla MRI is needed.

However, Level 2 centers can provide care across the whole age span and for a
broad spectrum of etiologies, even for patients with normal MRI, poorly defined
MRI lesions, or foci in the eloquent cortex. A wider range of diagnostic
technologies must be available, and the multidisciplinary team needs to be
supported by neurophysiology, neuroradiology, epilepsy neurosurgery,
neuropsychology, neuroanesthesia, neurocritical care, and psychiatry services.58
Apart from seizure outcomes, interest is increasing in cognitive and
neurodevelopmental outcomes. Cognitive function seems to be stabilized and
preserved after different types of epilepsy surgery; in the long term, clear
benefits have been demonstrated related to seizure freedom and weaning from
antiseizure medications.59,60 The TimeToStop study was a pan-European study
based on a pediatric epilepsy surgery cohort that included patients younger than
18 years and from 15 centers in Europe (undergoing surgery between January 1,
2000, and October 1, 2008) who had at least 1 year of postoperative follow-up
and who started antiseizure medication reduction after having reached
postoperative seizure freedom.61 According to the results, the time interval to
CASE 7-3 A girl first presented with tonic seizures at 3 months of age. She was born
by lower-segment cesarean delivery because of prolonged labor and
mild fetal distress. Normal early development was reported. Her first
seizure was 4 days after her second immunization; she became rigid with
eye deviation up and to the left. Over the first year of life, she required
monthly admissions to the hospital for multiple seizures occurring for
longer than 24 hours. She had a steady escalation in seizure frequency
and intermittent dystonic posturing. Interictal EEG was normal. Tonic
seizures were recorded on ictal EEG.
The patient had acquired microcephaly and slow neurodevelopment.
She was not ambulant and had no language.
Brain MRI was normal, neurometabolic investigations were negative,
and she had no response to pyridoxine. She had little response to
antiseizure medications over several years, including cannabidiol. She
had annual admissions with clusters of seizures and neurodevelopmental
regression over 1- to 2-month periods and subsequent resolution with
periods of few or no seizures.
At the age of 9 years, a gene panel evaluation revealed a gain-of-
function mutation in SCN8A (c.5615G>A). Parental testing revealed no
such variant, confirming it was de novo. She was initiated on
carbamazepine (not used previously) and became seizure free. At the age
of 15 years, she remained on carbamazepine monotherapy. Since the
initiation of carbamazepine, she had breakthrough seizures on one
occasion at the time of a chest infection. She remained nonambulatory
but was increasingly interactive with a good quality of life.
COMMENT This case exemplifies how the identification of an underlying genetic

etiology can permit the application of a more targeted therapy (ie, sodium
channel blocker in this case) with a beneficial impact on the patient.
450 APRIL 2022

medication reduction was the only independent prognostic factor of seizure KEY POINT
relapse, a finding that favors early withdrawal of medications when
● Treatment with
postoperative seizure freedom has been achieved.61 antiseizure medications
leads to seizure freedom in
Precision Medicine Therapies almost two-thirds of cases,
The increased availability of multigene next-generation sequencing techniques and ketogenic diet and
epilepsy surgery represent
has led to the identification of a genetic etiology in a significant number of
valid therapeutic options for
patients with epilepsy. Subsequent functional studies have shed light on the children with drug-resistant
mechanism interrupted by gene mutations and revealed potential targets for epilepsy. Precision medicine
drug development. In this way, the concept of targeted treatment early in life treatments are also
available for patients with
promises to replace the traditional empirical “trial-and-error” approach to
specific genetic epilepsies.
epilepsy therapy.62 It is already known that some of the available therapeutic
agents are either particularly beneficiary or contraindicated for specific epilepsy
types/syndromes. For example, ketogenic diet represents a targeted treatment
providing an alternative fuel to glucose for children with GLUT1 deficiency,
whereas carbamazepine or lamotrigine (ie, sodium ion channel blockers) may
worsen seizures in children with SCN1A mutations (eg, Dravet syndrome).62
SCN2A-related epilepsies also provide a good example of how pathogenic
variants in the same gene can affect the gene product function in opposite
directions, with important implications for response to specific antiseizure
medications. More specifically, early-onset cases (patients younger than
3 months old) with gain-of-function mutations show a favorable response to
sodium channel blocking antiseizure medications, whereas the opposite happens
in late-onset cases associated with loss-of-function mutations (CASE 7-3).63 In
parallel, specialized pharmacologic agents are now available for several genetic
epilepsies, either closely related to the underlying pathophysiology or not
(eg, stiripentol and fenfluramine for Dravet syndrome, pyridoxine for ALDH7A1
deficiency, quinidine for KCNT1-related epilepsies, memantine for GRIN2A-
related epilepsies, radiprodil for GRIN2B-related epilepsies, mammalian target of
rapamycin [mTOR] inhibitors for tuberous sclerosis).1 New potentially
transformative genetic therapeutic approaches currently being explored are
aimed at reversing the functional consequences of a pathogenic variant.
General Comments About Treatment

In general, treatment of epilepsy in children is now highly individualized at each
and every management step. Child neurologists and epileptologists taking care of
children with epilepsy often must address a series of dilemmas regarding the
most appropriate treatment option (eg, whether to treat after the first episode of
seizures, whether to treat electroencephalographic seizures in neonates, whether
to escalate antiseizure medications, or whether to offer epilepsy surgery in
children with well-controlled seizures). What needs highlighting is that epilepsy
is commonly an unstable condition with fluctuations in seizure frequencies that
are unpredictable and do not always require a change in treatment, while positive
responses to treatment changes are not always the rule.64 More systematically
designed studies will help with evidence-based therapeutic decisions. In parallel,
therapeutic priorities and plans must be analyzed and discussed with parents and
children to raise family awareness about aspects of the disease, prognosis, and
treatment strategies. A fine balance needs to be maintained between negative
impacts of the disease itself and adverse events of antiseizure treatment. Escalating
antiseizure treatment may not always be the option; on the contrary, prompt

recognition of seizure episodes, careful monitoring, and recording of seizures

often prove to be clinically more essential in the management of these patients.64
FUTURE CHALLENGES
Optimization of care for children with epilepsy is an ongoing challenge. The
importance of early intervention has been widely recognized, the overall well-
being of patients is prioritized, and treatment goals are reconsidered.
Seeing Beyond Seizures

Despite the tremendous progress seen over recent years in more precisely
defining seizure phenotypes, isolating underlying genetic causes, and designing
novel targeted therapies, much more work needs to be done. Epilepsy creates
huge life challenges and impacts on many daily activities, and often a gap exists
between medical issues and the needs of children and their families. The
educational and social consequences (short-term and long-term) of the disease
(eg, poor social interaction, stigma, risk of unemployment, missed school hours),
as well as long-term mental health disorders, may be overlooked and
undertreated.31,33 Therefore, it is essential that clinicians start thinking about and
discussing the full spectrum of needs of these patients. Νew evidence-based
psychological and educational interventions aimed at addressing the mental
health needs of patients with epilepsy should be explored or refined. In parallel,
inclusion of health education programs in textbooks and curricula for teachers
and school children can help bring a change in attitude, behavior, and
clinical practices.65
Reshape Treatment Goals With Early Access to Optimal Treatment

Trends in the management of children with epilepsy are now moving beyond
seizure control and include improvement in quality of life, protection of future
neurodevelopment, and a reduction in the global burden of the disease. To
achieve all those targets, an early referral for optimal therapeutic choices and
appropriate centers is needed to benefit from brain plasticity and modify, in part,
the natural course of the disease. Hargreaves and colleagues66 performed a
longitudinal data linkage study of pediatric epilepsy services in England and
found that referral of young patients with epilepsy to tertiary specialists in
pediatric care was associated with a reduction in mortality rates and the number
of hospital admissions. Nevertheless, an early approach remains a challenge in
many cases. Despite the well-reported safety and efficacy of epilepsy surgery,
especially in the young, it remains underutilized, and delays have been
significant in referring children with drug-resistant epilepsy to epilepsy surgery
centers. This delay is usually attributed to the extended presurgical
investigations required, as well as to reluctance and skepticism from
some clinicians.37
It has been documented that an early withdrawal of antiseizure medications
after epilepsy surgery is generally feasible, associated with an improvement in IQ
and psychomotor development, and strongly preferred by parents.60
Furthermore, 2019 data show that complete medication withdrawal can also
occur in a number of children under ketogenic diet treatment, at least during
treatment with the diet.67 The aforementioned findings also reflect the need to
broaden the concept of treatment outcomes and include additional aspects (eg,
decrease in antiseizure medication burden and associated adverse events) that
452 APRIL 2022

are meaningful to patients and their families and might make a difference in KEY POINT
everyday life.
● Beyond seizure control,
At the same time, a gap often exists between the much-promoted idea of clinicians need to consider
precision medicine in epilepsy and the real impact on daily clinical practice. the full spectrum of needs
Clinical outcomes after the identification of a genetic cause for an epilepsy show of children with epilepsy.
high variability and several ongoing practical issues that need to be considered Early referral for optimal
therapeutic choices in
(eg, lack of appropriate funding, no access to new treatments or clinical trials,
appropriate centers is
family reluctance, poor adherence, unpredictable adverse events). justified to enable
appropriate management
and optimize the natural
course of the disease.
CONCLUSION
The recent progress in the field of precision medicine and technologic
applications has dramatically changed the management of pediatric patients
with epilepsy. The concept of spectrums (ie, genetic spectrums, spectrums
of comorbidities) has now been embodied in clinical practice. Clinicians involved
in the care of children and adolescents with epilepsy need to think more
broadly and, apart from seizure control, consider additional aspects of the
disease (neuropsychological outcomes, social relationships, well-being of
family), while decisions about therapeutic approaches need to be communicated
to and discussed with parents and/or caregivers. The major future priority
is to incorporate emerging findings from basic and clinical research into
everyday management and translate research achievements into faster
diagnosis, optimal treatment, better quality of life, and an end of the stigma
for pediatric patients with epilepsy. No matter how promising emerging
treatments may be, early referral and equal access to them are still a
big challenge.
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456 APRIL 2022

Neuropsychiatric and REVIEW ARTICLE

Cognitive Comorbidities CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
in Epilepsy
By Marco Mula, MD, PhD, FRCP, FEAN; Honor Coleman, MPsych, PhD;
CITE AS:
Sarah J. Wilson, PhD, FAHMS, FASSA
2022;28(2, EPILEPSY):457–482.
Dr Marco Mula, Epilepsy Group,
ABSTRACT
Atkinson Morley Regional
PURPOSE OF REVIEW: This
article discusses psychiatric and cognitive Neuroscience Centre, St
comorbidities of epilepsy over the lifespan and illustrates opportunities to George’s University Hospital
NHS Foundation Trust,
improve the quality of care of children and adults with epilepsy. Blackshaw Road, London SW17
0QT, United Kingdom,
RECENT FINDINGS:One in 3 people with epilepsy have a lifetime history of mmula@sgul.ac.uk.
psychiatric disorders, and they represent an important prognostic marker RELATIONSHIP DISCLOSURE :
of epilepsy. Contributors are diverse and display a complex relationship. Dr Mula has received personal
Cognitive comorbidities are also common among those living with epilepsy compensation in the range of
$500 to $4999 for serving on a
and are increasingly recognized as a reflection of changes to underlying speakers bureau for Eisai Co,
brain networks. Among the cognitive comorbidities, intellectual disability Ltd, and UCB, Inc, and for
serving as an Associate Editor
and dementia are common and can complicate the diagnostic process for Epilepsy & Behavior; has
when cognitive and/or behavioral features resemble seizures. received publishing royalties
from Elsevier and Springer
Publishing Company; and has a
SUMMARY: Comorbidities require consideration from the first point of
compensated relationship with
contact with a patient because they can determine the presentation of the Korean League Against
symptoms, responsiveness to treatment, and the patient’s day-to-day Epilepsy and the Philippine
League Against Epilepsy.
functioning and quality of life. In epilepsy, psychiatric and cognitive Dr Coleman has received
comorbidities may prove a greater source of disability for the patient and personal compensation for
serving as a research lead for
family than the seizures themselves, and in the case of essential
the Epilepsy Foundation of
comorbidities, they are regarded as core to the disorder in terms of Australia. Dr Wilson has received
etiology, diagnosis, and treatment. personal compensation in the
range of $0 to $499 for serving
on a speakers bureau for Pretola
Global Health Consulting
Limited. The institution of
Dr Wilson has received research
INTRODUCTION support from the Austin Medical
I
n addition to seizures, psychiatric and cognitive problems represent potential Research Foundation, Australian
Research Council, Australian
major sources of disabilities in children and adults with epilepsy, and this is Government National Health
reflected in the new International League Against Epilepsy (ILAE) definition and Medical Research Council,
of epilepsy.1 In fact, epilepsy is now defined as a disorder of the brain and the Epilepsy Foundation.
characterized not only by recurrent seizures but also by its neurobiological, UNLABELED USE OF
cognitive, and psychosocial consequences.1 PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE :
Epidemiologic studies have shown that 1 in 3 people with epilepsy have a Drs Mula, Coleman, and Wilson
lifetime diagnosis of any psychiatric disorder, and 1 in 4 patients have a current report no disclosures.
psychiatric problem.2 As for all brain disorders, epilepsy is also burdened by
potential impairment in some aspects of cognition. Community-based studies in © 2022 American Academy
pediatric samples suggest an increased prevalence of cognitive abnormalities in of Neurology.

NEUROPSYCHIATRIC AND COGNITIVE COMORBIDITIES IN EPILEPSY
children with epilepsy, even in those with uncomplicated epilepsies, compared

with children without epilepsy.3
The reasons for psychiatric and cognitive problems in epilepsy are complex.
The epilepsy syndrome and the core features of the epilepsy, such as the age of
onset, duration of the disease, interictal epileptiform discharges, seizure
frequency, and side effects of antiseizure medications, are obviously crucial. At
the same time, brain development and aging, as well as the underlying brain
disorder and cause of the epilepsy, are equally important. This article discusses
psychiatric and cognitive comorbidities of epilepsy over the lifespan, illustrating
opportunities to improve the quality of care of children and adults with epilepsy.
PSYCHIATRIC DISORDERS IN EPILEPSY

Good data are now available on the epidemiology of psychiatric disorders in
adults and children with epilepsy, and studies concur that all psychiatric
disorders occur more frequently in patients with epilepsy than in the general
population.4
In adults, a meta-analysis of 14 population-based studies including more than
1,000,000 participants showed an overall prevalence of active (current or in
the past 12 months) depression in epilepsy of 23.1% with an increased overall risk
of 2.7 compared with the general population.5 A meta-analysis of 27 studies of
anxiety disorders in more than 3000 people with epilepsy showed a pooled
prevalence of 20.2% with generalized anxiety disorder being most common
(10.2%).6 A meta-analysis of the prevalence of psychosis, schizophrenia, and
schizophreniform illness in 57 studies with a total of more than 40,000
participants showed a pooled prevalence of psychosis of 5.6% in unselected
individuals increasing to 7% in people with temporal lobe epilepsy, with a pooled
odds ratio for risk of psychosis compared with the general population of 7.8.7 A
meta-analysis of the prevalence of psychogenic nonepileptic seizures (PNES) in
people with epilepsy showed a pooled prevalence of 12% whereas the prevalence
of epilepsy in those with PNES was 22%.8
Data from children with epilepsy are not different despite an obvious
emphasis on developmental disorders. A population-based study in 85 children
and adolescents (aged 5 to 15 years) with active epilepsy in England reported that
the prevalence of attention deficit hyperactivity disorder (ADHD) was around
33%, autism spectrum disorder was 21%, depression was 7%, and anxiety was
13%.9 A nationwide Norwegian registry study in an unselected pediatric
population of more than 1,000,000 children reported developmental and
psychiatric comorbidities in 43% of children with epilepsy with overall odds
ratios (compared with the general child population) of 10.7 for autism, 5.4 for
ADHD, 2.3 for anxiety disorders, and 1.8 for depression.10
The relationship between epilepsy and psychiatric disorders is complex and
reflects a combination of psychosocial and biological factors. Epilepsy is still a
highly stigmatized condition, leading to discrimination and marginalization.11
The social limitations (eg, loss of driving privileges), the unpredictable nature of
seizures, and the potential social embarrassment associated with them can lead to
poor self-esteem, social withdrawal, isolation, and distress. At the same time,
several biological factors contribute to the increased occurrence of psychiatric
disorders. Neuroimaging studies have identified network abnormalities
involving particularly the limbic structures in patients with epilepsy and
depression or psychosis.12,13 However, data from prospective observational
458 APRIL 2022

studies have indicated that the relationship between epilepsy and psychiatric KEY POINTS
disorders is bidirectional, meaning that not just patients with epilepsy are at
● Psychiatric disorders
increased risk of developing psychiatric disorders but patients with psychiatric occur more commonly in
disorders have an increased risk of developing epilepsy. This has been epilepsy than in the general
demonstrated for major depression, psychoses, ADHD, and autism spectrum population and are
disorder.14 For example, a large observational cohort study in the United increasingly recognized as a
major source of disability in
Kingdom involving more than 10,000,000 participants found that depression is
epilepsy.
associated with a 2.5-fold increased risk of developing epilepsy.15 Two
retrospective, large cohort studies, one in England and the other in Taiwan, ● The etiology of
reported that individuals with schizophrenia have a twofold to threefold psychiatric disorders in
increased risk of developing epilepsy16 with an incidence rate of 7 per 1000 epilepsy is complex and can
include both biological and
person-years.17 Taken together, all these findings suggest the existence of psychosocial factors,
common pathogenic mechanisms operating in epilepsy and major psychiatric including altered functioning
disorders. However, data on these common mechanisms are scant. Low of brain networks, stigma,
serotonin levels have been described in animal models of epilepsy, such as social limitations, and
distress.
genetically epilepsy-prone rats, the pilocarpine status epilepticus model, and
rhesus monkeys. Hyperactivation of the hypothalamic-pituitary-adrenal ● The relationship between
axis and high cortisol levels have been associated with plastic changes in the epilepsy and psychiatric
hippocampi, such as γ-aminobutyric acid (GABA) receptor downregulation in disorders is bidirectional,
including depression,
the hippocampi, which may increase the propensity for spontaneous
psychogenic nonepileptic
seizures.18 However, all these fascinating hypotheses need to be verified seizures, attention deficit
and tested. hyperactivity disorder,
Finally, psychiatric symptoms may be biologically linked to the neurobiology autism spectrum disorder,
and schizophrenia.
of seizures themselves. On one hand, peri-ictal psychiatric symptoms may occur
either before or after a seizure and are considered to be caused by the brain ● Consideration of
network changes operating during specific seizure types. On the other hand, psychiatric comorbidities is
psychiatric symptoms may arise because of the modulation of these clinically relevant for
neurobiological systems through epilepsy treatments, such as antiseizure neurologists because
comorbid psychiatric
medications or epilepsy surgery.19 conditions have been
associated with poorer
WHY NEUROLOGISTS SHOULD PAY ATTENTION TO PSYCHIATRIC treatment outcomes, as well
DISORDERS IN EPILEPSY as increased health care
utilization and increased
Psychiatric comorbidities have been historically associated with poor quality of mortality.
life in adults20 and children21 with epilepsy, and strong data now point out their
role as potential prognostic indicators.
A population-based cohort study suggested that depression is associated with
high comorbidity rates as measured by the Charlson Comorbidity Index and that
the severity of the depression itself (based on the type of treatment received)
correlates with lower odds of achieving seizure remission.15 Moreover,
psychiatric disorders are associated with a high risk of side effects of antiseizure
medication,22 especially cognitive23 and psychiatric symptoms,24 whereas
psychiatric comorbidities have been associated with 4 times the risk of drug
resistance in focal25 and generalized epilepsies.26
The impact of psychiatric comorbidities in terms of seizure outcome and
psychiatric outcome in epilepsy surgery is complex and yet to be established.
Regarding seizure outcome, some studies have found a lower probability of
achieving seizure freedom after temporal lobectomy in patients with preexisting
psychiatric comorbidity,27,28 whereas other authors have refuted these
findings.29 The same holds true for psychiatric outcomes, with some studies
showing an increased risk of recurrence of depression or anxiety during the first

3 to 12 months after surgery in people with epilepsy,30 whereas others have

shown improvement over the long term.31
Psychiatric comorbidities are associated with premature mortality in
epilepsy.32 This may be caused by a variety of reasons, including increased risk of
substance or alcohol abuse,33 increased risk of injury,34 and increased suicide
rates.35 Data from a nationwide, population-based study showed that female
patients with epilepsy and psychiatric comorbidities had a fivefold increased risk
of sudden unexpected death in epilepsy (SUDEP) compared with those without
such comorbidities.36
It is evident that psychiatric comorbidities increase the global burden of
epilepsy from a public health perspective with increased health costs.37 People
with epilepsy and psychiatric disorders have high health care resource utilization,
including increased emergency department admissions and outpatient visits.38
Data from a nationwide US inpatient analysis showed that psychiatric
comorbidities, in particular depression and psychosis, increase length-of-stay
and inpatient costs for people with epilepsy.39
Combined, these data show that the identification of these problems can
inform clinicians of the long-term prognosis of the epilepsy itself.
SCREENING FOR PSYCHIATRIC DISORDERS AND DIAGNOSTIC

CHALLENGES
Despite the epidemiologic evidence, psychiatric comorbidities are still
underdiagnosed and undertreated in epilepsy. Barriers to diagnosis and
treatment are complex and multifactorial, including, among other things,
cultural barriers to mental health issues in general, a lack of training of
neurologists and psychiatrists in the psychiatric aspects of neurologic disorders,
and a lack of clinical resource allocation to support a multidisciplinary
approach.40
In the general population, screening tools are available in primary and
secondary care settings for almost all major psychiatric conditions. These tools
have been shown to be cost-effective because they are short, standardized against
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
criteria, and less resource-intensive than a full clinical interview. In the past, the
validity of these instruments in people with epilepsy was a major barrier to their
use in routine clinical practice. However, good data are now available on the
validity of clinical instruments for depression and anxiety in adults and for
ADHD in children.
A systematic review of studies validating depression screening tools in adults
with epilepsy showed that the Neurological Disorders Depression Inventory for
Epilepsy (NDDI-E) is, at present, the most cost-effective screening instrument,
validated in a variety of settings and available in 13 languages.41 The NDDI-E has
also been validated for suicidality screening with good sensitivity and
specificity.42 Other well-known self-rating scales, such as the Beck Depression
Inventory II (BDI-II) and the Patient Health Questionnaire 9-item depression
scale (PHQ-9), have also been shown to be valid in epilepsy but require the use of
cutoff scores higher than those adopted in the general population (general
population BDI-II = 10, PHQ-9 = 5; epilepsy BDI-II = 15, PHQ-9 = 10).41 This can
be partly explained by the heterogeneity of clinical presentations of depression in
epilepsy but also highlights the need to adapt these questionnaires to the specific
needs of people with epilepsy to maximize their sensitivity and specificity.
460 APRIL 2022

Lastly, the Hamilton Depression Rating Scale has also been validated for use in KEY POINTS
people with epilepsy.43
● Barriers to diagnosis and
Regarding anxiety, the validity of the Hospital Anxiety and Depression Scale treatment can include a lack
(HADS) and the Generalized Anxiety Disorder Scale (GAD-7) has been of training of neurologists
investigated in adults with epilepsy. Although studies on the HADS in epilepsy and psychiatrists in the
provide conflicting results,44,45 the validity and cost-effectiveness of the GAD-7 psychiatric aspects of
neurologic disorders and a
seem to be well established.46,47 Inconsistencies among studies can arise for
lack of clinical resource
several reasons, including the fluctuating nature of anxiety symptoms and the allocation to support a
pleomorphic and atypical phenomenology of psychiatric symptoms in epilepsy.48 multidisciplinary approach,
Epilepsy-specific instruments, the 18-item Epilepsy Anxiety Survey Instrument as well as broader stigma
and cultural barriers to
(EASI) and its briefer version the 8-item EASI demonstrated a sensitivity of 76%
mental health support.
and a specificity of 84% for the identification of DSM-5 diagnosis of anxiety
disorders.49 ● Some useful tools to
Data on screening instruments in children with epilepsy are still limited. A screen for psychiatric
systematic review from an ad hoc task force of the ILAE supports the use of the conditions in epilepsy
include the Neurological
Strength and Difficulties Questionnaire (SDQ) for ADHD.50 Data on clinical Disorders Depression
instruments for depression and anxiety in the pediatric population are scant. Inventory for Epilepsy
A 12-item self-report screening tool for children aged 12 to 17 years, the (NDDI-E), Epilepsy Anxiety
NDDI-E-Youth, has been validated in epilepsy,51 but further studies in this area Survey Instrument (EASI),
the brief Epilepsy Anxiety
are still needed. Survey Instrument, the Beck
As for any medical condition, after a positive screen, it is important to Depression Inventory II (BDI-
establish the diagnosis. As already alluded to, psychiatric symptoms in epilepsy II), Patient Health
can arise for a variety of reasons, such as peri-ictal symptoms, side effects of Questionnaire 9 (PHQ-9), the
Hospital Anxiety and
epilepsy treatments, or comorbid psychiatric disorders. However, it is important
Depression Scale (HADS),
to point out that the boundaries between these scenarios are often blurred, and and the Generalized Anxiety
patients may develop symptoms due to multiple contributing factors. In fact, Disorder Scale (GAD-7).
people with a psychiatric comorbidity are also those at risk of psychiatric side
effects of antiseizure medication, and they may also present a worsening of their ● Diagnosis of psychiatric
conditions in epilepsy
background psychiatric comorbidity during, for example, the postictal phase.52 involves careful
The first challenge is, therefore, the identification of different contributing consideration of the timing
factors to develop the best management plan for the individual patient. For this of symptom onset and
reason, neurologists need to be aware of peri-ictal symptoms and side effects of progression to determine
the presence of postictal
epilepsy treatments. symptoms and/or possible
Despite many historical notes and several anecdotal reports, the prevalence contribution of antiseizure
and pathophysiology of peri-ictal symptoms are largely unknown, and most data medications.
come from adults. Postictal psychoses are probably those with the largest
literature; they seem to have a point prevalence of 2%7 and represent around 25%
of all cases of psychosis in epilepsy. Postictal psychoses are typically observed in
temporal lobe epilepsy, they can last for a few weeks, and they are associated
with higher rates of violent behaviors and suicide attempts than interictal
psychoses.53 For this reason, they need to be promptly recognized and managed.
Nonpsychotic postictal symptoms are largely unrecognized because they are
short-lasting and difficult to identify. However, data from a telemetry unit
showed that 43% of patients with drug-resistant focal epilepsy present with
postictal symptoms of depression, 45% with postictal anxiety, and 7% with
psychotic symptoms.52 These occurred following more than half of the seizures
captured and lasted for a median of 24 hours.52
Regarding psychiatric symptoms as side effects of epilepsy treatments, a
retrospective study from a large, unselected sample of more than 4000 adults
with epilepsy showed that 1 in 6 individuals develop drug-related psychiatric side

effects.54 Another retrospective study of more than 2600 people showed that 1 in
7 cases of psychosis are due to antiseizure medications.55 In 2008, the US Food
and Drug Administration (FDA) issued an alert to health care professionals about
an increased risk of suicide ideation and suicidal behavior in people treated with
antiseizure medications (known as antiepileptic drugs when the alert was issued).
In 2013, an ad hoc task force of the ILAE published an expert consensus
TABLE 8-1 Common Psychiatric Side Effects of Antiseizure Medicationsa
Drug Psychiatric side effects
Barbiturates (primidone and Depression

phenobarbital)
In children and individuals with intellectual disabilities: hyperactivity, irritability,
aggression
Benzodiazepines In children, older adults, and individuals with intellectual disabilities: hyperactivity,
irritability, aggression
Brivaracetam Aggressive behavior, depression, psychosis, but better tolerated than levetiracetam
Carbamazepine Not reported
Eslicarbazepine Not reported
Ethosuximide Psychosis
Felbamate Anxiety, psychosis
Gabapentin In children and individuals with intellectual disabilities: hyperactivity, aggression,

irritability
Lacosamide Not reported
Lamotrigine In individuals with intellectual disabilities: hyperactivity, irritability, aggression
Levetiracetam Irritability, aggression, anxiety, depression, psychosis
Oxcarbazepine Not reported
Phenytoin Psychosis (particularly at high serum levels)
Pregabalin Depression
Rufinamide Not reported
Stiripentol Hyperactivity, irritability, aggression
Tiagabine Irritability
Topiramate Depression, psychosis, irritability
Valproate Not reported
Vigabatrin Psychosis, depression

In children and individuals with intellectual disabilities: hyperactivity, aggression,
agitation
Zonisamide Psychosis, depression, irritability
a
Modified with permission from Mula M, et al, Neurol Clin Pract.2 © 2021 American Academy of Neurology.
462 APRIL 2022

statement pointing out the complexities of the relationship between suicide and KEY POINT
epilepsy.56 Although some, but not all, antiseizure medications can be associated
● Further research is
with psychiatric manifestations that can lead to suicide ideation and suicidal needed to examine the
behavior, the risk of stopping or refusing to start antiseizure medications is efficacy of treatment
significantly worse and can actually result in serious harm to the patient, approaches for psychiatric
including death. Suicidality in epilepsy is multifactorial, and different variables disorders in epilepsy, but
first-line treatment involves
are involved.57 Sodium channel blockers seem to be less frequently associated
psychoeducation and
with psychiatric side effects,24,54 but no robust head-to-head trials provide strong psychological interventions.
evidence of this. For this reason, clinicians should consider the possibility of
psychiatric side effects with any drug in predisposed individuals, such as those
with psychiatric comorbidities. Psychiatric side effects of antiseizure medications
reported to have a prevalence higher than 1% are summarized in TABLE 8-1.
The phenomenology of psychiatric disorders in epilepsy has itself been a
matter of debate.58,59 People with epilepsy may develop psychiatric disorders that
are clinically identical to those in individuals without epilepsy. However, it is
now established that some develop psychiatric syndromes characterized by
atypical features poorly captured by conventional classification systems such as
DSM-5 and International Classification of Diseases, Tenth Revision (ICD-10).58 This
has led to attempts to develop clinical instruments tailored for people with
epilepsy. However, apart from their use in research settings, the relative benefits
of these various instruments in the assessment of common psychopathology in
routine clinical practice are the subject of ongoing debate.
MANAGEMENT OF PSYCHIATRIC DISORDERS IN EPILEPSY

Full symptom remission should always be the ultimate goal of any psychiatric
intervention. Current evidence on the management of psychiatric comorbidities
in epilepsy is limited. There is, however, no reason to consider that
internationally adopted guidelines for treatment of psychiatric disorders may not
be valid in epilepsy. It seems reasonable, therefore, to follow standards of care in
psychiatry, taking into account the distinctive needs of people with epilepsy,
including interactions between psychotropic drugs and antiseizure medications,
as well as seizure risk (TABLE 8-2). The management plan should consider a
combination of interventions depending on the origin of symptoms. Although
guidelines of treatment of psychiatric disorders should be adopted for psychiatric
comorbidities or the acute treatment of psychiatric symptoms, seizure control is
the obvious long-term intervention for peri-ictal symptoms60,61 and drug
optimization for side effects of antiseizure medications.
In the general population, psychological interventions, alone or in
combination with drugs, are the first-line treatment for all anxiety disorders62
and for mild to moderate depression.63 It is reasonable to apply this guidance also
to people with epilepsy, but the evidence is still limited and mainly based on
quality-of-life data.64,65 A 2018 ILAE report confirmed that psychological
interventions are recommended in people with epilepsy and mild to moderate
depression, although again the evidence level is still moderate.66
Psychoeducation and psychological interventions still represent first-line
treatments in people with PNES.67 Explaining the diagnosis and educating
individuals and caregivers about the differences between epilepsy and PNES are
extremely important.68 However, no studies on the management of PNES in
patients with epilepsy exist. Outside epilepsy, controlled trials in patients with
PNES are also limited. Data from a US, multicenter, pilot, randomized, clinical

TABLE 8-2 Management of Psychiatric Comorbidities in Epilepsya
Management Comments
Peri-ictal symptoms Improve seizure control Psychiatric opinion in multidisciplinary

(psychiatric symptoms approach to clarify diagnosis and
Consider surgery where appropriate
occurring around seizures) management plan
Treat psychiatric comorbidity if present
Paraictal symptoms Consider reducing the dose of antiseizure Psychiatric opinion in multidisciplinary
(alternating psychiatric medicine or eventually switch to alternative approach to clarify diagnosis and
symptoms and seizures) medication management plan
Major depression Mild to moderate: psychological treatment Consider interaction with enzyme inducers
Severe: selective serotonin reuptake inhibitors Consider side effects of SSRIs (ie,
(SSRIs) (either sertraline 50 mg daily or hyponatremia, sexual dysfunction,
citalopram 20 mg daily) with or without osteoporosis, bleeding, weight gain)
psychological treatment
If two antidepressants fail, refer patient to
psychiatry
If suicidal ideation or psychotic symptoms,
urgent referral to psychiatry
Anxiety disorders Mild to moderate: psychological treatment Consider interaction with enzyme inducers
Severe: SSRIs (either sertraline 50 mg daily or Consider side effects of SSRIs (ie,
citalopram 20 mg daily) with or without hyponatremia, sexual dysfunction,
psychological treatment osteoporosis, bleeding, weight gain)
If fails two interventions refer to psychiatry
First-episode psychoses Urgent referral to psychiatry Consider interaction between quetiapine

and enzyme inducers (ie, undetectable levels
First choice: risperidone
of quetiapine up to 700 mg total daily dose
Second choice: olanzapine or quetiapine when in combination with carbamazepine)
Consider side effects of antipsychotics (eg,
sedation, weight gain with olanzapine)
Attention deficit Methylphenidate Review at transition to discuss opportunity

hyperactivity disorder of continuing treatment during adulthood
Psychological interventions
Psychogenic nonepileptic Explain diagnosis Individualized multidisciplinary approach is

seizures (PNES) always recommended
Educate patients and caregivers about
differences between PNES and epileptic
seizures
Psychoeducational and psychotherapeutic
interventions as in people with PNES only
Always refer to psychiatry to identify other
psychiatric disorders in comorbidity
Treat other psychiatric comorbidities (eg,
depression, anxiety)
a
Reprinted with permission from Mula M, et al, Neurol Clin Pract.2 © 2021 American Academy of Neurology.
464 APRIL 2022

trial of cognitive-behavioral therapy (CBT)-informed therapy with or without KEY POINT
sertraline in people with PNES showed a significant seizure reduction compared
● Choice of medication for
with treatment with sertraline only.69 However, a UK pragmatic, parallel-arm, psychiatric conditions
multicenter, randomized controlled trial failed to show any benefit of CBT in should include
addition to standard medical care for the reduction of monthly seizures.70 consideration of metabolic,
Further studies are needed to identify what patient group may benefit from extrapyramidal
cardiovascular, and
specific interventions.71
hormonal side effects and
In the general population, antidepressants are recommended for moderate to interactions with antiseizure
severe depression and for all anxiety disorders in combination with medications, including the
psychological treatments. possibility of amplifying side
effects of antiseizure
An ad hoc task force of the ILAE is developing the first clinical practice
medications.
recommendations for the pharmacologic treatment of depression in adults with
epilepsy.72 Selective serotonin reuptake inhibitors (SSRIs) can be considered as
first-line treatment when a pharmacologic treatment is needed. All enzyme-
inducing antiseizure medications seem to reduce SSRI blood levels by around
one-quarter, but it is unclear whether dose adjustments are needed.73 Clinical
monitoring is recommended, and antiseizure medication dose adjustments
should be considered depending on clinical response. However, fluoxetine,
fluvoxamine, and, to a lesser extent, sertraline may potentially increase
phenytoin blood levels and valproate blood levels, though to a lesser extent.73,74
The most important interaction of enzyme-inducing antiseizure medications is
with bupropion for which blood levels can be reduced by up to 90% when
combined with, for example, carbamazepine.74 Side effects of antidepressants
include weight gain, sexual dysfunction, hyponatremia, osteopenia, and heart
problems. Coprescription of antidepressants with antiseizure medications with a
similar spectrum of side effects may be obviously associated with an increased
likelihood of developing such side effects (TABLE 8-2).74
Regarding seizure risk, antidepressants have long been considered to be
associated with an increased risk of seizures. However, this is not a drug class
effect, and individual drugs or drug groups should be considered. An analysis of
seizure incidence in phase 2 to 3 clinical trials of psychotropic drugs approved by
the FDA between 1985 and 2004 involving more than 75,000 individuals found
that seizure incidence was not different from that associated with placebo for
SSRIs. Clomipramine at high doses (>150 mg) showed a standardized incidence
ratio of 4 (95% confidence interval [CI], 2.6 to 6.0).75 Bupropion immediate-
release formulation showed also a slightly increased incidence with a
standardized incidence ratio of 1.58 (95% CI, 1.03 to 2.32).75 However, the seizure
rate for the sustained-release formulation was reported similar to that of SSRIs
and in the region of 0.1% at doses of up to 300 mg/d.76 These findings have been
confirmed in a 2018 systematic review.77
Data on antipsychotics in epilepsy are almost nonexistent despite the fact that
this class of medications is used in several clinical contexts, from psychoses to
challenging behavior in people with learning disabilities and autism. For this
reason, internationally adopted guidelines of treatment of psychotic disorders
should be adapted, again taking into account specific issues of people with
epilepsy such as interactions with antiseizure medications and increased risk of
side effects.78
The choice of antipsychotic drug for a first episode of psychosis should
consider the likely benefits and possible side effects of each option, including
metabolic (ie, weight gain and diabetes), extrapyramidal (ie, akathisia,

dyskinesia, and dystonia), cardiovascular (ie, long QT interval), and hormonal

(ie, increased prolactin levels) side effects.79 Olanzapine, quetiapine, and
risperidone are often regarded as first-line treatments for first-episode
schizophrenia to balance safety and efficacy.80 In fact, clozapine and haloperidol
have the same level of evidence in terms of efficacy, but they are both burdened
by a low tolerability and safety profile.43
In epilepsy, postictal psychoses represent an epilepsy-specific problem, and
for this reason, it is not possible to apply evidence from other clinical
populations. Historically, a combination of benzodiazepines (ie, clobazam) and
atypical antipsychotics has been used,81 but no controlled trials have been
conducted. Similarly, no controlled studies have been performed on the use of
antipsychotics in people with epilepsy and autism and challenging behavior.
Regarding interactions, antiseizure medications with enzyme-inducing
properties (eg, phenytoin, carbamazepine, barbiturates) reduce blood levels of
all antipsychotics,73 and this interaction is particularly evident for quetiapine,
where the prescription with enzyme inducers such as carbamazepine can lead to
undetectable blood levels of quetiapine even at dosages of 700 mg/d.82 Although
valproate is usually considered an enzyme inhibitor, it seems to mildly induce the
metabolism of olanzapine, aripiprazole, clozapine, and quetiapine.83 Because
the clinical relevance of this interaction is not certain, it should be considered on
an individual basis. Antipsychotics do not seem to affect blood levels of
antiseizure medications. As discussed for antidepressants, neurologists should
bear in mind combining drugs with a similar spectrum of side effects. Sedation,
weight gain, and risk of arrhythmias or aplastic anemia are side effects to be
considered for specific combinations (TABLE 8-2).
Finally, regarding the seizure risk of antipsychotics, clozapine has a 9.5-times
increased risk compared with placebo,75 and such a risk is dose and titration
dependent.84 Olanzapine and quetiapine also seem to carry some risk, although
to a lesser extent than clozapine; risperidone does not seem to increase the risk of
seizures compared with placebo.75
An ad hoc ILAE task force reviewed studies on treatment of ADHD in children
with epilepsy.50 Response rates for methylphenidate in children with ADHD and
epilepsy range between 65% and 83% whereas only anecdotal evidence is
available for atomoxetine and amphetamines. Data on potential interactions
between methylphenidate and antiseizure medications are limited to older
compounds, but no evidence of clinically relevant interactions exists. A Swedish
study involving more than 21,000 children with seizures showed no evidence
of increased risk of seizures from ADHD medications,85 and this was endorsed by
the ILAE report.50
COGNITION AND EPILEPSY

Cognitive comorbidities represent a common aspect of the experience of living
with epilepsy and can detrimentally impact patient psychosocial functioning,
including educational and vocational trajectories, emotional and social
competence, and well-being.86,87 In general, difficulties with attention, executive
functioning, and memory are commonly reported by patients with epilepsy
and found in up to 70% of untreated patients before the onset of seizures or early
in the diagnostic process.88 These findings point to shared mechanisms that may
underlie cognitive and behavioral impairments as well as seizures in people with
epilepsy, referred to as essential comorbidities. This is further reflected in the
466 APRIL 2022

current understanding of epilepsy as a “network disease,” involving changes in KEY POINTS
underlying brain networks beyond a specific identifiable lesion. Because the
● Cognitive comorbidities
primary function of these networks is to support specific cognitive processes and are common among people
behaviors, this suggests that epilepsy is as much a disorder of cognition and living with epilepsy and can
behavior as it is of seizures.89 range from generalized
Significant variation exists in the manifestation and functional impact of cognitive impairment to
relatively circumscribed
network changes on cognition and behavior.90,91 Even when considering a
deficits.
particular type of epilepsy, individuals may exhibit heterogeneous cognitive
profiles. For example, recent research has described three empirically derived ● The International
cognitive phenotypes in temporal lobe epilepsy, namely those with (1) minimally Classification of Cognitive
impaired cognition, (2) intact language and intelligence with a primary memory Disorders in Epilepsy seeks
to advance the
impairment, and (3) generalized cognitive compromise.91 These groups also understanding of the
demonstrate differences in the presence and severity of neuroanatomic essential cognitive
abnormalities in networks.92 comorbidities of epilepsy.
Further complicating the picture, cognitive difficulties in epilepsy can occur
transiently as a result of seizure activity, may relate to interictal spikes, the side
effects of antiseizure medications, and can be exacerbated by mood and
behavioral difficulties.23,93-95 In an effort to address these complexities, the
Neuropsychology Task Force of the ILAE has introduced the development of a
new International Classification of Cognitive Disorders in Epilepsy to advance
our understanding of the essential cognitive comorbidities of epilepsy.96
Epidemiology of Intellectual Disability and Dementia in Epilepsy

Because intellectual disability and dementia are common comorbidities of
epilepsy, they are particularly important for the neurologist to bear in mind and,
thus, form the focus of the remainder of this article.
In DSM-5, the presence of an intellectual disability is typically defined as a
full-scale IQ of ≤65 to 75, reflecting cognitive functioning significantly below the
population mean of 100 (CASE 8-1).
By highlighting the “network” nature of epilepsy as discussed earlier, the
relationship between epilepsy and intellectual disability appears bidirectional.
This is supported by research findings indicating that children with epilepsy are
more likely to be diagnosed with a comorbid intellectual disability98 and
prevalence estimates of 1 in 5 individuals with intellectual disability diagnosed
with comorbid epilepsy.99 The prevalence of comorbid epilepsy typically
increases with increasing severity of intellectual disability. Pooled estimates of
epilepsy in moderate intellectual disability have been identified at 16.7% (95% CI,
10.8 to 25.0) compared with 27.0% (95% CI, 16.1 to 41.5) for severe intellectual
disability and 50.9% (95% CI, 36.1 to 65.5) for profound intellectual disability.99
Underscoring the importance of comprehensive care for this group compared
with those with intellectual disability without epilepsy, people living with
intellectual disability and epilepsy are at increased risk of a range of other
impairments. This can include increased risk of a speech handicap (73.6% versus
50.0%), motor handicap (54.4% versus 14.4%), joint disease (29.3% versus 16.8%),
gastrointestinal disease (34.5% versus 23.4%), and stroke (5.2% versus 1.9%).99
Among children living with epilepsy, rates of psychiatric and behavioral issues
are 2.5 times greater than for their healthy peers.98 For those living with moderate
to severe intellectual disability, the detection of psychiatric disorders can often
be “overshadowed” by behavioral issues such as aggression or self-injurious
behaviors.100 In this way, the presentation of anxiety and depression among

individuals with epilepsy and intellectual disability will often be “atypical,” and it
is important to assess any changes to behavior that may indicate mood changes.
When looking to treat psychiatric and behavioral issues among those living
with epilepsy and comorbid intellectual disability, it is important to consider that
the impact of intellectual disability is not necessarily restricted to cognitive
changes, such as difficulty with processing of new information, reasoning, and
problem-solving, but it also affects emotional intellect and the ability to express
and regulate one’s emotions.101,102 How differences in emotional intellect present
can vary and may be exacerbated by the nature of the intellectual disability
and cognitive difficulties. For example, research in this area has found that
people with intellectual disability are more able to identify an emotion than
verbally express it,103 which may be linked to underlying poor verbal intellect
and difficulty with complex cognitive functions such as abstract verbal
reasoning. Research identifying that 75% of adults with intellectual disability can
successfully link emotions to situations104 shows the benefit that people with
intellectual disability may get from “scaffolding,” or providing cues to support
correct emotion recognition and discussion.
A syndromic approach to classifying epilepsy can be particularly useful when
considering childhood epilepsies, with a syndrome diagnosis at presentation
possible in up to three-quarters of children.105 Several childhood epilepsy
syndromes involve significant developmental delay, intellectual disability, and
CASE 8-1 A 28-year-old woman was referred for surgical workup in the context of
temporal lobe epilepsy with hippocampal sclerosis. Preoperative
language functional MRI (fMRI) was inconclusive, showing bilateral
activation on some language tasks. This was due to a combination of
difficulty the patient experienced with the language tasks given, as well
as poor-quality imaging due to movement artifact. A preoperative
neuropsychological assessment confirmed intellectual disability, with an
estimated full-scale IQ of 68, as well as relative further reductions in
verbal new learning and memory. Collateral history from the family
aligned with the objective cognitive findings. The patient lived at home
with her parents and relied on her family for support with activities of
daily living. As such, both the patient and her family were included in the
preoperative counseling process. When asked about their expectations
for surgery, the family voiced concerns about the possible severe risks of
surgery, including stroke, and wondered if surgery would result in
significant loss of autobiographic memory (eg, forgetting people within
the family and where they live).
Presurgical counseling involved counseling regarding the typical
changes seen after a left anterior temporal lobectomy (eg, increased
word-finding difficulties and a possible drop in verbal memory) and
tailored counseling for this patient’s likely risks and benefits. Given the
patient’s premorbid intellectual disability, presurgical counseling also
included consideration of external supports, such as occupational
therapy, social work, and clinical psychology.
468 APRIL 2022

severe drug-resistant epilepsy (TABLE 8-3).106 These are often referred to as the
developmental epileptic encephalopathies and include syndromes such as
Lennox-Gastaut syndrome and Landau-Kleffner syndrome. Briefly, an epileptic
encephalopathy has been defined by the ILAE as “a condition in which the
epileptiform abnormalities themselves are believed to contribute to the
progressive disturbance in cerebral function.”107 Distinct from a
neurodegenerative condition, the epileptic encephalopathies can vary
significantly over the course of disease, and effective seizure control may be able
to improve the overall prognosis.108 Although antiseizure medications remain
the first line of treatment, other types of treatment such as vagus nerve
stimulation and the ketogenic diet are also used and more commonly among the
epileptic encephalopathies than among other epilepsy syndromes.109
Advances in genetics have also shed light on rare genetic epilepsy syndromes
that involve significant cognitive comorbidities, such as KCNQ2 and SYNGAP1.
These syndromes are rarely encountered in the clinic, with only approximately
200 individuals with SYNGAP1 identified, although more individuals are
suspected to have the gene.108,110 Improvements in genetic testing that have
allowed the provision of a diagnosis are important for identifying appropriate
treatment and can provide families with some sense of relief and a direction
forward, as well as a sense of community and peer support if they are able to
connect with others in a similar situation.110
This patient is a good candidate for epilepsy surgery, given she is young and COMMENT
has lesion-positive temporal lobe epilepsy with hippocampal sclerosis and a
memory deficit identified before surgery. As such, she is less likely to notice
a significant drop in her verbal memory postoperatively. However, the case
also illustrates how the presence of an intellectual disability can complicate
the preoperative workup because (1) the patient may not be a reliable
historian (necessitating a collateral report from the family); (2) disentangling
specific cognitive deficits (eg, language) can be difficult when generalized
cognitive impairment is present; this may have impacted fMRI findings in this
case, as the patient found typically “straightforward” language tasks
challenging; and (3) the presence of an intellectual disability raises
considerations in terms of gaining informed consent.
The International League Against Epilepsy (ILAE) currently recommends
the commencement of “prehabilitation” prior to surgery. In contrast to
traditional cognitive rehabilitation, which occurs after a neuropsychological
deficit has been sustained, candidates for epilepsy surgery can engage in
prehabilitation. This is the process of utilizing still-intact functions prior to
surgery to proactively establish compensatory strategies and routines in
preparation for postoperative changes.97 This process of presurgical
counseling should include expectation management for both the patient
and the family, as well as discussion of broader supports and cognitive
strategies that could be implemented in the household. Establishing rapport
and routine with support workers before surgery will help maximize
adjustment and postsurgical recovery.

