Continuum: Lifelong Learning in Neurology—Epilepsy, Volume 22, Issue 1, February 2016

Issue Overview

Epilepsy February 2016;22(1)

Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay

abreast of advances in the field while simultaneously developing lifelong self-directed learning

skills.

Learning Objectives

► Accurately diagnose epilepsy in view of the new practical definition and distinguish epileptic seizures
from other episodic disorders by history, examination, and appropriate application of
electroencephalographic and imaging investigations

► Assess patients presenting with their first seizure, determine their risk of having a second seizure, and
use this information to guide treatment decisions

► Discuss the epidemiology, causes, and management of febrile seizures

► Recognize common electroclinical syndromes in children and understand how these guide
investigations and therapy

► Describe the common seizure presentations, etiologies, EEG patterns, and imaging findings associated
with focal epilepsy

► Describe the diagnostic evaluation and management for patients with nonepileptic seizures

► Discuss the spectrum of efficacy, clinical pharmacology, and modes of use for individual antiepileptic
drugs

► Discuss the evaluation of a patient with drug-resistant epilepsy and recognize the role and indications
for surgical and nonsurgical options for patients with drug-resistant epilepsy

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

► Recognize and manage epilepsy emergencies

► Describe the common comorbid conditions that occur in individuals with seizures and epilepsy and
outline the key management options and strategies for mitigating these conditions to maximize quality of
life

► Counsel women with epilepsy on how seizures and antiepileptic drug treatment relate to their
reproductive health and reproductive outcomes

► Recognize and treat inflammatory causes of seizures and epilepsy

► Recognize the challenges in epilepsy treatment specific to patients over 60 years of age and potential
etiologies for seizures in the setting of an immunocompromised patient, and discuss issues related to bone
health in patients with epilepsy

► Identify ethical principles raised by a parent’s request for a prescription that is not the recommended
medical treatment for a child

► Discuss cultural barriers that contribute to medication nonadherence in patients with epilepsy

Core Competencies
The Continuum Headache issue covers the following core competencies:

► Patient Care and Procedural Skills

► Medical Knowledge

► Practice-Based Learning and Improvement

► Interpersonal and Communication Skills

► Professionalism

► Systems-Based Practice

Disclosures
CONTRIBUTORS

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Lara Jehi, MD, Guest Editor
Director of Research, Cleveland Clinic Epilepsy Center, Cleveland, Ohio
a
Dr Jehi has served as a reviewer for the Acute Neural Injury and Epilepsy (ANIE) Study Section, as a consultant
for the National Institute of Neurological Disorders and Stroke, and as a guest editor for Neurotherapeutics. Dr Jehi
has received research support from the National Center for Advancing Translational Sciences (NCATS) and UCB,
Inc.
b
Dr Jehi reports no disclosure.

Bassel W. Abou-Khalil, MD, FAAN

Professor of Neurology, Director, Epilepsy Division, Vanderbilt University Medical Center,
Nashville, Tennessee
a
Dr Abou-Khalil has served on the editorial boards of Clinical Neurophysiology and Epilepsy Research and
received royalties from Elsevier Inc.
b
Dr Abou-Khalil discusses the unlabeled/investigational use of primidone for the treatment of essential tremor,
valproate for the treatment of generalized myoclonic and generalized tonic-clonic seizures, gabapentin for the
treatment of headache and sleep disorders, lamotrigine as a first-line treatment for epilepsy, and zonisamide as
initial monotherapy for epilepsy.

Christopher T. Anderson, MD
Assistant Professor, Department of Neurology, Medical College of Wisconsin, Milwaukee,
Wisconsin
a
Dr Anderson reports no disclosure.
b
Dr Anderson discusses the use and/or initiation of antiepileptic drugs for special populations, several of which are
US Food and Drug Administration approved for adjunctive therapy for seizures but not for initial monotherapy.

Gregory K. Bergey, MD, FAAN

Professor of Neurology, Johns Hopkins School of Medicine, Director, Johns Hopkins Epilepsy
Center, Baltimore, Maryland
a
Dr Bergey has received personal compensation for serving as an associate editor of Neurotherapeutics and has
received research support from the National Institutes of Health.
b
Dr Bergey reports no disclosure.

Jeffrey R. Buchhalter, MD, PhD, FAAN

Professor, Paediatrics and Clinical Neurosciences, Director, Children’s Comprehensive Epilepsy
Centre, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
a
Dr Buchhalter has served as a consultant for Eisai Co, Ltd, and Upsher-Smith Laboratories, Inc, and receives
research support from the Alberta Children’s Hospital Foundation.
b
Dr Buchhalter reports no disclosure.

Chad Carlson, MD
Associate Professor of Neurology, Medical College of Wisconsin,
Milwaukee, Wisconsin
a
Dr Carlson reports no disclosure.
b
Dr Carlson discusses the use and/or initiation of antiepileptic drugs for special populations, several of which are
US Food and Drug Administration approved for adjunctive therapy for seizures but not for initial monotherapy.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Gregory D. Cascino, MD, FAAN
Whitney MacMillan Junior Professor of Neuroscience, Mayo Clinic College of Medicine, Mayo
Clinic, Rochester, Minnesota
a
Dr Cascino serves on the board of directors of the American Academy of Neurology and as an associate editor of
Neurology. Dr Cascino receives royalties from Mayo Medical Ventures and UpToDate, Inc.
b
Dr Cascino reports no disclosure.

David K. Chen, MD
Assistant Professor of Neurology, Baylor College of Medicine, Houston, Texas; Codirector,
Houston Epilepsy Center of Excellence, Michael E. DeBakey VA Medical Center, Houston,
Texas
a,b
Dr Chen reports no disclosures.

Daniel Friedman, MD, MSc

Assistant Professor (Clinical) of Neurology, New York University Langone School of Medicine,
New York, New York
a
Dr Friedman serves on the physician advisory board of the Epilepsy Foundation, on the editorial board of
Epilepsy.com, and as a consultant for Cyberonics, Inc. Dr Friedman has received personal compensation for
speaking engagements from the American College of Veterinary Internal Medicine and paid travel
accommodations/meeting expenses from Alexza Pharmaceuticals. Dr Friedman receives royalties from Oxford
University Press and research support from the Centers for Disease Control and Prevention, the Epilepsy
Foundation, the National Institute of Neurological Disorders and Stroke, and UCB, Inc.
b
Dr Friedman reports no disclosure.

Nicolas Gaspard, MD, PhD

Associate Professor, Department of Neurology, Hôpital Erasme, Université de Bruxelles,
Brussels, Belgium; Assistant Professor (Adjunct), Department of Neurology, Yale University
School of Medicine, New Haven, Connecticut
a
Dr Gaspard receives royalties from UpToDate, Inc, and Wolters Kluwer and research support from Fonds Erasme
Pour la Recherche Médicale and the Belgian National Fund for Scientific Research.
b
Dr Gaspard discusses the unlabeled/investigation use of steroids, IV immunoglobulins, plasma exchange,
tacrolimus, natalizumab, rituximab, and cyclophosphamide for the treatment of autoimmune encephalitis.

Elizabeth E. Gerard, MD
Associate Professor of Neurology, Northwestern University, Feinberg School of Medicine,
Chicago, Illinois
a
Dr Gerard has received honoraria from the American College of Physicians and research support from the
National Institute of Neurological Disorders and Stroke and SAGE Pharmaceuticals. Dr Gerard has served as a
research consultant on a trial sponsored by UCB, Inc.
b
Dr Gerard reports no disclosure.

Ajay Gupta, MD
Head, Pediatric Epilepsy/Neurological Institute, Associate Professor, Cleveland Clinic Lerner
College of Medicine, Cleveland, Ohio
a
Dr Gupta has served on the advisory board of Lundbeck and has received research support from the Tuberous
Sclerosis Alliance for the Natural History Database Study.
b
Dr Gupta discusses the unlabeled/investigational use of benzodiazepines for the treatment of febrile seizures.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Stephen Hantus, MD
Neurology Staff, Director of cEEG and Epilepsy Consult Service, Cleveland Clinic Epilepsy
Center, Cleveland, Ohio
a,b
Dr Hantus reports no disclosures.

Anna D. Hohler, MD, FAAN

Associate Professor of Neurology; Assistant Dean, Office of Academic Affairs, Boston
University Medical Campus, Boston, Massachusetts
a,b
Dr Hohler reports no disclosures.

W. Curt LaFrance Jr, MD, MPH, FAAN, FANPA, DFAPA

Associate Professor of Psychiatry and Neurology, Brown University, Providence, Rhode Island;
Director, Neuropsychiatry and Behavioral Neurology, Rhode Island Hospital, Providence, Rhode
Island
a
Dr LaFrance serves on the Epilepsy Foundation Professional Advisory Board; has served as a clinic development
consultant for the Cleveland Clinic, Emory University, Spectrum Health, and the University of Colorado Denver;
and has provided expert medicolegal testimony. Dr LaFrance receives royalties from Cambridge University Press
and Oxford University Press and has received research support from the American Epilepsy Society, the Epilepsy
Foundation, the Matthew Siravo Memorial Foundation Inc, the National Institutes of Health, and Rhode Island
Hospital.
b
Dr LaFrance reports no disclosure.

Kimford J. Meador, MD, FAAN

Professor of Neurology and Neurological Sciences, Stanford University, Stanford, California
a
Dr Meador serves as a consultant for the Epilepsy Study Consortium and on the editorial boards of Epilepsy and
Behavior, Journal of Clinical Neurophysiology, and Neurology. Dr Meador has received travel, meeting, and
accommodation compensation from UCB, Inc, and receives research support from the National Institute of
Neurological Disorders and Stroke and the Patient-Centered Outcomes Research Institute.
b
Dr Meador reports no disclosure.

Jill Miller-Horn, MD, MS

Assistant Professor of Neurology and Pediatrics, Stony Brook University, Stony Brook, New
York
a,b
Dr Miller-Horn reports no disclosures.

Georgia Montouris, MD
Associate Clinical Professor of Neurology, Director of Epilepsy Services, Boston Medical
Center, Boston University School of Medicine, Boston, Massachusetts
a
Dr Montouris serves on the expert panel for the UCB Antiepileptic Drugs Pregnancy Registry and on the scientific
advisory boards of Acorda Therapeutics; Eisai Co, Ltd; Lundbeck; and Upsher-Smith Laboratories, Inc.
b
Dr Montouris reports no disclosure.