An increasingly important cognitive comorbidity of epilepsy to consider is

dementia. Because of the aging population, dementia is a national health priority
for many countries and the focus of a significant amount of research. Epilepsy
and seizures are commonly associated with the occurrence of both stroke and
dementia, two of the most common neurologic conditions in an aging
population.111 The relationship between dementia and epilepsy appears
bidirectional, with an increased risk of seizures among those with dementia and
an increased risk of dementia for those with epilepsy.90,112 For example, the
period prevalence of an individual with epilepsy developing dementia has been
estimated between 8.1 and 17.5 per 100 people, and the period prevalence of
epilepsy among those with dementia has been estimated at 5 per 100 people in
TABLE 8-3 Childhood Epilepsy Syndromes Associated With Significant Developmental

Delay and/or Intellectual Disability
Epilepsy syndrome Description
Lennox-Gastaut syndrome Etiology: two of three cases are symptomatic of a variety of diffuse, multifocal, or focal brain
insults including some metabolic disorders
Prevalence: Lennox-Gastaut syndrome constitutes 1-2% of the epilepsies and 1-10% of
childhood-onset epilepsies (depending on the age considered); Lennox-Gastaut syndrome is
more common in boys than girls
Onset: from infancy to late childhood but peaks at 3-5 years of age
Seizure types: atonic, tonic, atypical absence
Comorbidities: developmental delay, severe intellectual disability, behavioral problems; a
good prognosis with normal cognitive functioning is reported in 10-15% of cases
Doose syndrome Etiology: considered a form of idiopathic generalized epilepsy

Prevalence: Doose syndrome constitutes approximately 1-2% of childhood-onset epilepsies
and is more common in boys than girls
Onset: early to midchildhood, peaking around 2-4 years
Seizure types: febrile and afebrile generalized tonic-clonic seizures, myoclonic-astatic
seizures, atonic, myoclonic, and absence
Comorbidities: cognitive comorbidities can vary in occurrence and severity; approximately
half eventually will achieve seizure freedom and normal or near-normal developmental
trajectories
Dravet syndrome Etiology: approximately 80% of those with Dravet syndrome have a mutation in the SCN1A
(severe myoclonic epilepsy of gene; Dravet syndrome lies at the severe end of the manifestation of this gene
infancy)
Prevalence: Dravet syndrome affects 1 in 15,700 individuals
Onset: in infancy (within the first year)
Seizure types: include myoclonic, hemiclonic, and/or generalized tonic-clonic; seizures are
frequent and prolonged
Comorbidities: developmental delay is not always evident until the first or second year of life.
Comorbidities include delayed language, behavioral difficulties, movement and balance
disorders, orthopedic disorders, sleeping difficulties, and chronic infections and
dysautonomia
470 APRIL 2022

population-based settings.113 To highlight the importance of understanding
cognitive comorbidities in epilepsy, those with epilepsy and intellectual disability
are also at greater risk of developing dementia than are individuals with epilepsy
without intellectual disability.99
When examining specific types of dementia, research often points to vascular
dementia and Alzheimer disease as particularly associated with the risk of
developing seizures.90,113 Other forms of dementia, such as frontotemporal
dementia or dementia with Lewy bodies (DLB), have received less attention in the
literature112; however, one 2020 study suggested a reasonably consistent prevalence
of epilepsy across dementia types, with a prevalence of recent-onset epilepsy
among those with Alzheimer disease at 1.82% versus 1.28% for frontotemporal
Epilepsy syndrome Description
Landau-Kleffner syndrome Etiology: a rare form of epilepsy, sometimes called progressive epileptic aphasia or aphasia
with convulsive disorder; develops in children with no structural brain abnormalities
Prevalence: estimates from a Japanese study indicate prevalence between 44.2 and 59.2 per
18 million106; affects twice as many boys as girls
Onset: early neurodevelopment is typically normal; onset is usually in early to midchildhood,
peaking at 5-7 years, and manifests as a slow or sudden loss of receptive and expressive
language
Seizure types: approximately 70% of children with Landau-Kleffner syndrome will have
seizures; seizures may be of different types (most commonly focal motor seizures) and are
typically infrequent
Comorbidities: cognitive comorbidities occur in a triad of symptoms, namely acquired
language problems, as well as general cognitive and behavioral abnormalities; approximately
half will experience remittance of symptoms and function normally in adult life
Rasmussen encephalitis Etiology: a rare, chronic neuroinflammatory condition; typically affects only one hemisphere
(half of the brain), but it can sometimes progress to involve the whole brain
Prevalence: estimates of prevalence are between 1.7 and 2.4 per 10 million
Onset: most commonly occurs before the age of 10 years but can also occur in adolescence
and adulthood
Seizure types: focal onset and frequent and severe; approximately half of those with
Rasmussen encephalitis will experience epilepsia partialis continua (recurrent and
unrelenting focal seizures with retained awareness that can last hours, days, or even years)
Comorbidities: progressive loss of neurologic functioning, including motor skills, speech, and
cognitive functioning; as it progresses, it may cause a hemiparesis; children with Rasmussen
encephalitis frequently enter a phase of permanent, but stable, neurologic deficits after 8 to
12 months; the disease in adults and adolescents may continue to progress slowly.

dementia and 2.47% for DLB.112 Given the more common presentation of
Alzheimer disease and vascular dementia in the clinic, however, these will likely be
the most encountered forms of dementia with epilepsy seen by clinicians.
A commonly considered mechanism for epileptogenesis in dementia is thought
to be increased cortical excitability caused by cortical deposition/aggregation of
pathologic proteins; however, the precise cause of epileptic seizures in patients
with dementia remains unknown.112 Researchers have also highlighted several
common underlying risk factors, including vascular risk factors that may
predispose to atherosclerosis and raised inflammatory markers, as well as lifestyle
factors such as decreased social interaction and reduced physical activity.90
Implications of Cognitive Comorbidities in the Diagnosis of Epilepsy

The presence of cognitive comorbidities has implications for the diagnostic
process and clinical decision making around treatment, including gaining
FIGURE 8-1
An overview of the process of neuropsychological formulation, taking into consideration not
only neurophysiologic factors (epilepsy dimension) but also developmental, intrinsic,
cognitive, psychological, and social factors.
Reprinted with permission from Gonzales LM and Wrennall JA, Seizure.123 © Elsevier Ltd.
472 APRIL 2022

informed consent and assessment of decision-making capacity. An KEY POINTS
understanding of cognitive capacity should be fundamental to how clinicians
● Cognitive difficulties may
structure clinical interactions, including establishing rapport, ensuring an extend beyond intellectual
adequate understanding of diagnostic information and treatment functions, such as attention
recommendations, and engaging family members/caregivers as part of the and memory, and may
extended clinical care team (CASE 8-1).114 include difficulties with
emotional expression and
Subjective cognitive concerns are common among people living with
regulation.
epilepsy,115 and identifying whether an objective cognitive deficit is present can
sometimes be difficult to determine at face value. The weight of the evidence to ● Several specific
date has indicated generally poor to modest (at best) associations between childhood epilepsy
subjective memory concerns and tested memory functions.116 In general, syndromes typically involve
significant developmental
memory concerns have been found to be more related to factors such as mood delay and/or intellectual
and anxiety disorders, general psychological distress beyond depression, and disability. Many of these
illness perceptions.116 Memory symptoms may also be linked to objective syndromes represent rare
cognitive performance in nonmemory domains, including language and genetic epilepsy syndromes.
attention.117 For patients with dementia, strident cognitive symptoms are often ● An epileptic
seen in the early stages of disease when the individual is experiencing mild encephalopathy has been
cognitive impairment. In the later stages of disease progression, the memory defined by the International
symptom is often vague and muted, reflecting loss of insight.118 League Against Epilepsy as
“a condition in which the
Cognitive deficits may be detected at several points during the interview and
epileptiform abnormalities
assessment of a patient. In conversation, it may be possible to notice changes in themselves are believed to
speech, including dysnomia or anomia (word-finding difficulties), a sense of contribute to the
vagueness and difficulty providing a clear history, confabulation,119 progressive disturbance in
cerebral function.”
inappropriate or disinhibited behaviors, and emotional lability. As such, it is
often important to gain permission to speak with a family member or caregiver to ● The recognition of a
obtain further insights into the patient’s cognitive functioning and how it bidirectional relationship
impacts daily living (CASE 8-1). between epilepsy and
Cognitive screening measures, such as the Montreal Cognitive Assessment dementia is growing, with an
increased risk of dementia
(MoCA) or Mini-Mental State Examination (MMSE), can also be useful in among people living with
identifying patients who require more detailed neuropsychological assessment to epilepsy and an increased
diagnose a cognitive comorbidity.120,121 Here, it is important to remember that risk of seizures in dementia.
screening measures are not diagnostic instruments, and individuals may obtain
● Increased risk of seizures
low scores on these measures for a range of reasons.122
has been identified across
To properly diagnose a cognitive deficit, a formal neuropsychological several different dementia
assessment should be conducted; it is a collaborative and holistic process that syndromes, including
takes into account biological, neurodevelopmental, psychological, and broader Alzheimer disease,
frontotemporal dementia,
social factors when considering the patient’s cognitive presentation
and dementia with Lewy
(FIGURE 8-1).122,123 Obtaining an accurate neuropsychological assessment at bodies.
baseline is important for identifying changes following treatment, including the
addition of new medications or surgery or both, as well as tracking progression ● Risk factors for seizures in
over time if a neurodegenerative process is suspected.124 Neuropsychological dementia include poor
cardiovascular health,
assessment of intellectual and communication skills also provides important data raised inflammatory
on a patient’s ability to comprehend, communicate, and problem-solve, as well as markers, decreased
their level of insight and ability for self-reflection. This is relevant to how well the physical fitness, and
patient can understand and retain new information and their level of readiness decreased social
interaction.
for certain treatments, such as epilepsy surgery or psychological therapy or both.
Some practical considerations for working with people with epilepsy and
cognitive comorbidities are summarized in TABLE 8-4.
In the diagnostic process, cognitive comorbidities may impact a person’s
ability to recall and/or describe seizure experiences well to the clinician, or they

TABLE 8-4 Recommended Adaptations to Psychological Therapy in Adults With

Intellectual Disabilitiesa
Therapeutic element Adaptations recommended
Establishing patient abilities
Assessment Full neuropsychological assessment (eg, intellect, language, memory)
Emotion recognition and cognitive regulation of emotions
Developmental level Intellectual ability, communication, and social skills
Treatment readiness: internal motivation and self-reflective capacity
Diagnosis Risk of diagnostic overshadowing (see text for details)
Consider both patient self-report and validation from other stakeholders

in patient care (eg, support services, other health practitioners)
Adaptations focused on improving cognitive

and emotional skills
Scaffolding Reduce complexity of therapy
Use psychoeducation as building blocks to therapy goals
Self-reflection Reinforce and utilize positive influences (eg, friendships, hobbies)
Encourage areas where self-management is evident
Acknowledge challenges (may include disability-specific factors)
Adaptations focused on improving

communication and patient “buy-in”
Language Appropriate for the patient’s level of understanding
Rapport Paraphrasing to aid reflection and probe questions to confirm mutual

understanding of discussion content
Use of pictorial representations, games, and nonverbal methods
External support (eg, caregivers) A more directive approach may be required
Providing a space for, and encouragement of, self-efficacy
Build self-motivation
Awareness of influential psychosocial factors (eg, finances)
Possible administrative engagement with community services
Involvement can support therapeutic goals
Therapy with and without supporters present enhances autonomy
Flexibility Dynamic engagement strategies (eg, therapy setting, involvement of

others, small goals to foster self-belief and “buy-in”)
a
Reprinted with permission from Trevis KJ, Wilson SJ, Springer International Publishing.114 © 2016 Springer International Publishing.
474 APRIL 2022

may manifest in ways that resemble seizure activity (eg, attentional or language KEY POINTS
difficulties). Moreover, epilepsy can often go undetected among those with
● Subjective cognitive
dementia because of diagnostic overshadowing or misattribution of the side concerns are not always
effects of medications.125 correlated with objective
Some have suggested that the variable clinical presentation of seizures in older cognitive performance and
adults is increased because of the relatively high prevalence of underlying may be influenced by mood,
lack of insight, and other
cerebrovascular disease, resulting in heterogeneity of the epileptogenic focus.90
psychological factors.
Several common seizure mimics can also be seen in older adults including
syncope, transient ischemic attacks, migraine, panic attacks, and sleep disorders, ● Different cognitive
as well as staring or behavioral spells in patients with static encephalopathy screening measures may
or dementia.90,125 include the Montreal
Cognitive Assessment
(MoCA) or the Mini-Mental
Management of Cognitive Comorbidities in Epilepsy State Examination (MMSE).
Despite the large amount of literature on cognitive problems in epilepsy, a However, cognitive
relatively small number of studies directly assess the efficacy of pharmacologic or comorbidity can only be
properly diagnosed
neuromodulatory interventions on cognition. As pointed out in a systematic following a comprehensive
review on this subject, available studies are limited by the small sample size, the workup that includes
heterogeneity of epilepsy types and antiseizure medications prescribed, formal neurologic,
variability in cognitive assessment tools, and inconsistent consideration of neuropsychological, and/or
neuropsychiatric
possible moderating factors such as mood.126 Studies that investigated cognitive assessment.
enhancement in epilepsy per se showed a lack of efficacy of classic
acetylcholinesterase inhibitors.127 This is probably because of the etiology of ● Consideration of a
memory dysfunction in epilepsy being mediated via mechanisms other than loss of patient’s cognitive
functioning is crucial in the
cholinergic neurons. Noninvasive neuromodulation in epilepsy is appealing
workup to epilepsy surgery.
because of the potential to have an impact on seizure frequency and/or interictal This is important not only in
epileptiform discharge frequency, but data on cognition are still limited.126 Data on considering the possible
the management of epilepsy in patients with cognitive disorders are also limited. cognitive risks of surgery but
Some authors suggested that epilepsy in Alzheimer disease responds better to also in how clinicians discuss
the surgery with patients
antiseizure medications compared with other types of dementia, although these and their family members
results may be affected by the relatively small numbers of those with other types and obtain informed
such as frontotemporal dementia and DLB.112 The treatment of epilepsy in consent. Cognitive aids,
dementia will no doubt be an area of much ongoing investigation in the future. such as written and/or
simplified information, may
When surgical treatment for epilepsy is considered, it is important for the be helpful for some
team to have thorough discussions with patients and their families, weighing the patients.
risks and benefits of undergoing surgery (CASE 8-1).128 In obtaining informed
consent for surgery, the clinician should consider alternative ways of
communicating possible risks and benefits to scaffold the patient’s
understanding. This could include diagrams and written information, as well as
connecting the patient with a “peer,” or someone with epilepsy who has been
through surgery before. This can provide them with a more concrete and tangible
understanding of some of the possible benefits and/or risks of surgery. It is also
important to include the family throughout the presurgical workup and
counseling process so that the family can (1) understand and retain the relevant
information to discuss with the patient later, (2) support the patient in asking
questions in what might feel like an intimidating clinical environment, and (3) be
provided with the opportunity to ask their own questions. The expectations of
both the patient and the family should be carefully explored and addressed in the
presurgical counseling process because the family may be expecting surgery to
produce changes in the individual’s cognitive and psychosocial functioning as
well as their seizure frequency.129,130

Although seizures and cognitive dysfunction are often symptomatic of shared

underlying network disease, postoperative improvement in seizure frequency
does not automatically translate to improved cognitive and/or behavioral
functioning. In some cases, seizure reduction can bring to the fore other signs
of cerebral dysfunction previously not noticed by the family because of their
focus or misattribution to seizures.129,130 This can add to the experience of
caregiver burden or stress and increase the likelihood of poor postoperative
adjustment.114,129,130
If epilepsy is to be recognized as more than a seizure disorder, treatment
choices need to consider more than antiseizure medications. Dementia,
intellectual disability, and epilepsy are all conditions where real and
perceived personal control over the environment is reduced. Loss of control,
whether real or perceived, is often associated with heightened anxiety
and distress.131
In the field of psychology, a growing body of research points to the benefits
of adapted therapeutic approaches, such as CBT, for the treatment of anxiety
and depression in patients with cognitive deficits.132 These approaches can
help foster greater self-awareness and insight, as well as increased emotional,
behavioral, and social self-regulation among those with epilepsy and mild
intellectual disability.114 For those with more severe cognitive deficits,
treatments may also need to involve behavioral interventions aimed at
reducing challenging behaviors, as well as psychoeducation and support for
the family.133
In the general population, psychosocial risk factors for cognitive decline in
older age can include decreased physical and mental activity.90 These factors are
more common among people living with epilepsy because of the associated
psychosocial restrictions of seizures, such as the inability to drive,
unemployment or underemployment, and experiences of stigma and
discrimination.134 This may have a cumulative effect over the course of a lifetime
for those with early-onset epilepsy but can also be a significant impediment to
socializing among those with older-onset epilepsy and cognitive comorbidities.
For people with epilepsy and intellectual disability, the experience of
psychosocial challenges is often reported to be heightened, including higher rates
of trauma and abuse, family stressors, unemployment and poverty, less
participation in the community, a lack of meaningful friendships or intimate
relationships, and elevated rates of mental health difficulties.114 These
psychosocial challenges significantly impact a person’s day-to-day functioning
and quality of life and are often perceived as more detrimental than seizures.122
People with epilepsy and intellectual disability face the added challenge of
living with often “hard-to-treat” epilepsy, for which information is limited on the
long-term effects of seizures on their cognitive and behavioral functioning.114
Both patients and their families, then, can often have apprehension about the
future, possible progression of cognitive symptoms, and the provision of long-
term care. For patients with dementia and epilepsy, although a degenerative
cognitive trajectory is expected, this is equally challenging for both patients and
their family/caregivers, particularly as patients become increasingly reliant on
those around them to manage their epilepsy. Beyond the individual, it is also
important to consider systemic factors that may present barriers to effective care.
Prevalence estimates suggest that nearly 80% of people living with epilepsy are in
low- or middle-income countries, with a rate of new cases up to twofold higher
476 APRIL 2022

than that of high-income countries.135 Limitations in resources mean that many KEY POINT
of these patients will not be able to access specialist care to optimize medical
● Consideration of
treatment of their epilepsy or have access to allied health support to manage the psychiatric well-being is
cognitive and psychosocial sequelae of epilepsy. Further barriers to care may important not only for
include cultural factors and illness beliefs and increased stigmatization around patients’ general well-being
epilepsy, as well as practical barriers such as difficulty traveling to clinics or but also for their subjective
cognitive functioning,
accessing alternatives such as telehealth.135-137
because the reduced
physical and social activity
that may be prompted by
CONCLUSION low mood can be
detrimental to cognition.
People living with epilepsy are at increased risk of both psychiatric and cognitive
comorbidities. These are now thought to represent “essential comorbidities” (ie,
the manifestation of changes to underlying brain networks). Consideration of
comorbidities should occur throughout the clinical interview, diagnostic, and
treatment process.
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epilepsy in older adults: what does it mean for 2322-2332. doi:10.1111/epi.1704
the primary care physician? Geriatrics 2005;
137 Sanchez N, Kajumba M, Kayegira J, et al.
60(10):30-35.
Stakeholder views of the practical and cultural
126 Jacobs CS, Willment KC, Sarkis RA. Non-invasive barriers to epilepsy care in Uganda. Epilepsy
cognitive enhancement in epilepsy. Front Neurol Behav 2021;114:107314. doi:10.1016/j.
2019;10(167). doi:10.3389/fneur.2019.00167 yebeh.2020.107314
127 Hamberger MJ, Palmese CA, Scarmeas N. A
randomized, double-blind, placebo-controlled
trial of donepezil to improve memory in
epilepsy. Epilepsia 2007;48(7):1283-1291.
doi:10.1111/j.1528-1167.2007.01114.x
482 APRIL 2022

Approach to the Medical REVIEW ARTICLE

Treatment of Epilepsy C O N T I N U UM A U D I O
ONLINE
By Francesco Brigo, MD; Anthony Marson, MBChB, MD, FRCP
ABSTRACT
PURPOSE OF REVIEW: This article discusses the use of antiseizure medications
in the treatment of focal and generalized epilepsies using an evidence-
based approach.
RECENT FINDINGS: In recent years, several new antiseizure medications with

differing mechanisms of action have been introduced in clinical practice,
and their efficacy and safety has been evaluated in randomized controlled
clinical trials. Currently, all antiseizure medications can prevent seizure
occurrence, but they have no proven disease-modifying or
antiepileptogenic effects in humans. The choice of therapy should
integrate the best available evidence of efficacy, tolerability, and
effectiveness derived from clinical trials with other pharmacologic
considerations, the clinical expertise of the treating physicians, and
patient values and preferences. After the failure of a first antiseizure
medication, inadequate evidence is available to inform policy. An
alternative monotherapy (especially if the failure is because of adverse
effects) or a dual therapy (especially if failure is because of inadequate
seizure control) can be used.
SUMMARY: Currently, several antiseizure medications are available for the

treatment of focal or generalized epilepsies. They differ in mechanisms of CITE AS:
action, frequency of administration, and pharmacologic properties, with a CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):483–499.
consequent risk of pharmacokinetic interactions. Major unmet needs
remain in epilepsy treatment. A substantial proportion of patients with Address correspondence to
epilepsy continue to experience seizures despite two or more antiseizure Dr Francesco Brigo, Department
of Neurology, Hospital of
medications, with a negative impact on quality of life. Therefore, more Merano, Via Rossini 5-39012,
antiseizure medications that could provide higher seizure control with Merano-Meran, Italy,
good tolerability and that could positively affect the underlying disease dr.francescobrigo@gmail.com.
are needed. RELATIONSHIP DISCLOSURE:

Dr Brigo reports no disclosure.
Dr Marson has received
publishing royalties from Oxford
University Press.
INTRODUCTION
T
his article discusses the use of antiseizure medications in the UNLABELED USE OF
treatment of focal and generalized epilepsies. An evidence-based PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
approach is used, focusing where possible on the results of high- Drs Brigo and Marson report no
quality randomized controlled clinical trials and systematic reviews of disclosures.
randomized controlled trials. Priority is given to results of randomized
controlled trials, since their study design minimizes the risk of bias, enabling a © 2022 American Academy
more reliable inference of treatment effect associated with an intervention. of Neurology.

MEDICAL TREATMENT OF EPILEPSY
Where high-quality randomized trials are not available, information from

nonrandomized trials and observational studies is used. Evidence from
nonrandomized studies is particularly important when assessing harms (such
as teratogenicity) and longer-term effects that occur outside the time frame
of what is deliverable in randomized controlled trials.
The practice of evidence-based medicine includes the integration of the best
available research evidence with clinical expertise and patient values and
preferences in making decisions about the care of individuals1; therefore, every
clinical decision should always consider these three components. The clinical
experience of the authors is also reflected in this article.
The use of a drug in clinical practice requires rigorous evidence that it
positively affects a health outcome (ie, has efficacy) and is safe. In epilepsy, if an
antiseizure medication reduces the risk of seizure occurrence without
unacceptable adverse effects, it may be considered for use in clinical practice.
Clinical practice is best informed by evidence about the comparative efficacy
and safety of treatment options generated from head-to-head randomized
controlled trials; however, most epilepsy trials are placebo controlled, and few
head-to-head trials have been undertaken, especially for treating
refractory epilepsy.
The initial focus of antiseizure medication development is to meet the
requirements of the regulatory authorities (eg, the US Food and Drug
Administration [FDA] in the United States and the European Medicines Agency
in Europe) to gain a licensed indication.2 Antiseizure medications will typically
be tested first as adjunctive treatments in adults with drug-resistant focal
epilepsy in placebo-controlled trials that assess efficacy and safety over a 12- to
16-week period. This is usually followed by assessment in other scenarios, such as
in children with drug-resistant focal epilepsy, as adjunctive treatment in
generalized epilepsies or specific epilepsy syndromes, or as monotherapy.
Monotherapy licenses for new antiseizure medications therefore lag behind
licenses for add-on treatment.3
The regulatory adjunctive trials in drug-resistant epilepsy provide evidence of
efficacy by testing whether the drug works under ideal conditions. These trials
are usually conducted in a selected population with a high seizure frequency,
which limits their generalizability to those with drug-resistant epilepsy and to
other patient groups (eg, children). Being placebo controlled, they do not
provide direct evidence about the relative efficacy of antiseizure medications.
Furthermore, they are conducted over a limited time frame and hence do not
provide information on longer-term outcomes, which are vital to inform
treatment decisions for long-term conditions such as epilepsy. Although these
studies have high internal validity, having been designed to minimize the risk of
bias and provide an accurate evaluation of the causal relationship between
exposure to the drug and the selected outcome, they have poor external validity
(ie, low or poor generalizability of results) because of the strict and narrow
inclusion criteria, outcomes used, and short time frame over which they are
measured; they therefore have limited value in informing clinical practice.
To gain a license for monotherapy, the regulatory authorities have differing
requirements for trial design2: in Europe, the European Medicines Agency
requires head-to-head trials designed to show noninferiority against a standard
treatment for achieving 6 months’ remission from seizures. Conversely, the
FDA will not accept noninferiority designs because of concerns about assay
484 APRIL 2022

sensitivity.4 Instead, they require the demonstration of superiority, which has led KEY POINTS
to trials of doubtful ethical conduct and trials using historical controls.5
● The practice of evidence-
After regulatory requirements have been met, the drug is marketed. However, based medicine integrates
at this stage, the real-world clinical effectiveness is unknown and requires further the best available research
assessment. Ideally, this should be done in pragmatic randomized controlled evidence with clinical
trials, which are usually unblinded, include a broad population, and select the expertise and patient values
and preferences in making
outcomes that patients and clinicians are most interested in and are assessed over
decisions about the care of
a number of years. Although pragmatic trials can provide information that can individuals.
inform every clinical practice, because of the lack of blinding they can be more
prone to bias (lower internal validity with higher external validity). ● Evaluating and integrating
Evaluating and integrating data on efficacy and safety is essential to conclude data on efficacy, safety, and
effectiveness is essential to
whether a certain drug can improve a health outcome and, therefore, to obtain obtain the best information
the best information upon which to make treatment decisions.6 upon which to make
treatment decisions.
FIRST UNPROVOKED SEIZURE
● Estimating the risk of
Currently, all medications available for the treatment of epilepsy can prevent seizure recurrence for an
seizure occurrence but have no significant impact on the underlying disease individual and the effect of
process.7 Thus, they should be regarded as antiseizure medications rather than antiseizure medication on
antiepileptic drugs.8 Estimating the risk of seizure recurrence for an individual as that recurrence risk is
crucial to inform the
well as the effect of antiseizure medication on that recurrence risk is therefore
decision on whether to start
crucial to help inform the decision on whether to start antiseizure medication antiseizure medication
treatment. According to the current International League Against Epilepsy treatment.
(ILAE) definition,9 it is possible to make a diagnosis of epilepsy even after a
single unprovoked seizure, provided that the risk of seizure recurrence for an ● Antiseizure medication
treatment following a first
individual can be reliably predicted. Some evidence from observational studies unprovoked seizure reduces
and clinical trials identifies subgroups of patients at a higher risk of seizure the risk of a seizure
recurrence, but the ability to precisely predict seizure recurrence risk for recurrence with no impact
individual patients is limited. Important risk factors include elements of the on longer-term seizure
remission rates.
history, physical examination, and findings on EEG and neuroimaging
investigations.10 For example, an EEG showing generalized 3-Hz spike-and-wave
discharges in a patient with a first-ever generalized tonic-clonic seizure indicates
idiopathic generalized epilepsy and a higher seizure recurrence risk. Individual
patient data from a large randomized trial of immediate versus deferred
antiseizure treatment11 have been used to develop predictive models to enable
identification of patients at low, medium, or high risk of seizure recurrence.10
The risk of recurrence for unprovoked seizures is mainly determined by their
etiology.12 For example, a single seizure occurring more than 1 week after a stroke
is associated with a risk of seizure recurrence of 71.5% (95% confidence interval,
59.7% to 81.9%; P=.001) over 10 years of follow-up. Conversely, the risk of
seizure recurrence following a single unprovoked seizure with other etiologies
(eg, dementia, traumatic brain injury, or central nervous system infection) can
vary and depends on individual factors.12,13 In these conditions, more studies
are needed for individualized prediction of recurrence risk (CASE 9-1).
Randomized controlled trials have shown that antiseizure medication
treatment following a first unprovoked seizure reduces the risk of a seizure
recurrence14 but has no impact on longer-term seizure remission rates.11 In
addition, antiseizure medications are associated with adverse effects that can
diminish quality of life.15 The impact of antiseizure medications on seizure
recurrence risk is, however, modest; prognostic modeling10 has indicated that the
risk of seizure recurrence at 3 years is reduced from 50% to 35% in those at

medium risk (unprovoked seizure and abnormal EEG) and from 67% to 46% for
those at high risk of recurrence (abnormal EEG and neurologic deficit). In
practice, it is those at high risk of seizure recurrence who are likely to opt for
antiseizure medication, although in the authors’ experience, many would prefer
to await another seizure before doing so. It is important, therefore, to consider
each case separately and disconnect the fact that that some individuals might be
given a diagnosis of epilepsy following a single seizure with the need to start
CLASSIFICATION OF EPILEPSIES
The current classification of epilepsies was proposed by the ILAE in 2017.16 It is a
multilevel classification that starts by classifying the type of seizure (first level)
and then the patient’s type of epilepsy (second level) based on the history, results
CASE 9-1 A 68-year-old man was admitted for sudden onset of a left hemiparesis.
Initial investigations revealed atrial fibrillation and a hypodensity in the
right middle cerebral artery territory. Twenty hours later, he had a focal
motor clonic seizure (left hand and arm jerks). Levetiracetam up to
1000 mg/d and warfarin were initiated, and the patient was discharged
with a residual left hemiparesis. Four weeks after the stroke, the
levetiracetam was tapered off and discontinued. Six months after
levetiracetam discontinuation, the patient had a focal motor seizure
evolving to a bilateral tonic-clonic seizure. Levetiracetam was restarted,
and no further seizures occurred.
COMMENT This case illustrates the importance of evaluating the risk of seizure
recurrence to inform the decision on whether to start antiseizure
medication treatment. This patient had a first seizure occurring in close
temporal association with ischemic stroke. Such a seizure can be
considered as an acute symptomatic (provoked/reactive) seizure. Acute
symptomatic seizures occur at the time of a systemic insult or in close
temporal correlation with a documented brain insult and are not suggestive
of an enduring predisposition of the brain to generate epileptic seizures.
Acute symptomatic seizures occurring within 7 days of a stroke are
associated with a low risk of long-term recurrence, although they can
increase the risk of developing poststroke epilepsy with recurrent
unprovoked seizures. Consequently, it was decided to stop the initial
antiseizure medication therapy. The patient later had a second seizure
occurring some months after the stroke (unprovoked seizure). The risk of
seizure recurrence after an unprovoked late-onset seizure occurring more
than 1 week after a stroke is associated with a risk of recurrence of 71.5%
(95% confidence interval, 59.7% to 81.9%; P=.001) over 10 years of follow-up.
Therefore, levetiracetam was reintroduced and maintained as long-term
treatment. Levetiracetam, an antiseizure medication devoid of
pharmacokinetic interactions with other drugs, was chosen considering the
concomitant treatment with warfarin.
486 APRIL 2022

of the EEG, neuroimaging studies, and other investigations of the underlying KEY POINTS
etiology. If sufficient information is available, a specific epilepsy syndrome
● According to the
diagnosis is made (third level). According to the classification, every attempt International League Against
should be made to consider and incorporate etiology, as it often has relevant Epilepsy classification,
treatment implications. Seizure types can be classified as focal onset, generalized every attempt should be
onset, or unknown onset. According to the seizure types experienced by the made to consider and
incorporate etiology when
patient, epilepsies can hence be classified as focal, generalized, combined
classifying epilepsies, as it
generalized and focal, or unknown. The underlying etiology of seizures, often has relevant treatment
epilepsies, and epilepsy syndromes can be classified as structural, genetic, implications.
infectious, metabolic, immune, or unknown.
Generalized epilepsies include a range of seizure types, including absence, ● The choice of initial
antiseizure medication
myoclonic, atonic, tonic, and tonic-clonic seizures. The diagnosis of generalized therapy should integrate the
epilepsy is based on the clinical features and is supported by the finding of best available evidence
characteristic interictal EEG discharges typically showing generalized spike-and- from clinical trials, other
wave activity. In patients with a normal EEG despite generalized tonic-clonic pharmacologic
considerations, the clinical
seizures, supportive evidence is required for a diagnosis of generalized epilepsy, expertise of the treating
such as myoclonic jerks or positive family history.16 Idiopathic generalized physicians, and patient
epilepsies are a well-defined subgroup of generalized epilepsies and encompass values and preferences.
four specific syndromes: childhood absence epilepsy, juvenile absence epilepsy,
juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone.16
Focal epilepsies include a range of seizure types that involve one hemisphere.
They can be classified as focal aware seizures, focal impaired awareness seizures,
focal motor seizures, focal nonmotor seizures, and focal to bilateral tonic-
clonic seizures.16
Finally, the 2017 ILAE classification has introduced the new group of
combined generalized and focal epilepsies in which both seizure types can occur,
such as in Dravet syndrome and Lennox-Gastaut syndrome.16
INITIAL MONOTHERAPY TREATMENT CHOICE

The choice of initial therapy should integrate the best available evidence of
efficacy, safety, and tolerability derived from clinical trials and take into account
other pharmacologic considerations, such as drug interaction and teratogenicity,
the clinical expertise of the treating physicians, and patient values and
preferences. Furthermore, the selection of the most suitable initial monotherapy
should take into consideration the presence of comorbidities. For example, in
a patient with obesity, antiseizure medications associated with weight gain
(eg, valproic acid) are not advisable and the use of drugs with no effect on weight
(eg, lamotrigine) or even drugs associated with weight loss (eg, zonisamide or,
less likely, topiramate because of its poor tolerability) could be considered
(CASE 9-2).
Focal Epilepsy
Carbamazepine has been used as a first-line antiseizure medication for
monotherapy of focal epilepsy for many years. In a seminal multicenter
double-blind trial, carbamazepine, phenobarbital, phenytoin, and primidone
were compared in the treatment of focal-onset seizures and focal-onset seizures
evolving to bilateral tonic-clonic seizures in 622 adults who were predominantly
male military veterans.17 Patients were followed for 2 years or until the drug
failed to control seizures or caused unacceptable side effects. The proportion of
patients remaining on treatment (retention rate) was highest with carbamazepine

and phenytoin, intermediate with phenobarbital, and lowest with primidone

( P<.002). This difference was mainly because of poorer tolerability of primidone.
No significant difference was found in control of focal-onset seizures evolving to
bilateral tonic-clonic seizures, whereas for focal-onset seizures that did not evolve
to bilateral tonic-clonic seizures, carbamazepine was associated with a higher
seizure freedom rate than primidone or phenobarbital ( P<.03).
In a subsequent study, carbamazepine was compared to valproate in 480
adults with focal impaired awareness seizures (206 patients) or focal-onset
seizures evolving to bilateral tonic-clonic seizures (274 patients).18 No difference
was found in the control of focal-onset seizures evolving to bilateral tonic-clonic
seizure, whereas in focal seizure with impaired awareness, carbamazepine was
more effective than valproate and had fewer long-term adverse effects.
Based on these studies, carbamazepine became the first-line treatment for
focal epilepsy and has also been used as a standard active comparator in
regulatory trials evaluating the efficacy and tolerability of newer-generation
antiseizure medications as monotherapy.19-22 These randomized double-blind
trials demonstrated that a number of antiseizure medications (eg, levetiracetam,
lacosamide) are noninferior to carbamazepine for 6-month seizure remission
rates. However, these trials do not adequately inform treatment decisions as they
measure outcomes over too short a time for a chronic condition such as epilepsy
and have strict inclusion and exclusion criteria limiting their generalizability.
The longer-term comparative effectiveness of newer antiseizure medications
compared to older antiseizure medications has been evaluated in two
randomized controlled trials that have tried to answer the question of whether
carbamazepine should still be considered a first-line agent for the treatment of
focal-onset epilepsy and whether valproate should still be considered a first-line
agent for the treatment of generalized/unclassified epilepsy.23,24
CASE 9-2 A 65-year-old woman was in a severe car accident that resulted in head
trauma and subsequently developed posttraumatic focal epilepsy. Her
past medical history was notable for bipolar disorder treated with
lithium. Treatment with valproic acid was recommended. After reaching
the total daily dose of valproic acid of 1500 mg/d, her concomitant
therapy with lithium was gradually reduced and eventually withdrawn. On
follow-up, the patient had achieved seizure freedom and maintained
mood stability.
COMMENT This case illustrates the importance of integrating the best available
evidence from clinical trials, other pharmacologic and clinical
considerations (including comorbidities), the clinical expertise of the
treating physicians, and patient values and preferences. The selection of
valproic acid as initial therapy appears to be an advisable option for the
presence of bipolar disorder. Eventually, the patient reduced and
suspended the prior therapy with lithium, receiving only valproic acid, a
drug effective against both bipolar disorder and epilepsy. In this case, the
strategy of “killing two birds with one stone” proved effective.
488 APRIL 2022

The SANAD (Standard and New Antiepileptic Drugs) trial was a pragmatic
unblinded randomized controlled trial conducted in the United Kingdom that
compared the effectiveness and cost-effectiveness of standard and new
antiseizure medications available as monotherapy options. Arm A recruited 1721
patients for whom carbamazepine was considered by the treating physician to
be standard treatment (ie, patients with focal-onset epilepsy).23 Participants
were then randomly assigned to carbamazepine, gabapentin, lamotrigine,
oxcarbazepine, or topiramate. Lamotrigine performed significantly better than
carbamazepine, gabapentin, and topiramate for time to treatment failure, with a
nonsignificant trend compared with oxcarbazepine. For time to 12-month
remission, carbamazepine performed significantly better than gabapentin, with a
nonsignificant trend compared to lamotrigine, topiramate, and oxcarbazepine.
Based on this pragmatic trial, lamotrigine proved better than carbamazepine for
time to treatment failure outcomes and as a cost-effective drug for initial
monotherapy of focal epilepsy.
A second study, SANAD-II, adopted a similar design and compared
lamotrigine with levetiracetam or zonisamide in patients with newly diagnosed
focal epilepsy.24 For time to treatment failure, lamotrigine performed
significantly better than levetiracetam or zonisamide. The per-protocol analysis
for time to 12-month remission also found lamotrigine to be significantly superior
to levetiracetam or zonisamide.
Overall, results from the literature suggest that lamotrigine is clinically more
effective than carbamazepine for time to treatment failure and noninferior to
it for 12-month remission.24 Neither levetiracetam nor zonisamide appears to be
a clinically or cost-effective alternative.24
However, the choice of the initial monotherapy should not rely only on
possible differences in efficacy and tolerability but should also take into
consideration other issues, such as the intervals of administration, the
pharmacokinetic properties with the consequent risk of drug interactions, and
patient preferences. For example, in patients with poor adherence, antiseizure
medications that can be administered once daily at bedtime (eg, eslicarbazepine
acetate, perampanel, phenobarbital, zonisamide) are preferred. Patients at
increased risk of prolonged seizures or status epilepticus or who are temporarily
unable to swallow can benefit from antiseizure medications that also have an IV
formulation (eg, brivaracetam, lacosamide, phenytoin). Furthermore, in some
circumstances the time required to achieve the target dose should also be
considered (although it may vary between individuals and can be difficult to
know it in advance). For example, in patients requiring rapid seizure control
because of high seizure frequency, the use of lamotrigine is not advisable as it
requires a slow titration to minimize the risk of serious skin rashes.
Generalized Epilepsy
Evaluating the overall evidence for the use of antiseizure medications as first-line
monotherapy for generalized epilepsy is complicated by the intrinsic clinical
heterogeneity of generalized epilepsy, with only very few studies having been
conducted in specific epilepsy syndromes. Merging evidence from randomized
controlled trials conducted in specific syndromes (eg, idiopathic generalized
epilepsy with typical absence seizures) and studies conducted in various other
generalized epilepsies carries the risk of making specific conclusions in the face of
considerable clinical heterogeneity.

KEY POINT Childhood absence epilepsy is the generalized epilepsy syndrome that has
most commonly been assessed in randomized controlled trials, which indicate
● Despite the increased
availability of antiseizure
that ethosuximide and valproate have similar efficacy when used as first-line
medications, the prognosis monotherapy for children and adolescents.25 Both drugs have higher seizure
of patients with newly freedom rates at 12 months than lamotrigine. Because of better tolerability,
diagnosed epilepsy has not ethosuximide is preferred in patients with only typical absence seizures.
significantly improved.
However, ethosuximide is probably ineffective against generalized tonic-clonic
seizures and should be regarded as a narrow-spectrum antiseizure medication
(TABLE 9-1); thus, if generalized tonic-clonic seizures occur together with typical
absences, valproate should be preferred or, as a second-line option, lamotrigine.25
Valproate has long been considered the first-line treatment for generalized
seizures, irrespective of the specific generalized epilepsy syndrome, because of
its broad-spectrum efficacy (TABLE 9-1). Its comparative effectiveness with
newer antiseizure medications has been evaluated in two pragmatic randomized
controlled trials. The unblinded pragmatic randomized controlled SANAD
study compared the longer-term effectiveness of valproate, lamotrigine, and
topiramate for the treatment of generalized-onset seizures or seizures that are
difficult to classify (arm B).23 The study recruited 716 patients for whom
valproate was considered to be standard treatment and randomly assigned
participants to one of the three antiseizure medications. Valproate was found to
be more effective than lamotrigine and topiramate in patients with idiopathic
generalized epilepsy as assessed by time to treatment failure. Valproate was
found to be significantly better than topiramate for time to treatment failure and
significantly better than lamotrigine for time to 12-month remission in the whole
study group and in the subgroup of patients with idiopathic generalized epilepsy.
SANAD-II compared sodium valproate with levetiracetam in 520 patients
with generalized and unclassifiable epilepsy (arm B).24 For time to 12-month
remission, levetiracetam did not meet the criteria for noninferiority in the
intention-to-treat analysis, whereas the per-protocol analysis showed valproate
was superior to levetiracetam. Valproate was also superior for time to treatment
failure. Adverse reactions were reported by 37% of the participants receiving
valproate and 42% of the participants assigned to levetiracetam.
Based on these results, sodium valproate is an effective first-line treatment for
generalized tonic-clonic seizures (with or without other generalized seizure
types). However, the use of valproate is limited by the serious concerns about its
teratogenic potential, particularly for spina bifida as well as for cardiac, craniofacial,
skeletal, and limb defects.26,27 Furthermore, prenatal exposure to valproate is
associated with an increased prevalence of neurodevelopmental disorders.28
Consequently, lamotrigine and levetiracetam appear suitable, although less
effective, alternatives as first-line treatment for women of childbearing
potential20; these drugs carry the lowest risk of overall congenital malformation.27
PROGNOSIS
In recent years, several new antiseizure medications with different mechanisms
of action have been introduced in clinical practice. However, despite the increased
availability of antiseizure medications, the prognosis of patients with newly
diagnosed epilepsy has not significantly improved over time. It is also important
to highlight that although antiseizure medications suppress seizures, they have no
proven disease-modifying or antiepileptogenic effects. Most patients achieve seizure
freedom with the first or second antiseizure medication, and the probability of
490 APRIL 2022

complete seizure control decreases sharply with each subsequent medication
regimen administered.
A 2018 observational cohort study of 1795 patients showed that among those
achieving 1-year seizure freedom (1144 patients), 993 (86.8%) were taking
monotherapy and 1028 (89.9%) achieved seizure freedom with the first or second
medical regimen.29 If the initial antiseizure medication was ineffective, the
second regimen provided an additional 11.6% likelihood of achieving complete
Efficacy Spectrum of Antiseizure Medications TABLE 9-1
Broad-spectrum antiseizure medications (effective against both focal and generalized-onset

seizures)
◆ Brivaracetam
◆ Clobazam
◆ Felbamate
◆ Lamotriginea
◆ Levetiracetam
◆ Perampanel
◆ Rufinamide
◆ Topiramate
◆ Valproate
◆ Zonisamide
Narrow-spectrum antiseizure medications (effective primarily against focal-onset seizures
and focal evolving to bilateral tonic-clonic seizures)
◆ Carbamazepineb
◆ Cenobamate
◆ Eslicarbazepine acetate
◆ Ethosuximidec
◆ Gabapentin
◆ Lacosamide
◆ Oxcarbazepine
◆ Phenobarbitalb
◆ Phenytoinb
◆ Pregabalin
◆ Primidoneb
◆ Stiripentol
◆ Tiagabine
◆ Vigabatrin
a
May worsen myoclonic seizures.
b
Some efficacy also against generalized onset tonic-clonic seizures but may aggravate other generalized
seizures (particularly absence seizures).
c
Active only against absence seizures.