Dileep R. Nair, MD
Head of Adult Epilepsy, Cleveland Clinic, Cleveland, Ohio
a
Dr Nair serves as a consultant for Brain Sentinel and has received personal compensation for speaking
engagements from NeuroPace, Inc.
b
Dr Nair discusses the unlabeled/investigational use of cannabinoids in the treatment of epilepsy.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Marc R. Nuwer, MD, PhD, FAAN
Professor and Vice Chair of Clinical Neurology, David Geffen School of Medicine at University
of California, Los Angeles, Los Angeles, California
a
Dr Nuwer has received personal compensation for speaking engagements from the American Clinical
Neurophysiology Society and the Virginia Commonwealth University, serves as a consultant for CortiCare, Inc, and
has provided expert legal testimony. Dr Nuwer receives royalties from Cambridge University Press and research
support from the National Institutes of Health and the US Army.
b
Dr Nuwer reports no disclosure.

Joseph I. Sirven, MD, FAAN

Professor and Chairman, Department of Neurology, Mayo Clinic, Phoenix, Arizona
a
Dr Sirven serves on the advisory board of Upsher-Smith Laboratories, Inc; on the data safety monitoring board of
Acorda Therapeutics; and as a consultant for the Epilepsy Foundation. Dr Sirven receives research support from
NeuroPace, Inc.
b
Dr Sirven reports no disclosure.

Christopher T. Skidmore, MD
Assistant Professor of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania
a
Dr Skidmore serves as a consultant for Upsher-Smith Laboratories, Inc, and has received research support from
NeuroPace, Inc.
b
Dr Skidmore reports no disclosure.

Erik K. St. Louis, MD, MS, FAAN

Associate Professor of Neurology, Associate Dean, Mayo School of Continuous Professional
Development, Mayo Clinic, Rochester, Minnesota
a
Dr St. Louis receives research support from the Mayo Foundation and the National Institutes of Health.
b
Dr St. Louis reports no disclosure.

Korwyn Williams, MD, PhD

Section Chief, Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital,
Phoenix, Arizona; Clinical Assistant Professor, Department of Child Health, University of
Arizona, Phoenix Arizona; Assistant Professor of Neurology, College of Medicine, Mayo Clinic,
Scottsdale, Arizona
a,b
Dr Williams reports no disclosures.

Elaine Wirrell, MD
Director of Pediatric Epilepsy, Professor of Epilepsy and Child and Adolescent Neurology,
Mayo Clinic, Rochester, Minnesota
a
Dr Wirrell receives royalties from UpToDate, Inc, and research support from the American Epilepsy Society
Infrastructure Award and the Dravet Syndrome Foundation.
b
Dr Wirrell reports no disclosure.

D. Joanne Lynn, MD, FAAN

Associate Dean for Student Life and Clinical Professor of Neurology, The Ohio State University
College of Medicine, Columbus, Ohio
a
Dr Lynn receives book royalties from Lippincott Williams & Wilkins and holds stock in Abbott Laboratories,
Bristol-Myers Squibb Company, Corning Incorporated, Express Scripts Holding Company, General Electric,
Hospira, Inc, and Varian Medical Systems, Inc.
b
Dr Lynn reports no disclosure.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

James W. M. Owens Jr, MD, PhD
Associate Professor of Neurology and Adjunct Associate Professor of Pediatrics, University of
Washington, Seattle, Washington
a
Dr Owens receives personal compensation for medicolegal record review and royalties from UpToDate, Inc.
b
Dr Owens reports no disclosure.

a
Relationship Disclosure
b
Unlabeled Use of Products/Investigational Use Disclosure

Methods of Participation and Instructions for Use

Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay

abreast of advances in the field while simultaneously developing lifelong self-directed learning

skills. In Continuum, the process of absorbing, integrating, and applying the material presented is

as important as, if not more important than, the material itself.

The goals of Continuum include disseminating up-to-date information to the practicing

neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;

encouraging critical thinking; and, in the final analysis, strengthening and improving patient

care.

Each Continuum issue is prepared by distinguished faculty who are acknowledged leaders in

their respective fields. Six issues are published annually and are composed of review articles,

case-based discussions on ethical and practice issues related to the issue topic, coding

information, , and comprehensive CME and self-assessment offerings, including a self-

assessment pretest, multiple-choice questions with preferred responses, and a patient

management problem. For detailed instructions regarding Continuum CME and self-assessment

activities, visit aan.com/continuum/cme.

The review articles emphasize clinical issues emerging in the field in recent years. Case reports

and vignettes are used liberally, as are tables and illustrations. Video material relating to the

issue topic accompanies issues when applicable.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

The text can be reviewed and digested most effectively by establishing a regular schedule of

study in the office or at home, either alone or in an interactive group. If subscribers use such

regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns

can be met.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 LIFELONG LEARNING IN NEUROLOGY ®

Epilepsy
Volume 22 Number 1 February 2016

CONTRIBUTORS
Lara Jehi, MD, Guest Editor
Director of Research, Cleveland Clinic Epilepsy Center, Cleveland, Ohio
aDr Jehi has served as a reviewer for the Acute Neural Injury and Epilepsy (ANIE) Study Section,
as a consultant for the National Institute of Neurological Disorders and Stroke, and as a guest
editor for Neurotherapeutics. Dr Jehi has received research support from the National Center
for Advancing Translational Sciences (NCATS) and UCB, Inc.
bDr Jehi reports no disclosure.