FIGURE 9-1
Treatment strategy after failure of the first antiseizure medication.
" = increase; # = decrease.
Modified with permission from Zaccara G, et al, Epilepsy Behav.34 © 2021 Elsevier Inc.
seizure control, and the third regimen provided an additional 4.4% likelihood of
achieving complete seizure control, whereas subsequent antiseizure medications
led to seizure freedom in a further 2.12% of patients.
Subgroup analyses of data from the SANAD trial have identified some clinical
factors (sex, age, treatment history, time from first seizure, EEG results, seizure
type, neurologic insult, total number of seizures before randomization) that
could affect the probability of treatment failure and the likelihood of achieving
12 months of remission.30 If validated, these variables could lead to outcome
prediction models aimed at identifying patients at risk of a poor treatment
outcome who may benefit from more regular follow-up.
TREATMENT OPTIONS AFTER FAILURE OF THE FIRST ANTISEIZURE

MEDICATION
After the failure of a first antiseizure medication because of adverse effects,
switching to an alternative monotherapy is the most common treatment decision.
When an antiseizure medication fails because of inadequate seizure control, the
main options are an alternative monotherapy or a dual therapy that adds a second
antiseizure medication to the first medication. Both of these alternatives are also
available for therapies that fail because of a combination of inadequate seizure
control and adverse effects; dual therapy is possible if the dose of the first drug
can be reduced to eliminate the adverse effects. Post hoc analyses of the first
SANAD trial showed that, following the failure of a first antiseizure medication,
70% of patients had achieved a 12-month remission at 5 years (65% of those with a
492 APRIL 2022

first treatment failure due to inadequate seizure control and 80% of those with a KEY POINTS
first failure due to adverse events).31 Risk factors for not achieving 12-month seizure
● After monotherapy failure
remission included tonic-clonic seizure, focal epilepsy, younger age, and female sex. because of inadequate
Alternative monotherapy and dual therapy have been compared in two seizure control, the main
randomized controlled trials, which did not find significant differences in options are an alternative
efficacy and tolerability.32,33 Both these studies were conducted in patients with monotherapy or a dual
therapy.
focal epilepsy and were open label; in one study, neurologists were randomly
assigned to prescribe either alternative monotherapy or dual therapy (cluster ● Several antiseizure
trial).33 These were small studies, and it is therefore possible that the lack of medications are available
significant results is attributable to inadequate statistical power. for treating focal epilepsy
Because of the lack of differences in efficacy and tolerability between these with seizures refractory to a
first or alternative
two strategies, other aspects should be taken into consideration when choosing monotherapy.
the appropriate therapy (FIGURE 9-134). An alternative monotherapy appears
preferable and advisable for patients with poor adherence. Similarly, if the failure
of the first antiseizure medication is because of lack of tolerability, an alternative
monotherapy with a different drug also seems advisable. In patients for whom
the initial monotherapy was effective but not tolerated because of dose-related
adverse effects, the target dose should be evaluated to determine whether it
was too high; potential pharmacokinetic interactions with concomitant
enzyme-inhibiting drugs that could lead to an increased antiseizure medication
level should also be evaluated. In these scenarios, the dose could be reduced
before opting for an alternative monotherapy.
Conversely, if the failure of the first monotherapy is because of lack of
efficacy, it is important to first exclude causes of pseudoinefficacy, such as use of
an inappropriate drug for the patient´s epilepsy or seizure type with worsening
of seizures or lack of seizure control, poor treatment adherence, initial target
dose too low to provide adequate antiseizure control, and pharmacokinetic
interactions with concomitant enzyme-inducing drugs leading to reduced
antiseizure medication level. After these issues have been ruled out, a dual
therapy with an adjunctive drug is an advisable choice (CASE 9-3).
DRUG-RESISTANT EPILEPSY
The following sections summarize the add-on treatments for drug-resistant focal
and generalized epilepsies, discuss the limitations of the evidence for these
treatments, and briefly discuss the issue of rational polytherapy.
Focal Epilepsy
Several antiseizure medications are currently available for the treatment of focal
epilepsy with seizures refractory to a first or alternative monotherapy, all of
which have been shown superior to placebo in regulatory randomized controlled
trials. Antiseizure medications that are commonly used in clinical practice as
adjunctive treatments for drug-resistant focal epilepsy include brivaracetam,
clobazam, eslicarbazepine acetate, gabapentin, lacosamide, lamotrigine,
levetiracetam, oxcarbazepine, perampanel, pregabalin, topiramate, valproate,
vigabatrin, and zonisamide.
Generalized Epilepsy
Although most patients with idiopathic generalized epilepsies achieve seizure
freedom with monotherapy, 35% to 40% of patients may continue to experience
seizures, requiring the use of adjunctive antiseizure medications.35,36 In a study of

162 patients aged 12 years and older with drug-resistant primary generalized
tonic-clonic seizures due to idiopathic generalized epilepsy, adjunctive
perampanel reduced the seizure frequency by 76.5% (compared to 38.4% with
placebo; P<.0001).37
Lamotrigine, levetiracetam, perampanel, and topiramate have demonstrated
efficacy as adjunctive treatments for primary generalized tonic-clonic seizures
not controlled by a first or alternative monotherapy. Their efficacy has been
evaluated in randomized double-blind placebo-controlled trials adopting
different methodologies. The size of the full analysis sets in these studies ranged
from 45 to 164 patients, whereas the median reduction in the frequency of
primary generalized tonic-clonic seizures ranged from 56.7% with topiramate
(compared to 9.0% with placebo; P=.019) to 77.6% with levetiracetam
(compared to 44.6% with placebo; P<.001).37
Combining Antiseizure Medications

In patients for whom first or alternative monotherapy fails to control seizures,
adding a second antiseizure medication is required. Evidence on the efficacy
and tolerability of adjunctive treatments in focal drug-resistant epilepsy has
traditionally relied on the results of randomized controlled trials showing
superiority over add-on placebo. It is extremely unlikely that substantive
head-to-head randomized controlled trials of adjunctive antiseizure medications
CASE 9-3 A 34-year-old man was diagnosed with focal epilepsy due to right-sided
hippocampal sclerosis. He was initially treated with controlled-release
carbamazepine, which was gradually increased up to a maximum total
daily dose of 1400 mg/d. Although the therapy was well tolerated and the
patient took the drug regularly, he continued experiencing three to four
focal impaired awareness seizures per month. Levetiracetam was added
to the carbamazepine and gradually increased to a total daily dose of
1500 mg/d. The patient continued having seizures, although less
frequently. The levetiracetam was increased to a total daily dose of
3000 mg/d, and the patient eventually achieved seizure freedom.
COMMENT In this patient, the failure of the first monotherapy was not because of poor
tolerance but lack of efficacy. Causes of pseudoinefficacy were ruled out:
carbamazepine was an appropriate antiseizure medication for the patient’s
epilepsy type and was administered at an adequate dose, and the patient
had a good treatment adherence and received no other concomitant drugs
(no risk of drug interactions leading to increased metabolism and
consequent reduced efficacy of carbamazepine). Therefore, levetiracetam
was added to carbamazepine (dual therapy). Considering the optimal
efficacy of the combination and the patient’s high seizure frequency under
carbamazepine monotherapy, it was decided to maintain both drugs rather
than opting for an alternative monotherapy with levetiracetam by gradually
reducing and eventually withdrawing carbamazepine.
494 APRIL 2022

will ever be conducted; the industry is unlikely to fund them as they are not KEY POINTS
required by regulators and significant challenges exist with design and
● When choosing the add-
interpretation, particularly for noninferiority trials in which a finding of on treatment, several
noninferiority requires a distinction between similar efficacy and lack of efficacy. aspects need to be
These are challenges the international community has so far failed to address. considered in addition to its
Add-on studies using placebo as a comparator carry several methodologic and efficacy and tolerability,
including frequency of
ethical issues, including the high number of seizures at baseline and during
administration;
titration and the increased risk of sudden unexpected death in epilepsy (SUDEP) pharmacokinetic properties,
among patients randomly assigned to placebo.38 Furthermore, although add-on including the risk of drug
studies using placebo as a comparator provide evidence of efficacy to inform interactions; and patient
preferences.
regulatory and licensing decisions, they do not inform clinical practice as they do
not provide data on the relative effects of different alternative antiseizure ● The ideal rational
medications. Randomized controlled trials evaluating the efficacy and safety of polytherapy should have
add-on antiseizure medications have been conducted across an extended time supraadditive or synergistic
period. These studies differ substantially both methodologically and clinically, effects in efficacy (ie, their
combined efficacy should
including in the number and type of concurrent antiseizure medications used be greater than the sum of
and other patient characteristics. For example, participants recruited to more efficacy of each antiseizure
recently completed trials could be more drug-resistant than those included in medication alone) with
earlier trials,39 and this reduces the comparability of study results. infraadditive toxicity (ie,
their combined toxicity
When choosing an add-on treatment, it is thus important to consider other should be less than the sum
aspects in addition to efficacy and tolerability, including frequency of of the toxicity of each
administration, pharmacokinetic properties with the risk of drug interactions, antiseizure medication
and patient preferences. In the absence of reliable evidence from randomized alone).
controlled trials to inform practice, one proposal has been “rational polytherapy,”40
which largely focuses on antiseizure medication mechanisms of action. Although
theoretically attractive, the evidence supporting rational polytherapy is sparse
and based primarily on animal models and preclinical studies. The clinical studies
available are small, provide only imprecise results and low-level evidence, and
are usually observational studies or post hoc or subgroup analyses of randomized
controlled trials, which can be affected by confounding; these results should be
interpreted with caution.
Combining two or more antiseizure medications is aimed at maximizing efficacy
and minimizing side effects. The ideal rational polytherapy should therefore have
supraadditive or synergistic effects in efficacy (ie, their combined efficacy should
be superior to the sum of efficacy of each antiseizure medication alone), with
infraadditive toxicity (ie, their combined toxicity should be less than the sum of the
toxicity of each antiseizure medication alone).41 Favorable combinations are mainly
those between antiseizure medications with different mechanisms of action or
between antiseizure medications with multiple mechanisms of action.42 Combining
antiseizure medications with different mechanisms of action is considered useful
to achieve optimal outcomes, such as higher retention of treatment and lower
risks for hospitalization and emergency department visits.43
Some antiseizure medication combinations appear to be particularly effective in
focal drug-resistant epilepsy (eg, phenobarbital and phenytoin for tonic seizures;
lamotrigine and valproate for various epilepsy/seizure types).42 Cannabidiol (used
as an add-on treatment for Lennox-Gastaut syndrome, Dravet syndrome, and
tuberous sclerosis complex) is an enzyme-inhibiting drug that can increase serum
concentrations of the active metabolite of clobazam. This could synergically
potentiate the antiseizure efficacy of the combined drugs41,42 but may also explain the
increased risk of somnolence among patients using these combination therapies.44

The clinical evidence supporting rational polytherapy for the treatment of

generalized epilepsies is scarce. The combination with the highest evidence for
synergistic efficacy is valproic acid and lamotrigine; patients who have not
responded to a maximally tolerated dose of either lamotrigine or valproic acid
can achieve seizure control with a combination of the two.45 This supraadditive
efficacy is due to a pharmacodynamic interaction and could prove useful in
treating seizures in patients with generalized epilepsy.
So far, no clear evidence-based recommendations can be made to inform
physicians in the choice of a specific drug association for treating focal drug-
resistant epilepsy. Specific antiseizure medication combinations represent a sort
of “irrational polytherapy” characterized by infraadditive antiseizure effect
(ie, their combined efficacy is less than the sum of the efficacy of each antiseizure
medication alone) and synergistic toxicity and thus should be avoided or
considered very carefully. An example is the pharmacodynamic interactions
between lacosamide and other sodium channel blockers, which can lead to
increased risk of central nervous system adverse effects (CASE 9-4).46 However,
even in this case, the evidence available so far is not robust enough to inform
clinical decisions.
CONCLUSION
Currently, several antiseizure medications are available for the treatment of focal
or generalized epilepsies. They differ in terms of mechanisms of action,
CASE 9-4 A 64-year-old man with focal structural epilepsy due to a hemorrhagic
stroke was initially treated with controlled-release carbamazepine
(1200 mg/d). His past medical history was also notable for hypertension
and type 2 diabetes.
The treatment with carbamazepine was well tolerated, but because he
had persistent focal seizures, lacosamide was added (dual therapy) and
gradually uptitrated to 200 mg/d. Shortly after starting lacosamide, the
patient reported dizziness and drowsiness, with increasing asthenia and
without a relevant improvement in seizure control. Lacosamide was thus
replaced with levetiracetam (up to a total daily dose of 1500 mg/d), which
resulted in disappearance of the adverse effects and satisfactory seizure
control.
COMMENT This patient’s seizures were uncontrolled with a first monotherapy and
were therefore treated with a dual therapy by adding a second antiseizure
medication. However, the combination of carbamazepine and lacosamide,
both sodium channel blockers, led to neurotoxic adverse effects. The
combination of lacosamide and other sodium channel blockers represents
an example of “irrational polytherapy,” characterized by infraadditive
antiseizure effect (ie, their combined efficacy is less than the sum of
efficacy of each antiseizure medication alone) and synergistic toxicity
(increased risk of central nervous system adverse effects).
496 APRIL 2022

frequency of administration, and pharmacologic properties, with a consequent
risk of pharmacokinetic interactions. Major unmet needs in epilepsy treatment
remain. A substantial proportion of patients with epilepsy continue to experience
seizures despite two or more antiseizure medications, with a negative impact on
quality of life. More antiseizure medications that can provide higher seizure
control with good tolerability and that could positively affect the underlying
disease are needed.
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00000

REVIEW ARTICLE

Update on Antiseizure
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Medications 2022
By Bassel W. Abou-Khalil, MD, FAAN
EDITOR’S NOTE
The article “Update on Antiseizure Medications 2022” by Dr Abou-Khalil
was first published in the February 2016 Epilepsy issue of Continuum:
Lifelong Learning in Neurology as “Antiepileptic Drugs,” and at the request
of the Editor-in-Chief was updated by Dr Abou-Khalil for the 2019 issue and
again for this issue.
CITE AS:
2022;28(2, EPILEPSY):500–535.
ABSTRACT
PURPOSE OF REVIEW: This article is an update from the article on antiepileptic
Dr Bassel W. Abou-Khalil, drug therapy (now referred to as antiseizure medication therapy) published
Vanderbilt University, A-0118 in the two previous Continuum issues on epilepsy and is intended to cover
Medical Center North,
Neurology Department, the vast majority of agents currently available to the neurologist in the
Nashville, TN 37232, management of patients with epilepsy.
Bassel.abou-khalil@vumc.org.
Treatment of epilepsy starts with antiseizure medication monotherapy.
RELATIONSHIP DISCLOSURE: Knowledge of the spectrum of efficacy, clinical pharmacology, and modes
Dr Abou-Khalil has served on the of use for individual antiseizure medications is essential for optimal
editorial board of Clinical
Neurophysiology. The institution
treatment for epilepsy. This article addresses antiseizure medications
of Dr Abou-Khalil has received individually, focusing on key pharmacokinetic characteristics, indications,
research support from Biogen, and modes of use.
Cerevel Therapeutics, Human
Epilepsy Project, Otsuka America
Pharmaceutical, Inc, SK-Pharma, RECENT FINDINGS: Since the most recent version of this article was published,
Sunovion Pharmaceuticals Inc, two new antiseizure medications, cenobamate and fenfluramine, have
UCB SA, and Xenon.
been approved by the US Food and Drug Administration (FDA), and the
UNLABELED USE OF PRODUCTS/ indications of some approved medications have been expanded.
INVESTIGATIONAL USE
DISCLOSURE:
Older antiseizure medications are effective but have tolerability and
Dr Abou-Khalil discusses the pharmacokinetic disadvantages. Several newer antiseizure medications
unlabeled/investigational use of have undergone comparative trials demonstrating efficacy equal to and
cannabidiol and clobazam for the
treatment of focal-onset
tolerability at least equal to or better than older antiseizure medications as
seizures, gabapentin for the first-line therapy for focal epilepsy. The list includes lamotrigine,
treatment of headache and oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide.
sleep disorders, lamotrigine as a
first-line treatment for epilepsy, Pregabalin was found to be less effective than lamotrigine. Lacosamide,
perampanel for myoclonus, pregabalin, and eslicarbazepine have undergone successful trials of
primidone for the treatment of
conversion to monotherapy for focal epilepsy. Other newer antiseizure
essential tremor, valproate for
the treatment of generalized medications with a variety of mechanisms of action are suitable for
myoclonic and generalized tonic- adjunctive therapy. Antiseizure medications marketed since 2016 have
clonic seizures, and zonisamide
as initial monotherapy for
benefited from the FDA policy allowing a drug’s efficacy as adjunctive
epilepsy. therapy in adults to be extrapolated to efficacy in monotherapy. In
addition, efficacy in adults can be extrapolated for efficacy in children
© 2022 American Academy 4 years of age and older. Both extrapolations require data demonstrating
of Neurology. that an antiseizure medication has equivalent pharmacokinetics between
500 APRIL 2022

its original approved use and its extrapolated use. Rational antiseizure KEY POINT
medication combinations should avoid antiseizure medications with
● Phenobarbital,
unfavorable pharmacokinetic interactions or pharmacodynamic primidone, phenytoin, and
interactions related to mechanism of action. carbamazepine are potent
inducers of liver enzymes,
SUMMARY: Knowledge of antiseizure medication pharmacokinetics, reducing the efficacy of
efficacy, and tolerability profiles facilitates the choice of appropriate drugs metabolized by the
cytochrome P450 enzyme
antiseizure medication therapy for patients with epilepsy. system.
INTRODUCTION
A
ntiseizure medications are the mainstay of epilepsy therapy. Until
1993, the choice of antiseizure medication was limited to seven
or eight major agents. However, more than 19 new antiseizure
medications have been approved and marketed since then. With
such a large choice of antiseizure medications, much guidance is
needed in the choice of antiseizure medications for initial therapy, later
replacement monotherapy, or adjunctive therapy. Considerations in antiseizure
medication choice must include the spectrum of efficacy of the antiseizure
medication (TABLE 10-1), its pharmacokinetic properties (TABLE 10-2), its safety
and tolerability profile, and its efficacy against comorbidities, as relevant to the
patient’s specific circumstances. This article addresses each antiseizure medication,
focusing on indications, tolerability, and clinical use. Relevant pharmacokinetic
properties are also discussed. This article focuses on antiseizure medication use
in adults with suggested dosing in TABLE 10-3; however, salient features related
to use in children are highlighted throughout the text. TABLE 10-4 summarizes
antiseizure medication dosing in children, and TABLE 10-5 summarizes
teratogenicity data for antiseizure medications.1-3 The order in which antiseizure
medications are presented in this article is roughly based on the order in which
they were marketed, although related antiseizure medications will be discussed
together with their oldest relative.
PHENOBARBITAL
Phenobarbital has been in clinical use since 1912, although initially used as a
sedative and sleep aid. Its main mechanism of action is through binding the
γ-aminobutyric acid A (GABAA) receptor, prolonging the opening of the
associated chloride channel. It is available as an oral preparation as well as a
parenteral solution. It has excellent oral bioavailability and relatively low protein
binding. It is mostly metabolized in the liver, but approximately one-quarter
of the dose is eliminated unchanged in the urine. It has a long half-life of
approximately 80 to 100 hours. Phenobarbital is a potent hepatic P450 enzyme
inducer, accelerating the metabolism of medications processed by this enzyme
system and reducing their plasma concentration. This affects its use in
combination therapy because it may render concomitant antiseizure medications
less effective if they are metabolized by the liver.
Phenobarbital is effective against focal-onset seizures and generalized
tonic-clonic seizures but is not effective against generalized absence seizures.
The parenteral solution has been used effectively for status epilepticus.
The suggested maintenance dose is 1 mg/kg/d to 2.5 mg/kg/d,4 but a much
lower starting dose is recommended, such as 30 mg to 60 mg at bedtime. The

ANTISEIZURE MEDICATIONS
dose can be increased by 30 mg to 60 mg every 1 to 2 weeks as needed, depending

on seizure control and tolerability. A once-daily dose at bedtime may reduce
sedation and is adequate because of its long half-life. The recommended serum
concentration is 15 μg/mL to 40 μg/mL.
Phenobarbital’s main possible adverse effects are sedation, decreased
concentration, and mood changes, particularly depression. In children, it can cause
hyperactivity. Long-term use is associated with decreased bone density, Dupuytren
contractures, plantar fibromatosis, and frozen shoulder. It is not recommended in
TABLE 10-1 Spectrum of Efficacy of Select Antiseizure Medications
Lennox-Gastaut
syndrome/infantile
Generalized Generalized spasms/Dravet
Antiseizure tonic-clonic Generalized myoclonic syndrome/tuberous
medication Focal seizures seizures absence seizures seizures sclerosisa
Brivaracetam Class I trials Unknown Unknown Unknown
Carbamazepine Class I trials Suggested, but Not effective Not effective

not proven in
Class I trials
Cannabidiol Class IV Unknown Unknown Unknown Class I trials in Lennox-

evidence Gastaut syndrome,
Dravet syndrome, and
tuberous sclerosis
Cenobamate Class I trials Unknown Unknown Unknown
Clobazam Suggested, but Suggested, but Suggested, but Suggested, but Class I trials in Lennox-
not proven in not proven in not proven in not proven in Gastaut syndrome
Class I trials Class I trials Class I trials Class I trials
Eslicarbazepine Class I trials Unknown Not effective Not effective

acetate
Ethosuximide Not effective Not effective Class I trials Not effective
Felbamate Class I trials Suggested, but Unknown Unknown Class I trial in Lennox-
not proven in Gastaut syndrome
Class I trials
Fenfluramine Unknown Unknown Unknown Unknown Class I trial in Dravet

syndrome
Gabapentin Class I trials Not effective Not effective Not effective
Lacosamide Class I trials Unknown Not effective Not effective
Lamotrigine Class I trials Class I trials Suggested, but Variable Class I trial in Lennox-
not proven in Gastaut syndrome
Class I trials
Levetiracetam Class I trials Class I trials Suggested, but Class I trials

not proven in
Class I trials
502 APRIL 2022

pregnancy because of teratogenicity with increased risk of cardiac malformations in
the exposed fetus. Evidence also exists of decreased cognitive abilities in males
exposed in utero. Phenobarbital is a controlled substance.
Place in Therapy
Because of its adverse effect on cognitive function and its enzyme induction,
phenobarbital is used very infrequently as first-line therapy in high-income
countries, with the exception of its use to treat neonatal seizures. However, its
Lennox-Gastaut
syndrome/infantile
Generalized Generalized spasms/Dravet
Antiseizure tonic-clonic Generalized myoclonic syndrome/tuberous
medication Focal seizures seizures absence seizures seizures sclerosisa
Oxcarbazepine Class I trials Unknown Not effective Not effective
Perampanel Class I trials Class I trials Unknown Class IV evidence
Phenobarbital Class I trials Suggested, but Not effective Class IV evidence

not proven in
Class I trials
Phenytoin Class I trials Suggested, but Not effective Not effective

not proven in
Class I trials
Pregabalin Class I trials Not effective Not effective Not effective
Rufinamide Class I trials, but Suggested, but Unknown Unknown Class I trial in Lennox-
not FDA not proven in Gastaut syndrome
approved Class I trials
Stiripentol Unknown Unknown Unknown Unknown Class I trials in Dravet

syndrome
Tiagabine Class I trials Not effective Not effective Not effective
Topiramate Class I trials Class I trials Not effective in Unknown Class I trial in Lennox-
one Class I trial Gastaut syndrome
Valproate Class I trials Suggested, but Class I trials Suggested, but Suggested, but not
not proven in not proven in proven in Class I trials
Class I trials Class I trials
Vigabatrin Class I trials Not effective Not effective Not effective Class I trial in infantile
spasms
Zonisamide Class I trials Suggested, but Suggested, but Suggested, but

not proven in not proven in not proven in
Class I trials Class I trials Class I trials
FDA = US Food and Drug Administration.

a
Blank cells in this column represent no convincing or Class I data.

TABLE 10-2 Select Pharmacokinetic Parameters of Antiseizure Medications
Key Half-life (in adults, Potential for

Antiseizure mechanisms Oral Protein Metabolism/ in absence of pharmacokinetic
medication of action bioavailability bindinga elimination inducers/inhibitors) interactions
Brivaracetam Binding Good Low Extensive ~7-8 hours Moderate

SV2A hepatic
Carbamazepine Blocking Na Good Intermediate Extensive 12-17 hours (after High

channels hepatic autoinduction is
complete)
Cannabidiol Enhancing Low High Extensive 56-61 hours High

GABA, hepatic
modulation
of
intracellular
Ca
Cenobamate Blocking Na Good Intermediate Extensive 50-60 hours High

channels hepatic
Clobazam Enhancing Good High Extensive 10-30 hours, 36- High

GABA hepatic 46 hours for active
N-
desmethylclobazam
metabolite
Eslicarbazepine Blocking Na Good Low ~40% hepatic, 13-20 hours Moderate

acetate channels 60% renal
unchanged
Ethosuximide Blocking Good Low Extensive 30-60 hours Moderate

T-type Ca hepatic
channels
Felbamate NMDA Good Low ~50% hepatic, 20-23 hours High

antagonism, 40-50%
blocking Na unchanged in
channels, urine
enhancing
GABA
Fenfluramine Enhancing Low Intermediate >75% hepatic, ~20 hours High

serotonin <25%
unchanged or
active
metabolite in
urine
Gabapentin Binding α2δ Low Low None 5-7 hours No/minimal

Ca channel
subunit
Lacosamide Blocking Na Good Low ~60% hepatic, ~13 hours No/minimal

channels 40%
unchanged in
urine
504 APRIL 2022


Lamotrigine Blocking Na Good Intermediate Extensive ~24 hours Moderate

channels hepatic
Levetiracetam Binding Good Low ~30% 6-8 hours No/minimal

SV2A nonhepatic,
66%
unchanged
renal
Oxcarbazepine Blocking Na Good Low Extensive 8-10 hours (for active Moderate
channels hepatic metabolite)
Perampanel AMPA Good High Extensive ~105 hours Moderate

antagonism hepatic
Phenobarbital Enhancing Good Low >70% 80-100 hours High

GABA metabolized in
liver, 20-25%
eliminated
renally
unchanged
Phenytoin Blocking Na Variable High Extensive Average 22 hours High

channels hepatic, (longer with toxicity)
nonlinear
Pregabalin Binding α2δ Good Low None ~6 hours No/minimal

Ca channel
subunit
Primidone Enhancing Good Low 25% converted 10-15 hours High

GABA to
phenobarbital,
40% excreted
unchanged in
urine
Rufinamide Blocking Na Good Intermediate Extensive 6-10 hours Moderate

channels hepatic
Stiripentol Enhancing Good High Extensive 4.5-13 hours High

GABA hepatic
Tiagabine Enhancing Good High Extensive 7-9 hours High

GABA hepatic
Topiramate Blocking Na Good Low ~30% hepatic ~21 hours No/minimal

channels,
70%
AMPA/
unchanged in
glutamate
urine
antagonism,
enhancing
GABA


Valproate Blocking Na Good High Extensive 13-16 hours High
channels, hepatic
enhancing
GABA,
blocking
T-type Ca
channels
Vigabatrin Enhancing Good Low None ~10.5 hours No/minimal

GABA
Zonisamide Blocking Na Good Low ~65% ~60 hours Moderate

channels,
blocking
T-type Ca
channels
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate.

a
Low: <50%; intermediate: 50% to 85%; high: >85%.
low cost and wide availability make it the only affordable antiseizure medication
in much of the developing world. In addition, there has been some debate about
adverse cognitive effects; one study in rural China reported no major negative
cognitive effects, and some cognitive gains, likely related to improved seizure
control.5
PRIMIDONE
Primidone is converted in the liver to phenobarbital and phenylethylmalonamide,
which is also an active metabolite. It is available only as an oral preparation. When
used in monotherapy, about 25% of oral primidone is converted to phenobarbital.
The half-life of primidone is 10 to 15 hours in monotherapy and 6.5 to 8.3 hours
with enzyme inducers. Primidone is a potent enzyme inducer.
Primidone is effective against focal-onset seizures and generalized tonic-
clonic seizures. Anecdotal evidence also exists of efficacy against myoclonic
seizures.6 Primidone is also effective in controlling essential tremor.7
In addition to sedation and other adverse effects of phenobarbital, primidone
use may be associated with an acute toxic reaction unrelated to phenobarbital,
with potentially debilitating drowsiness, dizziness, ataxia, nausea, and vomiting.
Place in Therapy
Primidone was the least-tolerated agent in the large cooperative US Department
of Veterans Affairs trial comparing the efficacy and tolerability of carbamazepine,
phenobarbital, phenytoin, and primidone in adult patients with previously
untreated or undertreated focal epilepsy.8 As a result, it is infrequently used. In
view of the acute toxic adverse effects, primidone should be started at a low dose,
for example 50 mg to 125 mg at bedtime, then increased gradually by 50 mg to
125 mg every 3 to 7 days to 250 mg 3 times a day.
506 APRIL 2022

Suggested Adult Antiseizure Medication Dosing TABLE 10-3
Initial target total daily dose;

Antiseizure Starting total daily usual maximal dose (for some
medication dose Titration antiseizure medications)a
Brivaracetam 50-100 mg 50 mg as needed 100 mg; maximum 200 mg
Carbamazepine 200 mg 200 mg every 3 days 400-800 mg
Cannabidiol 5 mg/kg Increase by 5 mg/kg every week as needed 10 mg/kg; maximum 20 mg/kg
Cenobamate 12.5 mg Increase to 25 mg after 2 weeks, 50 mg 100-200 mg; maximum 400 mg

2 weeks later, then by 50 mg/2 wk
Clobazam 10 mg 10 mg/2 wk as needed 20-40 mg
Eslicarbazepine 400 mg 400 mg/wk as needed 800-1200 mg; maximum

acetate 1600 mg
Ethosuximide 500 mg 250 mg/wk as needed 750 mg; maximum 1500 mg
Felbamate 1200 mg 600-1200 mg/wk 3600 mg
Gabapentin 300-400 mg 300-400 mg/d 1200 mg; maximum 4800 mg
Lacosamide 100 mg 100 mg/wk as needed 200 mg; maximum 600 mg
Lamotrigine Monotherapy for Monotherapy for weeks 3 and 4: 50 mg; then 200-300 mg
weeks 1 and 2: increase by 50 mg every 1-2 weeks
25 mg
Levetiracetam 500 mg 500 mg/wk as needed 1000 mg; maximum 4000 mg
Oxcarbazepine 300-600 mg 300 mg/wk as needed 600-1200 mg; maximum

2400 mg
Perampanel 2 mg 2 mg/3 wk 4 mg; maximum 8 mg
Phenobarbital 30-60 mg 30-60 mg every 1-2 wk as needed 120-180 mg
Phenytoin 200-400 mg No titration needed, dose adjustment with 30- to 200-400 mg

60-mg increments as needed for seizure control
Pregabalin 75-150 mg 75-150 mg/wk as needed 300 mg; maximum 600 mg
Primidone 50-125 mg 50-125 mg every 3-7 days 750-1000 mg
Rufinamide 400 mg 400 mg every 2 days 3200 mg
Tiagabine 4 mg 4 mg/wk 24 mg; maximum 56 mg
Topiramate 25 mg 25 mg/wk 100 mg; maximum 400 mg
Valproate 500 mg 250-500 mg/wk as needed 1000-2000 mg
Vigabatrin 1000 mg 500 mg/wk as needed 3000 mg; maximum 6000 mg
Zonisamide 100 mg 100 mg/1-2 wk as needed 200 mg; maximum 600 mg
a
The schedule depends on the formulation used and the half-life of the antiseizure medication.

TABLE 10-4 Suggested Pediatric Antiseizure Medication Dosinga
Antiseizure Starting total daily Target total daily dose; usual

medication dose Titration maximal effective dose
Brivaracetamb 1-2 mg/kg/d Dose adjustment based on 1-5 mg/kg/d (pediatric patients weighing
response >50 kg [110 lb]: initial dose of 50-100 mg/d
with maximum dose of 200 mg/d)
Carbamazepine 10-20 mg/kg/d Increase weekly using 100-mg 20 mg/kg/d; usually <35 mg/kg/d
increments
Cannabidiol 5 mg/kg/d Increase by 5 mg/kg/d every 20 mg/kg/d

week as needed
Clobazam 0.1 mg/kg/d Increase by 0.1 mg/kg/d every 0.5-1.0 mg/kg/d

week as needed
Eslicarbazepine 10-20 mg/kg/d 200-400 mg/wk as needed 20-60 mg/kg/d (400-1200 mg/d
acetate (200-400 mg/d depending on weight)
depending on weight)
Ethosuximide 10-15 mg/kg/d 5 mg/kg/d every week as 20-30 mg/kg/d; up to 40 mg/kg/d

needed
Felbamate 15 mg/kg/d 15 mg/kg/d every week 45 mg/kg/d
Fenfluramine 0.2 mg/kg/d Increase weekly as needed 0.7 mg/kg/d; maximum of 26 mg/d
0.4 mg/kg/d in presence of stiripentol
and clobazam; maximum 17 mg/d
Gabapentin 10-15 mg/kg/d 10 mg/kg/d every day 40 mg/kg/d; up to 50 mg/kg/d
Lacosamideb 2 mg/kg/d 2 mg/kg/d every week 4-8 mg/kg/d

6-12 mg/kg/d for patients weighting
<30 kg (66 lb)
Lamotrigine Monotherapy for Monotherapy for weeks 3 and 4: Maintenance dose for monotherapy:
weeks 1 and 0.6 mg/kg/d; week 5 and on: 4.5-7.5 mg/kg/d
2: 0.3 mg/kg/d increase by 0.6 mg/kg/d every
1-2 weeks
With valproate for With valproate for weeks 3 and 4: With valproate: 1-5 mg/kg/d
weeks 1 and 2: 0.3 mg/kg/d; week 5 and on:
0.15 mg/kg/d increase by 0.3 mg/kg/d every
1-2 weeks
With enzyme inducer With enzyme-inducer for weeks With enzyme inducers: 5-15 mg/kg/d
for weeks 1 and 2: 3 and 4: 1.2 mg/kg/d; week 5 and
0.6 mg/kg/d on: increase by 1.2 mg/kg/d
every 1-2 weeks
508 APRIL 2022

Antiseizure Starting total daily Target total daily dose; usual

medication dose Titration maximal effective dose
Levetiracetam 20 mg/kg/d (infants 10 mg/kg/d every 1-2 weeks Children 4 years to <16 years: 60 mg/kg/d;
1 month to <6 months children 6 months to <4 years: 50 mg/kg/d;
of age: 14 mg/kg/d) infants 1 month to <6 months: 42 mg/kg/d
Oxcarbazepine 8-10 mg/kg/d 5-10 mg/kg/d every 3-7 days as 30-50 mg/kg/d; usually <60 mg/kg/d
needed
Perampanel 2 mg/d Increase by 2 mg as needed, no 8-12 mg/d

more frequently than weekly
Phenobarbital 1-3 mg/kg/d 1 mg/kg/d every 1-2 weeks 3 mg/kg/d; up to 8 mg/kg/d
Phenytoin 5-7 mg/kg/d No titration needed 6-8 mg/kg/d; up to 10 mg/kg/d (may be

guided by serum concentration)
Pregabalin 2.5 mg/kg/d if patient Increase by 2.5 mg/kg/d weekly 10 mg/kg if patient weighs ≥30 kg (66 lb)
weighs ≥30 kg (66 lb) as needed
14 mg/kg if patient weighs <30 kg (66 lb)
3.5 mg/kg/d if patient
weighs <30 kg (66 lb)
Rufinamide 10 mg/kg/d Increase by 10 mg/kg/d every 45 mg/kg/d

other day
With valproate, the With valproate, titration rate With valproate, target dose should be
starting dose should be should be ~5 mg/kg/d every 20-30 mg/kg/d
~5 mg/kg/d other day
Stiripentol 50 mg/kg/d - 3000 mg/d
Topiramate 1-3 mg/kg/d 1-3 mg/kg/d every 1-2 weeks 5-9 mg/kg/d
Valproate 15 mg/kg/d 5-10 mg/kg/d every week 30 mg/kg/d; up to 60 mg/kg/d with

enzyme-inducing antiseizure medications
Vigabatrin 20 mg/kg/d 20 mg/kg/d every week as 40-60 mg/kg/d

needed
Infantile spasms: Infantile spasms: increase to Infantile spasms: 100 mg/kg/d; maximum
50 mg/kg/d 100 mg/kg/d after 5 days 150 mg/kg/d
Zonisamidec 1 mg/kg/d 2 mg/kg/d every 2 weeks as Usual dose of 4-8 mg/kg/d; with
needed maximum dose of 12 mg/kg/d
a
Generally applicable to children younger than 12 years of age; pediatric dosing may vary depending on the patient’s weight. The dosing is provided
for antiseizure medications that have at least been tested in children.
b
Applicable to children weighing 11-50 kg (24-110 lb).
c
Not US Food and Drug Administration (FDA)-approved for children.

TABLE 10-5 Antiseizure Medication Teratogenicitya
Antiseizure medication Number of monotherapy exposures Major malformation rateb
Brivaracetam Insufficient exposure Unknown
Carbamazepine >4800 Intermediate
Cannabidiol Insufficient exposure Unknown
Cenobamate Insufficient exposure Unknown
Clobazam Insufficient exposure Unknown
Clonazepam >100 Low
Eslicarbazepine acetate Insufficient exposure Unknown
Ethosuximide Insufficient exposure Unknown
Felbamate Insufficient exposure Unknown
Fenfluramine Insufficient exposure Unknown
Gabapentin >200 Low
Lacosamide Insufficient exposure Unknown
Lamotrigine >7000 Low
Levetiracetam >2100 Low
Oxcarbazepine >600 Low
Perampanel Insufficient exposure Unknown
Phenobarbitalc >500 High
Phenytoin >600 Intermediate
Pregabalin Insufficient exposure Unknown
Primidone Insufficient exposure Unknown
Rufinamide Insufficient exposure Unknown
Stiripentol Insufficient exposure Unknown
Tiagabine Insufficient exposure Unknown
Topiramate >700 Intermediate
Valproated >2900 Very high
Vigabatrin Insufficient exposure Unknown
Zonisamide >200 Low
a
Data are extracted from North American, European, and UK registries.2-4 A weighted average was used.
Data reported only for antiseizure medications with >100 monotherapy exposures.
b
Low: ≤3%; intermediate: 3.1% to 6%; high: 6.1% to 8%; very high: >8%.
c
An additional negative effect is decreased IQ in male offspring.
d
Additional negative effects are decreased verbal IQ and autism.
510 APRIL 2022

PHENYTOIN KEY POINTS
Phenytoin has been in clinical use since 1938 when its efficacy in the maximum
● Long-term phenobarbital
electroshock animal model was discovered. Phenytoin binds to the active state of use is associated with
the sodium channel to prolong its fast inactivated state, thus reducing high- decreased bone density,
frequency firing as might occur during a seizure, while allowing normal action Dupuytren contractures,
potentials to occur. It is available as an oral preparation and a parenteral solution, plantar fibromatosis, and
frozen shoulder.
and a phenytoin prodrug, fosphenytoin, is available for IV and
IM administration. ● In addition to sedation
Phenytoin bioavailability is reduced with coadministration of calcium, and other adverse effects of
antacids, and nasogastric feedings. It is highly protein bound at approximately phenobarbital, primidone
90%. It is metabolized in the liver, mostly by cytochrome P450 (CYP) 2C9 and, to use may be associated with
an acute toxic reaction
a lesser extent, CYP2C19. Phenytoin’s metabolism is saturable, resulting in unrelated to phenobarbital,
nonlinear kinetics. As the serum concentration increases, it reaches a point with potentially debilitating
within the recommended therapeutic range after which the half-life starts drowsiness, dizziness,
increasing. Beyond that point, the phenytoin plasma level increases ataxia, nausea, and
vomiting.
disproportionately with an increase in the dose (FIGURE 10-1).
Phenytoin is a potent enzyme inducer that reduces the efficacy of drugs ● Phenytoin has saturable
metabolized by the P450 enzyme system. Phenytoin is also affected by a number nonlinear kinetics. Beyond a
of agents that reduce its metabolism and cause it to accumulate. These include certain serum
concentration, usually
amiodarone, fluoxetine, fluvoxamine, isoniazid, and azole antifungal agents. The
within the accepted
phenytoin protein-free fraction may increase with hepatic and renal failure, in therapeutic range,
low-protein states, during pregnancy, in old age, and in the presence of highly phenytoin concentration
protein-bound drugs, such as increases disproportionately
with an increase in the dose.
valproate, that compete for
Small increments are
protein binding. This is of clinical necessary when increasing
relevance when decisions are the dose at a serum
made based on total phenytoin concentration in the
serum concentration. therapeutic range.
Phenytoin is effective against ● The traditional sodium

focal-onset seizures and channel blockers phenytoin,
generalized tonic-clonic seizures. carbamazepine, and
Phenytoin is not effective against oxcarbazepine may
exacerbate generalized
generalized myoclonic or absence and myoclonic
generalized absence seizures and seizures and should be
may even exacerbate these avoided in idiopathic
seizures; hence, it is not a drug of generalized epilepsy. Other
antiseizure medications that
choice in idiopathic
have similar potential are
generalized epilepsy. gabapentin, pregabalin,
The usual phenytoin initiation tiagabine, and vigabatrin.
dose is 200 mg/d to 400 mg/d,
initially given as a bedtime dose.
Titration is primarily based on
FIGURE 10-1 clinical response but also takes
Example of the nonlinear kinetics of phenytoin.
An increase in the daily dose beyond 300 mg is
into consideration the serum
associated with a disproportionate increase in concentration. The
serum concentration. At a dose of 400 mg/d, the recommended “therapeutic”
serum concentration is about 13 μg/mL. If seizures serum concentration is 10 μg/mL
are still not controlled at this dose, an increment
of 100 mg pushes the serum concentration beyond
to 20 μg/mL; the protein-free
30 μg/mL, with clinical toxicity. An increment of recommended “therapeutic”
30 mg would be more appropriate. serum concentration is 1 μg/mL

to 2 μg/mL. Protein-free phenytoin levels should be checked in clinical situations

where the protein-free fraction is expected to be increased. In view of nonlinear
kinetics, small increments (eg, 30 mg to 60 mg) should be used when the
phenytoin level is in the “therapeutic range” but the clinical situation warrants
optimization of therapy. Extended-release capsules are preferred. Dosing 2 times a
day may be needed when seizures are drug resistant. Phenytoin can be loaded
orally at 18 mg/kg divided into 3 doses given 2 to 3 hours apart (or even as a single
dose if needed).
The IV preparation of phenytoin may be associated with local reactions,
including burning pain, phlebitis, cellulitis, and, rarely, the purple glove
syndrome. IM administration is contraindicated because of erratic absorption
and sterile abscess formation. The phenytoin water-soluble prodrug
fosphenytoin is preferred for parenteral use. It has a lower incidence of local
reactions with IV administration. It is also well absorbed after IM administration,
which can be considered in the absence of IV access. When administered
intravenously in an awake individual, it may be associated with paresthesia
and pruritis, most often in the groin region. IV administration of either
phenytoin or fosphenytoin can be associated with hypotension and arrhythmias,
so ECG and blood pressure monitoring are recommended, and the rate of IV
administration should not exceed 50 mg/min for phenytoin and 150 mg/min
for fosphenytoin.
Phenytoin is less sedating than phenobarbital but nevertheless may have
cognitive adverse effects in some individuals, even within the therapeutic range.
Adverse effects that occur with high concentrations include ataxia,
incoordination, dysarthria, nystagmus, and diplopia. A paradoxical increase in
seizures has been documented with concentrations exceeding 30 μg/mL.
Idiosyncratic reactions may include allergic rash (almost 6% in a study based on
clinical practice)9 and, rarely, Stevens-Johnson syndrome, toxic epidermal
necrolysis, or hypersensitivity syndrome with fever, rash, lymphadenopathy,
eosinophilia, and liver and renal impairment. Adverse effects associated with
long-term use include gingival hyperplasia, acne, hirsutism, cerebellar atrophy,
decreased bone density, anemia, and peripheral neuropathy.
Place in Therapy
Phenytoin was the most frequently used antiseizure medication for many years,
but its use has declined considerably since the appearance of newer antiseizure
medications with improved tolerability and pharmacokinetic profiles. Other
factors in its declining use are its narrow therapeutic window and the challenge
in maintaining the recommended therapeutic concentration range without
producing toxicity or underdosing, because of nonlinear kinetics as well as
variable absorption.
CARBAMAZEPINE
Carbamazepine’s mechanism of action is similar to that of phenytoin. It blocks
the sodium channel in a voltage-dependent and use-dependent fashion, reducing
high-frequency neuronal firing.
Carbamazepine was only available as an oral preparation until a parenteral
preparation was approved in 2016 as temporary replacement therapy when oral
administration is not feasible. Carbamazepine has good oral bioavailability. Its
protein binding of about 75% is not of clinical importance. It is metabolized in the
512 APRIL 2022

liver, mainly by CYP3A4; the most important metabolite is carbamazepine-10, KEY POINTS
11-epoxide. It is an active metabolite also responsible for some adverse effects.
● Unlike phenytoin, the
Carbamazepine is a potent enzyme inducer, reducing the levels of drugs as well phenytoin prodrug
as endogenous substances metabolized by the CYP enzyme system. fosphenytoin may be
Carbamazepine also induces its own metabolism, a process known as administered
autoinduction, which results in increased clearance over 2 to 4 weeks, with intramuscularly, with
reliable absorption, in the
shortened half-life and lower serum concentration. Carbamazepine may
absence of IV access.
accumulate when coadministered with inhibitors of CYP3A4, such as
erythromycin and other macrolide antibiotics (except azithromycin), fluoxetine, ● Carbamazepine induces
propoxyphene, and grapefruit juice. Carbamazepine epoxide levels increase with its own metabolism, so it has
concomitant use of some inhibitors, such as valproate and felbamate. to be titrated gradually to
the target dose.
Carbamazepine is effective against focal-onset seizures and generalized tonic-
clonic seizures. However, it may exacerbate absence, myoclonic, and atonic ● The HLA-B1502 allele is
seizures. Hence, it is not a good choice in idiopathic generalized epilepsy. It has predictive of a
US Food and Drug Administration (FDA) indications for trigeminal neuralgia carbamazepine-induced
severe rash in individuals of
and for acute mania and bipolar disorder. The starting dose is 100 mg 2 times a Asian descent.
day or 200 mg at bedtime when the extended-release preparation is used. The
dose can be increased by 200 mg every 3 days to a target total daily dosage of
400 mg to 800 mg in 2 divided doses, and the dose can be increased further, if
needed, for persistent seizures. When immediate-release formulations of
carbamazepine are used, administration in 3 divided doses is recommended,
although patients may have difficulty adhering to this more complex dosing
schedule. The extended-release preparation, indicated for dosing 2 times a day,
provides steadier levels with evidence for improved tolerability as well as
efficacy.10,11 The recommended therapeutic range of carbamazepine
Adverse effects noted with carbamazepine may include nausea, dizziness,
sedation, and tiredness. Cognitive impairment has been reported on
neuropsychological testing.12 With elevated levels, there may be blurred vision,
diplopia, nystagmus, unsteadiness, incoordination, and tremor. Hyponatremia
may occur. Weight gain and decreased bone density are reported with long-term
use. Mild leukopenia seen in 10% to 20% of patients is usually benign, although
it may be persistent; the more serious aplastic anemia is rare (estimated at 1 in
200,000). It is advisable to check a complete blood cell count and liver enzymes
before initiating therapy, after 2 to 3 months of treatment, then every 6 to
12 months as needed depending on the clinical setting. Idiosyncratic adverse
experiences may include rash, which may be less common than with phenytoin.
Stevens-Johnson syndrome and toxic epidermal necrolysis are rare but more
likely with the HLA-B1502 allele in individuals of Asian descent, for whom
genetic testing of HLA-B polymorphisms is indicated prior to initiation. Other
rare idiosyncratic adverse effects may include a lupuslike syndrome,
hepatotoxicity, and hypersensitivity syndrome with fever, rash, and organ
involvement. Carbamazepine use in polytherapy has been associated with
increased risk of spina bifida in infants exposed during gestation. Abrupt
withdrawal may be associated with severe rebound seizures.13,14
Place in Therapy
Carbamazepine had the best balance of efficacy and tolerability in the large
cooperative US Department of Veterans Affairs study that also included
phenytoin, phenobarbital, and primidone.8 As a result, it became the standard

treatment for focal-onset seizures. No drug has been demonstrated to be more

effective than carbamazepine, but its use has declined with the marketing of new
antiseizure medications that have pharmacokinetic advantages. Lamotrigine,
oxcarbazepine, and gabapentin have better tolerability than immediate-release
carbamazepine.15-21 However, comparative trials using extended-release
carbamazepine have failed to show superior tolerability of lamotrigine,
levetiracetam, zonisamide, or lacosamide.22-26 Nevertheless, enzyme induction
and pharmacokinetic interactions have been issues favoring newer antiseizure
medications. On the other hand, economic considerations favor the
less-expensive carbamazepine.
OXCARBAZEPINE
Oxcarbazepine is a structural analogue of carbamazepine, but the minor
structural differences have resulted in major differences in metabolism and
induction of metabolic pathways. Like carbamazepine and phenytoin,
oxcarbazepine binds to the sodium channel, inhibiting high-frequency repetitive
neuronal firing. Oxcarbazepine is only available as an oral preparation.
Oxcarbazepine has excellent oral bioavailability. It is very rapidly converted to
the monohydroxy derivative, which has two enantiomers, the active
S-licarbazepine, responsible for most of oxcarbazepine’s antiseizure activity
(80%), and R-licarbazepine (less active but contributes to adverse effects). Its
protein binding is not clinically important. The half-life of oxcarbazepine is only
1 to 3.7 hours, and that of the monohydroxy derivatives is 8 to 10 hours.
Oxcarbazepine is a weak inducer of CYP3A4, which is responsible for estrogen
metabolism, and reduces the efficacy of the oral contraceptive pill at high doses,
usually greater than 900 mg/d. It is a weak inhibitor of CYP2C19, thus raising the
phenytoin level when used at high doses. It does not induce its own metabolism.
Unlike carbamazepine, it is not affected by CYP3A4 inhibitors, such as
erythromycin, fluoxetine, propoxyphene, and grapefruit juice.
Oxcarbazepine is effective against focal-onset seizures. It may exacerbate absence
and myoclonic seizures and should be avoided in patients with generalized epilepsy.
It can be started at a dose of 300 mg 2 times a day, but in the absence of urgency,
it is better to start at 150 mg 2 times a day. The dose can be titrated by 300 mg
per week as needed. The highest dose used in clinical trials was 1200 mg 2 times a
day. An extended-release preparation is available, allowing for once-daily dosing.
The recommended therapeutic range for the monohydroxy derivative is 15 μg/mL
to 35 μg/mL. Conversion from carbamazepine can be made overnight by
using 300 mg of oxcarbazepine for every 200 mg of carbamazepine when
the carbamazepine dose is 800 mg or less. A slower conversion and lower
ratio are advisable with higher carbamazepine doses. Conversion from
carbamazepine may be accompanied by reduction in sodium concentration and
increased levels of concomitant medications metabolized by the CYP
enzyme system.
Oxcarbazepine may cause drowsiness, headache, and fatigue. Higher doses
can cause dizziness, blurred vision, diplopia, nausea, vomiting, and ataxia. Rash
may occur in 2% to 4% of individuals; oxcarbazepine has 25% cross-reactivity
with carbamazepine. Oxcarbazepine is more likely to cause hyponatremia than
carbamazepine is27,28; symptomatic hyponatremia is more likely in older
individuals and those taking a diuretic. Abrupt withdrawal may be associated
with severe rebound seizures.29
514 APRIL 2022