Bassel W. Abou-Khalil, MD, FAAN

Professor of Neurology, Director, Epilepsy Division, Vanderbilt University Medical
Center, Nashville, Tennessee
aDr Abou-Khalil has served on the editorial boards of Clinical Neurophysiology and Epilepsy
Research and received royalties from Elsevier Inc.
bDr Abou-Khalil discusses the unlabeled/investigational use of primidone for the treatment
of essential tremor, valproate for the treatment of generalized myoclonic and generalized
tonic-clonic seizures, gabapentin for the treatment of headache and sleep disorders,
lamotrigine as a first-line treatment for epilepsy, and zonisamide as initial monotherapy
for epilepsy.

Christopher T. Anderson, MD
Assistant Professor, Department of Neurology, Medical College of Wisconsin,
Milwaukee, Wisconsin
aDr Anderson reports no disclosure.
bDr Anderson discusses the use and/or initiation of antiepileptic drugs for special
populations, several of which are US Food and Drug Administration approved for
adjunctive therapy for seizures but not for initial monotherapy.

Gregory K. Bergey, MD, FAAN

Professor of Neurology, Johns Hopkins School of Medicine, Director,
Johns Hopkins Epilepsy Center, Baltimore, Maryland
aDr Bergey has received personal compensation for serving as an associate editor of
Neurotherapeutics and has received research support from the National Institutes of Health.
bDr Bergey reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2016;22(1) www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Jeffrey R. Buchhalter, MD, PhD, FAAN
Professor, Paediatrics and Clinical Neurosciences, Director, Children’s
Comprehensive Epilepsy Centre, Cumming School of Medicine,
University of Calgary, Calgary, Alberta, Canada
aDr Buchhalter has served as a consultant for Eisai Co, Ltd, and Upsher-Smith Laboratories,
Inc, and receives research support from the Alberta Children’s Hospital Foundation.
bDr Buchhalter reports no disclosure.

Chad Carlson, MD
Associate Professor of Neurology, Medical College of Wisconsin,
Milwaukee, Wisconsin
aDr Carlson reports no disclosure.
bDr Carlson discusses the use and/or initiation of antiepileptic drugs for special populations,
several of which are US Food and Drug Administration approved for adjunctive therapy for
seizures but not for initial monotherapy.

Gregory D. Cascino, MD, FAAN

Whitney MacMillan Junior Professor of Neuroscience, Mayo Clinic College
of Medicine, Mayo Clinic, Rochester, Minnesota
aDr Cascino serves on the board of directors of the American Academy of Neurology and as
an associate editor of Neurology. Dr Cascino receives royalties from Mayo Medical Ventures
and UpToDate, Inc.
bDr Cascino reports no disclosure.

David K. Chen, MD
Assistant Professor of Neurology, Baylor College of Medicine, Houston,
Texas; Codirector, Houston Epilepsy Center of Excellence,
Michael E. DeBakey VA Medical Center, Houston, Texas
a,bDr Chen reports no disclosures.

Daniel Friedman, MD, MSc

Assistant Professor (Clinical) of Neurology, New York University Langone School
of Medicine, New York, New York
aDr Friedman serves on the physician advisory board of the Epilepsy Foundation, on the
editorial board of Epilepsy.com, and as a consultant for Cyberonics, Inc. Dr Friedman has
received personal compensation for speaking engagements from the American College
of Veterinary Internal Medicine and paid travel accommodations/meeting expenses from
Alexza Pharmaceuticals. Dr Friedman receives royalties from Oxford University Press
and research support from the Centers for Disease Control and Prevention, the Epilepsy
Foundation, the National Institute of Neurological Disorders and Stroke, and UCB, Inc.
bDr Friedman reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

www.ContinuumJournal.com February 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Nicolas Gaspard, MD, PhD
Associate Professor, Department of Neurology, Hôpital Erasme, Université de
Bruxelles, Brussels, Belgium; Assistant Professor (Adjunct), Department of
Neurology, Yale University School of Medicine, New Haven, Connecticut
aDr Gaspard receives royalties from UpToDate, Inc, and Wolters Kluwer and research
support from Fonds Erasme Pour la Recherche Médicale and the Belgian National Fund
for Scientific Research.
bDr Gaspard discusses the unlabeled/investigation use of steroids, IV immunoglobulins,
plasma exchange, tacrolimus, natalizumab, rituximab, and cyclophosphamide for the
treatment of autoimmune encephalitis.

Elizabeth E. Gerard, MD
Associate Professor of Neurology, Northwestern University, Feinberg School
of Medicine, Chicago, Illinois
aDr Gerard has received honoraria from the American College of Physicians and research
support from the National Institute of Neurological Disorders and Stroke and SAGE
Pharmaceuticals. Dr Gerard has served as a research consultant on a trial sponsored
by UCB, Inc.
bDr Gerard reports no disclosure.

Ajay Gupta, MD
Head, Pediatric Epilepsy/Neurological Institute, Associate Professor,
Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio
aDr Gupta has served on the advisory board of Lundbeck and has received research support
from the Tuberous Sclerosis Alliance for the Natural History Database Study.
bDr Gupta discusses the unlabeled/investigational use of benzodiazepines for the treatment
of febrile seizures.