Place in Therapy KEY POINTS
Oxcarbazepine is approved as a first-line monotherapy for focal-onset seizures.
● Oxcarbazepine is more
Multiple comparative monotherapy trials for new-onset focal epilepsy have likely to cause hyponatremia
demonstrated that oxcarbazepine is equal in efficacy to phenytoin and immediate- than carbamazepine. Older
release carbamazepine but with possibly superior tolerability.30,31 Combining individuals taking a diuretic
oxcarbazepine with other classic sodium channel blockers, such as carbamazepine, are at particularly high risk.
lamotrigine, and phenytoin, may limit tolerability because of dizziness, diplopia,
● Eslicarbazepine has a long
and ataxia. half-life in CSF, justifying
once-daily oral dosing.
ESLICARBAZEPINE ACETATE
Eslicarbazepine acetate was approved for marketing in the United States in 2014, but
it is listed here because it represents a third-generation relative of carbamazepine
and oxcarbazepine. It is a prodrug rapidly converted to the active metabolite
S-licarbazepine, also known as eslicarbazepine, the active enantiomer of the
monohydroxy derivative of oxcarbazepine. Eslicarbazepine acts by blocking sodium
channels and stabilizing the inactive state of the voltage-gated sodium channel. A
2015 study suggested that, unlike carbamazepine, it may enhance slow inactivation
of voltage-gated sodium channels.32 It is available only as an oral preparation.
Eslicarbazepine is metabolized to inactive compounds, but more than 50% is
excreted in the urine as unchanged eslicarbazepine. The half-life of eslicarbazepine
is 13 to 20 hours in plasma and 20 to 24 hours in CSF, justifying once-daily dosing.
Unlike oxcarbazepine, eslicarbazepine acetate is not followed by a CSF spike,
which is suspected to be responsible for acute adverse effects.33
Eslicarbazepine is a weak inducer of CYP3A4, potentially decreasing plasma
concentrations of estrogen and other molecules metabolized by this enzyme, and
a weak inhibitor of CYP2C19, potentially increasing the plasma concentration of
phenytoin and other drugs metabolized by this enzyme.
Eslicarbazepine acetate is effective against focal-onset seizures. The
recommended starting dose is 400 mg once daily, to be increased to 800 mg once
daily after 1 week. If needed, the dose can be increased again to 1200 mg/d after
1 week. In a successful conversion to monotherapy study, a dose of 1600 mg/d
was used.34 However, in an initial monotherapy study that allowed dosing levels
of 800 mg/d, 1200 mg/d, and 1600 mg/d, two-thirds of patients did not require
titration beyond 800 mg/d throughout the 6 months of treatment,26 and the vast
majority of patients maintained this dose during long-term follow-up.35
Eslicarbazepine acetate has adverse effects similar to oxcarbazepine, although
less frequent. The most common possible dose-related adverse effects are
dizziness, somnolence, headache, diplopia, nausea, vomiting, fatigue, and ataxia.
Hyponatremia was less commonly reported than in oxcarbazepine trials. Sodium
levels of 125 mEq/L or lower were reported in up to 1.5% of individuals taking
1200 mg/d. Rash occurs in up to 3% of individuals at 1200 mg/d. It had less
pronounced neuropsychological adverse effects than carbamazepine.36
Place in Therapy
Eslicarbazepine acetate was first approved by the FDA as adjunctive treatment
for focal-onset seizures. It is best to avoid combining it with a classic sodium
channel drug, although the combination with lamotrigine is less problematic
than with carbamazepine.37 A monotherapy indication followed after successful
completion of a conversion to monotherapy trial.34 Like oxcarbazepine, it should
be avoided in idiopathic generalized epilepsy. Eslicarbazepine acetate could be

considered a first-line monotherapy for focal-onset seizures, with tolerability

advantages over immediate-release oxcarbazepine. However, financial
considerations may be an obstacle.
VALPROIC ACID/DIVALPROEX SODIUM (VALPROATE)

Valproate has multiple mechanisms of action, including GABA potentiation,
blocking of T-type calcium channels (predictive of efficacy against absence
seizures), and blocking of sodium channels. It is available as oral preparations
(mainly in the form of divalproex sodium, a complex of valproate and sodium
valproate) and parenteral valproate sodium preparation. Oral bioavailability is
almost complete, although slightly less for the extended-release preparation. It is
highly protein bound at about 90%. The free fraction increases with increasing
total concentration and with coadministration of phenytoin, with which it
competes for protein binding.
Valproate is extensively metabolized by conjugation and oxidation. The
half-life in adults is 13 to 16 hours but shorter at about 9 hours with enzyme-
inducing drugs. It is a potent inhibitor, reducing the clearance of phenobarbital,
lamotrigine, rufinamide, and carbamazepine epoxide.
Valproate has a broad spectrum of efficacy against all focal and generalized
seizures, including generalized absence and myoclonic seizures. The divalproex
sodium formulation also has FDA indications for migraine prophylaxis and bipolar
disorder. It should be started at a low dose to improve tolerability. The extended-
release divalproex sodium preparation, which can be administered once daily, is
preferred. The recommended starting dose is 500 mg at bedtime for the extended-
release divalproex sodium preparation or 250 mg 2 times a day for the delayed-
release and immediate-release preparations. The dose can be increased gradually
as needed to achieve seizure control, up to 1000 mg/d to 2000 mg/d. It should be
avoided in female patients of childbearing potential because of teratogenic risk.
The recommended therapeutic serum concentration range is 50 μg/mL to
100 μg/mL. A protein-free concentration should be checked at high levels and in
other circumstances in which the protein-free fraction is expected to rise.
The adverse effects of valproate may include gastric irritation with nausea,
vomiting, and anorexia. Other possible adverse effects include diarrhea, fatigue,
drowsiness, tremor, weight gain, hair loss, peripheral edema, and confusion.
Tolerability is generally improved with the extended-release formulation.38,39
Dose-related thrombocytopenia may occur. Endocrine effects are most recognized
in women and include polycystic ovary syndrome, hyperandrogenism,
hyperinsulinemia, and insulin resistance.40,41 Reversible parkinsonism, gait
disorder, dementia, and brain atrophy have been described with chronic use in
seniors. Encephalopathy and hyperammonemia may occur in polytherapy.
Idiosyncratic hepatotoxicity and pancreatitis are potentially life threatening
but rare. Risk factors are polytherapy and young age. Valproate is associated with
a dose-related teratogenicity rate higher than any other marketed antiseizure
medication, with risk of major malformations higher than 30% at doses greater
than 1100 mg/d.42 In utero exposure is also associated with dose-dependent
reduced verbal IQ, other cognitive dysfunction, and autism.43-45
Place in Therapy
Valproate remains the most effective antiseizure medication for idiopathic
generalized epilepsy with generalized tonic-clonic seizures and should remain a
516 APRIL 2022

drug of first choice for men with generalized epilepsy.46 Although equally KEY POINTS
effective as ethosuximide for generalized absence seizures in children, it has
● Valproate has a broad
more cognitive adverse effects.47,48 A large cooperative US Department of spectrum of efficacy against
Veterans Affairs study found it less well tolerated and less effective than all focal and generalized
carbamazepine for focal impaired awareness seizures (formerly called complex seizure types.
partial seizures), although equally effective for focal to bilateral tonic-clonic
● Valproate has the highest
seizures (formerly called secondarily generalized tonic-clonic seizures).49
rate of teratogenicity among
antiseizure medications and
ETHOSUXIMIDE should be avoided in female
Ethosuximide blocks T-type calcium currents, which predicts efficacy against patients of childbearing
absence seizures. It has excellent oral bioavailability (greater than 90%). Protein potential.
binding is very low. Ethosuximide is extensively metabolized in the liver. It has a ● Ethosuximide is the drug
long half-life of 30 to 60 hours. of choice for typical
Ethosuximide is a narrow-spectrum antiseizure medication, indicated only for absence seizures as the only
generalized absence seizures. The starting dose is 250 mg/d for patients between 3 seizure type. While
valproate is equally
and 6 years of age and 250 mg 2 times a day for those older than 6 years of age. effective, it is associated
The dose can be increased by 250 mg every week as needed for persistent with more cognitive adverse
seizures, not to exceed 500 mg 3 times a day. The recommended therapeutic effects.
range is 40 μg/mL to 100 μg/mL.
Adverse effects may include nausea, abdominal discomfort, anorexia, vomiting,
diarrhea, drowsiness, insomnia, nervousness, dizziness, fatigue, ataxia, and
behavior changes. Most adverse effects are dose related and are helped by
administration of divided doses with meals. Headaches, psychosis, depression, and
hallucinations are not clearly dose related. Idiosyncratic adverse experiences include
rash, Stevens-Johnson syndrome, systemic lupus erythematosus, rare aplastic
anemia, thrombocytopenia, agranulocytosis, and rare autoimmune thyroiditis.
Place in Therapy
Ethosuximide is the antiseizure medication of choice for absence epilepsy with
generalized absence seizures as the only seizure type, a status supported by the
large multicenter double-blind randomized controlled trial comparing
ethosuximide, valproic acid, and lamotrigine.48,50
BENZODIAZEPINES
Benzodiazepines act mainly on the GABAA receptor, increasing the frequency
of GABA-mediated chloride channel openings. Clobazam is the only
1,5-benzodiazepine, referring to the position of nitrogen atoms in the
heterocyclic ring; other benzodiazepines are 1,4-benzodiazepines. Only
clonazepam and clobazam, used for chronic epilepsy management, are discussed
here. In the United States, they are available only as oral preparations.
Both have good oral bioavailability. Both are highly protein bound. However,
they differ in their metabolism.51 Clonazepam is converted to inactive metabolites,
while clobazam is metabolized in the liver to the active N-desmethylclobazam.
The active metabolite of clobazam is subject to interaction with inhibitors of
CYP2C19, which can result in its accumulation and associated sedation. These
inhibitors include felbamate, cannabidiol, and cenobamate. Both clonazepam and
clobazam have long half-lives, justifying once-daily dosing, although clobazam
was dosed 2 times a day in clinical trials. Both clonazepam and clobazam are
broad-spectrum agents, although their FDA indication is limited to generalized
seizure types.

Drowsiness is a common adverse effect that improves over time. It is less likely
with clobazam. With increasing doses, nystagmus, incoordination, unsteadiness,
and dysarthria may occur. Tolerance may develop to the therapeutic effect of
benzodiazepines, but this appears less likely with clobazam. Withdrawal seizures
may occur with abrupt discontinuation. All benzodiazepines are controlled
substances.
Place in Therapy
Both clonazepam and clobazam are typically used as adjunctive therapy and have
limited data to support monotherapy use. The clobazam FDA indication is for
adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in
patients 2 years of age or older. Class IV evidence of efficacy in adjunctive
treatment of drug-resistant focal epilepsy and idiopathic generalized epilepsy has
been reported.52
FELBAMATE
Felbamate was the first second-generation antiseizure medication approved in
the United States in 1993. It has multiple mechanisms of action, including
N-methyl-D-aspartate (NMDA) receptor antagonism, GABA enhancement, and
sodium channel blocking. It is available as an oral preparation.
Felbamate has excellent oral bioavailability; its protein binding is not
clinically significant. It is metabolized in the liver to inactive metabolites, with a
half-life of 20 to 23 hours. It is an inhibitor of CYP2C19, CYP1A2, and b-
oxidation, inhibiting the metabolism of phenobarbital, phenytoin, valproate,
carbamazepine epoxide, N-desmethylclobazam, and warfarin, and it is a weak
inducer of CYP3A4, decreasing carbamazepine levels and reducing oral
contraceptive efficacy.
Felbamate is a broad-spectrum agent effective against focal seizures as well as
generalized seizures in the setting of Lennox-Gastaut syndrome. The
recommended starting dose is 600 mg 2 times a day, with subsequent titration by
600 mg to 1200 mg per week up to 1200 mg 3 times a day.
The most common possible adverse effect of felbamate is gastrointestinal
irritation with anorexia, nausea, and vomiting, which can be helped by
administration with food. Felbamate may also cause insomnia, irritability,
headache, and weight loss. The most concerning toxicity is the potentially lethal
aplastic anemia, with an estimated risk of 1 in 5000 to 1 in 8000 patients, and
hepatic failure, with an estimated risk of 1 in 26,000 to 1 in 54,000 patients. Both
are unlikely after 1 year of treatment, and aplastic anemia has not been reported
in patients younger than 13 years of age. These two serious adverse effects have
resulted in a boxed warning suggesting that felbamate should be used only for
severe epilepsy where treatment benefits outweigh the risk. It is recommended
to check a complete blood cell count and liver function test prior to starting
felbamate and to repeat the tests every 2 weeks in the first 6 months of treatment.
The frequency of monitoring can be reduced considerably after 1 year of treatment.
Place in Therapy
Although felbamate was approved for monotherapy, it is not indicated as a first-
line treatment because of its potential serious idiosyncratic toxicity. Adjunctive
therapy or alternative monotherapy can be considered when other appropriate
and safer options have failed.
518 APRIL 2022

GABAPENTIN KEY POINTS
Gabapentin binds to the alpha-2-delta subunit of voltage-gated calcium channels,
● Tolerance may develop to
reducing the influx of calcium and associated neurotransmitter release under the therapeutic effect of
hyperexcitable conditions. It is available as an oral preparation only. benzodiazepines; this
Gabapentin bioavailability is low and variable between subjects and even appears less likely with
in the same subject. Because of its active saturable transport system from the clobazam than clonazepam.
gut, its bioavailability decreases with increasing doses, from 60% after a
● Felbamate-related
single dose of 300 mg to 29% for 1600 mg 3 times a day.53 Protein binding is aplastic anemia and liver
negligible. It is eliminated unchanged in the urine. Its half-life is 5 to 7 hours. It failure are unlikely to start
has no known interactions, other than potential antacid interference with after 1 year of treatment.
its absorption.
● Gabapentin bioavailability
Gabapentin is a narrow-spectrum agent against focal seizures. It may cause is low and decreases with
exacerbation of myoclonus.54 It is also FDA approved for the treatment of increasing doses.
postherpetic neuralgia. An extended-release preparation (gabapentin enacarbil)
has been approved for the treatment of restless legs syndrome and postherpetic ● Like gabapentin,
pregabalin has a narrow
neuralgia, and another (gastroretentive dosage form) has been approved for the
spectrum of efficacy against
management of postherpetic neuralgia. focal seizures and may
The recommended starting dose of gabapentin is 300 mg/d to 400 mg/d, to be exacerbate generalized
increased by 300 mg to 400 mg every day up to 300 mg to 400 mg 3 times a day. myoclonic and absence
seizures.
The dose can be increased as needed up to 4800 mg/d in 3 divided doses.
Adverse effects may include drowsiness, dizziness, ataxia, tiredness, and weight
gain. It may cause myoclonus. It may cause cognitive slowing in older adults and
emotional lability in children. Peripheral edema is more likely with increasing age.
Gabapentin was recently reclassified as a controlled substance in some states.
Place in Therapy
Gabapentin can be used as adjunctive treatment for focal seizures. It is often
chosen for its anecdotal benefit in the treatment of headache and other pain and
its benefit for sleep. Although approved in Europe for initial monotherapy, a
large randomized comparative trial found it less effective than lamotrigine.18
PREGABALIN
Pregabalin is structurally related to gabapentin and has a similar mechanism of
action. It is also available only as an oral preparation. Unlike gabapentin, pregabalin
has very good oral bioavailability, which is independent of dose. Like gabapentin, it
has no protein binding and is not metabolized in humans, and it has no known
interactions. It is excreted unchanged in the urine. Its half-life is about 6 hours.
Pregabalin is a narrow-spectrum drug against focal seizures. The official FDA
epilepsy indication is adjunctive therapy for adult patients with focal-onset
seizures. Like gabapentin, pregabalin has a narrow spectrum of efficacy against
focal seizures and may exacerbate generalized myoclonic and absence seizures. It
also has an FDA indication for neuropathic pain associated with diabetic
peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and neuropathic
pain associated with spinal cord injury. The starting dose is 75 mg 1 time (at
bedtime) or 2 times a day. The dose can then be increased by 75 mg to 150 mg
every week as needed, until seizure control, appearance of adverse effects, or
reaching a maximum dose of 300 mg 2 times a day.
The possible adverse effects of pregabalin include dizziness, somnolence,
increased appetite, weight gain, and peripheral edema. Myoclonus may occur
with higher doses in some individuals. Pregabalin is a controlled substance.

Place in Therapy
Pregabalin is indicated as adjunctive therapy for focal seizures. It was inferior to
lamotrigine as first-line therapy55 and should probably not be used as a first-line
treatment. However, a conversion-to-monotherapy study was successful.56
LAMOTRIGINE
Lamotrigine blocks sodium channels, like phenytoin and carbamazepine, but
must have other unrecognized actions to explain efficacy against absence
seizures. It is available as an oral preparation only.
Lamotrigine has an excellent oral bioavailability. Its protein binding is not
clinically significant. It is extensively metabolized in the liver, predominantly
by glucuronidation, and then eliminated in the urine. The half-life is about
24 hours in monotherapy, at least twice as long when used with valproate, and
about half as long when used with an enzyme inducer. Estrogen and
pregnancy increase lamotrigine clearance.
Lamotrigine is a broad-spectrum antiseizure medication, although its FDA
indications are limited to focal seizures, generalized tonic-clonic seizures, and
Lennox-Gastaut syndrome. It is less effective against generalized absence
seizures than valproate and ethosuximide.48 It may be effective against
myoclonic seizures in some patients but may exacerbate these seizures in others.
Lamotrigine also has an FDA indication for maintenance treatment in bipolar
I disorder.
Lamotrigine requires a very slow titration to avoid the development of rash.
In monotherapy, it should be initiated with a total daily dose of 25 mg/d for 2 weeks,
followed by 50 mg/d for 2 weeks, then 100 mg/d. The total daily dose can then be
increased as needed by 100 mg every 2 weeks. The titration rate is half as fast with
adjunctive valproic acid but can be twice as fast in the presence of an enzyme
inducer and absence of valproic acid. A serum concentration is helpful to guide
further titration if seizures are still not controlled at a total daily dose of 600 mg/d.
The suggested therapeutic range is 2 μg/mL to 20 μg/mL.57 The extended-release
preparation allows once-daily dosing and reduces toxicity from peak levels. It may
even improve efficacy when used 2 times a day in patients who are drug resistant.58
Dose-related adverse effects may include dizziness, blurred vision, diplopia,
unsteadiness, nausea and vomiting, headache, and tremor. A serum
concentration is indicated for symptoms that could be consistent with
lamotrigine toxicity, particularly if the baseline concentration is greater than
10 μg/mL.59 Rash is seen in about 3% of patients, with a higher incidence in
children, with coadministration of valproic acid, and with faster titration and
higher doses. The risk of rash is increased in patients with a prior rash on
carbamazepine or phenytoin.60 Stevens-Johnson syndrome, toxic epidermal
necrolysis, hypersensitivity syndrome, and hemophagocytic lymphohistiocytosis
are rare serious idiosyncratic adverse effects.
Place in Therapy
Lamotrigine is an important first-line antiseizure medication for focal seizures
and generalized tonic-clonic seizures. Several comparative trials have favored
lamotrigine over other antiseizure medications for focal seizures in the balance of
tolerability and efficacy.18,21 However, it was inferior to valproic acid for
idiopathic generalized epilepsy46 and inferior to ethosuximide for (generalized)
absence seizures.48 Lamotrigine is less sedating and has fewer cognitive
520 APRIL 2022

adverse effects than traditional antiseizure medications. Its monotherapy use is KEY POINT
associated with one of the lowest rates of teratogenicity, favoring its use in female
● Lamotrigine clearance is
patients of childbearing age. Lamotrigine may have pharmacodynamic decreased by valproate and
interactions with other classic sodium channel blockers, resulting in adverse increased by estrogen and
effects at lower-than-expected serum concentrations. However, its combination pregnancy as well as by
with valproate can be synergistic, with greater efficacy than predicted.61,62 enzyme inducers.
TOPIRAMATE
Topiramate has multiple mechanisms of action, including antagonism of
α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA)/kainate
receptors, augmentation of GABA activity, and blocking of voltage-gated
sodium channels. It is also a weak carbonic anhydrase inhibitor, but this
mechanism does not contribute significantly to its efficacy. It is available as an
oral preparation.
Topiramate has an excellent oral bioavailability. Its protein binding is not
clinically significant. It is partially metabolized in the liver, with about 70%
eliminated unchanged in the urine. Its half-life is approximately 21 hours. It is a
mild inducer of CYP3A4, reducing the efficacy of the oral contraceptive at a dose
equal to or greater than 200 mg/d, and a mild inhibitor of CYP2C19.
Topiramate is a broad-spectrum antiseizure medication effective against
focal and generalized tonic-clonic seizures. A pilot trial suggested it is not
effective for (generalized) absence seizures.63 It is FDA approved for migraine
prophylaxis and as a weight-loss preparation in combination with phentermine.
It is also frequently used off-label for bipolar disorder. Topiramate has to be
titrated gradually to manage cognitive adverse effects. It is suggested to start
with 25 mg/d and increase the dose by 25 mg every week up to a total daily dose
of 100 mg/d. Further titration by 25 mg to 50 mg every week can be considered,
up to a total daily dose of 400 mg/d in 2 divided doses. Extended-release
preparations with once-daily dosing may improve tolerability.
Topiramate is less well tolerated than lamotrigine, the main tolerability issue
being the possible cognitive adverse effects, including cognitive slowing,
decreased attention and memory, impaired executive function, word-finding
difficulty, and reduced verbal fluency. Patients may not be aware of these
cognitive difficulties.64,65 Other possible adverse effects include sedation,
fatigue, dizziness, ataxia, and depression. Kidney stones occur in about 1.5% of
individuals. Decreased appetite and weight loss may also occur. Paresthesia in the
hands and feet can occur with initiation and with dose increase but usually
resolve. This is due to the carbonic anhydrase inhibition activity of this drug.
Oligohidrosis, hyperthermia, and metabolic acidosis may occur, more commonly
in children. Acute myopia and secondary angle-closure glaucoma are reported
rarely. Hyperammonemia may occur when topiramate is used in conjunction
with valproate. Topiramate is associated with increased birth defects at a rate of
approximately 4%, particularly oral clefts.66
Place in Therapy
Although topiramate is FDA approved for initial monotherapy for focal seizures
and generalized tonic-clonic seizures, it is not a drug of first choice because of its
cognitive adverse effects, unless its use is justified by comorbidity, such as
migraine or obesity. It is effective as adjunctive therapy for focal and generalized
seizures in Lennox-Gastaut syndrome.

TIAGABINE
Tiagabine inhibits GABA reuptake at the synapse. It is available as an oral
preparation only.
Tiagabine has excellent oral bioavailability. It is 96% protein bound, but this is of
limited importance because dosing decisions are not dependent on the level, and its
serum concentration is so low that it does not significantly compete for protein
binding. It is extensively metabolized in the liver. Its half-life is 7 to 9 hours in
monotherapy, shortened to 2 to 5 hours in the presence of an enzyme inducer.
Tiagabine has a narrow spectrum of efficacy against focal seizures only. It may
exacerbate generalized absence and myoclonic seizures. It is used off-label in the
management of spasticity in multiple sclerosis, in the treatment of addiction, and
to increase deep sleep proportion. It should be started at 4 mg at bedtime and
increased by 4 mg every week to an initial target dose of 8 mg 3 times a day. The
dose can be increased further by 4 mg every week up to 12 mg to 16 mg 3 times a
day. A higher dose may be used in the presence of an enzyme inducer.
The most common adverse effects are dizziness, asthenia, nervousness,
tremor, depression, and emotional lability, which are more common during
titration. Tiagabine may be associated with dose-related episodes of
nonconvulsive status epilepticus or encephalopathy, which may occur even in
the absence of epilepsy.67,68
Place in Therapy
Tiagabine should be reserved for use as adjunctive therapy for focal seizures.
LEVETIRACETAM
Levetiracetam’s main mechanism of action is binding to the synaptic vesicle
protein SV2A. This seems to result in nonspecific decrease in neurotransmitter
release in a state of neuronal hyperactivation.69 Levetiracetam is available in oral
and IV formulations.
Levetiracetam has excellent oral bioavailability and very low protein binding.
It has no hepatic metabolism; 66% is excreted unchanged in the urine, and the
rest is hydrolyzed to inactive compounds. The half-life is 6 to 8 hours. It has no
known significant pharmacokinetic interactions.
Levetiracetam is a broad-spectrum drug, effective against focal seizures,
generalized tonic-clonic seizures, and generalized myoclonic seizures.
Levetiracetam is the only antiseizure medication with Class I evidence for
efficacy against myoclonic seizures. It is best to start with 500 mg/d in 2 divided
doses or once at bedtime with the extended-release preparation. The dose can
then be increased as needed and as tolerated up to a total daily dose of 3000 mg/d
to 4000 mg/d. However, post hoc analysis from clinical trials indicates that
efficacy is already maximal at the initial titration dose.70 Therefore, upward dose
adjustments should be limited when no added benefit is seen after one or two
increments. Alternative therapy or adjunctive therapy should then be considered.
The most common possible adverse effects include somnolence, dizziness, and
asthenia. Irritability and hostility may occur, more often in children. Depression,
anxiety, and, rarely, psychosis may also occur.
Place in Therapy
Although levetiracetam is not FDA approved for monotherapy in the United
States, it is used widely as a first-line treatment for focal and generalized
522 APRIL 2022

tonic-clonic seizures and is approved for initial monotherapy in Europe. It is also KEY POINTS
an excellent adjunctive treatment in view of its safety and absence of
● Tiagabine may be
interactions. The IV preparation has been used as a second-line agent in the associated with dose-
treatment of status epilepticus.71-74 related episodes of
nonconvulsive status
BRIVARACETAM epilepticus or
encephalopathy, even in
Brivaracetam is structurally related to levetiracetam and has a similar mechanism
subjects who do not have
of action through binding to SV2A but with approximately 20-fold higher epilepsy.
affinity and greater selectivity. It also has a higher brain permeability than
levetiracetam. It is available in oral and IV formulations. ● Levetiracetam is the only
Brivaracetam has excellent bioavailability after oral administration. It is antiseizure medication with
Class I evidence of efficacy
weakly bound to plasma proteins. Its half-life is approximately 7 to 8 hours. It is against generalized
renally excreted after extensive metabolism, primarily by hydrolysis and to a myoclonic seizures.
lesser extent hydroxylation mainly via CYP2C19. Brivaracetam has more
interactions than levetiracetam. Its clearance is increased by enzyme inducers. It ● Brivaracetam may have
fewer behavioral side
may increase carbamazepine epoxide and may also increase phenytoin effects than levetiracetam.
concentration by up to 20%.
Although brivaracetam has a broad spectrum of efficacy in preclinical
models, human Class I trials have only been conducted in patients with focal
seizures. However, open-label data support efficacy for generalized seizure
types, particularly in patients with juvenile myoclonic epilepsy.75 Pooled
analyses demonstrated efficacy greater than placebo at 50 mg/d, 100 mg/d,
and 200 mg/d administered in 2 divided doses as adjunctive therapy.76 Post
hoc analysis of pooled data showed that most (75% to 100%) responders
responded from the time of treatment initiation.77 The recommended starting
dose is 50 mg 2 times a day, followed by adjustment based on response and
tolerability, either down to 25 mg 2 times per day or up to 100 mg 2 times a
day. However, it is reasonable to start at 25 mg 2 times a day in older patients
or those at greater risk of adverse effects. The most commonly reported
adverse experiences occurring more often than placebo were somnolence,
dizziness, and fatigue. Irritability was reported only in 3.2% of patients
receiving brivaracetam compared with 1.1% of those receiving placebo.
Brivaracetam is a controlled substance.
Place in Therapy
Brivaracetam is FDA approved for the treatment of partial-onset seizures in
patients 4 years of age and older. This indication includes monotherapy and
adjunctive use of the drug, although it has not specifically undergone initial
monotherapy trials.
Brivaracetam is not effective when added to levetiracetam.78 Open-label studies
suggested that behavioral adverse effects from levetiracetam may improve after
switching to brivaracetam.79,80 As a result, one indication for using brivaracetam is
in patients who are unable to tolerate levetiracetam due to behavioral adverse effects
or deemed at risk of behavioral adverse effects from levetiracetam. The IV
brivaracetam preparation has been explored in the treatment of status epilepticus
because of its superior brain permeability.81
ZONISAMIDE
Zonisamide is structurally related to sulfonamides. It has multiple mechanisms of
action, including blocking T-type calcium channels (predictive of efficacy

against absence seizures), blocking sodium channels, and weak inhibition of

carbonic anhydrase activity. It is available only as an oral preparation.
Zonisamide has excellent oral bioavailability. Protein binding is not clinically
significant. It is metabolized in the liver to inactive metabolites. It has a long
half-life of about 60 hours. It is not a hepatic enzyme inducer or inhibitor.
Zonisamide is considered a broad-spectrum antiseizure medication, although
Class I trials have only been conducted in patients with focal seizures. The
starting dose is 100 mg at bedtime for 2 weeks, then 200 mg at bedtime. The dose
can be increased by 100 mg every 2 weeks as needed, up to 600 mg/d once at
bedtime or in two divided doses. The suggested therapeutic range for plasma
Possible adverse effects include sedation, ataxia, dizziness, nausea, fatigue,
agitation/irritability, and anorexia. Weight loss may occur. Cognitive slowing
and difficulty with concentration may be seen, particularly at higher doses, but
are less pronounced than with topiramate. Rarely, depression and psychosis may
occur. Serious rash, such as Stevens-Johnson syndrome and toxic epidermal
necrolysis, occurs rarely. Kidney stones occur in up to 4% of patients but may be
prevented with adequate hydration. Oligohidrosis, hyperthermia, and metabolic
acidosis occur rarely, more often in children.
Place in Therapy
Zonisamide is indicated as initial monotherapy for focal seizures in Europe. In
Japan, it is also indicated as monotherapy for generalized seizures. The official
FDA indication is for adjunctive therapy for focal seizures in adults. Zonisamide
is rarely the first-choice agent for initial monotherapy because of its cognitive
adverse effects. However, its long half-life could be an advantage, reducing the
impact of a missed dose.
LACOSAMIDE
Lacosamide blocks sodium channels, enhancing slow inactivation, unlike most
classic sodium channel blockers, which enhance fast sodium channel
inactivation. It is available in oral as well as parenteral formulations.
Oral bioavailability is excellent. Protein binding is not clinically significant.
Lacosamide is converted in the liver to inactive metabolites, but approximately 40%
is eliminated unchanged in the urine. The half-life is approximately 13 hours.
Lacosamide is effective against focal-onset seizures as well as generalized-
onset tonic-clonic seizures. It is not usually effective against generalized absence
or myoclonic seizures, but it is unlikely to exacerbate these seizures in the
majority of patients.82 The starting dose is 100 mg/d (once at bedtime or in 2
divided doses) for 1 week, then 100 mg 2 times a day. The dose can then be
titrated as needed by 100 mg every 1 to 2 weeks until seizures are controlled, side
effects appear, or a total daily dose of 600 mg/d is reached.
The most common possible adverse effects include dizziness, nausea,
vomiting, diplopia, fatigue, and sedation, all of which are more common at
higher doses. These adverse effects are also more likely when lacosamide is
used in conjunction with other sodium channel blockers.83 Lacosamide may
produce a dose-dependent prolongation in PR interval, which could be clinically
significant in patients with known cardiac conduction problems, or if it is
combined with other drugs that have a similar effect. Lacosamide is a
controlled substance.
524 APRIL 2022

Place in Therapy KEY POINTS
Lacosamide is indicated as monotherapy or adjunctive therapy for focal
● Zonisamide’s long half-
seizures and as adjunctive therapy in the treatment of generalized tonic-clonic life of about 60 hours may be
seizures in patients 4 years of age or older. The parenteral formulation is indicated as an advantage in reducing the
short-term replacement when oral administration is not feasible in patients taking impact of a missed dose.
oral lacosamide; it is effective against nonconvulsive seizures in critically ill
● Lacosamide may produce
patients.84 Several reports support efficacy in status epilepticus.85 When lacosamide
a dose-dependent
is used as adjunctive therapy, it may have greater efficacy and better tolerability if it prolongation in PR interval,
is combined with a non–sodium channel blocking drug.83 which could be clinically
significant in patients with
VIGABATRIN known cardiac conduction
problems, or if it is
Vigabatrin is an irreversible inhibitor of GABA transaminase, resulting in combined with other drugs
accumulation of GABA. It is available as an oral formulation. Vigabatrin has that have a similar effect.
excellent oral bioavailability and no protein binding. It is not significantly
metabolized and is eliminated unchanged in the urine. The half-life is 10.5 hours ● Long-term vigabatrin use
may be associated with
in young adults and 5 to 6 hours in infants. However, its duration of action irreversible visual field
outlasts its presence in serum.86 Vigabatrin is a weak inducer of CYP2C9. constriction; hence, it
Vigabatrin is a narrow-spectrum drug effective against focal seizures. It may should only be continued if
worsen absence and myoclonic seizures in idiopathic generalized epilepsy.54 it produces a remarkable
improvement in seizure
However, it is effective against infantile spasms, particularly in the presence of
control.
tuberous sclerosis. The starting adult dose is 500 mg 2 times a day, then it is
titrated by 500 mg per week up to 1.5 g 2 times a day. The dose can be increased ● Valproate reduces
further, as needed, up to 3 g 2 times a day, but this increases the risk of adverse rufinamide clearance; as a
effects with a low chance of additional therapeutic benefit. result, rufinamide has to be
started at a lower dose and
Common vigabatrin adverse effects include sedation, fatigue, dizziness, and titrated more slowly in the
ataxia. Irritability, behavior changes, psychosis, and depression may also be presence of valproate.
observed. Weight gain may occur. The most concerning possible adverse effect is
a progressive and permanent bilateral concentric visual field constriction, which
may occur in up to 30% to 40% of individuals.87 The risk increases with increased
daily dose and increased duration of therapy.88
Place in Therapy
Vigabatrin use is reserved for adjunctive therapy in subjects who have failed
several alternative treatments and monotherapy in infants with infantile spasms.
Because of the visual toxicity, periodic visual assessment is recommended at
baseline and every 3 months, and treatment should be continued only if
considerable benefit is observed in the first 3 months.
RUFINAMIDE
Rufinamide is a sodium channel blocker, although additional mechanisms of
action are likely. It is available only as an oral preparation. Oral bioavailability
is very good with food but is decreased in the absence of food. Protein binding
is not clinically significant. It is metabolized by enzymatic hydrolysis to an
inactive metabolite eliminated in the urine. The half-life is approximately 6 to
10 hours. It is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4 and
uridine diphosphate glucuronyltransferase (UDP-GT). The addition of
valproate decreases rufinamide clearance and increases rufinamide levels by
up to 70%.
Rufinamide is a broad-spectrum antiseizure medication, but its efficacy
against focal seizures was not sufficient for an FDA indication. The starting

dose is 400 mg/d, after which it is increased by 400 mg every other day until seizure
control or until a total daily dose of 3200 mg is reached (in 2 divided doses).
The possible adverse effects of rufinamide include dizziness, fatigue,
somnolence, and headache. Vomiting may occur in children. Rufinamide may
cause a shortening of the QT interval.
Place in Therapy
Rufinamide is FDA indicated as adjunctive treatment for seizures associated with
Lennox-Gastaut syndrome in pediatric patients 1 year of age and older and
in adults.
EZOGABINE (RETIGABINE)
Ezogabine (known as retigabine outside the United States) was a promising
new antiseizure medication with a novel mechanism of action as a potassium
channel opener. However, long-term use was associated with bluish pigmentation in
the skin, nails, and retina. Its use declined to the point that its maker withdrew it
from the market in 2017, which is why it will not be discussed further here.
PERAMPANEL
Perampanel is a selective noncompetitive AMPA glutamate receptor antagonist.
It is available as an oral preparation. It has excellent oral bioavailability and is 95%
protein bound. It is extensively metabolized in the liver. It has a long half-life of
about 105 hours. At a dose of 12 mg (not 8 mg), it accelerates the metabolism of
levonorgestrel, a progesterone component of the oral contraceptive pill.89
Perampanel is effective for focal seizures and generalized tonic-clonic seizures.90
The starting dose is 2 mg/d for 1 to 3 weeks, then 4 mg/d. The dose can be
increased further by 2 mg every 3 weeks as needed, up to 8 mg/d in monotherapy
and 12 mg/d when used with an enzyme-inducing agent.
The possible adverse effects of perampanel include dizziness, somnolence,
headache, fatigue, ataxia, and blurred vision. Aggression and hostility may occur,
with an estimated incidence of about 20% at a dose of 12 mg/d, resulting in a
boxed warning.91 Behavioral changes were more common in patients with
intellectual disability.92 Perampanel is a controlled substance.
Place in Therapy
Perampanel is indicated for focal seizures (adjunctive and monotherapy)
and as adjunctive treatment for generalized tonic-clonic seizures. Its long
half-life may be an advantage, with two studies showing its use to be associated
with a reduction in health care resource utilization, including hospitalizations
and outpatient visits.93,94 Although there is no FDA indication for myoclonic
seizures, several case reports and case series suggest particular efficacy in
progressive myoclonic epilepsies, which are usually resistant to therapy.95-98
CANNABIDIOL
Cannabidiol was marketed in the United States in November 2018. It is a
cannabinoid but does not interact with the cannabinoid receptor CB1 and does
not share the psychoactive properties of tetrahydrocannabinol. Its exact
mechanisms of action are not known, but it may enhance GABA activity through
allosteric modulation of the GABAA receptor and enhancement of currents
elicited by low GABA concentrations.99 It may also play a role in modulation of
526 APRIL 2022

intracellular calcium.100 Its bioavailability is increased by administration with a KEY POINTS
high-fat meal. It is highly protein bound (>94%). Cannabidiol is metabolized in
● Perampanel has a very
the liver, primarily by CYP2C19 and CYP3A4 enzymes, and converted to an active long half-life, justifying
then an inactive metabolite. Its clearance is increased by inducers and decreased once-daily dosing.
by inhibitors of CYP2C19 and CYP3A4. It interacts with several antiseizure
medications, most notably with clobazam, increasing the concentration of its ● Cannabidiol reduces
clearance of the active
active metabolite N-desmethylclobazam.101,102 Cannabidiol is available only as an
metabolite of clobazam,
oral solution. The recommended starting dose is 5 mg/kg/d in 2 divided doses for requiring reduction in the
1 week, then 10 mg/kg/d in 2 divided doses. Its most common possible adverse clobazam dose.
effects are sedation, fatigue, decreased appetite, and diarrhea. It may produce an
increase in liver enzymes, particularly when used in conjunction with valproate or
with valproate and clobazam. Liver enzymes and total bilirubin levels should be
obtained before treatment and at 1, 3, and 6 months after initiation of treatment.103
Place in Therapy
Cannabidiol is FDA indicated for the treatment of seizures associated with
Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in
patients 1 year of age and older, based on blinded controlled trials.104-107 Open-label
trials also suggest efficacy for other forms of epilepsy.108-110 Artisanal cannabidiol
formulations are used without prescription by many patients with epilepsy in the
United States, but their efficacy has not been evaluated in these settings.
STIRIPENTOL
Stiripentol was FDA approved for the treatment of seizures associated with
Dravet syndrome in patients 2 years or older also taking clobazam. Its mechanism
of action may involve both direct allosteric modulation of GABAA receptors,
preventing GABA reuptake, and inhibition of CYP enzyme activity resulting in
increased concentration of clobazam and its active metabolite.111 It has good
bioavailability and is 99% protein bound. The half-life is dose-dependent, longer
with increasing dose in adult volunteers112; the half-life also increased with
increasing weight in children with Dravet syndrome. Stiripentol is an inhibitor of
several liver enzymes, namely CYP2C9 and CYP2C19. Its addition causes elevation
of N-desmethylclobazam, the active metabolite of clobazam, and to a lesser extent
clobazam. It may also increase the concentration of valproate, so that a reduction in
clobazam and valproate doses is recommended upon initiation. The recommended
dose is 50 mg/kg/d administered in 2 or 3 divided doses, not to exceed a total daily
dose of 3000 mg/d. The most common adverse experiences occurring more
frequently than with placebo are somnolence, anorexia, nausea, and weight loss.
Place in Therapy
Stiripentol is currently indicated only for the adjunctive treatment of patients with
Dravet syndrome also taking clobazam; clinicians should keep in mind the need for
adjusting concomitant medications because of a high propensity for interactions.
CENOBAMATE
Cenobamate is an alkyl-carbamate with two mechanisms of action: blocking the
sodium channel, preferentially attenuating the persistent sodium current, and
enhancing GABA activity through positive allosteric modulation of the GABAA
receptor.113,114 Cenobamate has very good oral bioavailability of 3% to 8%. Its protein
binding of 60% is not clinically relevant. It is extensively metabolized by

glucuronidation and oxidation. It is excreted predominantly as inactive

metabolites in the urine. Its half-life is 50 to 60 hours, justifying once-daily dosing.
It has several important interactions. Its concentration is reduced by enzyme
inducers. It is an inhibitor of CYP2C19, reducing the clearance of phenytoin,
phenobarbital, and the active metabolite of clobazam. However, it induces
CYP3A4, which may reduce the efficacy of oral contraceptives. It may also reduce
lamotrigine concentration. The most common possible adverse effects were
somnolence, dizziness, and fatigue.115 DRESS (drug rash with eosinophilia and
systemic symptoms) syndrome, which occurred rarely in early studies, did not
recur in a large safety study with a slowed titration rate.116 The starting dose is 12.
5 mg/d for 2 weeks, 25 mg/d for 2 weeks, 50 mg/d for 2 weeks, and then 100 mg/d,
which is the lowest dose proven effective in one clinical trial.117 After that, the dose
can be increased as needed by 50 mg every 2 weeks, up to 400 mg/d. Cenobamate
is a controlled substance.
Place in Therapy
Cenobamate was FDA approved for the treatment of focal-onset seizures in
adults in November 2019 and was marketed as of May 2020. Its efficacy as
adjunctive therapy was exceptional, with higher seizure-free rates than reported
with any other antiseizure medication in the past 30 years.117,118 This supports
its early use in patients with drug-resistant epilepsy, as its safety is confirmed
with accumulated experience.
FENFLURAMINE
Fenfluramine is a repurposed medication, originally launched as an appetite
suppressant in the early 1970s, and used predominantly in combination with
phentermine. It was eventually withdrawn because of reports of heart valve
abnormalities and pulmonary hypertension. However, observations of benefit in
patients with epilepsy resulted in its reevaluation as an antiseizure medication. It
acts to increase serotonin by disrupting its vesicular storage and reversing serotonin
transporter function.119 Additionally, its active metabolite binds to and activates
serotonin receptors. It is currently approved for the treatment of seizures associated
with Dravet syndrome in patients 2 years of age and older. It is metabolized to the
active metabolite norfenfluramine, which is then converted to inactive metabolites.
Its half-life is approximately 20 hours. It does have important interactions. In
particular, coadministration with stiripentol and clobazam increases its plasma
concentration. The recommended starting dose is 0.1 mg/kg 2 times a day. The main
possible adverse effects are decreased appetite, fatigue, somnolence, and weight
decrease.119,120 Valvular disease or pulmonary hypertension have not been observed
in pediatric epilepsy studies, possibly because lower doses were used than for
appetite suppression and because of the younger age of epilepsy patients compared
with those treated for obesity in the past. Fenfluramine is a controlled substance.
Place in Therapy
Dravet syndrome is presently the only indication for fenfluramine, but it is under
investigation for Lennox-Gastaut syndrome.
USE OF ANTISEIZURE MEDICATIONS IN COMBINATION

If the first antiseizure medication fails because of lack of tolerability, it should be
replaced with an alternative monotherapy. If the first antiseizure medication fails
528 APRIL 2022

because of lack of efficacy, options of replacement monotherapy or adjunctive KEY POINTS
therapy seem to be equal.121 Substitution monotherapy is favored when the first
● Cenobamate requires a
antiseizure medication was not well tolerated or was totally ineffective. very slow titration to avoid
Substitution monotherapy would also be preferable in older adults who already allergic skin reactions.
take other medications, in female patients of childbearing potential contemplating
pregnancy, in patients with adherence challenges, and when financial restrictions ● Antiseizure medication
combinations with different
exist. Add-on therapy would be preferred if the first antiseizure medication was
mechanisms of action may
well tolerated and partially effective or if the projected add-on agent has not been have a greater probability of
tested in monotherapy. The add-on therapy should not have negative success.
pharmacokinetic interactions with the first antiseizure medication or other
concomitant medications.122 For example, the use of an enzyme inducer with an
antiseizure medication whose metabolism can be induced will reduce its efficacy.
Enzyme inhibition is less of a problem as long as dosing accommodations are
made. Evidence exists that combining two antiseizure medications with different
mechanisms of action is associated with greater balance of tolerability and
efficacy.123 Combining medications with similar mechanisms may be associated
with increased adverse effects. In particular, combining two sodium channel
blockers tends to be associated with pharmacodynamic interactions such that
adverse effects may be seen while serum concentrations are in the therapeutic
range. Several combinations seem to have synergistic efficacy in animal
models,124 but only one combination has been demonstrated to be synergistic in
humans, the combination of lamotrigine and valproate.62
CONCLUSION
In conclusion, many antiseizure medications are available for the treatment of
epilepsy, with specific advantages and disadvantages. Some antiseizure
medications have additional efficacy in the treatment of comorbidities such as
migraine or bipolar disorder. Considerations in antiseizure medication choice
include the antiseizure medication’s efficacy profile as well as patient-specific
factors. Antiseizure medication combinations should avoid unfavorable
pharmacokinetic and pharmacodynamic interactions.
The most notable developments since the last version of this article are the
FDA approval of two new antiseizure medications, cenobamate and
fenfluramine, and expansion of the indications of some antiseizure medications,
particularly the approval of lacosamide for primary generalized tonic-clonic
seizures. There has also been increasing awareness of autoimmune
pathophysiology underlying epilepsy in many patients, often requiring
immunotherapy for optimal management. Improved understanding of the
underlying pathophysiology of epilepsy in individual patients will allow more
specific antiseizure medication therapy in the future.
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REVIEW ARTICLE
Surgical Treatments
for Epilepsy

CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By George W. Culler IV, MD; Barbara C. Jobst, MD, Dr Med, FAAN
ABSTRACT
PURPOSE OF REVIEW: More than 20 new antiseizure medications have been
approved by the US Food and Drug Administration (FDA) in the past
3 decades; however, outcomes in newly diagnosed epilepsy have not
improved, and epilepsy remains drug resistant in up to 40% of patients.
Evidence supports improved seizure outcomes and quality of life in those
who have undergone epilepsy surgery, but epilepsy surgery remains
underutilized. This article outlines indications for epilepsy surgery,
describes the presurgical workup, and summarizes current available
CITE AS:
surgical approaches.
2022;28(2, EPILEPSY):536–558. RECENT FINDINGS: Class I evidence has demonstrated the superiority of
resective surgery compared to medical therapy for seizure control and
Dr George W. Culler, Geisel quality of life in patients with drug-resistant epilepsy. The use of minimally
School of Medicine at Dartmouth, invasive options, such as laser interstitial thermal therapy and stereotactic
Dartmouth-Hitchcock Medical
radiosurgery, are alternatives to resective surgery in well-selected
Center, One Medical Center
Dr, Lebanon, NH 03766, George. patients. Neuromodulation techniques, such as responsive
W.Culler.IV@hitchcock.org. neurostimulation, deep brain stimulation, and vagus nerve stimulation,
RELATIONSHIP DISCLOSURE:
offer a suitable alternative, especially in those where resective surgery is
Dr Culler reports no disclosure. contraindicated or where patients prefer nonresective surgery. Although
Dr Jobst has received personal neuromodulation approaches reduce seizure frequency, they are less
compensation of $20,000 for
serving as an Associate Editor likely to be associated with seizure freedom than resective surgery.
on Neurology. The institution of
Dr Jobst has received research SUMMARY: Appropriate patients with drug-resistant epilepsy benefit from
support from the American
Epilepsy Society, the Centers epilepsy surgery. If two well-chosen and tolerated medication trials do not
for Disease Control and achieve seizure control, referral to a comprehensive epilepsy center for a
Prevention, the Department of
Defense, the Epilepsy
thorough presurgical workup and discussion of surgical options is
Foundation, Harvard Pilgrim appropriate. Mounting Class I evidence supports a significantly higher
Health Care, Inc, the National chance of stopping disabling seizures with surgery than with further
Institutes of Health, and
NeuroPace, Inc.
medication trials.
UNLABELED USE OF
USE DISCLOSURE:
INTRODUCTION
Drs Culler and Jobst discuss
E
the unlabeled/investigational pilepsy is considered drug resistant if at least two appropriately chosen
use of neurostimulation for the and used antiseizure medications have failed to control seizures.1
treatment of refractory
genetic/idiopathic
Despite the availability of many new antiseizure medications with
generalized epilepsy. differing mechanisms of action, outcomes in newly diagnosed epilepsy
have not improved, and the proportion of patients with drug-resistant
© 2022 American Academy epilepsy is up to 40%.2-4 Drug-resistant epilepsy is associated with high rates of
of Neurology. morbidity, including loss of independence, depression, neurologic impairment
536 APRIL 2022

(eg, memory loss), and worse quality of life. Additionally, patients with drug- KEY POINTS
resistant epilepsy have a mortality rate 5 to 10 times that of the general population
● Drug-resistant epilepsy is
secondary to sudden unexpected death in epilepsy (SUDEP), accidents, diagnosed when a person
and suicide.5 continues to have seizures
The efficacy of epilepsy surgery, including resective surgery and despite adequate trials of
neurostimulation, has been demonstrated in several Class I studies. Since 2001, two appropriately chosen
and well-tolerated
three randomized controlled trials comparing surgical to medical management
have demonstrated resective surgical treatment is safe and effective for
drug-resistant epilepsy.6-8 Several randomized controlled trials and long-term ● One-third of patients with
open-label studies have also reported good seizure outcomes with the use of epilepsy have drug-resistant
neurostimulation (vagus nerve stimulation [VNS], responsive neurostimulation epilepsy. Drug-resistant
epilepsy is associated with
[RNS], and deep brain stimulation [DBS]) for drug-resistant epilepsy.9-11 higher rates of morbidity
Additionally, modern minimally invasive techniques, such as laser interstitial (eg, loss of independence,
thermal therapy (LITT) and stereotactic radiosurgery, are becoming popular depression, worse quality of
options in certain epilepsy centers. Overall, surgery may result in up to a 70% life) and mortality.
seizure freedom rate in carefully selected patients with drug-resistant epilepsy.12 ● Epilepsy surgery
evaluation is appropriate for
THE UNDERUTILIZATION OF EPILEPSY SURGERY anyone with focal disabling
Despite evidence supporting the efficacy of epilepsy surgery and practice seizures that continue to
occur despite treatment
parameters published by the American Academy of Neurology advising referral
with two appropriately
to an epilepsy center for surgical evaluation, epilepsy surgery remains chosen antiseizure
underutilized, with estimates of under 1% of eligible candidates referred for medications.
surgical evaluation.13 A 2020 study of children with epilepsy also concluded only
about 1% of children with a diagnostic code of drug-resistant epilepsy according ● Evaluation for surgery
begins at an established
to the International Classification of Diseases, Ninth Revision, Clinical Modification comprehensive epilepsy
(ICD-9-CM) received epilepsy surgical procedures.14 Although the center, where the diagnosis
above-mentioned studies have limitations, the low rates of epilepsy surgery are of epilepsy is confirmed.
likely multifactorial. Barriers include access issues (eg, lack of nearby epilepsy
program, transportation, lack of health insurance, inability to take time off
work), negative attitudes toward or fear of surgery, and lack of general education
or knowledge among referring providers and patients about epilepsy and
epilepsy surgery. TABLE 11-1 lists common misconceptions about epilepsy
surgery.
EPILEPSY SURGERY CANDIDATES

Evaluation for epilepsy surgery is appropriate for anyone with disabling seizures
that cause significant impairment in quality of life and continue to occur despite
treatment with two well-tolerated and appropriately chosen antiseizure
medications.15 Patients may have initially responded well to antiseizure
medications or have a history of prior remission but later become drug resistant
and thus suitable candidates for surgery.16
Referral to an established comprehensive epilepsy center for evaluation is
recommended, where video-EEG monitoring is usually performed. Video-EEG
helps to establish the diagnosis of epilepsy and rule out nonadherence to
antiseizure medications and pseudoresistance to antiseizure medications in
patients with nonepileptic seizures or those on the wrong antiseizure medication
for their syndrome.17
Surgical candidates with focal epilepsy may be broadly categorized into
several groups: patients with mesial temporal lobe epilepsy or neocortical
epilepsy, lesional epilepsy due to focal structural pathology (eg, low-grade

SURGICAL TREATMENTS FOR EPILEPSY
glioma, cavernous malformation), or nonlesional focal epilepsy. In patients with

focal epilepsy, a presurgical evaluation for resective surgery should be
performed. If resective surgery is not an option, neurostimulation should be
considered as an alternative.
Other resective surgical alternatives, such as hemispherectomy or
hemispherotomy, may be appropriate for patients with severe epilepsy and
preexisting hemiparesis. Surgical options are limited for generalized epilepsies;
however, for drug-resistant epilepsies such as Lennox-Gastaut syndrome and
others, corpus callosotomy may offer palliation for disabling drop attacks or
rapidly generalizing seizures. Neuromodulation (eg, DBS, VNS) may also be
considered in those with generalized epilepsy who have disabling seizures.
PRESURGICAL EVALUATION
The goal of the presurgical evaluation in patients with drug-resistant epilepsy is
to best identify the cortical area that is generating seizures, which, when
removed by surgery, will result in seizure freedom. This is referred to as the
epileptogenic zone, which is a theoretical concept defined as the minimum
amount of cortex that must be resected to produce seizure freedom.18 To best
TABLE 11-1 Common Misconceptions About Epilepsy Surgerya
Misconception Fact
All drugs need to be tried Seizure freedom is unlikely after two drugs have failed
Bilateral EEG spikes are a contraindication to surgery Patients with unilateral-onset seizures usually have
bilateral spikes
Normal MRI is a contraindication to surgery Other techniques often detect a single epileptogenic zone
in patients with normal MRIs
Multiple or diffuse lesions on MRI are a The epileptogenic zone may involve only a part of the lesion
contraindication to surgery
Surgery is not possible if primary cortex is involved Essential functions can be localized and protected
Surgery will make memory worse if the patient has Poor memory usually will not get worse and could get better
an existing memory deficit
Chronic psychosis is a contraindication to surgery Outcome depends on the type of epilepsy and the type
of surgery
IQ less than 70 is a contraindication to surgery Outcome depends on the type of epilepsy and the type
of surgery
Patients with focal epilepsy and a focal lesion can have the Focal lesions can be incidental findings unrelated to
lesion removed without detailed presurgical evaluation the epilepsy; epileptogenicity of a lesion should always
be confirmed
Generalized epilepsy is a contraindication to surgery Appropriately selected patients with generalized epilepsy
may be candidates for deep brain stimulation, vagus nerve
stimulation, or potentially thalamic responsive
neurostimulation
EEG = electroencephalography; IQ = intelligence quotient; MRI = magnetic resonance imaging.

a
Modified with permission from Engel J Jr, Neurology.17 © 2016 American Academy of Neurology.
538 APRIL 2022

estimate the epileptogenic zone boundaries, a variety of different diagnostic tools
are used (TABLE 11-2).
The diagnosis of epilepsy begins with a comprehensive history that focuses on
describing seizure symptomatology, frequency, and epilepsy duration to
understand the epilepsy subtype and begin localization of the epileptogenic zone.
The hallmarks of the presurgical evaluation include continuous video-EEG
monitoring for interictal and ictal analysis to confirm the diagnosis of epilepsy
and correlate the patient’s reported symptomatology to aid in localization of the
seizure-onset zone.19,20 Antiseizure medications are often reduced to record
several seizures and ensure that the patient is having only one seizure type.
Modifications to a standard 10-20 electrode placement may include additional
Presurgical Investigative Tools and Their Significance TABLE 11-2
Presurgical investigations Significance

Seizure history and general medical history Characterizes typical seizure types and symptomatology by the patient and
their relatives which are later verified on video-EEG monitoring
Ascertains all relevant past history and epilepsy risk factors (eg, history of
prolonged febrile convulsions, meningoencephalitis, family history of
epilepsy, head trauma)
General medical and neurologic examination Identifies focal neurologic deficits, which suggest an underlying lesion or
diagnosis of a syndrome associated with epilepsy (ie, neurocutaneous
abnormalities in tuberous sclerosis complex or Sturge-Weber syndrome)
Video-EEG monitoring Confirms the diagnosis of epilepsy; interictal and ictal analysis provides
information regarding the lateralization and localization of the
Interictal EEG
epileptogenic zone
Ictal EEG
Seizure symptomatology
Neuropsychological assessment Provides preoperative baseline and predicts risk of cognitive decline with
surgery; helps identify and evaluate comorbid psychiatric disorders
MRI Identifies structural abnormalities associated with seizures (eg,

hippocampal sclerosis, focal cortical dysplasias)
Functional imaging (PET, SPECT) Provides ancillary information for epileptogenic zone localization:
Interictal focal hypometabolism on FDG-PET
Interictal hypoperfusion and ictal hyperperfusion on SPECT
PET and SPECT coregistered with MRI may aid in sensitivity of identifying an
epileptogenic lesion (PET-MRI, SISCOM)
Electrical and magnetic source imaging Provides ancillary electrical and magnetic source localization of interictal
(ESI, MSI); EEG-fMRI, HD-EEG epileptiform discharges
May be used for functional mapping
Functional mapping (fMRI, Wada test) Assesses language dominance, verbal memory dominance, and prediction
of postoperative decline
EEG = electroencephalography; ESI = electrical source imaging; FDG-PET = fludeoxyglucose positron emission tomography; MRI = magnetic
resonance imaging; MSI = magnetic source imaging; PET = positron emission tomography; SISCOM = subtraction ictal SPECT coregistered to MRI;
SPECT = single-photon emission computed tomography.

10-10 distanced scalp electrodes, sphenoidal electrodes, or subtemporal

electrodes to aid in localization.
High-resolution brain MRI with a dedicated epilepsy protocol is necessary to
detect a potential structural abnormality most likely responsible for seizures. In
patients with suspected temporal lobe epilepsy, three-dimensional T1-weighted,
T2-weighted, and fluid-attenuated inversion recovery (FLAIR) sequences with
thin coronal cuts through the hippocampus may detect subtle signal change,
atrophy, and/or loss of internal structure associated with mesial temporal
sclerosis and increase the likelihood of a favorable surgical outcome.21
Higher-resolution 3-Tesla (3T) or 7T MRI scanners improve the identification
of structural lesions by up to 20% compared with a 1.5T scanner.22 Careful
evaluation of the MRI by an expert neuroradiologist provides additional
sensitivity, with identification of lesions such as depth-of-the-sulcus dysplasia or
periventricular nodular heterotopias.23
Comprehensive neuropsychological testing is necessary both to localize
preoperative deficits that may correlate with the seizure-onset zone and to
FIGURE 11-1
Simplified proposed surgical algorithm for drug-resistant epilepsy.
EEG = electroencephalography; fMRI = functional magnetic resonance imaging; HD-EEG = high-density
electroencephalography; MEG = magnetoencephalography; MRI = magnetic resonance imaging; PET =
positron emission tomography; SPECT = single-photon emission computed tomography.
a
In some patients who receive intracranial evaluation, the epileptogenic zone is not fully delineated (ie,
the seizure-onset zone is not captured), and subsequent invasive evaluation is necessary before offering
surgical therapy.
b
Corpus callosotomy may be considered to reduce the frequency and severity of drop seizures, which
include generalized tonic-clonic, tonic, and atonic seizures.
c
Responsive neurostimulation of the centromedian nucleus of the thalamus has been considered a viable
therapeutic option for patients with drug-resistant focal and generalized epilepsy in some centers.
540 APRIL 2022

predict postoperative cognitive outcome and seizure control.24 For example, KEY POINTS
better preoperative verbal memory performance is a strong predictor of
● A presurgical evaluation is
postoperative memory decline following surgery of the dominant (left, in most necessary to identify the
cases) temporal lobe.25 cortical area that is
Positron emission tomography (PET) has proven valuable because a focal region generating seizures, which,
of hypometabolism may help confirm general epileptogenic zone location and when removed, will result in
seizure freedom; this is
predict favorable outcome with surgery when MRI is negative.26 Ictal single-
known as the epileptogenic
photon emission computed tomography (SPECT) might be useful when zone.
demonstrating a region of hyperperfusion, especially when subtracting interictal
SPECT imaging.27 When available, magnetoencephalography (MEG) and electrical ● Video-EEG monitoring
source imaging are other ancillary tools that may help localize a seizure focus. confirms the diagnosis of
epilepsy type by recording
To ensure a safe and optimal surgical outcome, identification of eloquent the patient’s habitual
cortex and its relation to the epileptogenic zone is necessary. Functional MRI seizures and correlates the
(fMRI) is helpful for language lateralization and identifying motor and sensory patient’s reported
areas. fMRI for lateralization of verbal and visuospatial memory is performed in symptomatology to aid in
localization.
some centers but is not entirely reliable.28 Developed by Dr Juhn Wada more
than 60 years ago, the intracarotid amobarbital procedure, or Wada test, is still ● Abnormalities on initial
used in some centers for language lateralization and to assess the risk of brain MRI may be missed.
postoperative amnesia with hippocampal resection.25,29 Careful inspection by an
expert neuroradiologist and
When these studies are concordant in localizing the seizure-onset zone to the
the use of higher-resolution
nondominant mesial temporal lobe or the respective lesion, resective surgery MRI scanners and positron
may sometimes be performed without further diagnostic workup (FIGURE 11-1). emission tomography (PET)
However, if presurgical studies are discordant or if doubt exists about the may identify subtle lesions
(eg, dysplasia).
seizure-onset zone, further diagnostic investigation with intracranial EEG is
necessary, including for patients who have lesions with poorly defined borders ● Neuropsychological
(eg, focal cortical dysplasia), dual pathology or multiple lesions, or a prior history testing and functional
of surgical failure. Intracranial EEG is also necessary when the seizure-onset zone imaging help predict
is close to eloquent cortex. postoperative deficits and
localize eloquent cortex.
INTRACRANIAL VIDEO-EEG MONITORING ● Resective surgery may be

Between 30% and 50% of epilepsy surgeries in tertiary epilepsy centers require possible without intracranial
intracranial EEG.30 The aim of intracranial EEG is twofold: (1) to record ictal and EEG studies if presurgical
findings (eg, ictal and
interictal electrographic data for epileptogenic zone delineation to support or
interictal EEG, seizure
disprove a hypothesis regarding the site of seizure onset from presurgical symptomatology, and MRI)
investigations and (2) to determine the location of eloquent cortex in relation to are concordant to the
the epileptogenic zone and define safety margins for surgery with the use of nondominant temporal lobe.
electrical stimulation for functional mapping.
● The goals of intracranial
Intracranial video-EEG monitoring is typically indicated for nonlesional focal EEG are twofold: (1) to
epilepsies or if presurgical evaluations are discordant. For example, intracranial further localize the
evaluation is necessary in temporal lobe epilepsy when atypical clinical features epileptogenic zone and
are present (eg, extratemporal symptomatology, when neuroimaging prove/disprove a hypothesis
and (2) to determine the
abnormalities disagree with suspected seizure-onset zones), when a high risk of location of eloquent cortex
postoperative cognitive decline is present (ie, dominant temporal lobe epilepsy), with electrical stimulation.
or to answer the question of whether the patient has bitemporal lobe epilepsy
(FIGURE 11-1). The use of intracranial EEG is illustrated in CASE 11-1 and CASE 11-2.
Two common approaches to intracranial EEG monitoring are (1) craniotomy
for implantation of subdural electrodes, including grid and strip electrodes with
or without depth electrodes, and (2) stereo-EEG with depth electrode placed
without craniotomy. A combination of stereotactic and subdural electrodes may
also be used.

CASE 11-1 A 39-year-old right-handed man with a history of drug-resistant epilepsy

since 1 year of age was referred to an epilepsy center. His seizures started
with an aura of a “funny feeling” that progressed to loss of awareness,
unresponsiveness, and frequent blinking with hand
automatisms. Despite being on appropriate doses of three antiseizure
medications, he still had one focal impaired awareness seizure per
month, with rare progression to bilateral tonic-clonic seizures. Six
antiseizure medications had previously failed to control his seizures.
A video-EEG showed right temporal sharp waves, and several of his
typical seizures were recorded with a right temporal onset. Over
2 decades, serial brain MRIs with dedicated epilepsy protocols had shown
a stable cystic left mesial temporal lobe mass and progressive right
hippocampal sclerosis and atrophy (FIGURE 11-2). An ictal single-photon
emission computed tomography (SPECT) scan performed during his
phase I evaluation showed increased uptake in the right anterior temporal
lobe during a typical seizure. A Wada test confirmed he was left
hemisphere dominant for language. Memory was intact on the left but
severely impaired on the right.
Since the patient continued to have intractable seizures and the
presurgical findings were concordant with right temporal lobe epilepsy
with the exception of bilateral temporal lobe lesions, stereo-EEG was
performed to confirm his seizures were arising only from the right
temporal lobe and not from the left temporal lobe. Stereo-EEG
electrodes were placed in bilateral amygdalae, hippocampi,
orbitofrontal, and insula, with additional subdural strip electrodes to
bilateral temporooccipital junctions (FIGURE 11-3).
Intracranial EEG recorded frequent epileptiform discharges arising
from the right hippocampus and amygdala. Ictal recording recorded six
of the patient’s habitual
seizures, which began with
high-frequency gamma
activity arising from the
right anterior hippocampus
and spread to the right
amygdala and posterior
hippocampus (FIGURE 11-4).
At the end of invasive EEG
monitoring, the stereo-EEG
electrodes were removed
and a right selective
amygdalohippocampectomy
was performed with laser
interstitial thermal therapy
(FIGURE 11-5). At his last FIGURE 11-2
follow-up, 2.5 years after Imaging of the patient in CASE 11-1. Coronal T2-
surgery, he remained seizure weighted, epilepsy protocol MRI shows right
free and very pleased with hippocampal atrophy (white arrow) and a left
perihippocampal cystic lesion (yellow arrow).
the surgery.
542 APRIL 2022

FIGURE 11-3
Imaging of the patient in CASE 11-1. Postoperative anteroposterior and lateral skull x-rays
show bilateral intracranial electrode placement.
FIGURE 11-4
EEG of the patient in CASE 11-1. Ictal EEG shows high-frequency gamma activity beginning in the
right anterior hippocampus (RAHCD1-3, arrows). Note: Only select channels are featured.
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FIGURE 11-5
Postoperative imaging of the patient in CASE 11-1. Axial (A) and coronal (B) contrast-enhanced
T1-weighted MRI demonstrates selective ablation of the right hippocampus and amygdala
(selective amygdalohippocampectomy) with laser interstitial thermal therapy, with contrast
enhancement seen within the ablation cavity (arrows).
COMMENT This case exemplifies the utility of stereo-EEG in clarifying the

epileptogenic zone, demonstrating that the left mesial temporal lobe mass
in this patient was not associated with the ictal onset of his habitual clinical
seizure. The use of stereo-EEG also confirmed a secondary hypothesis that
all the patient’s clinical seizures began from the right hippocampus, which
was concordant with all other presurgical evaluations. This enabled the
surgical epilepsy team to be more confident that removal of the right
mesial temporal lesion would render a good outcome and seizure freedom
for the patient.
Complications are typically low with stereo-EEG, with the most prevalent risk
being hemorrhage (1%) or infections (0.8%).31 In a direct comparison of 260
patients undergoing stereo-EEG and subdural electrode implantation at a single
institution, major iatrogenic events such as symptomatic hemorrhage or
infection were higher (7.2%) in patients receiving subdural evaluation than in
patients receiving stereo-EEG (0%, P=.003).32 Potential advantages and
disadvantages of each type of intracranial monitoring are summarized in TABLE 11-3.
EPILEPSY SURGERY
Three Class I randomized controlled trials have shown the effectiveness of
surgery compared to ongoing medical treatment in patients with drug-resistant
epilepsy, not only for seizure control but also for quality of life.6-8 Studies by
Wiebe and colleagues6 and Engel and colleagues7 established surgical efficacy in
adults with temporal lobe epilepsy, whereas Dwivedi and colleagues8 confirmed
similar success in the pediatric patient population. In addition to resective
544 APRIL 2022

surgery, surgical options include laser ablation and three US Food and Drug KEY POINTS
Administration (FDA)–approved neurostimulation devices. A simplified
● Only 30% to 50% of
proposed surgical algorithm is shown in FIGURE 11-1. epilepsy surgeries require
To measure seizure outcomes after surgery, the Engel Epilepsy Surgery intracranial EEG, which
Outcome Scale and the International League Against Epilepsy (ILAE) epilepsy includes the use of
surgery outcome classification are frequently used, both of which classify stereotactic electrodes,
subdural grid electrodes, or
postoperative seizures along a range from favorable (Engel class I/II or ILAE
a combination of the two to
outcome classification 1-3) to no worthwhile improvement or worsening seizures aid in delineation of the
(Engel class IV or ILAE outcome classification 5-6) (TABLE 11-4).33,34 epileptogenic zone.
The following sections explore the different types of surgical options in more
detail. A simplified summary of seizure freedom rates and indications for ● Three Class I randomized
controlled trials have shown
different surgical options is presented in TABLE 11-5.35-39 the effectiveness of
resective surgery compared
Resective Surgery to continued medical
Resection of the epileptogenic zone remains the gold standard for the best seizure treatment in adults and
children with drug-resistant
outcome in drug-resistant epilepsy compared to best medical therapy. The epilepsy.
following subsections review specific seizure outcomes in three common classes
of focal epilepsy: temporal lobe, extratemporal lobe, and lesional epilepsy. ● Different surgical options
are available for drug-
resistant epilepsy, including
TEMPORAL LOBE EPILEPSY. Temporal lobe epilepsy is the most common type of
resection, laser ablation,
focal epilepsy and is further divided into mesial and neocortical temporal lobe and neurostimulation, which
epilepsy depending on where seizures actually originate. The clinical syndromes can be tailored to the
of mesial and neocortical temporal lobe epilepsy often overlap, and specific patient.
distinguishing between the two may be difficult unless an obvious lesion is
● Verbal memory deficits
present. The effectiveness of surgery for temporal lobe epilepsy is well are the most consistent
established. In the first randomized study of continued medical treatment adverse effect following
compared to surgical treatment for patients with drug-resistant temporal lobe dominant (typically left)
epilepsy (n = 80), 58% of the patients treated surgically were free of seizures with temporal resections when
compared to nondominant
impaired awareness at 1 year compared to 8% treated medically ( P<.001).6 resection.
Quality-of-life ratings were significantly higher in the postsurgical group. In a
separate study of 38 patients with mesial temporal lobe epilepsy who underwent
surgery within 2 years of developing drug-resistant epilepsy, seizure freedom
was achieved in 73% of patients treated surgically after 2 years compared with
0% of the patients treated medically.7
The most common procedure for temporal lobe epilepsy is an anterior
temporal lobe resection, which includes the anterior temporal pole,
hippocampus, and amygdala.12 Because of the risk of verbal deficits when the
language-dominant (typically left) side is resected, the posterior extent of the
resection is further from the temporal pole on the right compared to the left.40
Selective amygdalohippocampectomy remains an alternative to anterior
temporal lobectomy if the epileptogenic zone is confined to the mesial temporal
structures (eg, hippocampal sclerosis) and appears to have efficacy similar to
anterior temporal lobectomy in regard to seizure, cognitive, and psychiatric
outcomes.41 If seizures are confirmed to arise from neocortical temporal regions
(eg, lateral or basal temporal cortex), a tailored resection sparing the
hippocampus can be performed.
In a systematic review of focal surgical resections, major neurologic
complications were noted to occur in 4% of patients undergoing temporal lobe
resections and were more common in pediatric patients than in adults.42 Verbal
memory deficits are the most consistent adverse effect following left temporal

CASE 11-2 A 50-year-old right-handed woman with a history of drug-resistant

epilepsy since 6 years of age was referred to an epilepsy center. Her
initial seizure symptomatology started with an aura of fear, causing her to
cry out before progressing to a bilateral tonic-clonic seizure. When she
was in her thirties, acute gastroenteritis prevented her from taking her
antiseizure medications, and she subsequently went into status
epilepticus and was in the intensive care unit for nearly 2 months.
Afterward, a new predominant seizure type emerged, described as drop
attacks without loss of consciousness. Her seizures began with a right-
sided somatosensory aura that progressed quickly to brief tonic-
myoclonic movements of the right hemibody, resulting in falls. Seizures
occurred daily, were often clustered, and were disabling despite
adequate doses of levetiracetam, carbamazepine, and gabapentin. By
the time she was referred for presurgical workup, she had persistent
right-sided weakness and was wheelchair dependent.
The patient’s video-EEG showed left frontal sharp waves, and habitual
seizures were captured that correlated with left hemispheric slowing
diffusely. Brain MRI with a dedicated epilepsy protocol was otherwise
nonlesional, with the exception of a mildly asymmetric, left smaller than
right, hippocampus. Fludeoxyglucose positron emission tomography
(FDG-PET) was unremarkable. Neuropsychological testing was notable for
impaired executive function and attention and impaired motor skills on the
right side.
The patient underwent intracranial EEG with broad coverage of the left
frontocentral region, including interhemispheric and left frontal grids, left
frontoparietal strip (1 x 8 contact), and a hippocampal depth electrode
(FIGURE 11-6). Intracranial video-EEG recorded several habitual focal seizures
correlating to seizure onset arising from the left mesial frontal lobe near the
leg motor cortex.
Because of the proximity of the seizure-onset zone to eloquent motor
cortex, the patient underwent implantation of a responsive neurostimulator
with subdural strips (FIGURE 11-7). The patient’s habitual seizures were recorded
via subdural strip electrodes. Electrocorticography of the patient’s seizures
recorded before turning on stimulation therapy and after
electrocorticography-triggered stimulation was turned on is shown
in FIGURE 11-8.
At her 2-year follow-up, the patient reported significantly decreased
seizure frequency, which was verified on chronic electrocorticography
recordings, and was able to walk independently.
546 APRIL 2022

FIGURE 11-6
Postoperative imaging of the patient in CASE 11-2. A, Three-dimensional reconstruction of a
T1-weighted MRI fused with CT for visualization of subdural grid and strip electrodes
placed over the left hemisphere. B, Sagittal postcontrast T1-weighted MRI shows
contacts from which the intracranial seizure onset was recorded (red circle). C, Axial
postcontrast T1-weighted MRI shows the one transoccipital hippocampal depth
electrode placement.
FIGURE 11-7
Postoperative imaging of the patient in CASE 11-2. A, Sagittal T1-weighted MRI with two 1 x 4
subdural strips placed over the leg motor cortex and supplementary sensorimotor area.
B, Sagittal T1-weighted MRI shows placement of responsive neurostimulation battery and
stimulator under the scalp anterior to strip electrodes. An additional strip electrode can be
seen which was placed over the convexity of left frontal lobe. C, Lateral skull x-ray shows
generator and strip electrodes. Two extra 1 x 4 subdural strips can be seen superior to the
interhemispheric strips placed over the convexity of left frontal lobe; however, these
electrodes were not connected to the stimulator.
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FIGURE 11-8
Electrocorticography of the patient in CASE 11-2. A, Long-episode recording of a typical
seizure, which is detected by the responsive neurostimulation (RNS) in blue tracing in the
top and bottom panels (time base expanded). In the middle panel, RNS provides
quantitative analysis of the seizure. B, RNS delivers stimulation at the onset of a typical
seizure (blue) and is shown to have stopped the seizure.
COMMENT This patient’s seizure symptomatology, EEG findings, and

neuropsychological testing results demonstrated a likely left frontal or
central lobule epilepsy involving highly eloquent primary somatosensory
and motor cortex. Brain MRI was nonlesional with the exception of a mildly
asymmetric, left smaller than right, hippocampus, which was of unclear
significance. Intracranial EEG with strip, grids, and hippocampal depth
electrode identified seizures arising from the left mesial frontal lobe. A
resection was not possible because of the proximity of the seizure focus to
the primary leg motor cortex, and the epilepsy surgical team placed a
responsive neurostimulator as a therapeutic means with excellent outcome.
resection when compared to right temporal resection.12 Visual field deficits, most
commonly a superior quadrantanopia due to injury to the inferior optic
radiations, comprise half of all permanent neurologic deficits but are generally
well tolerated.42
EXTRATEMPORAL LOBE EPILEPSY. Surgical resection of neocortical and

extratemporal epilepsies is more challenging because of the difficulty of defining
the boundaries of the epileptogenic zone and the concern for clinically functional
cortex (eg, primary motor, visual, and language areas). Frontal lobe surgery is
the next most common resection after temporal lobe surgery. In a meta-analysis
of nearly 1200 patients with frontal lobe epilepsy, resection resulted in a
seizure-free outcome in 45.1%; seizure-free outcome was higher in patients with
lesional epilepsy (61%) than in patients with nonlesional epilepsy (39%).12,43
548 APRIL 2022

Furthermore, in a systematic review and meta-analysis of studies evaluating all
epilepsy surgery outcomes, parietooccipital epilepsy surgery resulted in seizure
freedom for 46% of patients.44 Patients with nonlesional neocortical epilepsies
inevitably need intracranial EEG evaluation to better localize the epileptogenic
zone and delineate the bounds of eloquent cortex. Epileptogenic zones that
overlap with primary language areas (ie, the Broca and Wernicke areas), the
primary sensorimotor cortex, or the visual cortex cannot be safely resected
without a likely postoperative deficit. Factors associated with seizure-free
outcome in a 2015 systematic review are detailed in TABLE 11-6.
LESIONAL EPILEPSY. Lesional epilepsy, which is defined as having an unequivocal

MRI abnormality responsible for seizures, is associated with a better outcome than
nonlesional epilepsy. A meta-analysis including 2860 patients reported a 2.5 times
greater likelihood of a seizure-free outcome when a discrete lesion was resected
compared to no discrete lesion.45 Common pathologic entities responsible for
drug-resistant lesional epilepsy include hippocampal sclerosis, malformations of
cortical development, cavernous malformations, and low-grade tumors.
Malformations of cortical development are a common cause of drug-resistant
epilepsy and encompass a broad range of disorders, the most common of which is
focal cortical dysplasia. Identifying focal cortical dysplasia can be challenging
because dysplasia may be diffuse or multilobar, is commonly not seen on MRI
(or “MRI-negative”), and often is identified only on histopathology. In a subset
of patients, MRI identification of a transmantle sign or the use of FDG-PET in
MRI-negative cases helps to improve detection of subtle areas of cortical
thickening and depth-of-the-sulcus dysplasias, which subsequently helps with
surgical prognosis.46 In a retrospective series of patients with seizures due to
polymicrogyria or periventricular nodular heterotopia, the use of intracranial
Advantages and Disadvantages of Stereoelectroencephalography and Subdural TABLE 11-3

Grid Electrodes
Advantages Disadvantages
Stereo-EEG Maps three-dimensional epileptogenic networks, including Limited spatial sampling of electrical activity
easier sampling of spatially distinct and deep regions (eg, from tissue directly around each electrode
periventricular gray matter heterotopia, insular, depth-of-
Does not map spatially continuous coverage of
sulcus regions)
brain surface gyri
Easily samples bilateral hemispheres
Less feasible in young children (requires bone
No craniotomy, decreased perioperative pain, and shorter thickness > 2 mm)
recovery time
Lower rate of serious adverse events
Subdural grid More precise functional mapping when the epileptogenic Higher rates of serious adverse events
electrodes zone involves cortical regions adjacent to eloquent cortex
Sampling of insula is difficult and high risk
Craniotomy has been performed, and resection can occur
Sampling bilateral hemispheres is challenging
when electrodes come out
(ie, bilateral craniotomies)
Depth electrodes may be added to sample deep structures
Cannot sample gray matter in sulci (eg, depth-
of interest; however, the accuracy may be affected
of-sulcus lesions)
because of shifting of the brain after craniotomy

EEG helped to localize the epileptogenic zone and seizure freedom was reported
in 72% of patients with polymicrogyria and 76% of patients with periventricular
nodular heteropia.47,48
Cavernous malformations and arteriovenous malformations are the most
common vascular lesions found in patients with focal epilepsy. In a case series of
168 patients with symptomatic epilepsy attributed to cavernous malformations,
more than two-thirds of patients were seizure free at 3 years after surgery.49 In
this study, predictors for good outcome included mesiotemporal location, size
less than 1.5 cm, and the absence of secondarily generalized seizures. Typically,
surgery consists of lesionectomy plus resection of surrounding epileptogenic
cortex, often guided by intracranial monitoring or intraoperative
electrocorticography.
Low-grade slow-growing tumors are often associated with seizures.
Gangliogliomas and dysembryoplastic neuroepithelial tumors (DNETs) account
for the majority of tumors found in adults with epilepsy. In a 2017 multicenter
retrospective study of 339 patients with low-grade tumors who underwent
epilepsy surgery, 88% of patients with associated drug-resistant epilepsy became
seizure free.50 Younger age at surgery, a temporal resection site, and complete
tumor removal were predictors of a favorable seizure outcome in this cohort.
Laser Interstitial Thermal Therapy

Stereotactic ablation of seizure foci has become increasingly popular as a
minimally invasive surgical option for those with drug-resistant epilepsy. LITT is
performed with a fiberoptic laser probe using real-time MRI thermography to
TABLE 11-4 Engel and International League Against Epilepsy Classifications of

Postoperative Seizure Outcome
Engel Epilepsy Surgery Outcome Scale33

◆ Class I: free of disabling seizures (Ia); nondisabling focal aware seizures or auras only (Ib);
some disabling seizures after surgery but free of disabling seizures for ≥2 years (Ic);
convulsions with seizure medication withdrawal only (Id)
◆ Class II: initially seizure free (IIa) but had rare disabling seizures (IIb) in the past 2 years (IIc);
nocturnal seizures only (IId)
◆ Class III: worthwhile seizure reduction (IIIa); prolonged seizure-free periods last less than
2 years but >50% of follow-up period (IIIb)
◆ Class IV: no worthwhile improvement; significant seizure reduction (IVa); no change (IVb);
worsened seizures (IVc)
International League Against Epilepsy Classification34
◆ Class 1: completely seizure free (if since surgery, 1a); no auras
◆ Class 2: only auras; no other seizures
◆ Class 3: 1-3 seizure days per year; with or without auras
◆ Class 4: 4 seizure days per year to 50% reduction in baseline number of seizure days; with or
without auras
◆ Class 5: <50% reduction in baseline number of seizure days to 100% increase in baseline
number of seizure days; with or without auras
◆ Class 6: >100% increase in baseline number of seizure days; with or without auras
550 APRIL 2022

track the temperature of ablated tissue and visualize surrounding structures to be
protected. In a retrospective review of 58 consecutive patients undergoing
stereotactic laser amygdalohippocampectomy, 53.4% of patients were free of
disabling seizures (Engel class I).51 In this study, quality-of-life scores were
significantly improved. MRI-guided LITT has successfully been used for ablation
of epileptogenic lesions such as cavernous malformations, hypothalamic
hamartomas, and focal cortical dysplasia.52,53
In mostly small observational studies of patients with mesial temporal lobe
epilepsy, treatment with LITT appeared to result in less postoperative
neuropsychological decline specific to object naming and face recognition.54
Summary of Surgical Treatment Options and Reported Seizure Freedom TABLE 11-5
Rates
Surgical treatment in drug-resistant Seizure

epilepsy freedoma Indication
6,7
Continued medical treatment 0-8.0% Patients may decline surgical intervention or if the risk of adverse
effects of surgical treatments outweigh the potential benefits
Surgical resection12
Overall (median) 64.2%b Focal cortical resection may be considered in any patient with drug-
resistant epilepsy if the region causing seizures can be removed
All focal epilepsy 52-67%
with minimal risk of disabling neurologic or cognitive dysfunction
Temporal lobe epilepsy 58-76%
Extratemporal lobe epilepsy 34-56%
Frontal lobe epilepsy 45%
Laser ablation for mesial temporal 38-78% Minimally invasive option for patients who are good resective
lobe epilepsy35 candidates, especially those with mesial temporal lobe epilepsy or
epileptogenic lesions (ie, cavernous malformations) who are
resistant to open surgery; laser ablation does not preclude a
subsequent open surgery, if needed
Stereotactic radiotherapy for mesial 51-74% Minimally invasive option for patients who would be good
temporal lobe epilepsy36 candidates for anterior temporal lobectomy for mesial temporal
lobe epilepsy but are resistant to open surgery
Neuromodulationc
Vagus nerve stimulation37 8.3% Patients with focal drug-resistant epilepsy who undergo full surgical
evaluation and are deemed poor candidates for resective surgery;
Responsive neurostimulation38 29%
also an option for patients with multifocal epilepsy, generalized
39
Deep brain stimulation 16% epilepsy, or those who are opposed to resective surgery
Responsive neurostimulation is a safe and effective targeted
treatment option for seizures that arise from eloquent regions of
cortex and up to two suspected epileptogenic foci
Vagus nerve stimulation and deep brain stimulation are most often
used for patients who have poorly localized or multifocal epilepsy
a
Criteria vary among studies for definition of seizure remission.
b
Median seizure freedom rate among all studies.12
c
Seizure-free interval of at least 6 months at last follow-up.