Stephen Hantus, MD
Neurology Staff, Director of cEEG and Epilepsy Consult Service, Cleveland Clinic
Epilepsy Center, Cleveland, Ohio
a,bDr Hantus reports no disclosures.

Anna D. Hohler, MD, FAAN

Associate Professor of Neurology; Assistant Dean, Office of Academic Affairs,
Boston University Medical Campus, Boston, Massachusetts
a,bDr Hohler reports no disclosures.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2016;22(1) www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
W. Curt LaFrance Jr, MD, MPH, FAAN, FANPA, DFAPA
Associate Professor of Psychiatry and Neurology, Brown University,
Providence, Rhode Island; Director, Neuropsychiatry and Behavioral Neurology,
Rhode Island Hospital, Providence, Rhode Island
aDr LaFrance serves on the Epilepsy Foundation Professional Advisory Board; has served
as a clinic development consultant for the Cleveland Clinic, Emory University, Spectrum
Health, and the University of Colorado Denver; and has provided expert medicolegal
testimony. Dr LaFrance receives royalties from Cambridge University Press and Oxford
University Press and has received research support from the American Epilepsy Society, the
Epilepsy Foundation, the Matthew Siravo Memorial Foundation Inc, the National Institutes
of Health, and Rhode Island Hospital.
bDr LaFrance reports no disclosure.

Kimford J. Meador, MD, FAAN

Professor of Neurology and Neurological Sciences, Stanford University,
Stanford, California
aDr Meador serves as a consultant for the Epilepsy Study Consortium and on the editorial
boards of Epilepsy and Behavior, Journal of Clinical Neurophysiology, and Neurology.
Dr Meador has received travel, meeting, and accommodation compensation from UCB, Inc,
and receives research support from the National Institute of Neurological Disorders and
Stroke and the Patient-Centered Outcomes Research Institute.
bDr Meador reports no disclosure.

Jill Miller-Horn, MD, MS

Assistant Professor of Neurology and Pediatrics, Stony Brook University,
Stony Brook, New York
a,bDr Miller-Horn reports no disclosures.

Georgia Montouris, MD
Associate Clinical Professor of Neurology, Director of Epilepsy Services, Boston
Medical Center, Boston University School of Medicine, Boston, Massachusetts
aDr Montouris serves on the expert panel for the UCB Antiepileptic Drugs Pregnancy
Registry and on the scientific advisory boards of Acorda Therapeutics; Eisai Co, Ltd;
Lundbeck; and Upsher-Smith Laboratories, Inc.
bDr Montouris reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

www.ContinuumJournal.com February 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Dileep R. Nair, MD
Head of Adult Epilepsy, Cleveland Clinic, Cleveland, Ohio
aDr Nair serves as a consultant for Brain Sentinel and has received personal compensation
for speaking engagements from NeuroPace, Inc.
bDr Nair discusses the unlabeled/investigational use of cannabinoids in the treatment
of epilepsy.

Marc R. Nuwer, MD, PhD, FAAN

Professor and Vice Chair of Clinical Neurology, David Geffen School of Medicine
at University of California, Los Angeles, Los Angeles, California
aDr Nuwer has received personal compensation for speaking engagements from the
American Clinical Neurophysiology Society and the Virginia Commonwealth University,
serves as a consultant for CortiCare, Inc, and has provided expert legal testimony. Dr Nuwer
receives royalties from Cambridge University Press and research support from the National
Institutes of Health and the US Army.
bDr Nuwer reports no disclosure.

Joseph I. Sirven, MD, FAAN

Professor and Chairman, Department of Neurology, Mayo Clinic, Phoenix, Arizona
aDr Sirven serves on the advisory board of Upsher-Smith Laboratories, Inc; on the data safety
monitoring board of Acorda Therapeutics; and as a consultant for the Epilepsy Foundation.
Dr Sirven receives research support from NeuroPace, Inc.
bDr Sirven reports no disclosure.

Christopher T. Skidmore, MD
Assistant Professor of Neurology, Thomas Jefferson University,
Philadelphia, Pennsylvania
aDr Skidmore serves as a consultant for Upsher-Smith Laboratories, Inc, and has received
research support from NeuroPace, Inc.
bDr Skidmore reports no disclosure.

Erik K. St. Louis, MD, MS, FAAN

Associate Professor of Neurology, Associate Dean, Mayo School of Continuous
Professional Development, Mayo Clinic, Rochester, Minnesota
aDr St. Louis receives research support from the Mayo Foundation and the National
Institutes of Health.
bDr St. Louis reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2016;22(1) www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Korwyn Williams, MD, PhD
Section Chief, Neurology, Barrow Neurological Institute at Phoenix Children’s
Hospital, Phoenix, Arizona; Clinical Assistant Professor, Department of Child
Health, University of Arizona, Phoenix Arizona; Assistant Professor of Neurology,
College of Medicine, Mayo Clinic, Scottsdale, Arizona
a,bDr Williams reports no disclosures.

Elaine Wirrell, MD
Director of Pediatric Epilepsy, Professor of Epilepsy and Child and Adolescent
Neurology, Mayo Clinic, Rochester, Minnesota
aDr Wirrell receives royalties from UpToDate, Inc, and research support from the American
Epilepsy Society Infrastructure Award and the Dravet Syndrome Foundation.
bDr Wirrell reports no disclosure.