Iatrogenic adverse events related to LITT are low and typically due to thermal
damage to surrounding structures. In a retrospective study of 57 patients who
underwent LITT for mesial temporal lobe epilepsy, lower rates of visual field
deficits and smaller deficits were seen than in patients who underwent historical
anterior temporal lobe resections.55 In another small series of 35 patients, one
patient developed a brain abscess.56
Randomized controlled trials comparing laser ablation to alternative therapies
have not been conducted; however, an open-label prospective study of LITT for
mesial temporal lobe epilepsy is ongoing.57 In nearly all cases, laser ablation
presents no barrier to subsequent open surgery, if needed, which may provide an
attractive alternative or first option for patients who are initially resistant to open
surgery. The use of LITT for the treatment of epilepsy is demonstrated in
CASE 11-1.
Stereotactic Radiosurgery
Stereotactic radiosurgery is a minimally invasive procedure performed with
radiation that has been considered as an alternative to open surgery for mesial
temporal lobe epilepsy. In the only prospective randomized trial of stereotactic
radiosurgery versus open temporal lobectomy (the ROSE [Radiosurgery or Open
Surgery for Epilepsy] trial), patients randomly assigned to the open temporal
lobectomy arm had an advantage in seizure remission over those treated with
TABLE 11-6 Factors Associated With Seizure-free Outcome After Resective Surgerya
Positive association
◆ Seizures without loss of awareness
◆ Complete resection of a lesion
◆ Febrile seizures in childhood
◆ Prolonged seizure freedom after surgery
Negative association
◆ Normal MRI
◆ Generalized tonic-clonic seizures
◆ Need for intracranial EEG (ie, stereo-EEG)
No association
◆ Sex
◆ Age
◆ Side of resection
Inconsistent association
◆ Duration of epilepsy
◆ Temporal versus extratemporal lobe epilepsy
◆ Pathology
EEG = electroencephalography; MRI = magnetic resonance imaging.

a
Modified with permission from Jobst BC, Cascino GD, JAMA.12 © 2015 American Medical Association.
552 APRIL 2022

stereotactic radiosurgery (78% compared to 52%), without a significant KEY POINTS
difference in verbal memory deficits.36 Adverse events related to stereotactic
● Visual field deficits, most
radiosurgery included transient cerebral edema and related symptoms after the commonly a superior
first year of treatment, which was expected. Long-term follow-up data are quadrantanopia, comprise
lacking. Stereotactic radiosurgery remains an alternative to anterior temporal half of all permanent
lobectomy at certain centers for patients reluctant to undergo open surgery. neurologic deficits after
temporal lobe resection and
are generally well tolerated.
HEMISPHERIC AND POORLY LOCALIZED EPILEPSY
Variations of surgical resection, such as corpus callosotomy, are reserved as a ● Surgery for lesional
means of palliation to reduce morbidity in patients with poorly localized or epilepsy, as defined by an
rapidly generalizing seizures that result in disabling drop attacks. The anterior unequivocal MRI
abnormality responsible for
two-thirds of the corpus callosum (partial callosotomy) are surgically divided; seizures, is associated with
however, sometimes a complete callosotomy is performed if seizures persist. In a better postoperative seizure
2019 systematic review of adults and children, approximately one-half of outcome than nonlesional
patients become free from debilitating drop attacks with either partial or epilepsy.
complete callosotomy.58 Hemispherectomy or functional hemispherotomy may ● The most common lesions
be used in select individual patients with catastrophic hemispheric epilepsy associated with seizures
syndromes, such as hemimegalencephaly, Sturge-Weber syndrome, large include malformations of
congenital hemiplegic strokes, and Rasmussen encephalitis. In a single-center cortical development, focal
cortical dysplasia,
retrospective review of patients undergoing hemispherectomy for epilepsy, 66%
cavernous and
(112 out of 170 patients) were reported to be seizure free at a median of 5.3 years.59 arteriovenous
malformations, and
NEUROMODULATION low-grade gliomas.
Three implantable neurostimulation therapies are now available for patients with
● Laser ablation and
drug-resistant epilepsy who undergo full surgical evaluation and are not stereotactic radiosurgery
candidates for resective surgery or prefer a less invasive approach as first-line are minimally invasive
surgical therapy. In most cases, these patients are not candidates for resective options available in some
surgery because of difficulty with localizing the seizure onset, multifocal seizure- centers for patients who are
candidates for resection but
onset zones, or an epileptogenic zone that overlaps with eloquent cortex. As a do not want a craniotomy.
class of therapy, neuromodulation demonstrates an initial seizure reduction that
improves over time. The following section explores the different ● Three implantable
neurostimulation options available for patients. neurostimulation therapies
are now available for
patients with drug-resistant
Responsive Neurostimulation epilepsy who undergo full
RNS is a closed-loop neurostimulation therapy that is triggered by early detection surgical evaluation and are
of epileptogenic activity. This is made possible by the stimulator’s ability to deemed poor candidates for
resective surgery.
continuously monitor intracranial EEG because of the implantation of two four-
contact depth or strip electrodes. EEG data can be downloaded and accessed by ● Responsive
the patient and physician to monitor therapy. The stimulator and battery are neurostimulation should be
placed under the patient’s scalp. RNS is a safe and effective treatment option, considered as a treatment
particularly for seizures that arise from eloquent regions of cortex and up to two option in those with seizures
that arise from eloquent
suspected epileptogenic foci. cortex and/or up to two
In the pivotal randomized controlled trial of RNS in adults with drug-resistant suspected seizure foci.
focal-onset seizures, a greater reduction in seizure frequency was seen in those
who received neurostimulation treatment (38%) than in the sham group (17%),
with no difference in adverse events.10 The 9-year prospective follow-up study of
this trial published in 2020 reported sustained and progressive improvement in
seizures over time, with greater than one-third of patients having a 90% or
greater reduction in seizure frequency.38 In a separate study of 126 patients with
focal neocortical epilepsy including seizures arising from eloquent cortex, a

median seizure reduction of 70% was seen in patients with frontal and parietal
seizure onsets, 58% in patients with temporal neocortical onset, and 51% in
patients with multilobar onsets.60 The successful use of RNS for epilepsy arising
from eloquent motor cortex is illustrated in CASE 11-2.
Significant improvement in overall quality of life and cognitive flexibility and
no deterioration in mood or neuropsychological function are reported with
RNS.61 Serious adverse events related to RNS include infection (4.1%) and
hemorrhage (2.7%) and are typically reported shortly after the surgical
procedure.38 The incidence of SUDEP has been reported as 2.8 per 1000 patient
stimulation years, which is lower than the published SUDEP rates in similar
epilepsy surgical candidates (9.3 per 1000 person-years).38
RNS demonstrates great flexibility in its use. Because of the ability to
continuously record intracranial EEG, carefully selected patients (eg, those with
mesial temporal lobe epilepsy) have been identified and achieved good outcomes
from a subsequent resection.62 Some centers will place RNS in addition to
performing a partial resection because the epileptogenic zone encompasses
eloquent cortex.63 A previous potential barrier, newer RNS models now allow for
the possibility of future 1.5T MRI if needed.
Deep Brain Stimulation

DBS is an open-loop deep brain stimulation that delivers continuous therapy to
the anterior nuclei of the thalamus. The DBS stimulator and battery are placed
under the skin in the upper chest. The mechanism by which DBS benefits
patients with epilepsy is still not well understood; however, animal models have
demonstrated that high-frequency stimulation of the anterior nucleus may raise
the cortical seizure threshold by causing inhibition of neuronal activity and/or
cortical desynchronization.64 Since resective surgery, laser ablation, and RNS
allow for targeted treatment of well-localized seizure-onset zones, DBS is
typically reserved as a treatment option for poorly localized epilepsy, patients
with multifocal or generalized epilepsy not amenable to the aforementioned
therapies, or those who are opposed to resective surgery.
In a pivotal study of drug-resistant focal epilepsy, bilateral stimulation of the
anterior nuclei of the thalamus was associated with a decrease in seizure
frequency of 29% during the study period and 56% at 2 years.11 The long-term
follow-up study showed sustained and improved efficacy, with 68% of patients
responding to DBS treatment at 5 years.39
Statistical improvements in quality-of-life measurements and low rates of
SUDEP (2.9 per 1000 patient stimulation years) are reported in long-term
follow-up studies.39 DBS is generally well tolerated, with low rates of adverse
events occurring around the time of device implantation limited to infection
(12.7%) and paresthesia (18.2%).11 Subjective worsening of memory and
depression was reported in the initial treatment group, but objective
neuropsychological testing showed no postoperative differences.11
Vagus Nerve Stimulation

VNS was initially developed as an open-loop stimulator; the device resembles
a cardiac pacemaker and delivers intermittent electrical impulses to the left
vagus nerve. The exact mechanisms of action on seizure reduction are
unknown. Hypotheses include changes in blood flow to different parts of the
brain, including the thalamus; desynchronization of hypersynchronized
554 APRIL 2022

cortical activity; or stimulating the release of neurotransmitters via afferent KEY POINTS
vagal projections to the brainstem and thalamus.65 Similar to DBS, VNS
● Deep brain stimulation
therapy is considered for those who are not candidates for or are opposed to and vagus nerve stimulation
resective surgery or have poorly localized multifocal epilepsy. Because of the are reserved as options for
limited surgical treatment options available for generalized epilepsy, VNS is poorly localized epilepsy or
also considered as a potential treatment option for drug-resistant multifocal epilepsy.
generalized epilepsy.37
● All three available
The initial multicenter randomized controlled trials showed mean seizure neurostimulation devices
reduction in the high-stimulation group of 25% compared to the 6% in the low- are associated with seizure
stimulation (sham) group.66 Subsequent studies showed that response, as reduction, which improves
defined by greater than 50% reduction in seizure freedom, was seen in 23% to over time. Rates of adverse
events are low and typically
57% of patients.66,67 Similar to the above-mentioned neurostimulators, perioperative or related to
progressive increases in seizure control are seen with increasing duration stimulation, which can be
of implant.68 modified.
Additional quality-of-life measures independent of seizure outcomes have
been reported to improve over time in children and adults, although the exact
mechanism of this finding is unclear.69 Similar to other neurostimulation
therapies, the risk of SUDEP in VNS is lower (1.68 per 1000 patient stimulation
years) than published SUDEP rates in similar surgical candidates (3.7 per
1000 person-years). However, VNS has the lowest reported seizure-freedom
rates at last follow-up (<10%) of the three neurostimulation therapies. VNS
implantation is a relatively safe procedure, with the most common complications
being postoperative hematoma (1.9%), infection (2.6%), and vocal cord
paralysis (1.4%).70
Modern VNS systems are now customizable, with programming options that
include manual stimulation with a magnet swipe by a patient or caregiver at the
onset of a seizure or additional automatic stimulation delivery upon detection of
a predetermined tachycardia threshold (closed-loop stimulation). The latter
therapy is especially useful if patients experience an increase in heart rate with
their seizures.
CONCLUSION
Despite many new antiseizure medications with differing mechanisms of action
becoming available over the past several decades, rates of drug-resistant epilepsy
have not improved and remain up to 40% in patients with epilepsy. The
probability of achieving seizure freedom declines rapidly after two adequate
doses of antiseizure medication, and early referral for surgical therapy should
be considered.
Resective surgery has the highest rates of seizure freedom in temporal lobe
epilepsy, especially when localized to the mesial structures or when seizures arise
from a focal structural lesion. The use of minimally invasive options, such as laser
ablation and stereotactic radiosurgery, is an alternative to resective surgery in
well-selected patients.
As a class, neurostimulation has demonstrated sustained and progressive
improvements in efficacy over time. RNS is favored in patients with a high
preoperative risk of memory decline and an epileptogenic zone overlapping with
eloquent cortex. DBS and VNS are also good options for multifocal, generalized,
and poorly localized epilepsies. RNS, DBS, and VNS are also options for those
who are opposed to resective surgery.

Drug-resistant epilepsy causes irreversible psychological and social problems,

a lifetime of disability, and increased risk of death. Surgical therapy improves
seizure outcomes and quality of life in addition to decreasing morbidity and
mortality in patients with drug-resistant epilepsy.
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781-794. doi:10.1002/ana.25081 WNL.0b013e31827dead9
49 Baumann CR, Acciarri N, Bertalanffy H, et al. 60 Jobst BC, Kapur R, Barkley GL, et al. Brain-
Seizure outcome after resection of responsive neurostimulation in patients with
supratentorial cavernous malformations: a study medically intractable seizures arising from
of 168 patients. Epilepsia 2007;48(3):559-563. eloquent and other neocortical areas. Epilepsia
doi:10.1111/j.1528-1167.2006.00941.x 2017;58(6):1005-1014. doi:10.1111/epi.13739
50 Giulioni M, Marucci G, Pelliccia V, et al. Epilepsy 61 Loring DW, Kapur R, Meador KJ, Morrell MJ.
surgery of “low grade epilepsy associated Differential neuropsychological outcomes
neuroepithelial tumors”: a retrospective following targeted responsive neurostimulation
nationwide Italian study. Epilepsia 2017;58(11): for partial-onset epilepsy. Epilepsia 2015;56(11):
1832-1841. doi:10.1111/epi.13866 1836-1844. doi:10.1111/epi.13191
51 Gross RE, Stern MA, Willie JT, et al. Stereotactic 62 Hirsch LJ, Mirro EA, Salanova V, et al. Mesial
laser amygdalohippocampotomy for mesial temporal resection following long-term
temporal lobe epilepsy. Ann Neurol 2018;83(3): ambulatory intracranial EEG monitoring with a
575-587. doi:10.1002/ana.25180 direct brain-responsive neurostimulation
system. Epilepsia 2020;61(3):408-420. doi:10.1111/
52 McCracken DJ, Willie JT, Fernald B, et al.
epi.16442
Magnetic resonance thermometry-guided
stereotactic laser ablation of cavernous 63 Ma BB, Fields MC, Knowlton RC, et al. Responsive
malformations in drug-resistant epilepsy: neurostimulation for regional neocortical
imaging and clinical results. Oper Neurosurg epilepsy. Epilepsia 2020;61(1):96-106. doi:10.1111/
(Hagerstown) 2016;12(1):39-48. doi:10.1227/NEU. epi.16409
0000000000001033
64 Mirski MA, Rossell LA, Terry JB, Fisher RS.
53 Lewis EC, Weil AG, Duchowny M, et al. MR- Anticonvulsant effect of anterior thalamic high
guided laser interstitial thermal therapy for frequency electrical stimulation in the rat.
pediatric drug-resistant lesional epilepsy. Epilepsy Res 1997;28(2):89-100. doi:10.1016/
Epilepsia 2015;56(10):1590-1598. doi:10.1111/ s0920-1211(97)00034-x
epi.13106
65 Narayanan JT, Watts R, Haddad N, et al. Cerebral
54 Drane DL, Loring DW, Voets NL, et al. Better activation during vagus nerve stimulation: a
object recognition and naming outcome with functional MR study. Epilepsia 2002;43(12):
MRI-guided stereotactic laser 1509-1514. doi:10.1046/j.1528-1157.2002.16102.x
amygdalohippocampotomy for temporal lobe
66 Ben-Menachem E, Manon-Espaillat R, Ristanovic
epilepsy. Epilepsia 2015;56(1):101-113. doi:10.1111/
R, et al. Vagus nerve stimulation for treatment of
epi.12860
partial seizures: 1. A controlled study of effect on
55 Donos C, Rollo P, Tombridge K, et al. Visual field seizures. First International Vagus Nerve
deficits following laser ablation of the Stimulation Study Group. Epilepsia 1994;35(3):
hippocampus. Neurology 2020;94(12): 616-626. doi:10.1111/j.1528-1157.1994.tb02482.x
e1303-e1313. doi:10.1212/
67 Klinkenberg S, Majoie HJ, van der Heijden MM,
WNL.0000000000008940
et al. Vagus nerve stimulation has a positive
56 Gupta K, Cabaniss B, Kheder A, et al. Stereotactic effect on mood in patients with refractory
MRI-guided laser interstitial thermal therapy for epilepsy. Clin Neurol Neurosurg 2012;114(4):
extratemporal lobe epilepsy. Epilepsia 2020; 336-340. doi:10.1016/j.clineuro.2011.11.016
61(8):1723-1734. doi:10.1111/epi.16614
68 Englot DJ, Rolston JD, Wright CW, et al. Rates and
57 Stereotactic laser ablation for temporal lobe predictors of seizure freedom with vagus nerve
epilepsy. ClinicalTrials.gov identifier: stimulation for intractable epilepsy.
NCT02844465. Posted July 26, 2016. Updated Neurosurgery 2016;79(3):345-353. doi:10.1227/
September 28, 2021. Accessed November 18, NEU.0000000000001165
2021. clinicaltrials.gov/ct2/show/NCT02844465
69 Englot DJ, Hassnain KH, Rolston JD, et al. Quality-
58 Chan AY, Rolston JD, Lee B, et al. Rates and of-life metrics with vagus nerve stimulation for
predictors of seizure outcome after corpus epilepsy from provider survey data. Epilepsy
callosotomy for drug-resistant epilepsy: a Behav 2017;66:4-9. doi:10.1016/j.
meta-analysis. J Neurosurg 2019;130(4):1193-1202. yebeh.2016.10.005
doi:10.3171/2017.12.JNS172331
70 Revesz D, Rydenhag B, Ben-Menachem E.
Complications and safety of vagus nerve
stimulation: 25 years of experience at a single
center. J Neurosurg Pediatr 2016;18(1):97-104.
doi:10.3171/2016.1.PEDS15534
558 APRIL 2022

Management of Status REVIEW ARTICLE

Epilepticus, Refractory C O N T I N UU M A U D I O
I NT E R V I E W A V A I L A B L E
ONLINE
Status Epilepticus, and

Super-refractory Status CITE AS:
Epilepticus CONTINUUM (MINNEAP MINN)

2022;28(2, EPILEPSY):559–602.
By Eugen Trinka, MD, MSc, FRCP; Markus Leitinger, MD, MSc Address correspondence to
Prof Eugen Trinka, Department
of Neurology, Neurointensive
Care, and Neurorehabilitation,
Christian Doppler University
Hospital, Paracelsus Medical
ABSTRACT University, Ignaz Harrer Straße
PURPOSE OF REVIEW: Status epilepticus is a serious condition caused by 79, A-5020 Salzburg, Austria,
disorders and diseases that affect the central nervous system. In status e.trinka@salk.at.
epilepticus, hypersynchronous epileptic activity lasts longer than the usual RELATIONSHIP DISCLOSURE :
duration of isolated self-limited seizures (time t1), which causes neuronal Dr Trinka has received personal
damage or alteration of neuronal networks at a certain time point (time t2), $500 to $4999 for serving as a
depending on the type of and duration of status epilepticus. The Chief Executive Officer of
successful management of status epilepticus includes both the early Neuroconsult Ges.m.b.H and
for serving as a consultant for
termination of seizure activity and the earliest possible identification of a Arvelle Therapeutics, Bial,
causative etiology, which may require independent acute treatment. In Biogen, Boehringer Ingelheim
nonconvulsive status epilepticus, patients present only with subtle clinical International GmbH, Eisai Co,
Ltd, Ever Pharma,
signs or even without any visible clinical manifestations. In these cases, GlaxoSmithKline plc, GW
EEG allows for the assessment of cerebral function and identification of Pharmaceuticals plc, LivaNova
PLC, Marinus Pharmaceuticals,
patterns in need of urgent treatment.
Inc, Medtronic, NewBridge
Pharmaceuticals, Novartis AG,
RECENT FINDINGS:In 2015, the International League Against Epilepsy Sandoz International GmbH,
Sanofi, Sunovion Pharmaceuticals
proposed a new definition and classification of status epilepticus, Inc, Takeda Pharmaceutical
encompassing four axes: symptomatology, etiology, EEG, and age. Various Company Limited, and UCB, Inc,
validation studies determined the practical usefulness of EEG criteria and has received research
support from the Austrian
to identify nonconvulsive status epilepticus. The American Clinical Science Fund (FWF), Bayer AG,
Neurophysiology Society has incorporated these criteria into their Biogen, Eisai Co, Ltd, the
most recent critical care EEG terminology in 2021. Etiology, age, European Union, GlaxoSmithKline
plc, Novartis AG,
symptomatology, and the metabolic demand associated with an increasing Oesterreichische Nationalbank,
duration of status epilepticus are the most important determinants of Red Bull, and UCB, Inc.
Dr Leitinger reports no disclosure.
prognosis. The consequences of status epilepticus can be visualized in vivo
by MRI studies. UNLABELED USE OF
SUMMARY: The current knowledge about status epilepticus allows for a more USE DISCLOSURE:
Drs Trinka and Leitinger discuss
reliable diagnosis, earlier treatment, and improved cerebral imaging of its the unlabeled/investigational
consequences. Outcome prediction is a soft tool for estimating the need use of antiseizure medications
for the treatment of status
for intensive care resources.
epilepticus.
© 2022 American Academy

of Neurology.

STATUS EPILEPTICUS
INTRODUCTION
S
tatus epilepticus, particularly in its most severe form of presentation,
tonic-clonic (convulsive) status epilepticus, is a neurologic emergency
that needs to be promptly recognized and treated to reduce morbidity
and mortality.1-5 The outcome of status epilepticus depends on
etiology, age, symptomatology, and duration of status epilepticus,6-11
and patients benefit from carefully chosen but rapidly administered efficacious
antiseizure medication and appropriate management of status epilepticus.12-14
Over the past decades, the timelines for the definition of status epilepticus have
been progressively shortened. Eventually, the Commission of Classification and
Terminology of the International League Against Epilepsy (ILAE) and the
Commission on Epidemiology proposed the following definition:
Status epilepticus is a condition resulting either from the failure of the

mechanisms responsible for seizure termination or from the initiation of
mechanisms, which lead to abnormally prolonged seizures (after time
point t1). It is a condition, which can have long-term consequences (after
time point t2), including neuronal death, neuronal injury, and alteration of
neuronal networks, depending on the type and duration of seizures.1
This definition of status epilepticus gives clear guidance as to when emergency

treatment must be considered. In general, time point t1 is the time at which
seizures usually do not stop spontaneously anymore, and hence, treatment
should be initiated, which is at 5 minutes for bilateral tonic-clonic (convulsive)
status epilepticus and at 10 minutes for focal status with or without impairment
of consciousness and absences (TABLE 12-1). Time point t2 marks the time at
which neuronal damage or self-perpetuating alteration of neuronal networks
may begin and indicates that status epilepticus should be controlled at the latest
by that time (ie, 30 minutes in the case of bilateral tonic-clonic status epilepticus)
(TABLE 12-1). Although these times t1 and especially t2 were set by the task force
based on expert opinion and clinical judgment, clinical evidence supporting these
timelines is increasing.15-19
TABLE 12-1 The Operational Definition of Time t1 and Time t2a
Type of status epilepticus Time t1 Time t2
Seizure activity does not stop spontaneously Seizure activity may cause long-term
with a high probability, therefore, time t1 is sequelae, therefore, time t2 is the time at
the time at which emergency treatment of which treatment should be successful to
status epilepticus should be started prevent long-term consequences
Bilateral tonic-clonic status 5 minutes 30 minutes

epilepticus
Focal status epilepticus with and 10 minutes 60 minutes

without impairment of
consciousness, absences
a
Modified with permission from Trinka E, et al, Epilepsia.1 © 2015 International League Against Epilepsy.
560 APRIL 2022

The current pathophysiologic concepts of status epilepticus are beyond the
scope of this article (more information can be found in previously published
reviews20-23), but so far, the pathomechanisms including γ-aminobutyric
acid–mediated (GABA-ergic) failure and glutamatergic hyperactivity are the
basis for the staged treatment approach that is recommended today: rapid first-
line administration of benzodiazepines IV or via alternative routes immediately
after diagnosing status epilepticus (stage 1), followed by IV antiseizure
medications (stage 2, FIGURE 12-1).3,24 Anesthetic drugs to induce therapeutic
coma are the mainstay of therapy in later stages (stages 3 and 4, or refractory and
super-refractory status epilepticus). In addition, critical care management and
other treatment options such as immune therapies,25,26 dietary treatments,27,28
and neurostimulation provide important additional treatments.29,30
The clinical evidence is good for the earlier treatment stages, but refractory
status epilepticus and super-refractory status epilepticus can still be considered
an “evidence-free area.”31
This article does not follow the traditional scholarly approach but instead
reviews status epilepticus as a process, spanning from the initial onset of
symptoms to the application of continuous EEG in the neurologic intensive care
unit (FIGURE 12-2). After some introductory information on definitions,
classifications, epidemiology, and treatment principles, the article follows a
patient’s pathway through the treatment stages and focuses on the practicalities,
supported by scientific evidence wherever possible.
FIGURE 12-1
Clinical course of convulsive status epilepticus and its therapeutic implications.
IM = intramuscular; IN = intranasal; IV = intravenous; SE = status epilepticus.
Modified with permission from Trinka E, et al, Drugs 2015.3 © The Authors.

STATUS EPILEPTICUS
FIGURE 12-2
The process of management of status epilepticus. The red triangles represent two examples
of etiologies (eg, encephalitis or stroke). The boxes to their right represent an example of the
course of status epilepticus starting with aphasic status evolving to focal motor status,
convulsive symptomatology, and nonconvulsive status epilepticus, first with nonprominent
jerks that later cease. The status epilepticus is termed convulsive status because of the
appearance of bilateral tonic-clonic symptomatology at any time along the course.
Therefore, it is important to note all the different stages in the report.
ASM = antiseizure medication; BTC = bilateral tonic-clonic; EEG = electroencephalography; ICU = intensive
care unit; NCSE-c = nonconvulsive status epilepticus in coma; SE = status epilepticus.
DEFINITION AND CLASSIFICATION

The recent definition of time criteria by the ILAE was an important step toward
diagnostic standardization.1 The ILAE classification distinguishes between status
epilepticus without prominent motor phenomena (synonymous term: nonconvulsive
status epilepticus) and status epilepticus with prominent motor phenomena including
bilateral tonic-clonic status epilepticus (ie, convulsive status epilepticus) and focal,
myoclonic, tonic, and hyperkinetic status epilepticus (FIGURE 12-3 and TABLE 12-1).1
Clinical symptomatology may change over the time course of one status epilepticus
episode, which is called evolution of symptomatology (FIGURE 12-2).7 This evolution
of symptomatology has an impact on outcomes with convulsive status
epilepticus with only convulsive symptomatology (“convulsive status epilepticus
only”) having a better outcome than the sequence nonconvulsive status
epilepticus evolving to convulsive status epilepticus (“nonconvulsive status
epilepticus → convulsive status epilepticus”), which is even better than
convulsive status epilepticus evolving to nonconvulsive status epilepticus
(“convulsive status epilepticus → nonconvulsive status epilepticus”).7 The
symptomatology that came later in the evolution determined the outcome.7
However, the terminology rates only the most prominent motor phenomenon,
that is, the term convulsive status epilepticus applies to each form of status
epilepticus including bilateral tonic-clonic symptomatology in any position along
562 APRIL 2022

FIGURE 12-3
The classification of status epilepticus (SE) by the International League Against Epilepsy.
Data from Trinka E, et al, Epilepsia.1
the symptomatic sequence and in any combination with other symptomatology.1

Concerning the level of consciousness, the distinction between “nonconvulsive
status epilepticus in coma” and “nonconvulsive status epilepticus without coma”
puts a great emphasis on the presence of coma. However, in a retrospective
study, the outcomes differed between the groups “nonconvulsive status
epilepticus awake with or without reduced cognition” and “nonconvulsive status
epilepticus with somnolence, stupor, and coma.”7 Thus, a thorough assessment
of the evolution of the symptomatology, including the level of impairment of
consciousness, is critical.1,7,32 Recent work has independently confirmed the
association between symptomatology type and various outcomes. Clusters of
subtypes of status epilepticus with etiologies, EEG patterns, and degrees of
impairment that have a poorer outcome than others have been described.10,11
In clinical practice, the terms refractory status epilepticus and super-refractory
status epilepticus have been established. They are defined by an international
consensus group as follows24:
u Refractory status epilepticus: status epilepticus persisting despite administration of at

least two appropriately selected and dosed parenteral medications including a
benzodiazepine. No specific seizure duration is required.
u Super-refractory status epilepticus: status epilepticus persisting at least 24 hours after
onset of anesthesia, either without interruption despite appropriate treatment with
anesthesia, recurring while on appropriate anesthetic treatment, or recurring after
withdrawal of anesthesia and requiring anesthetic reintroduction. “Anesthesia” includes
commonly used agents such as midazolam, propofol, pentobarbital, thiopental,
ketamine, and others, so long as they are used at anesthetic doses.

STATUS EPILEPTICUS
EPIDEMIOLOGY
The epidemiology of status epilepticus is influenced by the time criterion used to
define status epilepticus (5 minutes versus 10 minutes versus 30 minutes), the
inclusion of only first episodes of status epilepticus, and the inclusion of people
with preexisting epilepsy.33 Case ascertainment is also important because
different results can be expected depending on how patient cases are identified,
be it by detailed chart review or solely using the International Statistical
Classification of Diseases and Related Health Problems (ICD).33 Other factors,
which are necessary to consider in epidemiologic studies of status epilepticus are
the inclusion of both adults and children as two mutually independent high-risk
groups, the definition of age of adulthood, the percentage of very old patients as a
high-incidence subgroup within the adult group, the prevailing etiologies in the
study area, and the shape of the population pyramid of the reference population
to which the data were adjusted.33
A population-based study from Austria used the 2015 ILAE criteria for status
epilepticus and found an incidence of all types of status epilepticus in adults of
36.1 per 100,000 per year (95% confidence interval [CI], 26.2 to 48.5) and for
nonconvulsive status epilepticus of 12.1 per 100,000 per year (95% CI, 6.8 to
20.0).7 The incidence of refractory status epilepticus was 7.2 per 100,000 adults
per year (95% CI, 3.3 to 13.8), which included all status epilepticus episodes
refractory to one benzodiazepine and one other antiseizure medication.7 Super-
refractory status epilepticus occurred with an incidence of 1.2 per 100,000 per
year (95% CI, 0.1 to 5.1).7 Population-based studies from Finland revealed similar
incidence rates, using a slightly different case ascertainment strategy. The
incidence of intensive care unit (ICU)-treated and anesthesia-treated refractory
status epilepticus was 3.0 per 100,000 per year (95% CI, 2.4 to 3.8) and of super-
refractory status epilepticus 0.6 per 100,000 per year (95% CI, 0.4 to 1.0).34-36 A
German population-based study of children (0 to 18 years), detailed a slightly
lower incidence with a crude status epilepticus incidence of 17.6 per 100,000 per
year.37 The incidence of refractory status epilepticus was 3.9 per 100,000 per
year, and super-refractory status epilepticus 2.3 per 100,000 per year.
Super-refractory status epilepticus incidence peaked in the 0- to 1-year-old age
subgroup, accounting for 48.3% of all pediatric super-refractory status
epilepticus admissions.37 Studies using older definitions of status epilepticus
reported lower incidence rates: In the United States, the Rochester, Minnesota,
study revealed an incidence of 18.3 per 100,000 total population,38 which
increased from 8.0 per 100,000 in 1935 to 1944 to 18.1 per 1,000,000 in 1975 to
1984.33,39 ICD-code based epidemiologic studies may underestimate the
incidence of status epilepticus if status was not coded in the primary diagnostic
position.33,40-42 However, these studies may also overestimate the incidence
because ICD-based studies cannot distinguish first status epilepticus episodes
from recurring ones.33 All studies on the incidence of status epilepticus found a
prominent increase with age. A 2019 study reported an age- and sex-adjusted
incidence rate in older adults of 79.9 (95% CI, 53.4 to 114.8) per 100,000 adults
(89.6 [95% CI, 54.0 to 139.7] in older women and 67.6 [95% CI, 32.3 to 124.7] in
older men) with an associated case fatality of 22.5% (95% CI, 16.4% to 29.9%)
(27.8% [95% CI 19.9% to 37.5%] in women and 12.0% [95% CI 5.3% to 24.2%] in
men) (FIGURE 12-4).7
A systematic review analyzed the time trends of in-hospital mortality or
30-day case fatality expressed as proportional mortality. Sixty-one studies from
564 APRIL 2022

KEY POINTS
● The outcome of status

epilepticus depends on
etiology, age,
symptomatology, and
duration of status
epilepticus.
● At time t1, the diagnosis of

status epilepticus is
established and therapy is
started.
● At time t2, treatment

should be successful in
preventing neuronal
damage.
● For convulsive (bilateral

tonic-clonic) status
epilepticus, time t1 is
5 minutes.
● For focal status

epilepticus with or without
FIGURE 12-4 impairment of
Age-related increase in the incidence of status epilepticus (SE) in older adults. Error bars consciousness, time t1 is
indicate 95% confidence intervals. 10 minutes.
CSE = convulsive status epilepticus; NCSE = nonconvulsive status epilepticus; SE-PM = status epilepticus
with prominent motor phenomena. ● Unsuccessful therapy
Modified with permission from Leitinger M, et al, Epilepsia.7 © 2019 The Authors. with a benzodiazepine and
one antiseizure medication
defines refractory status
epilepticus.
high-income countries found mortality rates of 15.9% (95% CI, 12.7% to 19.2%)
for adults and 3.6% (95% CI, 2.0% to 5.2%) for children.43 Mortality was 17.3% ● The management of
(95% CI, 9.8% to 24.7%) for refractory status epilepticus.43 In another review status epilepticus should be
on the epidemiology of status epilepticus, case fatalities ranged in-hospital from viewed as a process.
5.0% to 24.4% and at 30 days from 4.6% to 39%.33 Mortality in status epilepticus
● The changing
is seen as a result of ongoing epileptic activity with its increased metabolic symptomatology within one
demand and its deleterious consequences on neuronal networks and nerve tissue, episode of status
but also, and even more significantly, because of the etiology of the status epilepticus is called
epilepticus.6,43,44 evolution of
symptomatology; the status
epilepticus symptomatology
CAUSES OF STATUS EPILEPTICUS that comes later determines
Etiology varies largely with geography. Infectious diseases are common causes in outcomes.
lower-income countries whereas cerebrovascular and degenerative cerebral
● The epidemiology of
etiologies prevail in higher-income countries.45 Metabolic etiologies and
nonadherence to medication occur in both regions.45 The ILAE classified the determined by several
etiology of status epilepticus into acute, remote, progressive, defined electroclinical factors.
syndromes, and unknown etiology (ie, cryptogenic).1 However, the assignment into
these categories appears heterogeneous among the various studies (TABLE 12-2).33 ● The etiology of status
epilepticus can be divided
From a practical perspective, it is advisable to distinguish common causes, into symptomatic (acute,
which usually can be identified in the first hours, from the uncommon and rare remote, progressive, and
causes, which need an intensive workup to start appropriate treatment.9,45,62,63 electroclinical syndromes)
Common and easily recognized causes of status epilepticus include and cryptogenic.

STATUS EPILEPTICUS
TABLE 12-2 Population-based Studies of Adults With Status Epilepticus of Different

Etiologiesa
History of Acute Remote Defined Febrile Case

First epilepsy, symptomatic, symptomatic, Progressive, electroclinical Cryptogenic, status,b fatality,
author % % % % syndrome, % % % %
Logroscino39 Not 53.8c 46.2c Excluded 24d

available
(NA)
Hesdorffer38 46 50.3 19.6 8.5 13.6 8 NA
Dham40 1.8-7 NA NA NA NA NA NA 9.2

46,47
DeLorenzo 42 NA 24 NA NA NA NA 22d
Wu41 NA NA NA NA NA NA NA 10.7
42
Betjemann NA NA NA NA NA NA NA NA
Jallon48 32.8 50.8 26.2 23.0 6.6

49
Coeytaux 43 62.7 18.6 9.8 2.9 5.8 NA 7.6
Knake50 33e >33f 62.7f 12.0g NA 8.7 0 9.3d
Vignatelli51 39 34h 34 11 7 0 39d
Vignatelli52 40.7 29.6i 25.9 11.1 NA 7.4 0 7d
Govoni53 40 25.0 45.0 15 15 NA 5
Strzelczyk54 44.6 24.8 Not reported NR NR 4.3 NR 14.8

(NR)
Leitinger7,j 40.7 36.2 46.6 14.0 1.4 1.8 0 16.3

55
Rodin 43.9 26.8 48.8 7.3 NA 17.1 0 24.4
Kantanen36 17.5 41.6 45.3 12.4 NA 10.9 0 9.0d
Nazerian56,j 57.6 68.7 37.8 27.3 NA 6.1 0 13.1
Ong57 NA NA NA NA NA NA NA 8.8
58
Tiamkao NA NA NA NA NA NA 0 8.4
Tiamkao59 1.2 NA NA NA NA NA 0 12.0

60 g
Bhalla 0 35.4 44.6 3.1 NA 16.9 NA 18.5
Bergin61 60.6k 43.3 43.6 5.2 3.5 17.7 21.0 4.6d
a
Reprinted with permission from Leitinger M, et al, Epilepsy Behav.33 © 2019 The Authors.
b
Only in children.
c
1975-1984.
d
Case fatality at 30 days, otherwise in hospital.
e
Primary service area.
f
In most cases, more than one factor. Percentages were calculated from 150 patients with status epilepticus and also included patients outside
the primary service area.
g
Tumors.
h
Multifactorial: additional 14%.
i
Multifactorial: additional 25.9%.
j
Proposal for definition and classification of status epilepticus by the International League Against Epilepsy in 2015.
k
Calculated per status epilepticus episodes and not per patients.
566 APRIL 2022

cerebrovascular disorders, brain trauma, infections, alcohol- and drug-related, KEY POINTS
and low antiseizure medication levels in patients with epilepsy (FIGURE 12-5).
● Rare causes of status
Uncommon causes fall into five categories62: epilepticus include
immunologically mediated
u Immunologically mediated disorders (TABLE 12-3) disorders, mitochondrial
diseases, uncommon
u Mitochondrial diseases (Rahman64,65 provides a comprehensive review) (TABLE 12-4) infective disorders, genetic
u Uncommon infective disorders (TABLE 12-5) disorders, and drugs or
toxins.
u Genetic disorders
u Drugs or toxins ● Status epilepticus and
acute stroke share many
features (eg, time is brain,
Other rare causes exist, which have to be considered early in the diagnostic the onset is often not
workup because they are reversible or treatable in many cases (TABLE 12-6). witnessed, and both need a
structured diagnostic and
therapeutic approach).
STATUS EPILEPTICUS AT THE SCENE (OUT OF THE HOSPITAL AND IN
THE HOSPITAL)
Although the hospital setting seems to be quite different from situations
occurring in family or caregiver environments, they share important relevant
features. In both settings, the onset of status epilepticus may not be witnessed
and the patient is often found seizing. Similar to stroke, the time of “last seen
well” is taken as a substitute to estimate the time already elapsed since onset. This
time is crucial both for the effects of status epilepticus but also if acute treatment
of the underlying etiology is mandatory: “time is brain.”12 From the perspective
of risk management, the first critical information transfer occurs between the
witnesses and emergency medical services (EMS), comparable to the
observations communicated between the nurses and patients without status
FIGURE 12-5
Common and easily recognized causes of status epilepticus (SE).
Reprinted with permission from Trinka E, et al, Epilepsia.62 © 2012 International League Against Epilepsy.
AED = antiepileptic drug; Cardiovasc. = cardiovascular; CNS = central nervous system.

STATUS EPILEPTICUS
epilepticus and the in-hospital emergency team (FIGURE 12-2). For optimal
documentation, EMS already uses proven and tested standard protocols.66 In the
hospital, status epilepticus checklists help document information from the
earliest moments including when emergency medications were given in the
emergency department or on the ward (TABLE 12-7 and FIGURE 12-6).67
In the past years, several efficacious antiseizure medications have been
developed, which are suitable for out-of-hospital administration via alternative
routes. Historically, rectal diazepam was the first non-IV drug available for
emergency use.68 Midazolam is a water-soluble benzodiazepine, which may be
administered by different routes: IV, IM, buccal, and intranasal. Thus, it is ideally
suited for early out-of-hospital treatment by caregivers and paramedic personnel.
The efficacy and safety of non-IV midazolam were compared with rectal diazepam
in a meta-analysis including 19 studies with 1933 seizures in 1602 patients (some
trials included patients with more than one seizure).69 For seizure cessation, non-IV
midazolam was as effective as diazepam (any route) (relative risk, 1.03; 95% CI,
0.98 to 1.08).69 No difference in adverse effects was found between non-IV
midazolam and diazepam by any route (relative risk, 0.87; 95% CI, 0.50 to 1.50).69
Buccal midazolam was more effective than rectal diazepam in terminating status
epilepticus (relative risk, 1.78; 95% CI, 1.11 to 2.85).69 The time interval between
arrival and seizure cessation was significantly shorter with non-IV midazolam by
any route than with diazepam by any route (mean difference, -3.67 minutes; 95%
TABLE 12-3 Examples of Immunologic Disorders Causing Status Epilepticusa
◆ Paraneoplastic encephalitis
◆ Steroid-responsive encephalopathy with associated autoimmune thyroiditis (SREAT)
◆ Autoimmune thyroiditis
◆ Anti–N-methyl-D-aspartate (NMDA)-receptor encephalitis
◆ Anti–leucine-rich, glioma inactivated 1 (LGI1) encephalitis
◆ Anti–α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-receptor encephalitis
◆ Anti–γ-aminobutyric acid (GABA)-receptor encephalitis
◆ Rasmussen syndrome
◆ Cerebral lupus erythematosus
◆ Adult-onset Still disease
◆ Anti–glutamic acid decarboxylase (GAD) antibody–associated encephalitis
◆ Goodpasture syndrome
◆ Multiple sclerosis
◆ Thrombotic thrombocytopenic purpura
◆ Antibody-negative limbic encephalitis
◆ Ulcerative colitis
◆ Behçet syndrome
◆ Celiac disease
a
Reprinted with permission from Trinka E, et al, Epilepsia.62 © 2012 Wiley Periodicals, Inc.
568 APRIL 2022

CI, -5.98 to -1.36); a similar result was found for the time from arrival to drug
administration (mean difference, -3.56 minutes; 95% CI, -5.00 to -2.11).69
Based on these findings and another common reference network meta-
analysis,70 buccal or intranasal midazolam can be regarded as the first-choice
treatment for out-of-hospital repetitive seizures or status epilepticus.3 However,
this first-line non-IV treatment will not stop status epilepticus in around 20% to
30% of cases,71 which requires rapid admission to an emergency department.
STATUS EPILEPTICUS IN THE EMERGENCY DEPARTMENT

On arrival to the emergency department (FIGURE 12-7), the management of
status epilepticus requires parallel work on different domains such as (1)
standardized information transfer from EMS to the emergency department team
(TABLE 12-7 and FIGURE 12-6), (2) acute stabilization and monitoring of vital signs
(FIGURE 12-7), (3) rapid identification of etiologies with independently essential
acute treatment (TABLE 12-8), and (4) start or continuation of status epilepticus
treatment (FIGURE 12-8, TABLE 12-9, TABLE 12-10, and CASE 12-1).72-75
The “time is brain” principle is most crucial in status epilepticus with
prominent motor phenomena, especially convulsive status epilepticus.
Symptomatic treatments with antiseizure medications must be applied rapidly
and, if needed, escalated toward anesthetics to prevent severe metabolic
derangements and long-term consequences after time point t2.2-4,73-76 The risks
of treatment have to be weighed against the benefits of early seizure termination.
The evidence is good for benzodiazepine administration in stage 1 (early status
epilepticus), and the safety and efficacy of IV lorazepam, diazepam, clonazepam,
or IM midazolam seem to have clinical equipoise.69,70,73,77 Each antiseizure
medication has advantages and disadvantages (TABLE 12-9),3 which need to be
considered in the emergency department, especially, when confronted with a
patient with one, or several, comorbidities or specific situations (TABLE 12-10).
This is even more the case when status epilepticus cannot be controlled by initial
benzodiazepines and patients move to benzodiazepine-refractory status epilepticus,
in which IV treatment with antiseizure medications is needed. A 2019 landmark
article78 and two other high-class clinical trials79,80 could not find a statistical
difference in efficacy and tolerability among levetiracetam, fosphenytoin, and
valproic acid. Seizures will be controlled in about 50% of patients with any of these
antiseizure medications. A recent network meta-analysis including five randomized
controlled trials involving 349 patients compared valproate (20 mg/kg to 30 mg/kg),
Examples of Mitochondrial Diseases Causing Status Epilepticusa TABLE 12-4
◆ Alpers disease
◆ Occipital lobe epilepsy/mitochondrial spinocerebellar ataxia and epilepsy (MSCAE)
◆ Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS)
◆ Leigh syndrome
◆ Myoclonic encephalopathy with ragged red fibers (MERRF)
◆ Neuropathy, ataxia, and retinitis pigmentosa (NARP)
a

STATUS EPILEPTICUS
phenytoin (20 mg/kg), diazepam (0.2 mg/kg, then 4 mg/h), phenobarbital

(20 mg/kg, then 100 mg every 6 h), lacosamide (400 mg), and levetiracetam
(20 mg/kg) in benzodiazepine-resistant status epilepticus (stage 2).81 Phenobarbital
was superior to phenytoin, valproate, diazepam, levetiracetam, and lacosamide
with respect to status epilepticus cessation and performed better concerning
seizure freedom at 24 hours than valproate, diazepam, and lacosamide. According
to this analysis, phenobarbital had the greatest probability of achieving status
epilepticus control and seizure freedom at 24 hours, whereas valproate and
lacosamide ranked best in terms of safety outcomes.81,82
The problem in a real-world setting, which cannot be overestimated, is
underdosing. In a registry study of 1049 patients, bolus doses of the first
TABLE 12-5 Uncommon Infectious Diseases Causing Status Epilepticusa
Atypical bacterial infections

◆ Bartonella/catscratch disease
◆ Coxiella burnetii (Q fever)
◆ Neurosyphilis
◆ Scrub typhus
◆ Shigellosis
◆ Mycoplasma pneumoniae
◆ Chlamydophila psittaci
Viral infections
◆ Human immunodeficiency virus (HIV) and HIV-related infections
◆ West Nile encephalitis
◆ JC virus (progressive multifocal leukoencephalopathy)
◆ Parvovirus B19
◆ Varicella zoster virus encephalitis
◆ Subacute sclerosing panencephalitis
◆ Measles encephalitis
◆ Rubella encephalitis
◆ Rous sarcoma virus–associated status epilepticus
◆ Polioencephalomyelitis
◆ St. Louis encephalitis
Prion disease
◆ Creutzfeldt-Jakob disease
Other infections
◆ Paragonimiasis
◆ Mucormycosis
◆ Paracoccidioidomycosis
a
570 APRIL 2022

treatment step were lower than recommended by current guidelines in 76% of
convulsive status epilepticus.83 As a result of underdosing, 70% of patients were
still in status epilepticus 1 hour after initiating treatment, compared with
randomized controlled trials in which benzodiazepines terminated status
epilepticus in at least 60% with the initial treatment during stage 1. It can be
expected that the same proportion is also underdosed in benzodiazepine-
refractory status epilepticus, but data on this critical issue are missing.
In the nonconvulsive forms of status epilepticus, therapy may include two or
more antiseizure medications to prevent escalation to IV anesthetics in an ICU,
with the aim of minimizing the burden of treatment in patients who will be difficult
to wean from the respirator because of comorbidities (TABLE 12-10).84-88 Similarly,
the cause of status epilepticus has to be identified rapidly and treated accordingly.
Other Causes of Status Epilepticusa TABLE 12-6
Iatrogenic
◆ Electroconvulsive therapy
◆ Temporal lobectomy and other neurosurgery
◆ Insertion of intracranial electrode
◆ Ventriculoperitoneal shunt
◆ Blood transfusion
◆ Carotid angioplasty and stenting
◆ Deep-brain stimulation
Other medical conditions and epilepsy syndromes
◆ Hypertension-induced posterior reversible encephalopathy syndrome
◆ Panayiotopoulos syndrome
◆ Thyroid disease
◆ Pyridoxine-dependent seizure
◆ Neuroleptic malignant syndrome
◆ Cobalamin deficiency
◆ Amyloid angiopathy
◆ Folinic acid–responsive seizures
◆ Renal artery stenosis
◆ Pituitary apoplexy
◆ Renal artery dissection
◆ Hypomelanosis of Ito
◆ Cerebral palsy
◆ Hemophagocytic lymphohistiocytosis
◆ Anhidrotic ectodermal dysplasia
◆ Methemoglobinemia
a
Modified with permission from Trinka E, et al, Epilepsia.62 © 2012 Wiley Periodicals, Inc.

STATUS EPILEPTICUS
Nonepileptic psychogenic events are an important mimic of status epilepticus,

which may receive potentially harmful medication when mistaken for drug-
resistant status epilepticus.89 It has been shown that patients with nonepileptic
psychogenic events show a paradoxical increase of activity with increasing
benzodiazepine doses and often end up in ICUs with central venous access.90
Early recognition and appropriate treatment are needed to prevent harm to these
patients. Psychogenic nonepileptic events may be distinguished from epileptic
seizures by several criteria such as speed of onset, absence of tongue biting, the
state of the eyelids during the event, skin color, duration of convulsion, speed of
postictal reorientation, and absence of postictal stertorous breathing.91
STATUS EPILEPTICUS IN THE INTENSIVE CARE UNIT

The ICU offers the right environment to escalate treatments while monitoring
patients’ cardiorespiratory and brain functions. The key clinical questions are
the following:
u Is the patient still in status epilepticus on admission to the ICU?
u What is the cause of status epilepticus?
u Did the treatment successfully and persistently terminate status epilepticus?
u Did status epilepticus–related brain damage take place?
TABLE 12-7 Admission to the Hospital: A Critical Interface for Information Transfer
Information Relevance
Last seen well, time of onset, and any Relevant for cerebral ischemia as differential diagnosis and potential etiology of
full recovery in between status epileptius, time criteria for status epilepticus, and cluster of seizures
Initial symptoms and signs Clues to etiology and cerebral symptomatogenic zone
Preceding or concomitant symptoms Vomiting as a hint for increased cerebral pressure or cause of aspiration; cough
(vomiting, cough, ear pain, fever, rash) indicative of pneumonia as a trigger or complication (aspiration); ear pain for
pneumococcal infection, fever for cerebral or systemic infection; rash for
systemic illness, thrombocytopenia, and coagulopathy
Any bilateral tonic-clonic Determines a convulsive status epilepticus, patient may be in subtle status
symptomatology epilepticus on admission
Any nonprominent motor Minor jerks in fingers, toes, abdominal muscles, perioral or periorbicular region;
symptomatology recurrent spontaneous pupillary dilatation and constriction; gaze deviation away
from cerebral lesion; nystagmus
Reactivity to speech or tactile stimuli Speed of deterioration of alertness and consciousness gives clue to etiology,
before admission allows estimation of Glasgow Coma Scale
Witness’s report and telephone number Clues to acute etiologies, time of onset, and symptomatic evolution of status
epilepticus
Amount and time of medication applied Prevents overdosing of first-line drugs and delay in escalation of status
by physicians at the scene and by treatment, allows for body weight–adapted dosing, time frame allows for
emergency medical services pharmacokinetic estimations
Neurologic examination on admission Sometimes very brief because of the need to urgently manage neurologic and
related medical issues but essential for further comparisons (improvement/
deterioration)
572 APRIL 2022

KEY POINTS
● Acute etiologies of status

epilepticus may need a
specific emergency
treatment (eg, ischemic
stroke).
● The main reason for

unsuccessful treatment of
underdosing.
FIGURE 12-6
Documentation of status epilepticus (SE) on patient admission or on the ward in the hospital.
CT = computed tomography; CTA = computed tomography angiography; DZP = diazepam;
EEG = electroencephalogram; FOS = fosphenytoin; L = left; Lab = laboratory; LCM = lacosamide;
LEV = levetiracetam; LZP = lorazepam; MDZ = midazolam; MRA = magnetic resonance angiography;
MRI = magnetic resonance imaging; R = right; Tox = toxicology; VPA = valproate.
Modified with permission from Leitinger M, et al, Epilepsy Behav.67 © 2015 The Authors.

STATUS EPILEPTICUS
FIGURE 12-7
Strategic thoughts on the initial management of status epilepticus on admission or
identification in the hospital.
CT = computed tomography; ECG = electrocardiogram; EMS = emergency medical services; FLAIR = fluid-
attenuated inversion recovery; MRI = magnetic resonance imaging; TOF-MR = time-of-flight magnetic
resonance.
Patients with successfully treated status epilepticus usually gradually regain

their previous level of consciousness within a few minutes or hours, but this may
take longer in older patients. The distinction between the postictal state and
ongoing nonconvulsive status epilepticus remains difficult on clinical judgment
alone.92 Additional investigations are needed to clarify and clearly assign the
clinical phenomenology.1,32 In particular, if no sign of improvement is seen, it can
be uncertain whether the patient is in nonconvulsive status epilepticus or not. An
EEG is essential in all those patients without clinical signs of subtle jerks, gaze
deviation, or hippus.93 Of note, many severely affected patients will demonstrate
substantial changes on EEG, but clearly not every highly pathologic EEG qualifies
as status epilepticus.32,93,94 The Salzburg nonconvulsive status epilepticus
diagnostic criteria provide an essential standardized approach to prevent
overdiagnosis in EEGs severely affected solely by the underlying condition. At
this point, sound clinical, electrophysiologic, and radiologic judgment is of
significant importance. The concept of the “electro-paraclinical gap” (ie, the
phenomenon that the changes in EEG exceed what can be expected from clinical,
laboratory, and imaging data) can help with decision making. Based on the
relationship among epileptic brain dysfunction, structural brain damage, and
impairment of consciousness (FIGURE 12-10)32 in the different forms of status
epilepticus, the paraclinical data (imaging, laboratory, and toxicologic
investigations) are further integrated into this scheme to assess the electro-
paraclinical gap. If the underlying pathology, for instance acute renal failure, is
the cause of the stereotyped EEG patterns, there seems to be no additional
seizure burden which could be reversed with intensive antiseizure treatment
574 APRIL 2022

(CASE 12-2). Thus, no electro-paraclinical gap is present, and consequently,
aggressive treatment should be avoided. The treatment should be aimed toward
the underlying renal failure (CASE 12-2).
If the EEG changes exceed what can be expected from imaging, laboratory,
and toxicology findings, this indicates a significant electro-paraclinical gap
caused by the seizure burden so that nonconvulsive status epilepticus should be
suspected and consequent treatment with antiseizure medication should be
initiated or continued at the earliest possible time (CASE 12-3).
The refinement of diagnostic criteria for nonconvulsive status epilepticus has
been ongoing since the first criteria by Young and colleagues in 1996,95 with more
precise criteria provided by Chong and Hirsch in 2005,96 a distinction between
Common Acute Causes and Most Important Mimics of Status Epilepticus TABLE 12-8
and Their Treatment Approaches
Clues from history (relatives, witnesses,

Etiology of status epilepticus emergency medical services) Therapeutic approach
Cerebral ischemia Sudden onset neurologic symptoms and Systemic thrombolysis, mechanical clot
signs before seizure activity retrieval
Parenchymal hemorrhage Sudden onset neurologic symptoms and Use clotting factors to reverse anticoagulation
signs before seizure activity with warfarin or use idarucizumab or andexanet
alfa to reverse oral direct inhibitors of
activated coagulation factor X
Bacterial meningitis Rapid deterioration of performance, fever, Dexamethasone, antibiotics

altered mental status,
Viral encephalitis Rapid deterioration of neurologic symptoms, For herpes simplex virus: acyclovir
fever (optional), recent travel, skin changes
Intoxication (prescribed Ongoing medication despite decreased Activated charcoal, antidote

drugs, illicit drugs, renal function; drug abuse, contact with
environmental toxins) industrial goods (eg, solvents, herbicides,
insecticides, chemicals in workplace or
spare time activity)
Traumatic brain injury Lying beside ladder or bottom of stairs, skin Surgical evacuation of subdural or epidural
lacerations hematoma, stabilization of concomitant
fracture of cervical vertebrae
Mimic of status epilepticus
Psychogenic seizures Very irregular movements, changing side EEG normal or near normal: reduce staff, use
and region of body abruptly without a calm reassuring talking
“marchlike” propagation; waxing and
If EEG is not available: allow 3 minutes for
waning; overarching of trunk (arc de cercle);
reevaluation of diagnosis of status epilepticus
rapid head shaking; history of dissociative
disorders or psychological trauma
Cerebral hypoperfusion Reported palpitations or pain in the heart, Check adequate cardiocirculatory function
(cardiocirculatory arrest) neck, arm, epigastrium; “blood pressure not (palpation of carotid or femoral pulses,
measurable”; pale or cyanotic skin; flush monitoring of blood pressure and ECG)
during reperfusion
ECG = electrocardiogram; EEG = electroencephalogram.

STATUS EPILEPTICUS
FIGURE 12-8
Proposed algorithm for convulsive status epilepticus by the American Epilepsy Society.73,74
D12.5W = dextrose 12.5% in water; D25W = dextrose 25% in water; D50W = dextrose 50% in water;
ECG = electrocardiogram; exam = examination; IV = intravenous; PE = phenytoin sodium equivalents.
Reprinted with permission from the American Epilepsy Society.74 © 2021 American Epilepsy Society.
with or without preexisting encephalopathy by Kaplan in 2007,97 and the

Salzburg Consensus Criteria developed by an expert group at the fourth
London-Innsbruck Colloquium on acute seizures and status epilepticus98 and
published by Beniczky and colleagues in 2013.99 A critical view and the addition
of clinical and paraclinical criteria and suggestions to standardize testing and
gauging of the response to antiseizure medication were provided by Leitinger
and colleagues in 2015.94,100 The Salzburg Consensus Criteria were validated
retrospectively in a multicenter study with very good test performance
characteristics101-103 and can be implemented in the ICU environment with
576 APRIL 2022

continuous EEG recordings.104-106 The American Clinical Neurophysiology KEY POINTS
Society adopted the Salzburg Consensus Criteria into their most recent Standard
● The electro-paraclinical
Critical Care EEG Terminology 2021 (FIGURE 12-13).107 FIGURE 12-14 shows a gap exists if the EEG findings
synopsis that includes the integration of the established Salzburg Consensus cannot sufficiently be
Criteria for EEG together with the essential pathways to diagnose nonconvulsive explained by imaging,
status epilepticus (CASE 12-4).94,99,100,107 laboratory, or toxicologic
investigations.
The current set of criteria have several advantages. The main advantage is
the clear characterization of several status epilepticus patterns and the ictal- ● The electro-paraclinical
interictal continuum.107 However, a few notes of caution should be added. On gap is a useful tool to
the one hand, clinicians may misinterpret the neurophysiologist’s diagnosis of diagnose nonconvulsive
“possible status” as “status epilepticus” without critically reviewing the full status epilepticus and to
increase specificity.
clinical and paraclinical information (imaging, laboratory, toxicology) as to
whether the diagnosis of nonconvulsive status epilepticus should be ● The Salzburg diagnostic
confirmed or rejected (FIGURE 12-11 and FIGURE 12-14). On the other hand, EEG criteria for
clinicians reading “ictal-interictal continuum” in the report may be satisfied nonconvulsive status
epilepticus are part of the
and not further investigate the patient with ictal MRI or ictal SPECT to recent American Clinical
confirm status epilepticus (FIGURE 12-14). Because the terms ictal-interictal Neurophysiology Society
continuum and possible electrographic status epilepticus are synonyms, the Standard Criteria for Critical
authors of this article recommend using all available clinical, imaging, Care EEG Terminology.
laboratory, and toxicologic information to understand as to what extent
pathologic EEG patterns are the result of structural or metabolic
derangements (concept for high specificity) (FIGURE 12-11, FIGURE 12-12,
FIGURE 12-13, and FIGURE 12-14). Concerning the EEG or clinical response to IV
administered antiseizure medication, no consensus has been reached as to
which time points to test and which criteria define an EEG-based or clinical
improvement.100 EEG improvement may occur if encephalopathic waves are
treated with benzodiazepines.108,109 Further, evidence is growing that the
metabolic demand is already increased at frequencies less than 2.5 Hz. This
border zone is not yet well defined, in particular, concerning modulating
factors aggravating or alleviating the metabolic burden associated with
periodic discharges.1,110-115
Status epilepticus in neonates differ significantly from children and adults
because of very dynamic maturation processes and the causes. Therefore, they
are treated according to guidelines tailored to their specific needs.116
The further identification of the etiology goes in parallel with the stabilization
of the patient, the interpretation of EEG, and the treatment response. Once
treatment has been escalated to therapeutic coma with suppression of status
activity, the relevant question “Did the treatment successfully and persistently
abort status epilepticus?” has to be addressed again after a period of 24 to
48 hours. Here, the EEG gives guidance as to when weaning from the respirator
can be safely performed.87 Despite the clarity of the Salzburg Consensus Criteria
for EEG, several EEG patterns in the severely injured brain reflect disturbed
function but not necessarily ongoing nonconvulsive status epilepticus; in other
words, no electro-paraclinical gap is present (CASE 12-2).32,93,94,100,117,118
Continuous EEG provides the opportunity to monitor cerebral function
without interruption and, therefore, to quantify the load of the various patterns,
which is characterized as the “seizure burden.” Lalgudi Ganesan and Hahn119
provided a detailed review emphasizing the spatial extent of the brain involved
and the temporal proximity of the status activity to the brain injury (known as
temporal evolution of seizure burden). Seizure burden was analyzed in a more

STATUS EPILEPTICUS
detailed study of 50 patients with seizures in a total cohort of 402 patients

diagnosed with subarachnoid hemorrhage.120 The seizure burden was defined as
the duration, in hours, and a median length of 6 hours (interquartile range, 1 to
13 hours) was recorded. The seizure burden was shown to be significantly
associated with an unfavorable functional and cognitive outcome at 3 months
with a significant odds ratio for every hour of seizure.120 In a retrospective cohort
of 23 patients with nonconvulsive status epilepticus out of 127 patients with
continuous EEG with various acute and remote etiologies, mortality was 57%,
with seizure duration being significantly associated with increased mortality
with an hourly increased odds ratio (1.131/h, P=.0057) after multivariate logistic
regression analysis.95
It must be emphasized that the approach of determining the burden (ie,
exposure of the brain to a potentially toxic agent, in this case an electrically
mediated metabolic derangement) differs substantially from pure association
TABLE 12-9 Advantages and Disadvantages of Drugs Commonly Used in Early and
Established Status Epilepticusa
Drug Advantages Disadvantages

Diazepam Rapid onset of action following IV Rapid redistribution responsible for short
administration, non-IV formulation available duration of action; sedation, hypotension,
(rectal), long-standing clinical experience in respiratory depression; risk of drug
adults and children, efficacy and safety accumulation after repeated doses and
evaluated in randomized controlled trials, infusion; risk of reaction at the injection site
relatively inexpensive and widely available
Lorazepam Rapid onset of action following IV Sedation, hypotension, respiratory depression;

administration, longer effect (>24 hours) after risk of reaction at the injection site
administration compared with diazepam, long-
standing clinical experience in adults and
children, efficacy and safety evaluated in
randomized controlled trials, little risk of drug
accumulation
Midazolam Non-IV formulations available (buccal, Risk of seizure recurrence because of short
intranasal, IM), rapid onset of action after duration of action; sedation, hypotension,
administration by any route, efficacy and safety respiratory depression
of all formulations evaluated in randomized
controlled trials, administration is easy and
rapid, better social acceptance than drugs
administered rectally, little risk of drug
accumulation
Clonazepam Rapid onset of action following IV Lack of randomized controlled

administration, longer effect after trials
administration compared with diazepam, little
risk of drug accumulation
Phenobarbital Rapid onset of action following IV Sedation, hypotension, respiratory depression;

administration, long-standing clinical risk of clinically significant drug interactions; risk
experience in adults and children, efficacy and of reaction at the injection site
safety evaluated in randomized controlled
trials, inexpensive and widespread availability
578 APRIL 2022

studies as it paves the way for deep understanding and modeling of
pathophysiologic processes.119 In particular, the correlation of seizure burden
with MRI changes will provide evidence about the relative harm of various EEG
patterns.15,16,121 However, the interplay of these factors is complex (FIGURE 12-16)
and can be integrated into a model including structural damage and metabolic
derangement, burden of status epilepticus, success of treatment, burden of
treatment, functional reserve, severity of decompensation, and impact of burden
(ie, the “impact of burden” model) (FIGURE 12-16). In short, the seizure burden
adds to variable degrees of metabolic exhaustion and the structural damage
caused by the underlying brain injury, which may result in functional
decompensation leading to neuronal injury and neuronal death (FIGURE 12-16).
The success of treatment may alleviate seizure burden. However, medical
aggressiveness may pose a burden of treatment. In patients with large structural
and metabolic reserves, the burdens of status epilepticus and its treatment will be
Drug Advantages Disadvantages

Phenytoin Long-standing clinical experience in adults and Rapid onset of action following IV
children, efficacy and safety evaluated in administration, long-standing clinical
randomized controlled trials, lack of sedation, experience in adults and children, efficacy and
inexpensive (not fosphenytoin) and widespread safety evaluated in randomized controlled
availability trials, low incidence of adverse events overall,
good cardiovascular and respiratory tolerability,
relatively inexpensive and widespread
availability
Valproate Rapid onset of action following IV Dizziness, thrombocytopenia, and mild

administration, long-standing clinical hypotension (uncommon side effects); risk of
experience in adults and children, efficacy and acute encephalopathy usually associated with
safety evaluated in randomized controlled hepatic abnormalities or hyperammonemia; risk
trials, low incidence of adverse events overall, of pancreatitis and liver failure
good cardiovascular and respiratory tolerability,
relatively inexpensive and widespread
availability
Levetiracetam Long-standing clinical experience in adults and Somnolence, sedation, agitation, and
children, lack of drug interactions, low thrombocytopenia (uncommon side effects);
incidence of adverse events overall, good relatively expensive
cardiovascular and respiratory tolerability
Lacosamide Rapid onset of action following IV Little clinical experience and lack of
administration, low incidence of adverse events randomized controlled trials, risk of cardiac
overall, good cardiovascular and respiratory arrhythmias
tolerability
a
Reprinted with permission from Trinka E, et al, Expert Opin Pharmacother.75 © 2016 Taylor & Francis Group.

STATUS EPILEPTICUS
better compensated and, therefore, lead to increased patient survival than in

those with only marginal reserves. This relationship heavily impacts the
appropriate choice of study end point parameters. Functional or imaging
outcomes are more suitable in patient cohorts with large reserves because
mortality will demonstrate a floor effect and vice versa. In deeply sedated
patients, various EEG patterns may arise spontaneously or as the result of
stimulation, such as stimulus-induced rhythmic, periodic, or ictal discharges
(SIRPIDs).32,93,94,100,122 However, their pathogenetic role and the degree to which
these patterns should be treated remain to be elucidated.123 The clinical
assessment is limited in this context, and other methods to monitor brain
functions are needed. The increased metabolic demand associated with ongoing
or recurring seizure/status activity may be measured by multimodal monitoring,
including perfusion measures with single-photon emission computed
tomography (SPECT), perfusion CT, or perfusion MRI. Increased secondary
hyperperfusion has been revealed by cerebral hexamethylpropyleneamine oxime
(HMPAO)-SPECT.124-127 Lateralized periodic discharges (LPDs) faster than
2.0 Hz have been associated with a drop in partial pressure of oxygen in
interstitial brain tissue,114 suggesting a failure to compensate the increased
metabolic demand coming with the periodic discharges (FIGURE 12-16).
MRI AND STATUS EPILEPTICUS

MRI represents a useful technique to identify peri-ictal MRI abnormalities
related to status epilepticus. Highly variable MRI alterations have been reported
during or after status epilepticus, related to the underlying cause or the ongoing
TABLE 12-10 Patient Groups and Specific Situations Where Special Consideration Is
Needed When Initiating Treatment for Status Epilepticus
Patient group/specific situation Caution
Chronic obstructive pulmonary disease, Benzodiazepines may cause hypercapnia and respiratory depression, keep
bronchial asthma intubation equipment and staff available
Chronic heart failure, children Rapid administration of antiseizure medication may result in fluid overload and
congestive heart failure
Renal failure, hepatic failure Accumulation of previously administered antiseizure medication could
contribute to compromised clinical condition
Mitochondrial disorders in children and Valproic acid contraindicated

adults
Patients with low blood pressure on Risk of further drop in blood pressure with midazolam, phenytoin, propofol,
admission and narcotics
Suspicion of nonconvulsive status Wait for EEG if no clinical hints of nonconvulsive status epilepticus especially in
epilepticus in comatose patients coma (intoxication, eg, with benzodiazepines, may be misinterpreted as
nonconvulsive status epilepticus)
No venous access readily available Consider buccal, nasal, and IM routes of administration; in selected cases, also
intraosseous access (special equipment required) should be considered
580 APRIL 2022

A 65-year-old man was transported to the emergency department by CASE 12-1
emergency medical services. At 4:00 PM, the control center notified the
emergency department of the impending arrival of the patient with
bilateral tonic-clonic seizure activity for 15 minutes. On the patient’s
arrival at 4:15 pm, the physician in the emergency department filled out
the checklist as shown in FIGURE 12-9.
FIGURE 12-9
Strategy for the initial management of status epilepticus for the patient in CASE 12-1.
BP = blood pressure; BTC = bilateral tonic-clinic; ECG = electrocardiogram; IV = intravenous; L = left;
MCA = left middle cerebral artery; MRI = magnetic resonance imaging; R = right; SE = status
epilepticus; STOPP = end of status, or status epilepticus successfully treated; TOF-MR = time-of-flight
magnetic resonance.
The key message of this example is that focusing on the treatment of status COMMENT
epilepticus may result in missing the acute underlying etiology that needs a
specific emergency treatment. Checklists such as that in FIGURE 12-6 help
minimize in-time identification of coexisting emergencies and minimize
focus error, which refers to a situation when the attention of the treating
team is too focused on one detail, thereby overlooking other highly
important deteriorations.
This case provides a practical example of how the concept shown in
FIGURE 12-7 can be applied in daily work. Some considerations need to be
documented in a sheet, such as in FIGURE 12-6, whereas others are essential
for differential diagnosis and patient management. Intramuscular or
intraosseous application routes do not apply if sufficient venous access is
available (grayed out text in FIGURE 12-9).

STATUS EPILEPTICUS
FIGURE 12-10
Relationship of EEG changes and impairment of consciousness.
NCSE = nonconvulsive status epilepticus; SE = status epilepticus
Reprinted with permission from Bauer G, Trinka E, Epilepsia.32 © 2009 International League Against Epilepsy.
seizure activity directly.15,16,121 The key information that can be derived from
ictal MRI studies is twofold: First, cerebral hyperperfusion (conventional MRI
perfusion with contrast dye or arterial spin labeling) directly reflects the
increased metabolic demand of brain tissue due to ongoing ictal activity.128
Second, cytotoxic edema reflects neuronal damage, as expected to occur at
time t2. Despite the undoubtful importance of MRI in identifying peri-ictal
abnormalities, no large prospective series have been conducted. What is known
so far? Thalamic diffusion restriction was found in 48% in a study of 62 patients
with focal-onset status epilepticus who underwent an MRI during an episode of
status epilepticus, of whom 75.9% showed involvement of the medial pulvinar.129
Temporal lobe status epilepticus was associated with thalamic diffusion-
weighted imaging (DWI) changes in 60.6% compared with only 27.3% and 6.7%
in status epilepticus in the parietal and frontal lobes, respectively.129 Arterial spin
labeling was successfully applied to reveal hyperperfusion in several patients
with nonconvulsive status epilepticus.130 In 60 patients with status epilepticus,
DWI and T2-weighted abnormalities were highly associated with a poor
outcome.131 In another study including 69 patients, the EEG of patients
with status epilepticus with peri-ictal DWI restrictions was predominated by
circumscribed “periodic lateralized discharges (PLEDs)” and by repetitive
seizures.132 This association of LPDs was corroborated in a large series of 277
patients of whom 12% showed peri-ictal MRI changes.16 Arterial spin labeling
demonstrates ictal hyperperfusion and can be positive even in patients who are
DWI negative.128
SUPER-REFRACTORY STATUS EPILEPTICUS

The majority of status epilepticus episodes can be successfully treated with a
benzodiazepine and one or two antiseizure medications provided they were
582 APRIL 2022

given early in the course in an adequate dose.83 As soon as the combination KEY POINTS
of one benzodiazepine and one antiseizure medication has failed, status
● The impact of the burden
epilepticus is called refractory (FIGURE 12-1).24 Especially in convulsive status model integrates structural
epilepticus, the application of anesthetics is inevitable.3,75,133,134 The persisting damage and metabolic
need for anesthetics in super-refractory status epilepticus for at least 7 days derangement, the burden of
determines a prolonged super-refractory status epilepticus whereas a refractory status epilepticus, the
success and burden of
status epilepticus of the same duration but without anesthetics is called prolonged
treatment, and the impact of
refractory status epilepticus. Although this categorization seems clinically useful, burden.
the terms have not been used widely in the community yet (FIGURE 12-1).24 The
time criteria were arbitrarily set with a focus on practicality and to allow for the ● The amount of structural
selection of subgroups with status epilepticus that may share similar etiologies or and metabolic reserves
determines the optimal end
treatment strategies. In this respect, the term new-onset refractory status epilepticus point parameters in studies.
(NORSE) proved very valuable. It specifies neither a specific etiology nor
diagnosis but rather a clinical presentation that is used in patients with new-onset ● MRI is useful to
refractory status epilepticus but without preexisting relevant neurologic demonstrate ictal
hyperperfusion by arterial
disorders including active epilepsy and without a clear acute or active structural, spin labeling in those with
metabolic, or toxic cause.24 Febrile infection–related epilepsy syndrome (FIRES) status epilepticus.
is considered a subcategory of NORSE. FIRES is applicable to any age and
requires a prior febrile infection starting between 2 weeks and 24 hours before ● New-onset refractory
status epilepticus (NORSE)
the onset of refractory status epilepticus whereas the presence of fever at the
is a form of a clinical
onset of status epilepticus is not a defining criterion.24 Reports of meaningful presentation of refractory
results of biopsy in patients with NORSE are sparse and include rabies; primary status epilepticus.
angiitis of the central nervous system; lymphocytic infiltration with simian virus
40 (SV40) inclusion in oligodendrocytes; spongiform necrosis in limbic system ● Febrile infection–related
epilepsy syndrome (FIRES)
associated with autoantibodies against GD1a, GT1b, and GQ1b; herpes simplex denotes a condition in which
virus with negative polymerase chain reaction (PCR); Candida with negative a febrile infection preceded
culture; and acute disseminated encephalomyelitis (ADEM).135-139 In one case NORSE.
series, gliosis without infiltration was found in seven children.140 In a series of 26
patients, 73% of patients with biopsy had an unknown and unidentified etiology
(cryptogenic).139 In 50 individuals with FIRES, including 23 single probands and
27 patient-parent trios, no pathologies were found in established genes for
neurodevelopmental disorders or epilepsy.141 Among adult patients without
cryptogenic NORSE, the most often identified cause is autoimmune encephalitis,
either nonparaneoplastic or paraneoplastic.142 Infections are the most prevalent
etiology of pediatric NORSE.143 Genetic and congenital disorders can have a
causative role in NORSE, and toxic, vascular, and degenerative conditions
have also been described.65,142 NORSE is a heterogeneous and clinically
challenging presentation. In a 2019 review by Gofton and colleagues,142 an
extensive workup was suggested, which serves the purpose of encouraging
standardized protocol-driven investigations (TABLE 12-11). In this very
rare condition, progress can only be made by collecting data with
multinational registries.144
In a study with 83 patients with status epilepticus with prominent motor
symptoms, a clinical score predicting cryptogenic NORSE early in the course of
illness included (1) a high resistance to conventional antiseizure medication
treatment, (2) a previously healthy individual before onset, (3) the presence of
prodromal high fever of unknown origin before onset, (4) the absence of
prodromal psychobehavioral or memory alterations, (5) the absence of
sustained orofacial and limb dyskinesias despite a profoundly decreased
level of consciousness, and (6) symmetric DWI or T2/fluid-attenuated inversion

STATUS EPILEPTICUS
CASE 12-2 A 59-year-old woman was brought to the emergency department in a

comatose state after having been found in her home; she was last seen
well 3 days before. Reportedly, she had been experiencing symptoms of
gastroenteritis. Diffusion-weighted imaging revealed normal restriction
(except technical artifact of bilateral frontomesial regions) (FIGURE 12-11).
The patient’s laboratory values are listed in the grid below.
Parameter Concentration Range

Chloride, mmol/L 73 97-108
Potassium, mmol/L 6.3 3.6-5.0
Sodium, mmol/L 124 135-148
Creatinine, mg/dL 11.1a 0.5-1.1

a
Blood urea nitrogen, mmol/L 5.3 0.17-0.83
Calcium, mmol/L 1.82 2.13-2.63
C-reactive protein, mg/dL 4.0 <0.6
Aspartate transaminase (AST), U/L 59 10-35
Alanine transaminase (ALT), U/L 71 10-35
Lactate dehydrogenase, U/L 348 135-225
γ-Glutamyl transferase, U/L 81 5-39
Creatine kinase, U/L 1574 26-140
a
Note the pronounced abnormality.
584 APRIL 2022

FIGURE 12-11
Information on the patient in CASE 12-2. A, EEG during the symptomatic period (generalized
periodic discharges at 1.1 Hz). B, Axial diffusion-weighted MRI image showing normal
restrictions (except technical artifact of bilateral frontomesial regions). C, A model
integrating all features. The structural damage increases along the x-axis (1, light brown
triangle). The EEG findings (black bracket) perfectly match what can be expected from
renal failure (brown bracket). Therefore, there is no burden of status epilepticus, which
would have been indicated by the black bracket extending to the blue lines.
EEG = electroencephalogram; NCSE = nonconvulsive status epilepticus.
In this patient, the EEG changes, that is, the generalized periodic discharges COMMENT
at slightly greater than 1 Hz, can be explained by the laboratory abnormalities
identified (eg, increased blood urea nitrogen and creatinine) due to acute
renal failure from a clinical perspective. Therefore, no “electro-paraclinical
gap” between EEG changes and what is seen on the paraclinical
investigations (imaging and labs) is seen. Without an electro-paraclinical gap,
the pattern does not qualify for nonconvulsive status epilepticus from a
clinical perspective.

STATUS EPILEPTICUS
CASE 12-3 A 51-year-old woman was found unresponsive with jerking of her right
shoulder. The emergency response team administered 7.5 mg midazolam
IV resulting in cessation of the jerking. However, the jerking resumed on
arrival in the emergency department. Lorazepam 4 mg IV and
levetiracetam 2000 mg IV were administered with cessation of the jerking
again. One hour later, an EEG was performed because of a lack of
improvement in cognitive status.
The patient had been treated with carbamazepine 400 mg/d for
symptomatic epilepsy due to remote traumatic brain injury with
subarachnoid hemorrhage (shunt system in place). CT revealed no
regional marked hypodensity (FIGURE 12-12). The patient’s laboratory values
are listed in the grid below.
Parameter Concentration Range

Chloride, mmol/L 104 97-108
Potassium, mmol/L 4.09 3.6-5.0
Sodium, mmol/L 140 135-148
Creatinine, mg/dL 0.70 0.5-1.1
Blood urea nitrogen, mmol/L 0.43 0.17-0.83
Calcium, mmol/L 2.15 2.13-2.63
C-reactive protein, mg/dL 0.6 <0.6
Alanine transaminase (ALT), U/L 14 10-35
Lactate dehydrogenase, U/L Hemolyzed specimen 135-225
γ-Glutamyl transferase, U/L 79 5-39
Creatine kinase, U/L 43 26-140
Carbamazepine, μg/mL 6.7 4-10
COMMENT In this patient, the EEG changes with more than 25 epileptiform discharges
per 10 seconds cannot be explained by cerebral imaging, laboratory
derangements, or toxicologic results. Hence, an “electro-paraclinical gap“
exists between EEG changes and what can be expected from paraclinical
investigations (imaging, laboratory, and toxicologic investigations). This
electro-paraclinical gap qualifies for a diagnosis of nonconvulsive status
epilepticus.
586 APRIL 2022

FIGURE 12-12
Information on the patient in CASE 12-3. A, Ictal EEG (more than 25 epileptiform discharges in
10 seconds over the left temporal region). B, Axial noncontrast head CT shows no regional
marked hypodensity. C, A model integrating all features. The structural damage increases
along the x-axis (1, light brown triangle). The EEG findings (black bracket) exceed what can be
expected from traumatic brain injury (brown bracket). In this example, the black bracket
reaches moderate burden of status epilepticus (middle blue line).
EEG = electrocardiogram; NCSE nonconvulsive status epilepticus; SAH = subarachnoid hemorrhage;
TBI = traumatic brain injury.

STATUS EPILEPTICUS
FIGURE 12-13
Salzburg EEG criteria and American Clinical Neurophysiology Society critical care EEG
terminology.99,101,107 Epileptiform discharges and evolution patterns may qualify for
electrographic status epilepticus. A time-locked clinical correlate and the combined EEG and
clinical improvement to IV antiseizure medications determine electroclinical status epilepticus.
The ictal-interictal continuum (synonym: possible electrographic status epilepticus) is
composed of periodic discharges, spike-and-wave, or lateralized rhythmic delta activity
fulfilling certain frequency criteria and the presence of plus modifiers or fluctuation.
EEG = electroencephalogram; IV = intravenous; PD = periodic discharges; RDA = rhythmic delta activity;
SW = spike-and-wave.
a
Status epilepticus if ≥10 continuous minutes OR ≥20% of any hour; seizure if neither is true.
Data from Hirsch LJ, et al, J Clin Neurophysiol.107
recovery (FLAIR) hyperintensities.145 In a study with 39 patients with

NORSE, leptomeningeal enhancement (43%) and hippocampal/cortical atrophy
(48%) were related to poor functional outcomes and drug-resistant epilepsy.121
Insular involvement was associated with a delayed time to first antiseizure
medication.121 Only three patients had claustrum pathologies.121 Duration of
status epilepticus tended to have a linear association with atrophy of the
hippocampi.121 In a case report, NORSE was associated with reversible
splenial lesion.146
Multicenter Studies and Registries

NORSE is a rare condition with a high lethality in which even a most extensive
workup referring to cutting-edge knowledge including extensive genetic and
metabolic investigations frequently fails to identify the underlying causes and
pathomechanisms. The low incidence leads to very few patients presenting
even to tertiary referral centers. This can be overcome by collecting global
experience with registries being filled by as many centers as possible.
Excellent examples for existing registries include, but are not limited to,
the NORSE Institute with its family registry of patients with NORSE and
FIRES (norseinstitute.org). Admittedly, registries currently collect patients
only sharing the common clinical presentation, which will prove to be caused
by a large number of different etiologies over the next years or decades.
588 APRIL 2022

FIGURE 12-14
Overview of the pathways essential for diagnosing nonconvulsive status epilepticus
implementing the Salzburg EEG criteria into clinical practice.1,94,100,107 In case of “possible
nonconvulsive status epilepticus,” further investigations such as ictal MRI or ictal SPECT are
needed. An ictal MRI should include at least arterial spin labeling or other perfusion studies,
diffusion-weighted imaging (DWI), apparent diffusion coefficient maps, and fluid-attenuated
inversion recovery (FLAIR) images. If none of these is available, the clinical diagnosis of
nonconvulsive status epilepticus can be established in a case with compelling clinical
evidence by taking clinical presentation, brain imaging, and laboratory and toxicologic
findings into account.
EEG = electroencephalogram; IV = intravenous; MRI = magnetic resonance imaging; NCSE = nonconvulsive
status epilepticus; SPECT = single-photon emission computed tomography.
a
Status epilepticus if ≥10 continuous minutes OR ≥20% of any hour; seizure if neither is true.
Modified with permission from Trinka E and Leitinger M, Epilepsy Behav.94 © 2015 The Authors.
However, the identification of any single treatable etiology saves lives, and
even each identified pathomechanism without current specific treatment
options improves our understanding and gives way to further dedicated
developments.
ADEQUATE USE AND INTERPRETATION OF SCORES

Patients with status epilepticus are most successfully treated in the emergency
department. Scores for outcome estimation are useful when deciding
whether to treat and observe these patients in the intensive care unit or on a
regular ward. Importantly, none of the scores has a perfect test performance.
Knowing the profile of each score is crucial. It is essential to remember that
even a “perfect sensitivity and specificity” can only be translated into “perfect
positive and negative predictive value” if the scores are applied in populations
with adequate prevalence. Even in one single hospital, the prevalence may
vary substantially with differently selected subpopulations (eg, each admission
to the emergency department or each refractory patient). It is also essential to

STATUS EPILEPTICUS
correctly interpret study results concerning predictive scores. Even if a score is

“significantly associated” with certain outcomes, then this is mostly a group
phenomenon in which the score is used as one of many surrogate markers,
whereas the proper application of a predictive score is to support decision
making for individual patients, which is much more challenging. A very high
negative predictive value allows for the identification of patients at low risk,
whereas a very high positive predictive value identifies patients with a high
probability for a substantial risk. Although at least the negative predictive value
or the positive predictive value should be perfect, the respective other parameter
CASE 12-4 An 89-year-old woman was found confused with minor movements of her
extremities and later in her face. The patient had no preexisting epilepsy
(FIGURE 12-15).
FIGURE 12-15
EEG from the patient in CASE 12-4. The contralateral muscle artifacts prove the
time-locked relationship between the periodic discharges (green rectangles) and the
clinical phenomena (red rectangles).
COMMENT The EEG identified the subtle jerks as epileptic in origin (FIGURE 12-15). In this
recording, the contralateral muscle artifacts prove the time-locked
relationship between the periodic discharges and the clinical phenomena.
However, in most cases with lateralized periodic discharges, the patient
must be carefully examined for subtle clinical signs.
590 APRIL 2022

FIGURE 12-16
The impact of burden model for status epilepticus: Model for the interaction of structural
damage and metabolic derangement, burden of status epilepticus, success of treatment,
burden of treatment, functional reserve and decompensation, and impact of burden in status
epilepticus. The patient has a disease, which is the etiology of status epilepticus and is
accompanied by structural damage or metabolic derangement of the brain (1, light brown
triangle). The higher this damage or derangement, the lower the functional reserve (green
triangle) and vice versa. The burden of status epilepticus (2) reduces this functional reserve
depending on duration, spatial extension, timing between brain damage and status, and
metabolic impact (blue diagonal parallel lines). However, the burden of status epilepticus
may be compensated by successful treatment (3). The extent of compensation can, at best,
be of the same magnitude as the burden of status epilepticus but cannot exceed it. The
treatment may expose a burden by itself (4) (eg, low blood pressure or deep sedation with
need of ventilator support). The integration of the burden of status epilepticus, the success
of treatment, and burden of treatment is either still within the functional reserve (green
triangle) or may lead to metabolic decompensation (yellow, orange, or red line). The extent
of decompensation (5) has a correlating impact of burden (6), which may lead to further
structural damage and metabolic derangement (1) in the surviving patient or may result in
death in severe cases. Note that with high structural damage or metabolic derangement,
status epilepticus alone may lead to metabolic decompensation and threatening of life.
should not be too low. In an extreme case, a perfect negative predictive value
associated with a poor positive predictive value might be of limited value if
nearly all admissions were scored as at high risk, which was already assumed
otherwise, demonstrated by the very fact that the patients were brought to
the hospital.
The Status Epilepticus Severity Score (STESS) includes (1) consciousness
(alert or somnolent/confused versus stuporous or comatose), (2) worst seizure
type (nonconvulsive status epilepticus in coma versus generalized convulsive
versus focal with or without impaired consciousness/awareness, absence, and
myoclonic complicating idiopathic generalized epilepsy), (3) the age (younger
than 65 years versus 65 years of age or older), and (4) history of previous seizure.
A score of three or more points indicated high risk and was associated with an
excellent negative predictive value.147 Importantly, STESS can be applied quickly
and reliably even in very busy emergency departments without EEG being

STATUS EPILEPTICUS
TABLE 12-11 Diagnostic Workup in New-onset Refractory Status Epilepticusa
Within the first 24 hours

◆ Initiate institution status epilepticus protocol
◆ Evaluate time to treatment and determine related prognostic risks
◆ Obtain thorough history, especially regarding immunosuppression, medications and
supplements, recent travel to endemic areas, accidental or occupational exposure to
animals, insects, pathogens, drugs, or toxins
◆ Consider treatment for possible herpes simplex virus (HSV) encephalitis
◆ Triage for appropriate cardiopulmonary support
◆ MRI of the brain with and without contrast with magnetic resonance angiogram and
magnetic resonance venogram of the head
◆ Initiate continuous EEG, regardless of cessation of convulsive activity
◆ Serologic/imaging tests for patients with new-onset refractory status epilepticus (NORSE)
(see below)
◇ Screen and disease/agent tested
→ Infectious
– Recommended in most or all patients
Serologic: Complete blood cell count, bacterial and fungal cultures, purified protein
derivative placement, syphilis, human immunodeficiency virus (HIV)-1/2 immunoassay
with confirmatory viral load if appropriate
Serum and CSF: IgG and IgM testing for Chlamydia pneumoniae, Bartonella henselae,
Mycoplasma pneumoniae, Coxiella burnetii, Shigella species, and Chlamydia psittraci
Nares: Respiratory viral direct fluorescent-antibody assay panel
CSF: Cell counts, protein, and glucose, bacterial and fungal stains and cultures,
polymerase chain reaction (PCR) for HSV1, HSV2, varicella zoster virus, Epstein-Barr
virus (EBV), HIV, syphilis testing, PCR for tuberculosis
– Recommended in immunocompromised patients
Serologic: IgG Cryptococcus species, IgM and IgG Histoplasma capsulatum, IgG
Toxoplasma gondii
Sputum: Molecular test for tuberculosis
Serum and CSF: Toxoplasma IgG
CSF: Eosinophils, silver stain for central nervous system fungi, PCR for JC virus,
cytomegalovirus, EBV, human herpesvirus-6, Eastern equine encephalitis, enterovirus,
influenza A/B, HIV, West Nile virus, parvovirus, Listeria antibody, measles (rubeola)
Stool: Adenovirus PCR, enterovirus PCR
– Recommended if geographic/seasonal/occupational risk of exposure
Serum buffy coat and peripheral smear
Lyme enzyme immunoassay with IgM and IgG reflex
Send further serum and CSF samples to Centers for Disease Control and Prevention
Arbovirus Diagnostic Laboratory, CSF and serum Rickettsial disease panel, Flavivirus
panel, Bunyavirus panel
Serum testing for Acanthamoeba species, Balamuthia mandrillaris, Baylisascaris procyonis
Other
592 APRIL 2022

→ Autoimmune/paraneoplastic
– Recommended
Serum and CSF paraneoplastic and autoimmune epilepsy antibody panel to
include antibodies to leucine-rich, glioma inactivated 1 (LGI1), contactin-associated
proteinlike 2 (CASPR2), Ma2/Ta dipeptidyl-peptidase–like protein 6, glutamic
acid decarboxylase 65 (GAD65), N-methyl-D-aspartate (NMDA), α-amino-3-
hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), γ-aminobutyric acid
B (GABAB), GABAA, glycine receptor, anti-Tr, amphiphysin, CV2/collapsin response
mediator protein-5 (CRMP-5), neurexin-3α, adenylate kinase. antineuronal
nuclear antibody types 1/2/3 (Hu, Yo, and Ri), Purkinje cell cytoplasmic antibody
types 1, 2
Serologic: Also send antinuclear antibody (ANA), antineutrophil cytoplasmic antibody
(ANCA), antithyroid antibodies, anti–double-stranded DNA, erythrocyte
sedimentation rate, C-reactive protein, extractable nuclear antigen, serum protein
electrophoresis, immunofixation electrophoresis, antibodies for Jo-1, Ro, La, Scl-70;
check rheumatoid factor, angiotensin-converting enzyme, anti–tissue
transglutaminase, anti–endomysium antibodies, cold and warm agglutinins
– Optional
Consider storing extra frozen CSF and serum for possible further autoimmune testing
in a research laboratory
→ Neoplastic
– Recommended
CT of the chest/abdomen/pelvis, scrotal ultrasound, mammogram, CSF cytology,
flow cytometry, pelvic MRI
– Optional
Bone marrow biopsy, whole-body PET/CT, cancer serum markers
→ Metabolic
– Recommended
Urea/creatinine, lactate dehydrogenase, urinalysis with microscopic urinalysis, liver
function tests, electrolytes, calcium/magnesium/phosphate, ammonia, porphyria
screen (spot urine)
– Consider
Vitamin B1 level, vitamin B12 level, folate, lactate, pyruvate, creatine kinase, troponin;
tests for mitochondrial disorder (lactate, pyruvate, magnetic resonance
spectroscopy, muscle biopsy), tests for macrophage activation syndrome/
hemophagocytic lymphohistiocytosis (serum triglycerides and soluble interleukin-2
receptors [sIL2-r])
→ Toxicologic
– Recommended
Benzodiazepines, amphetamines, cocaine, fentanyl, alcohol, ecstasy, heavy metals,
synthetic cannabinoids, bath salts
– Consider
Extended opiate and overdose panel, lysergic acid diethylamide, heroin,
phencyclidine, marijuana


STATUS EPILEPTICUS
CONTINUED FROM PAGE 593 CONTINUED FROM PAGE 593

→ Genetic
– Consider
Obtain genetics consult, if possible; genetic screens for myoclonic epilepsy with
ragged red fibers, mitochondrial encephalomyopathy lactic-acidosis and strokelike
episodes, POLG1, and very long chain fatty acid screen; consider ceruloplasmin and
24-hour urine copper
At 48 hours
◆ Assess returned testing, initiate appropriate treatments
◆ If patient continues to have refractory status epilepticus or coma, transfer to a higher level
of care for appropriate further treatment of NORSE at a center with experience in these
cases, including continuous video-EEG monitoring
At 72 hours
◆ Consider initiation of 5-day course of high-dose parenteral corticosteroids; transfer to a
higher level of care for consideration of IVIg, plasma exchange, or further
immunomodulatory therapy if no clear diagnosis, if still having seizures, if no continuous
EEG monitoring available, or if still comatose
CSF = cerebrospinal fluid; CT = computed tomography; DNA = deoxyribonucleic acid;

EEG = electroencephalogram; IG = immunoglobulin; IV = intravenous; MRI = magnetic resonance imaging;
PET/CT = positron emission tomography/computed tomography.
a
Reprinted with permission from Grofton TE, et al, Neurology.142 © 2019 American Academy of Neurology.
immediately available.147 A first external evaluation recommended increasing

the cutoff value of three points (STESS-3) to four points (STESS-4) to
optimize the test yield based on the Youden Index, a tool that compares test
performances depending on cutoff values.148 However, every increase in
specificity and positive predictive value comes at the cost of sensitivity and
negative predictive value, and this endangers the concept that a clinically useful
score must have at least one “perfect” parameter to assist clinical reasoning in
triage situations.
The physicians who developed the Epidemiology-Based Mortality Score in
Status Epilepticus (EMSE) wondered whether the rather large categories of
STESS could benefit from a more gradual approach, that is, (1) points for each
decade of life instead of using one cutoff age of 65 years, (2) several etiologies
instead of the presence or absence of seizures, and the inclusion of (3) EEG
findings and (4) comorbidities.6 In a retrospective explorative study, this
combination of parameters proved to be even more helpful, and in an external
evaluation, it allowed not only for estimating mortality but also predicting
functional outcome.6,43 EMSE was also intended to allow for regional adaptations
around the globe as etiologies and outcomes vary in different geographical
regions (eg, cerebrovascular versus infectious etiologies) and allows for
adaptation over time when new treatment options emerge with an
improvement of outcomes and respectively fewer risk points in the score.
EMSE has already been studied in various continents.149-154 However,
comparability among studies is hampered by using different combinations of
parameters and cutoff values.
594 APRIL 2022