SELF-ASSESSMENT AND CME TEST WRITERS

D. Joanne Lynn, MD, FAAN
Associate Dean for Student Life and Clinical Professor of Neurology,
The Ohio State University College of Medicine, Columbus, Ohio
aDr Lynn receives book royalties from Lippincott Williams & Wilkins and holds stock in
Abbott Laboratories, Bristol-Myers Squibb Company, Corning Incorporated, Express Scripts
Holding Company, General Electric, Hospira, Inc, and Varian Medical Systems, Inc.
bDr Lynn reports no disclosure.

James W. M. Owens Jr, MD, PhD

Associate Professor of Neurology and Adjunct Associate Professor of Pediatrics,
University of Washington, Seattle, Washington
aDr Owens receives personal compensation for medicolegal record review and royalties
from UpToDate, Inc.
bDr Owens reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

www.ContinuumJournal.com February 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Volume 22 n Number 1 n February 2016

LIFELONG LEARNING IN NEUROLOGY ®

www.ContinuumJournal.com

Epilepsy Denotes Video Content

Guest Editor: Lara Jehi, MD Denotes Supplemental Digital Content

Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

REVIEW ARTICLES
Diagnosis of Epilepsy and Related Episodic Disorders . . . . . . . . . . . . . . . . . . . . . . . . 15
Erik K. St. Louis, MD, MS, FAAN; Gregory D. Cascino, MD, FAAN
Management of a First Seizure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Gregory K. Bergey, MD, FAAN
Febrile Seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Ajay Gupta, MD
Infantile, Childhood, and Adolescent Epilepsies. . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Elaine Wirrell, MD
Adult Focal Epilepsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Christopher T. Skidmore, MD
Diagnosis and Treatment of Nonepileptic Seizures. . . . . . . . . . . . . . . . . . . . . . . 116
David K. Chen, MD; W. Curt LaFrance Jr, MD, MPH, FAAN, FANPA, DFAPA
Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Bassel W. Abou-Khalil, MD, FAAN
Management of Drug-Resistant Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Dileep R. Nair, MD
Epilepsy Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Stephen Hantus, MD
Management of Epilepsy Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Joseph I. Sirven, MD, FAAN
Managing Epilepsy in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Elizabeth E. Gerard, MD; Kimford J. Meador, MD, FAAN
Autoimmune Epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Nicolas Gaspard, MD, PhD
Special Issues in Epilepsy: The Elderly, the Immunocompromised,
and Bone Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Chad Carlson, MD; Christopher T. Anderson, MD

Volume 22 n Number 1 www.ContinuumJournal.com 9

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 LIFELONG LEARNING IN NEUROLOGY ®

ETHICAL PERSPECTIVES
Ethical Considerations in Balancing Parental Autonomy With
Protecting a Child With Epilepsy From Harm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
Jill Miller-Horn, MD, MS

PRACTICE ISSUES
Cultural Barriers to Medication Adherence in Epilepsy . . . . . . . . . . . . . . . . . . . 266
Georgia Montouris, MD; Anna D. Hohler, MD, FAAN
Diagnostic Coding for Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
Korwyn Williams, MD, PhD; Marc R. Nuwer, MD, PhD, FAAN;
Jeffrey R. Buchhalter, MD, PhD, FAAN

APPENDICES
Appendix A: Summary of Evidence-Based Guideline for Clinicians:
Management of an Unprovoked First Seizure in Adults . . . . . . . . . . . . . . . . . . 281
Appendix B: AAN Summary of Evidence-Based Guideline for Clinicians:
Management Issues for Women With Epilepsy—Focus on Pregnancy:
Obstetrical Complications and Change in Seizure Frequency . . . . . . . . . . . . . 283
Appendix C: AAN Summary of Evidence-Based Guideline for Clinicians:
Management Issues for Women With Epilepsy—Focus on Pregnancy:
Vitamin K, Folic Acid, Blood Levels, and Breastfeeding . . . . . . . . . . . . . . . . . . . 285
Appendix D: Summary of Evidence-Based Guideline for Clinicians:
Antiepileptic Drug Selection for People With HIV/AIDS . . . . . . . . . . . . . . . . . . 287

SELF-ASSESSMENT AND CME

Learning Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Instructions for Completing Postreading Self-Assessment and
CME Test and Tally Sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Postreading Self-Assessment and CME Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Postreading Self-Assessment and CME Test—Preferred Responses . . . . . . . 307
D. Joanne Lynn, MD, FAAN; James W. M. Owens Jr, MD, PhD
Patient Management Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Patient Management Problem—Preferred Responses . . . . . . . . . . . . . . . . . . . . 335
Daniel Friedman, MD, MSc

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Back Cover

10 www.ContinuumJournal.com February 2016

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 Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology
Epilepsy issue, participants will be able to:

s Accurately diagnose epilepsy in view of the new practical definition and distinguish
epileptic seizures from other episodic disorders by history, examination, and
appropriate application of electroencephalographic and imaging investigations
Assess patients presenting with their first seizure, determine their risk of having
s

a second seizure, and use this information to guide treatment decisions

Discuss the epidemiology, causes, and management of febrile seizures
s

Recognize common electroclinical syndromes in children and understand

s

how these guide investigations and therapy

Describe the common seizure presentations, etiologies, EEG patterns,
s

and imaging findings associated with focal epilepsy

Describe the diagnostic evaluation and management for patients with
s

nonepileptic seizures
Discuss the spectrum of efficacy, clinical pharmacology, and modes of
s

use for individual antiepileptic drugs

Discuss the evaluation of a patient with drug-resistant epilepsy and recognize
s

the role and indications for surgical and nonsurgical options for patients
with drug-resistant epilepsy
Recognize and manage epilepsy emergencies
s