The END-IT score consists of (1) the presence of encephalitis, (2) KEY POINTS
nonconvulsive status epilepticus, (3) diazepam resistance, (4) imaging
● Data from patients with
findings (bilateral lesions/diffuse cerebral edema versus unilateral lesions NORSE should be collected
versus no responsible lesions, and (5) tracheal intubation and was successfully in international registries.
tested in a retrospective cohort with a significantly better receiver operating
characteristics curve in which the area under the curve represents the ● A predictive score should
have at least a very high
test performance.155,156
positive or negative
As a principle, scores may be a valuable piece in the mosaic of the whole predictive value.
clinical situation that supports decision making, but they should never be relied
on as the only criterion. Scores help focus attention on outcome-relevant
parameters in clinical routine.
CONCLUSION
Optimal management of patients with status epilepticus requires not only a large
amount of medical knowledge, keen clinical observation, and good clinical
judgment, it also requires an orchestrated transformation of information and the
procedural interplay of patients, caregivers, family members, witnesses,
emergency medical services, and all other involved professions. Thus, a high
degree of organization is needed, and teams have to be trained to achieve the
optimal outcome. Status epilepticus is still characterized by many evidence-free
zones, and multicenter collaborations are needed to improve the treatment and
care of patients with status epilepticus.
USEFUL WEBSITE
NORSE INSTITUTE
The NORSE Institute maintains a registry of patients
with NORSE and FIRES to help develop a shared
community among researchers and families.
norseinstitute.org
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6 Leitinger M, Höller Y, Kalss G, et al.
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114 Witsch J, Frey HP, Schmidt JM, et al.
126 Helbok R, Claassen J. Multimodal invasive
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127 Jaraba S, Reynés-Llompart G, Sala-Padró J, et al.
115 Subramaniam T, Jain A, Hall LT, et al. Lateralized
Usefulness of HMPAO-SPECT in the diagnosis of
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116 Rennie JM, de Vries LS, Blennow M, et al.
128 Shimogawa T, Morioka T, Sayama T, et al. The
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117 Sutter R, Kaplan PW. Electroencephalographic
129 Capecchi F, Mothersill I, Imbach LL. The medial
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130 Mutoh T, Eguchi K, Yamamoto S, et al. Arterial
118 Kapinos G, Trinka E, Kaplan PW. Multimodal
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an ictal-interictal continuum spectral severity
two cases. Am J Case Rep 2019;20:1883-1887.
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131 Requena M, Sarria-Estrada S, Santamarina E, 143 Sculier C, Barcia Aguilar C, Gaspard N, et al.
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in status epilepticus: temporal relationship status epilepticus in children (the pSERG
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144 Kazazian K, Kellogg M, Wong N, et al. How to help
132 Rennebaum F, Kassubek J, Pinkhardt E, et al. your patients enroll in the New-Onset Refractory
Status epilepticus: clinical characteristics and Status Epilepticus (NORSE) and Febrile
EEG patterns associated with and without MRI Infection-Related Epilepsy Syndrome (FIRES)
diffusion restriction in 69 patients. Epilepsy Res family registry, and other rare epilepsy registries.
2016;120:55-64. doi:10.1016/j.eplepsyres. Epilepsy Curr 2021;5:1535759721998329. doi:10.
2015.12.004 1177/1535759721998329
133 Ferlisi M, Hocker S, Trinka E, et al. The anesthetic 145 Yanagida A, Kanazawa N, Kaneko J, et al.
drug treatment of refractory and super- Clinically based score predicting cryptogenic
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results from a global audit. Epilepsy Behav 2019; Neurol Neuroimmunol Neuroinflamm 2020;7(5):
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134 Shorvon S, Ferlisi M. The treatment of super- 146 Mizutani AU, Shindo A, Arikawa S, et al.
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135 Villamar MF, Smith JH, Wilson D, Smith VD. 147 Rossetti AO, Logroscino G, Milligan TA, et al.
Rabies encephalitis presenting with new-onset Status Epilepticus Severity Score (STESS): a tool
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148 Sutter R, Kaplan PW, Rüegg S. Independent
136 Matar RK, Alshamsan B, Alsaleh S, et al. New external validation of the status epilepticus
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149 Sairanen JJ, Kantanen AM, Hyppölä HT,
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151 Atmaca MM, Bebek N, Baykan B, et al. Predictors
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139 Matthews E, Alkhachroum A, Massad N, et al. epilepticus: a prospective study. Epilepsy Behav
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153 Zhang Y, Chen D, Xu D, et al. Clinical utility of
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602 APRIL 2022

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POSTREADING TEST
ARTICLE 1: EVALUATION OF FIRST SEIZURE AND NEWLY DIAGNOSED

EPILEPSY
1 To meet the criteria for the diagnosis of epilepsy, someone who has had
a single unprovoked seizure must have which of the following
characteristics?
A abnormal findings on brain imaging

B abnormal findings on neurologic examination
C at least 60% probability of another seizure within the next 10 years
D at least 90% probability of another seizure within the next year
E subclinical seizure activity on EEG
2 A 24-year-old woman began having seizures 2 years ago, 3 months after

evacuation of a right frontal subdural hematoma that occurred when
she hit her head on a diving board. All of the seizures begin the same
way, with jerking movements of her left hand. Most of the time, this
resolves within 30 seconds, with no alteration of consciousness or other
symptoms, but about once every 3 months, the jerking spreads
throughout the left side of her body, and within seconds, she has
generalized tonic-clonic activity throughout her body. This lasts 1 to
2 minutes and is followed by 5 to 10 minutes of confusion. With four of
these more severe seizures, she has bitten her tongue, and with two of
them, she has been incontinent of urine. Which of the following types of
epilepsy does she have?
A combined generalized and focal

B focal
C generalized
D idiopathic
E unknown
3 Which of the following tests is recommended for all patients with

adult-onset focal epilepsy?
A brain MRI
B genetic testing
C lumbar puncture
D prolonged video-EEG monitoring
E toxicology screening
606 APRIL 2022

4 In an adult who has had a single unprovoked seizure, epileptiform
abnormalities on a standard EEG have which of the following
implications for another seizure within 5 years?
A likelihood 2 times as high as someone with a normal EEG

B likelihood 5 times as high as someone with a normal EEG
C likelihood 10 times as high as someone with a normal EEG
D nearly 100% likelihood
E the same likelihood as someone with a normal EEG
ARTICLE 2: EEG AT A GLANCE
5 The electrophysiologic currents detected in EEG arise from which of the

following sources?
A action potentials in the initial axonal segment of layer I

interneurons
B action potentials in the initial axonal segment of layer IV and V
pyramidal cells
C glial-derived local field potentials arising from layers I and II
D postsynaptic potentials in apical dendrites of layer I interneurons
E postsynaptic potentials in apical dendrites of layer IV and V
pyramidal cells
6 From slowest to fastest, what are the frequencies seen in clinical EEG
interpretation?
A alpha, beta, delta, theta

B beta, alpha, theta, delta
C delta, theta, alpha, beta
D theta, delta, beta, alpha
7 An EEG demonstrating a diffusely slow background, multifocal

independent spike discharges, and slow spike and waves would be most
suggestive of which of the following epilepsy syndromes?
A childhood absence epilepsy

B juvenile myoclonic epilepsy
C Lennox-Gastaut syndrome
D myoclonic-astatic epilepsy
E West syndrome

POSTREADING TEST
ARTICLE 3: NEUROIMAGING OF EPILEPSY
8 According to the Neuroimaging Task Force of the International League

Against Epilepsy, which of the following MRI sequences is mandatory
when evaluating patients with epilepsy?
A contrast-enhanced T1-weighted
B contrast-enhanced T2-weighted
C diffusion-weighted imaging (DWI)
D fluid-attenuated inversion recovery (FLAIR)
E susceptibility-weighted imaging (SWI)
9 A 78-year-old woman awoke on her bathroom floor and had no idea

what had happened. In the emergency department an hour later, her
examination is normal. Which of the following MRI findings would be
associated with the lowest likelihood that she will ultimately prove to
have epilepsy?
A arachnoid cyst in the occipital region

B cerebral cavernous malformation in the frontal lobe
C encephalocele in the anterior temporal lobe
D low-grade glioma in the parietal lobe
E multinodular and vacuolating neuronal tumor (MVNT) in the frontal
lobe
10 A patient being evaluated for epilepsy and behavioral changes has a

normal noncontrast MRI scan, but contrast-enhanced T1-weighted
images show diffuse perivascular enhancement radiating out from the
lateral ventricles. This patient most likely has which of the following
conditions?
A arteriovenous malformation
B autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy
C cerebral amyloid angiopathy-related inflammation
D primary angiitis of the central nervous system
E reversible cerebral vasoconstriction syndrome
608 APRIL 2022

ARTICLE 4: GENETIC EPILEPSY SYNDROMES
11 An 11-year-old girl is brought to clinic with concern for episodes of

staring and unresponsiveness as well as a recent generalized convulsion.
Her staring events began when she was 9 years old, and the family had
hoped she would outgrow them, but that has not yet occurred. Her
convulsive episode lasted approximately 1 minute and was described as
generalized stiffening with a loud grunt followed by synchronous
rhythmic jerking of all extremities. A routine EEG demonstrated a
normal background for age, brief interictal bursts of 3- to 4-Hz anterior
dominant generalized spike-and-slow-wave activity, and two typical
events during hyperventilation in which she stopped and stared with
fumbling of her hands for 20 seconds. These episodes were associated
with a 3- to 4-Hz spike-and-slow-wave electrographic discharge. Her
development and neurologic examination are normal. Which of the
following disorders is most likely in this patient?
A childhood absence epilepsy

B Doose syndrome
C juvenile absence epilepsy
D juvenile myoclonic epilepsy
E Panayiotopoulos syndrome
12 In which of the following childhood epilepsies should the ketogenic diet

be considered early if patients do not respond to initial medical therapy?
A atypical childhood epilepsy with centrotemporal spikes

B Dravet syndrome
C epilepsy with eyelid myoclonias
D Gastaut syndrome
E myoclonic-atonic epilepsy
13 A 9-year-old girl began having seizures 4 years ago, characterized by

hemifacial twitching and paresthesia, at times with progression to
bilateral tonic-clonic expression. Approximately 1 year later, she began
having other types of seizures: myoclonus (both positive and negative),
atonic drop attacks, and occasional atypical absence. Her cognitive
development has slowed somewhat over the past 4 years, and she now
requires assistance with reading and math. An interictal EEG demonstrates
a mildly slow background with frequent centrotemporal spikes arising
independently from the two hemispheres. A mutation in which of the
following genes would be most likely responsible for her condition?
A CHRNA2
B GRIN2A
C KCNQ2
D SCN1A
E SLC2A1

POSTREADING TEST
14 A 13-month-old boy who initially presented with febrile hemiclonic

status epilepticus at 6 months of age has now developed afebrile
generalized tonic-clinic and myoclonic seizures, which have proved
unresponsive to levetiracetam, valproic acid, and clobazam. He met his
early milestones on time, but he has not yet started to walk or say any
words other than “mama.” His first interictal EEG, performed 4 weeks
after his initial seizure, was normal. A study performed 1 month ago
was abnormal in the presence of a somewhat slow background and
occasional multifocal interictal epileptiform abnormalities. Use of
which of the following interventions in this condition is supported by
recent data?
A amantadine
B eslicarbazepine
C fenfluramine
D quinidine
E vigabatrin
ARTICLE 5: AUTOIMMUNE-ASSOCIATED SEIZURES
15 A 34-year-old woman has been experiencing spells characterized by

simultaneous contraction of the muscles of her left arm and left side of
her neck and face, with no alteration of consciousness. They last for
only a few seconds, but they happen 10 to 30 times a day. These spells
are most characteristic of autoimmune encephalitis associated with
antibodies to which of the following antigens?
A α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)

receptor
B dipeptidyl-peptidase–like protein 6 (DPPX)
C γ-aminobutyric-acid A (GABAA) receptor
D leucine-rich glioma inactivated 1 (LGI1)
E N-methyl-D-aspartate (NMDA) receptor
16 An EEG showing generalized rhythmic delta activity with

superimposed 1- to 2-second bursts of low-amplitude, high-frequency
(beta or gamma) activity would be most characteristic of autoimmune
encephalitis associated with antibodies to which of the following
antigens?

receptor
B dipeptidyl-peptidase–like protein 6 (DPPX)
C γ-aminobutyric-acid A (GABAA) receptor
610 APRIL 2022

17 The clinical triad of weight loss/gastrointestinal symptoms, limbic
symptoms, and central nervous system hyperexcitability (seizures,
myoclonus, hyperekplexia, or tremor) is most characteristic of
autoimmune encephalitis associated with antibodies to which of the
following antigens?

receptor
B dipeptidyl-peptidase—like protein 6 (DPPX)
C γ-aminobutyric-acid A receptor (GABAA) receptor
18 A 10-year-old girl with Rasmussen encephalitis has multiple seizures

per day that have been refractory to adequate trials of carbamazepine,
lacosamide, levetiracetam, and valproic acid. Which of the following
treatments is most likely to result in seizure freedom?
A gabapentin
B hemispheric disconnection surgery
C IVIg
D mycophenolate mofetil
E pyridoxine
ARTICLE 6: WOMEN’S ISSUES IN EPILEPSY
19 In a prospective observational cohort study, what was found regarding

fertility in women with epilepsy compared with a control group?
A higher miscarriage rates

B higher rate of anovulatory cycles
C lower pregnancy rates
D lower rate of live births
E no difference in time to pregnancy
20 Which of the following antiseizure medications has no effect on and is

unaffected by hormonal oral contraceptives?
A clobazam
B oxcarbazepine
C perampanel
D rufinamide
E zonisamide

POSTREADING TEST
21 Which of the following antiseizure medication has the lowest risk of

major congenital malformations when taken during pregnancy?
A carbamazepine
B levetiracetam
C phenobarbital
D phenytoin
E topiramate
ARTICLE 7: SEIZURES AND EPILEPSY IN CHILDHOOD
22 Which of the following is the most common underlying cause of

neonatal seizures?
A congenital malformation
B genetic disorder
C hypoxic-ischemic encephalopathy
D infection
E periventricular leukomalacia
23 A 3-year-old child has a febrile seizure in the setting of an upper

respiratory infection. Which of the following features would increase
the likelihood that the child will subsequently develop epilepsy?
A family history of febrile seizures

B focal seizure onset
C headache (lasting 2 hours) after the seizure
D seizure duration of 90 seconds
E short interval (45 minutes) between fever onset and seizure onset
24 Among children with epilepsy, which of the following features is

associated with an increased risk of sudden unexpected death in
epilepsy (SUDEP)?
A late age of seizure onset

B low seizure frequency
C nocturnal generalized tonic-clonic seizures
D normal brain MRI
E use of only a single antiseizure medication
612 APRIL 2022

25 Which of the following medication combinations is most effective for
infantile spasms?
A levetiracetam and levothyroxine

B oxcarbazepine and cannabidiol
C prednisone and acetazolamide
D topiramate and pyridoxine
E vigabatrin and adrenocorticotropic hormone (ACTH)
ARTICLE 8: NEUROPSYCHIATRIC AND COGNITIVE COMORBIDITIES IN

EPILEPSY
26 Which of the following antiseizure medications is least likely to be

associated with psychiatric side effects?
A levetiracetam
B oxcarbazepine
C phenobarbital
D pregabalin
E zonisamide
27 For a first episode of psychosis in a patient with epilepsy, what would

be the first-choice antipsychotic medication?
A aripiprazole
B clomipramine
C fluphenazine
D haloperidol
E risperidone
28 For children with attention deficit hyperactivity disorder and epilepsy,

treatment with an antiseizure medication and a stimulant is associated with
which of the following?
A decreased serum antiseizure medication levels

B improved attention in the majority of patients
C increased risk of antiseizure medication side effects
D increased risk of breakthrough seizures
E increased risk of stimulant medication side effects

POSTREADING TEST
ARTICLE 9: APPROACH TO THE MEDICAL TREATMENT OF EPILEPSY
29 Which of the following is the main reason that the initial licensure for a
new antiseizure medication is usually as adjunctive (add-on) treatment
rather than monotherapy?
A drug-drug interactions will be identified more quickly if a new

antiseizure medication is only used in combination with other
medications
B higher doses are usually required when antiseizure medications
are used as monotherapy than when they are used adjunctively
C if unexpected developments force the sudden withdrawal of the
new medication from the market, patients will still be taking at
least one antiseizure medication
D medications used adjunctively are more profitable than
medications used as monotherapy
E new antiseizure medications are usually first tested for efficacy as
adjunctive treatment in people with drug-resistant epilepsy
30 Which of the following medications is the preferred drug for a 6-year-

old child who has both typical absence seizures and generalized tonic-
clonic seizures?
A carbamazepine
B ethosuximide
C oxcarbazepine
D valproate
E vigabatrin
31 In patients with generalized epilepsy who continue to have generalized

tonic-clonic seizures despite treatment with monotherapy, adjunctive
use of which of the following antiseizure medications has been shown
to reduce seizure frequency?
A carbamazepine
B phenobarbital
C phenytoin
D topiramate
E vigabatrin
614 APRIL 2022

ARTICLE 10: UPDATE ON ANTISEIZURE MEDICATIONS 2022
32 Which of the following mechanisms of action is utilized by

cenobamate?
A binding SV2A protein

B blocking calcium channels
C blocking sodium channels
D enhancing potassium current
E N-methyl-D-aspartate (NMDA) receptor antagonism
33 A 25-year-old man with focal epilepsy, poorly controlled on clobazam

and eslicarbazepine, is started on prescription cannabidiol. As his dose
is increased, he becomes increasingly sleepy. Which of the following
mechanisms is mostly responsible for this side effect?
A impaired nocturnal sleep

B increased cannabidiol levels
C increased clobazam metabolite levels
D increased cannabidiol metabolite levels
E worsening seizure burden
34 Ophthalmologic evaluation is important with the use of which of the

following antiseizure medications?
A cenobamate
B fenfluramine
C rufinamide
D vigabatrin
E zonisamide
ARTICLE 11: SURGICAL TREATMENTS FOR EPILEPSY
35 In a patient undergoing evaluation for epilepsy surgery, which of the

following features would be a reason to do intracranial EEG recording?
A cavernous malformation
B hyperreflexia contralateral to the seizure focus
C mesial temporal sclerosis
D prior failure of more than four antiseizure medications
E prior surgical failure

POSTREADING TEST
36 Which of the following adverse results is more common after left

temporal lobe resection than it is after right temporal lobe resection?
A anosmia
B hemiparesis
C hemorrhage
D impaired verbal memory
E superior quadrantanopia
37 Which of the following surgical procedures would be the most

reasonable consideration in a 48-year-old person with drug-resistant
epilepsy who has an epileptogenic zone in the left temporal lobe that is
too close to eloquent cortex to perform anterior temporal lobe
resection or selective amygdalohippocampectomy safely?
A corpus callosotomy
B hemispherectomy
C laser interstitial thermal therapy
D responsive neurostimulation
E stereotactic radiosurgery
38 Which of the following surgical procedures would be the most

reasonable consideration in a 48-year-old person with drug-resistant
epilepsy who has an epileptogenic zone in the left temporal lobe,
another epileptogenic zone in the left frontal lobe, and a third
epileptogenic zone in the right frontal lobe?
A corpus callosotomy
B hemispherectomy
C responsive neurostimulation
D selective amygdalohippocampectomy
E vagus nerve stimulation
ARTICLE 12: MANAGEMENT OF STATUS EPILEPTICUS, REFRACTORY STATUS

EPILEPTICUS, AND SUPER-REFRACTORY STATUS EPILEPTICUS
39 Which of the following treatments is considered the first-choice

treatment for out-of-hospital repetitive seizures or status epilepticus?
A buccal diazepam
B intranasal midazolam
C IV diazepam
D IV midazolam
E rectal diazepam
616 APRIL 2022

40 What is the most prevalent etiology of pediatric new-onset refractory
status epilepticus (NORSE)?
A autoimmune disorders
B congenital brain malformations
C degenerative disorders
D genetic disorders
E infections

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
Responses
By Douglas J. Gelb, MD, PhD, FAAN; James W. M. Owens Jr, MD, PhD
EPILEPSY
Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon
completion of the Postreading Self-Assessment and
CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the University of Calgary Office of Continuing Medical
Education and Professional Development. Refer to the CME tab on
ContinuumJournal.com for dates of accreditation. Canadian participants
should visit MAINPORT (mainport.org) to record learning and outcomes.
Canadian participants can claim a maximum of 20 hours per issue (credits
are automatically calculated).
ARTICLE 1: EVALUATION OF FIRST SEIZURE AND NEWLY DIAGNOSED

EPILEPSY
1 The preferred response is C (at least 60% probability of another seizure

within the next 10 years). According to the 2014 International League
Against Epilepsy (ILAE) definition, a patient meeting any of the following
three criteria has epilepsy: (1) at least two unprovoked (or reflex) seizures
occurring more than 24 hours apart, (2) one unprovoked (or reflex) seizure
and a probability of further seizures similar to the general recurrence risk
618 APRIL 2022

(at least 60%) after two unprovoked seizures, occurring over the next
10 years, or (3) diagnosis of an epilepsy syndrome. For more information,
refer to pages 230-231 of Continuum article “Evaluation of First Seizure
and Newly Diagnosed Epilepsy.”
2 The preferred response is B (focal). All of this patient’s seizures are focal
because they clearly begin in the right hemisphere based on her clinical
symptoms. Some of them evolve to bilateral convulsive activity, but that
does not make them generalized seizures. Because all of her seizures are
focal, her epilepsy is classified as focal epilepsy. Again, the fact that
some of her focal seizures evolve to bilateral convulsive activity does not
change that classification. To be classified as having combined
generalized and focal epilepsy, a person must have some seizures that
are focal and other seizures that are generalized (ie, generalized from
onset). The term idiopathic epilepsy comes from a previous classification
system. It was applied to distinctive, well-defined epilepsy syndromes
with a known or likely genetic mechanism (in that classification system,
this patient’s epilepsy would have been classified as localization-
related). In the current classification system, the term idiopathic
generalized epilepsies refers to a set of four generalized epilepsy
syndromes: childhood absence epilepsy, juvenile absence epilepsy,
juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone.
For more information, refer to page 237 of Continuum article “Evaluation
of First Seizure and Newly Diagnosed Epilepsy.”
3 The preferred response is A (brain MRI). The Commission on

Neuroimaging of the International League Against Epilepsy recommends
that everyone with epilepsy should have a brain MRI, except those with a
clearly defined, drug-responsive idiopathic generalized epilepsy
syndrome or self-limited focal epilepsy of childhood. For more
information, refer to pages 253-254 of Continuum article “Evaluation of
First Seizure and Newly Diagnosed Epilepsy.”
4 The preferred response is A (likelihood 2 times as high as someone with

a normal EEG). An EEG with epileptiform abnormalities is associated with
a relative rate increase for seizure recurrence within 1 to 5 years of 2.16
compared with the rate in patients without EEG abnormalities. For more
information, refer to page 253 of Continuum article “Evaluation of First
Seizure and Newly Diagnosed Epilepsy.”
ARTICLE 2: EEG ESSENTIALS
5 The preferred response is E (postsynaptic potentials in apical dendrites

of layer IV and V pyramidal cells). The currents detected during an EEG

POSTREADING TEST—PREFERRED RESPONSES
recording arise from excitatory and inhibitory postsynaptic potentials in

apical dendrites of layer IV and V pyramidal cells. For more information,
refer to page 263 of the Continuum article, “EEG Essentials.”
6 The preferred response is C (delta, theta, alpha, beta). The frequencies

seen in clinical EEG interpretation are delta (0.5 to less than 4 Hz), theta
(4 to less than 8 Hz), alpha (8 to less than 13 Hz), and beta (13 to 30 Hz).
For more information, refer to pages 266 and 268 of the Continuum
article, “EEG Essentials.”
7 The preferred response is C (Lennox-Gastaut syndrome). EEG

recordings in patients with Lennox-Gastaut syndrome are often
characterized by a diffusely slow background, multifocal independent
spike discharges, and bursts of generalized paroxysmal fast activity. For
more information, refer to page 288 of the Continuum article, “EEG
Essentials.”
ARTICLE 3: NEUROIMAGING OF EPILEPSY
8 The preferred response is D (fluid-attenuated inversion recovery

[FLAIR]). The Neuroimaging Task Force of the International League
Against Epilepsy (ILAE) considers the T1-weighted, FLAIR, and coronal
T2-weighted sequences mandatory for the evaluation of patients with
epilepsy. Contrast-enhanced and susceptibility-weighted (SWI)
sequences are considered optional. For more information, refer to
page 309 of Continuum article “Neuroimaging of Epilepsy.”
9 The preferred response is A (arachnoid cyst in the occipital region). An

arachnoid cyst is usually an incidental finding in patients being evaluated
for possible seizures and can generally be dismissed unless the location
correlates closely with the site that is presumed to be the seizure focus
based on clinical features of the spells or EEG abnormalities. All of the
other listed brain lesions are frequently epileptogenic. For more
information, refer to pages 311-312 of Continuum article “Neuroimaging of
Epilepsy.”
10 The preferred response is B (autoimmune glial fibrillary acidic protein

[GFAP] astrocytopathy). The characteristic MRI finding in autoimmune
GFAP astrocytopathy is diffuse perivascular enhancement radiating out
from the lateral ventricles. For more information, refer to pages 324 and
326 of Continuum article “Neuroimaging of Epilepsy.”
620 APRIL 2022

ARTICLE 4: GENETIC EPILEPSY SYNDROMES
11 The preferred response is A (childhood absence epilepsy). This

patient’s events, EEG, and normal neurologic examination would all
strongly support the diagnosis of childhood absence epilepsy. For more
information, refer to page 342 of the Continuum article “Genetic
Epilepsy Syndromes.”
12 The preferred response is E (myoclonic-atonic epilepsy). Although

treatment with the ketogenic diet is often considered for many types of
medically refractory epilepsy, it is only considered early in the treatment
protocol in a few epilepsies, including myoclonic-atonic epilepsy,
because of the demonstrated efficacy of the diet in this condition,
which far exceeds that which would be expected with trials of a second
or third medication. For more information, refer to page 352 of the
Continuum article “Genetic Epilepsy Syndromes.”
13 The preferred response is B (GRIN2A). This patient’s presentation is

most consistent with atypical childhood epilepsy with centrotemporal
spikes, a condition in which some patients have been reported with
pathogenic variants in GRIN2A. Mutations in CHRNA2 are associated
with sleep-related hypermotor epilepsy. KCNQ2 mutations can cause,
among other conditions, self-limited infantile epilepsy. SCN1A mutations
can cause Dravet syndrome whereas mutations in SLC2A1 cause the
conditions associated with GLUT1 deficiency including myoclonic-atonic
epilepsy. For more information, refer to page 348 of the Continuum
article “Genetic Epilepsy Syndromes.”
14 The preferred response is C (fenfluramine). This patient’s presentation

is highly suggestive of Dravet syndrome, and recent evidence
suggests the utility of fenfluramine as an antiseizure medication in these
patients. For more information, refer to page 351 of the Continuum
article “Genetic Epilepsy Syndromes.”
ARTICLE 5: AUTOIMMUNE-ASSOCIATED SEIZURES
15 The preferred response is D (leucine-rich glioma inactivated 1 [LGI1]).

The description of these spells is typical of faciobrachial dystonic
seizures, which are the most characteristic type of seizures that occur in
patients with seizures associated with anti-LGI1 encephalitis, although
they occur in fewer than 50% of people with that condition. For more
information, refer to pages 366 and 368 of Continuum article
“Autoimmune-Associated Seizures.”

16 The preferred response is E (N-methyl-D-aspartate [NMDA] receptor).

The “extreme delta brush” pattern, consisting of generalized rhythmic
delta activity with superimposed 1- to 2-second bursts of low-
amplitude, high-frequency (beta or gamma) activity, is a characteristic
EEG finding in patients with anti–NMDA receptor encephalitis, but it is
present in at most 30% of people with this disorder. For more
information, refer to page 369 of Continuum article “Autoimmune-
Associated Seizures.”
17 The preferred response is B (dipeptidyl-peptidase–like protein 6

[DPPX]). The most common presentation of anti-DPPX encephalitis is
with a triad of weight loss/gastrointestinal symptoms, limbic symptoms,
and central nervous system hyperexcitability (seizures, myoclonus,
hyperekplexia, or tremor). For more information, refer to page 376 of
Continuum article “Autoimmune-Associated Seizures.”
18 The preferred response is B (hemispheric disconnection surgery).

Hemispheric disconnection surgery can result in seizure freedom in 60%
to 85% of people with Rasmussen encephalitis. Immunotherapy is
inconsistently effective. The seizures are often refractory to traditional
antiseizure medications, and patients who have not achieved seizure
control with adequate trials of four antiseizure medications are unlikely
to have a response to a different one. For more information, refer to
pages 380-381 of Continuum article “Autoimmune-Associated Seizures.”
ARTICLE 6: WOMEN’S ISSUES IN EPILEPSY
19 The preferred response is E (no difference in time to pregnancy). In the

first-ever observational cohort group study discussed in this article, no
difference was found between women with epilepsy and controls in
measures of fertility including in the time to pregnancy. For more
information, refer to page 404 of the Continuum article, “Women’s
Issues in Epilepsy.”
20 The preferred response is E (zonisamide). Of the medications

mentioned, only zonisamide has no effect on and is unaffected by
hormonal oral contraceptives. Clobazam, oxcarbazepine, and
rufinamide decrease both ethinylestradiol and progestins whereas
perampanel decreases just progestins. For more information, refer to
page 410 of the Continuum article, “Women’s Issues in Epilepsy.”
21 The preferred response is B (levetiracetam). Levetiracetam has a

relatively low risk of major congenital malformations whereas
622 APRIL 2022

carbamazepine, phenobarbital, phenytoin, and topiramate all carry an
intermediate risk. For more information, refer to page 411 of the
Continuum article, “Women’s Issues in Epilepsy.”
ARTICLE 7: SEIZURES AND EPILEPSY IN CHILDHOOD
22 The preferred response is C (hypoxic-ischemic encephalopathy).

Hypoxic-ischemic encephalopathy is the most common underlying
cause of neonatal seizures, accounting for 35% to 45%. For more
information, refer to page 438 of the Continuum article “Seizures and
Epilepsy in Childhood.”
23 The preferred response is B (focal seizure onset). Most children who

experience febrile seizures do not develop epilepsy. The risk of
developing epilepsy is greater when a child has a family history of
epilepsy or preexisting neurologic abnormalities or when the febrile
seizure is complex (focal onset, duration longer than 15 minutes, or
multiple seizures within 24 hours of the fever). For more information,
refer to page 439 of the Continuum article “Seizures and Epilepsy
in Childhood.”
24 The preferred response is C (nocturnal generalized tonic-clonic

seizures). Nocturnal generalized tonic-clonic seizures are a significant
risk factor for sudden unexpected death in epilepsy (SUDEP). For more
information, refer to pages 446-447 of the Continuum article “Seizures
and Epilepsy in Childhood.”
25 The preferred response is E (vigabatrin and adrenocorticotropic

hormone [ACTH]). Vigabatrin and hormonal therapy (steroids or ACTH)
are first-line treatments for infantile spasms, and the combination is
significantly more effective than hormonal therapy alone. For more
information, refer to page 447 of the Continuum article “Seizures and
Epilepsy in Childhood.”
ARTICLE 8: NEUROPSYCHIATRIC AND COGNITIVE COMORBIDITIES IN

EPILEPSY
26 The preferred response is B (oxcarbazepine). Drugs that act primarily on

the voltage-gated sodium channel such as oxcarbazepine are
associated with a very low risk of psychiatric side effects. For more
information, refer to page 462 of the Continuum article,
“Neuropsychiatric and Cognitive Comorbidities in Epilepsy.”

27 The preferred response is E (risperidone). Balancing efficacy and side

effects, olanzapine, quetiapine, and risperidone are considered first-
line treatments for patients with epilepsy who experience a first
episode of psychosis. For more information, refer to pages 465-466 of
the Continuum article, “Neuropsychiatric and Cognitive Comorbidities
in Epilepsy.”
28 The preferred response is B (improved attention in the majority of

patients). Use of stimulant medication in children with epilepsy is
associated with response rates of 65% to 83% without evidence of
increased risk of seizures or clinically relevant drug-drug interactions.
For more information, refer to page 466 of the Continuum article,
“Neuropsychiatric and Cognitive Comorbidities in Epilepsy.”
ARTICLE 9: APPROACH TO THE MEDICAL TREATMENT OF EPILEPSY
29 The preferred response is E (new antiseizure medications are usually

first tested for efficacy as adjunctive treatment in people with drug-
resistant epilepsy). For ethical reasons, new antiseizure medications
are usually first tested for efficacy as adjunctive treatment in people
with drug-resistant epilepsy so that every study participant will receive
at least one antiseizure medication that is known to be effective. As a
result, the initial licensure for a new antiseizure medication is usually as
adjunctive (add-on) treatment rather than monotherapy. Once
adjunctive efficacy has been demonstrated, it is easier to design ethical
studies in which the new antiseizure medication is used as
monotherapy. For more information, refer to page 484 of the
Continuum article “Approach to the Medical Treatment of Epilepsy.”
30 The preferred response is D (valproate). Ethosuximide is the preferred

drug for patients with childhood absence epilepsy; valproate has
similar efficacy, but it is less well tolerated. Ethosuximide is probably
ineffective for generalized tonic-clonic seizures, however, so for
patients with both typical absence seizures and generalized tonic-
clonic seizures, valproate is the preferred drug. For more information,
refer to page 490 of the Continuum article “Approach to the Medical
Treatment of Epilepsy.”
31 The preferred response is D (topiramate). Lamotrigine, levetiracetam,

perampanel, and topiramate have demonstrated efficacy as adjunctive
treatments for primary generalized tonic-clonic seizures not controlled
by a first or alternative monotherapy. For more information, refer to
pages 493 to 494 of the Continuum article “Approach to the Medical
Treatment of Epilepsy.”
624 APRIL 2022

ARTICLE 10: UPDATE ON ANTISEIZURE MEDICATIONS 2022
32 The preferred response is C (blocking sodium channels). Cenobamate

acts by blocking sodium channels and enhancing γ-aminobutyric acid
(GABA) activity. For more information, refer to page 527 of the
Continuum article, “Update on Antiseizure Medications 2022.”
33 The preferred response is C (increased clobazam metabolite levels).

Cannabidiol increases the concentration of N-desmethylclobazam, which
can result in somnolence. For more information, refer to pages 526-527 of
the Continuum article, “Update on Antiseizure Medications 2022.”
34 The preferred response is D (vigabatrin). Vigabatrin is associated with

permanent visual field restriction in a sizable minority of patients. For
more information, refer to page 525 of the Continuum article, “Update
on Antiseizure Medications 2022.”
ARTICLE 11: SURGICAL TREATMENTS FOR EPILEPSY
35 The preferred response is E (prior surgical failure). Indications for

intracranial EEG recording as a component of the presurgical evaluation
include proximity of the seizure-onset zone to eloquent cortex, lesions
with poorly defined borders, multiple lesions, discordant test results or
another source of uncertainty about the seizure-onset zone, and prior
history of surgical failure. For more information, refer to page 541 of the
Continuum article “Surgical Treatments for Epilepsy.”
36 The preferred response is D (impaired verbal memory). Verbal memory

deficits are more common after left temporal lobe resection than after
right temporal lobe resection; superior quadrantanopia is common
after both (occurring in about 50% of cases). For more information, refer
to pages 545 and 548 of the Continuum article “Surgical Treatments for
Epilepsy.”
37 The preferred response is D (responsive neurostimulation). In a

patient whose epileptogenic zone is too close to eloquent cortex to
perform anterior temporal lobe resection or selective
amygdalohippocampectomy safely, other procedures intended to
ablate or resect the epileptogenic zone would also be unsafe. This
situation is one of the indications for pursuing responsive
neurostimulation. For more information, refer to page 553 of the
Continuum article “Surgical Treatments for Epilepsy.”

38 The preferred response is E (vagus nerve stimulation). Vagus nerve

stimulation is an option for treating drug-resistant epilepsy in patients
who have multiple epileptogenic zones and therefore are not
candidates for resection, ablation, or responsive neurostimulation. For
more information, refer to pages 554-555 of the Continuum article
“Surgical Treatments for Epilepsy.”
ARTICLE 12: MANAGEMENT OF STATUS EPILEPTICUS, REFRACTORY

STATUS EPILEPTICUS, AND SUPER-REFRACTORY STATUS EPILEPTICUS
39 The preferred response is B (intranasal midazolam). Intranasal or

buccal midazolam is regarded as the first-choice treatment for
out-of-hospital repetitive seizures or status epilepticus given the ease
of use, pharmacokinetics, and efficacy. For more information, refer to
pages 568-569 of the Continuum article, “Management of Status
Epilepticus, Refractory Status Epilepticus, and Super-refractory
Status Epilepticus.”
40 The preferred response is E (infections). The most prevalent etiology

for cases of pediatric new-onset refractory status epilepticus (NORSE)
is infections whereas for noncryptogenic adult NORSE it is autoimmune
encephalitis. For more information, refer to page 583 of the Continuum
article, “Management of Status Epilepticus, Refractory Status
Epilepticus, and Super-refractory Status Epilepticus.”
626 APRIL 2022

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives ◆ Discuss the spectrum of efficacy, clinical

pharmacology, and modes of use for individual
Upon completion of this Continuum: Lifelong antiseizure medications
Learning in Neurology Epilepsy issue, participants
will be able to: ◆ Define drug-resistant epilepsy and discuss current
diagnostic tools for presurgical evaluation and current
◆ Distinguish new-onset seizures from nonepileptic evidence for surgical epilepsy therapies for patients
events and choose comprehensive but cost-effective with drug-resistant epilepsy
investigations for patients with new-onset seizures,
taking into account epilepsy type, syndrome, ◆ Integrate the presented process of management of
comorbidities, and probable etiology, to optimize status epilepticus into existing standard operating
treatment and clarify long-term prognosis procedures, evaluate the potential risks and benefits
of treatments, and create a care plan for patients with
status epilepticus
◆ Describe the essential features involved in recording
and interpreting EEG and recognize classic EEG
findings in patients with chronic epilepsy, as well
as the common EEG patterns found in critically ill Core Competencies
patients with acute neurologic disease
This Continuum: Lifelong Learning in Neurology
◆ Describe the principal structural and functional Epilepsy issue covers the following core
imaging modalities used in the diagnosis and
competencies:
evaluation of patients with epilepsy and discuss
the indications for their use at different stages of an
epilepsy evaluation ◆ Patient Care
◆ Discuss the clinical and electrographic features of ◆ Medical Knowledge

epilepsy syndromes thought to occur primarily due
to genetic factors and the known genetic factors ◆ Practice-Based Learning and Improvement
associated with specific phenotypes
◆ Interpersonal and Communication Skills
◆ Identify clinical features suggesting an autoimmune
etiology of the cause of seizures, use clinical scoring ◆ Professionalism
systems to aid diagnosis in autoimmune seizure
disorders, and initiate first-line treatments in patients ◆ Systems-Based Practice
with acute symptomatic seizures secondary to
autoimmune encephalitis
◆ Describe best practices in the management of women

with epilepsy, incorporating up-to-date evidence in
sex- and gender-specific issues including transgender
care, catamenial epilepsy, contraception, pregnancy,
infertility, and aging
◆ Discuss the basic concepts of childhood-onset

epilepsy and the diagnostic and therapeutic aspects
and specific considerations in this age group
◆ Discuss psychiatric and cognitive comorbidities of

epilepsy over the lifespan and identify opportunities
to improve the quality of care of patients with epilepsy
◆ Describe a general evidence-based approach to the

use of antiseizure medications in the treatment of
focal and generalized epilepsies
220 APRIL 2022

LIST OF ABBREVIATIONS
Epilepsy GPD Generalized periodic discharges

GRE Gradient recalled echo
HARNESS-MRI Harmonized Neuroimaging of Epilepsy Structural
Sequences
TC-HMPAO Technetium 99m–hexamethylpropyleneamine oxime
99m
HIV Human immunodeficiency virus
ACES Antibodies Contributing to Focal Epilepsy Signs ICD-9-CM International Classification of Diseases, Ninth Revision,
and Symptoms Clinical Modification
ACTH Adrenocorticotropic hormone ICD-10 International Classification of Diseases, Tenth Revision
ADEM Acute disseminated encephalomyelitis ICU Intensive care unit
ADHD Attention deficit hyperactivity disorder IgG Immunoglobulin G
ALT Alanine transaminase ILAE International League Against Epilepsy
AMPA a-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid IM Intramuscular
APE Antibody Prevalence in Epilepsy IQ Intelligence quotient
APE2 Antibody Prevalence in Epilepsy and Encephalopathy IUD Intrauterine device
APR Australian Pregnancy Register IV Intravenous
AST Aspartate transaminase JME Juvenile myoclonic epilepsy
BIRD Brief potentially ictal rhythmic discharge LGI1 Leucine-rich glioma inactivated protein 1
CASPR2 Contactin-associated proteinlike 2 LITT Laser interstitial thermal therapy
CBT Cognitive behavioral therapy LPD Lateralized periodic discharges
CI Confidence interval LPD+F Lateralized periodic discharges plus fast activity
CNS Central nervous system MCV Mean corpuscular volume
CSF Cerebrospinal fluid MED Magnetoencephalography
CT Computer tomography MEG Magnetoencephalography
CYP Cytochrome P450 mGluR5 Metabotropic glutamate receptor 5
DBS Deep brain stimulation MONEAD Maternal Outcomes and Neurodevelopmental Effects
DLB Dementia with Lewy bodies of Antiepileptic Drugs
DPPX Dipeptidyl-peptidase–like protein 6 MRI Magnetic resonance imaging
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, mTOR Mammalian target of rapamycin
Fifth Edition MVNT Multinodular and vacuolating neuronal tumor
DTI Diffusion tensor imaging NAAPR North American Antiepileptic Drug Pregnancy Registry
DWI Diffusion-weighted imaging NEAD Neurodevelopmental Effects of Antiepileptic Drugs
ECG Electrocardiogram NMDA N-methyl-
-methyl-D-aspartate
ED Emergency department NORSE New-onset refractory status epilepticus
EEG Electroencephalography PCR Polymerase chain reaction
ELISA Enzyme-linked immunosorbent assays PET Positron emission topography
EMS Emergency medical services PLED Periodic lateralized discharge
EMSE Epidemiology-Based Mortality Score in Status PNES Psychogenic nonepileptic seizures
Epilepticus
REM Rapid eye movement
EURAP European Registry of Antiepileptic Drugs
and Pregnancy RITE Response to Immunotherapy in Epilepsy
FDA US Food and Drug Administration RNS Responsive neurostimulation
FDG-PET Fludeoxyglucose positron emission tomography SIRPID Stimulus-induced rhythmic, periodic, or ictal
discharges
FIRDA Frontal intermittent rhythmic delta activity
SNALE Seronegative autoimmune limbic encephalitis
FIRES Febrile infection-related epilepsy syndrome
SNRI Selective norepinephrine reuptake inhibitor
FLAIR Fluid-attenuated inversion recovery
SPECT Single-photon emission computed tomography
fMRI Functional magnetic resonance imaging
SSRI Selective serotonin reuptake inhibitor
FTD Frontotemporal dementia
SUDEP Sudden unexpected death in epilepsy
GABA γ-Aminobutyric
-Aminobutyric acid
SV40 Simion virus 40
GABA-ergic γ-Aminobutyric
-Aminobutyric acid–mediated
SWI Susceptibility-weighted imaging
GAD65 Glutamic acid decarboxylase 65
TIRDA Temporal intermittent rhythmic delta activity
GEFS+ Genetic epilepsy with febrile seizures plus
VNS Vagus nerve stimulation
GFAP Glial fibrillary acidic protein
GLUT1 Glucose transporter type 1
© 2022 American Academy of Neurology.

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APRIL 2022

VOL. 28 NO. 2 Epilepsy

228 Editor’s Preface

230 Evaluation of First Seizure and Newly Diagnosed Epilepsy

261 EEG Essentials

306 Neuroimaging of Epilepsy

339 Genetic Epilepsy Syndromes

363 Autoimmune-Associated Seizures

399 Women’s Issues in Epilepsy

428 Seizures and Epilepsy in Childhood

457 Neuropsychiatric and Cognitive Comorbidities in Epilepsy

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

536 Surgical Treatments for Epilepsy

559 Management of Status Epilepticus, Refractory Status Epilepticus,

SELF-ASSESSMENT AND CME

220 Learning Objectives and Core Competencies

603 Instructions for Completing Postreading Self-Assessment and CME

605 Postreading Self-Assessment and CME Test

618 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Nathalie Jetté, MD, MSc, Francesco Brigo, MD

222 APRIL 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Barbara C. Jobst, MD, Dr Med, Markus Leitinger, MD, MSc

Unlabeled Use of Products/Investigational

224 APRIL 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Eugen Trinka, MD, MSc, FRCP Sarah J. Wilson, PhD, FAHMS,

226 APRIL 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Self-Assessment and CME Test Writers

Douglas J. Gelb, MD, PhD, James W. M. Owens Jr, MD, PhD

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

An Ictal and Interictal Continuum

228 APRIL 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

RECENT FINDINGS: New-onset seizures are a common presentation in neurologic

SUMMARY: Accurate diagnosis and classification of first seizures and

Address correspondence to INTRODUCTION

230 APRIL 2022

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 1-1 Common Seizure Mimics

Epilepsy mimic Clinical clues

Occurs in sleep only and abolished on waking

Otherwise normal infant

Often spreads in nonanatomic pattern

Otherwise normal infant

Often provoked by excitement or frustration

Otherwise normal infant

Breath-holding spells, Triggered by pain, crying, fright

Associated color change (cyanotic or pallid)

Often seen in neurologically abnormal children

Caused by gastroesophageal reflux

Hyperekplexia Infants are hypertonic but not spastic

CONTINUED ON PAGE 233

232 APRIL 2022

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