Describe the common comorbid conditions that occur in individuals with

s

seizures and epilepsy and outline the key management options and
strategies for mitigating these conditions to maximize quality of life
Counsel women with epilepsy on how seizures and antiepileptic drug
s

treatment relate to their reproductive health and reproductive outcomes

Recognize and treat inflammatory causes of seizures and epilepsy
s

Recognize the challenges in epilepsy treatment specific to patients over

s

60 years of age and potential etiologies for seizures in the setting of an

immunocompromised patient, and discuss issues related to bone health in
patients with epilepsy
Identify ethical principles raised by a parent’s request for a prescription that
s

is not the recommended medical treatment for a child

Discuss cultural barriers that contribute to medication nonadherence in
s

patients with epilepsy

Core Competencies
This Continuum: Lifelong Learning in Neurology Epilepsy issue covers the
following core competencies:

Patient Care and Procedural Skills

s

Medical Knowledge
s

Practice-Based Learning and Improvement

s

Interpersonal and Communication Skills

s

Professionalism
s

Systems-Based Practice
s

Continuum (Minneap Minn) 2016;22(1) www.ContinuumJournal.com

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Editor’s Preface

* 2016 American Academy

An Anthology of of Neurology.

Epileptology
This issue of Continuum is de- W. Curt LaFrance Jr next dis-
voted to the diagnosis and manage- cuss nonepileptic seizures,
ment of our patients with epilepsy with particular emphasis on
and seizures across the lifespan. psychogenic nonepileptic
To accomplish this critically im- seizures, including their di-
portant goal, Dr Lara Jehi, the di- agnostic (clinical and inves-
rector of research at the Cleveland tigational) differentiation
Clinic Epilepsy Center, has brought from epileptic seizures, psy-
an outstanding group of experts chological underpinnings
on board to so thoroughly inform and prognostic features,
each of us in our provision of the and management.
most up-to-date care of our patients Both antiepileptic drug
with these disorders. (AED) therapy and AED re-
The issue begins with an ar- sistance form the basis for the
ticle by Drs Erik K. St. Louis and next two articles in the issue.
Gregory D. Cascino that clearly out- First, Dr Bassel W. Abou-Khalil
Dr Lara JehiIhas brought reviews each one of the many
lines the new International League
an outstanding group of AEDs that are now available
Against Epilepsy practical clinical
experts on board to so to neurologists to manage our
definition of epilepsy, reviews the
differential diagnosis of seizures
thoroughly inform each patients with epilepsy, includ-
and other paroxysmal physiologic of us in our provision of ing its spectrum of efficacy,
spells, and discusses the approach the most up-to-date care pharmacokinetic properties,
to the initial diagnosis of epilepsy. of our patients with safety and tolerability pro-
Next, Dr Gregory K. Bergey dis- these disorders. file, and place in our current
cusses the management of a first therapeutic armamentarium.
seizure and clearly outlines the concepts and Next, Dr Dileep R. Nair discusses the definition
distinction between provoked and acute symp- and evaluation of drug-resistant epilepsy and its
tomatic seizures, as well as remote symptom- management options, including resective epi-
atic seizures, and their significance in relation lepsy surgery, electrical stimulation therapy, and
to seizure recurrence risk. dietary therapy.
The next two articles are devoted to the care Dr Stephen Hantus discusses the diagnosis
of our pediatric patients, starting with the article and treatment recommendations for epilepsy
by Dr Ajay Gupta, who reviews the diagnosis and emergencies, including acute repetitive seizures
management of febrile seizures, stressing the im- and status epilepticus. In the next article, Dr
portance of an individualized clinical assessment, Joseph I. Sirven reviews the management of the
risk stratification, and care plan for each patient many common comorbid conditions that occur
and caregiver. Dr Elaine Wirrell then reviews the in patients with epilepsy, including depression,
remarkable variety of (common and rarer) epi- anxiety, and memory problems, as well as other
lepsy syndromes that occur in infancy, childhood, important issues such as driving restrictions and
and adolescence, including their clinical and sudden unexpected death in epilepsy and its risk
electroencephalographic features, management, factors. Drs Elizabeth E. Gerard and Kimford J.
and prognosis. Meador review the many considerations in the
Dr Christopher T. Skidmore discusses the typ- management of women with epilepsy, including
ical clinical features and electroencephalographic AED selection (and risk of structural and cogni-
findings in the various forms of adult focal epi- tive teratogenesis) for women of childbearing
lepsy as defined by the anatomic localization of age, contraceptive options and recognition of
their onset, such as mesial temporal lobe epi- drug-drug interactions, and catamenial seizures.
lepsy, lateral (neocortical) temporal lobe epilepsy, Dr Nicolas Gaspard discusses the recent de-
and frontal lobe epilepsy. Drs David K. Chen and velopments in autoimmune epilepsy, including

Continuum (Minneap Minn) 2016;22(1):13–14 www.ContinuumJournal.com 13

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Editor’s Preface

the increasingly recognized syndromes of auto- by Drs D. Joanne Lynn and James W. M. Owens Jr,
immune encephalitis and their clinical diagnosis after reading the issue, you may earn up to 12 AMA
and management, as well as the emerging con- PRA Category 1 Creditsi toward self-assessment
cept of autoimmunity and its potential rela- and CME. The Patient Management Problem,
tionship to chronic epilepsy. In the final review written by Dr Daniel Friedman, describes the
article of the issue, Drs Chad Carlson and case of a 24-year-old woman who presents to the
Christopher T. Anderson review a variety of emergency department for evaluation of a wit-
importantVand commonly encounteredVissues nessed convulsion at work. By following her case
of special concern in patients with epilepsy, in- and answering multiple-choice questions corre-
cluding issues specific to the management of sponding to diagnostic and management deci-
elderly or immunosuppressed patients with epi- sion points along the course of her disorder, you
lepsy, and discuss risk factors and assessment for will have the opportunity to earn up to 2 AMA
bone disease and recommendations with regard PRA Category 1 CME Credits.
to bone health in patients with epilepsy. Finally, a few important changes have been
In this issue’s Ethical Perspectives article, made to the Continuum Editorial Board since
Dr Jill Miller-Horn analyzes the ethical dilemma the previous issue. Dr Daniel Larriviere has com-
created when the neurologist and a parent have pleted his tenure as Associate Editor of Ethics,
a disagreement over the optimal care of the child and I would like to sincerely thank him for his
with epilepsy. In the Practice Issues article, Drs dedication to this important section for the last
Georgia Montouris and Anna D. Hohler discuss 3 years. Dr Joseph Kass of Baylor College of
how cultural barriers can affect adherence to med- Medicine, a current editorial board member,
ications, of particular importance in AED therapy will be taking over this role, which will now be
for seizure disorders. Drs Korwyn Williams, Marc R. called Associate Editor of Ethics and Medicolegal
Nuwer, and Jeffrey R. Buchhalter review the many Issues. Recognizing that a number of important
considerations that neurologists need to be aware challenges are facing neurologists, some clearly
of with regard to diagnostic coding for seizures in the realm of ethics but many that also have
and epilepsy syndromes. legal implications, the scope of the ethics section
Given the above, it is clear that Dr Jehi has will expand to address important issues that have
put together a remarkably thorough and up-to- legal aspects that neurologists should know about.
date treatise on epilepsy, and perhaps the “last The plan is to alternate between more ethics-
word” on epilepsy for many of us for the time focused articles and more legal-focused ones in
being. But, speaking of “last words,” the “last successive issues. I am also pleased to announce
word” you will find in this issue is “semiology,” a that Dr Joseph Safdieh, also a current editorial
term that has been ubiquitous in the epilepsy board member, will be taking on the newly created
literature since the 1990s. Despite the common role of Associate Editor of Self-Assessment and
use of this word in the epilepsy literature, the CME, supervising and editing all of the question-
term is ill defined, although it seems mainly used writing and CME activities in Continuum.
in this context to refer to the clinical manifesta- I want to sincerely thank Dr Jehi for the
tions of a seizure and is rarely, if ever, used to painstaking work she put into the organization of
refer to the signs or symptoms of other neuro- this remarkable issue and her incredible respon-
logic or medical conditions. Although the Greek siveness and insights with all of the critical details
root of “semiology” means “sign,”1 in the broad that occur throughout the editing process. Ad-
medical context the term has classically referred ditional thanks to each of the expert faculty mem-
(typically outside of the United States) to a course bers in this issue, whose clear and thorough
of study in medical education relating to the articles provide us with such practical informa-
diagnosis of disease using the patient’s clinical tion to help us provide the most up-to-date care
history, symptoms, and signs. In keeping with to our patients with seizures and epilepsy.
my philosophy in Continuum to be as jargon
VSteven L. Lewis, MD, FAAN
free (and abbreviation free) as possible, for op-
Editor-in-Chief
timal educational purposes this issue is semiol-
ogy free (with the sole exception of a single table
that used the term in the original source).
As with every issue of Continuum, a number REFERENCE
of opportunities exist for CME. By taking the 1. Nöth W. Handbook of semiotics. Bloomington and
Postreading Self-Assessment and CME Test, written Indianapolis, IN: Indiana University Press, 1995:13.

14 www.ContinuumJournal.com February 2016

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 Review Article

Diagnosis of Epilepsy
Address correspondence to
Dr Gregory D. Cascino,
Department of Neurology,
Mayo Clinic, 200 First Street

and Related Episodic SW, Rochester, MN 55905,

[email protected].
Relationship Disclosure:

Disorders Dr St. Louis receives research

support from the Mayo
Foundation and the National
Institutes of Health.
Erik K. St. Louis, MD, MS, FAAN; Gregory D. Cascino, MD, FAAN Dr Cascino serves on the
board of directors of the
American Academy of
Neurology and as an associate
ABSTRACT editor of Neurology.
Purpose of Review: This review identifies the diverse and variable clinical presenta- Dr Cascino receives royalties
tions associated with epilepsy that may create challenges in diagnosis and treatment. from Mayo Medical Ventures
and UpToDate, Inc.
Recent Findings: Epilepsy has recently been redefined as a disease characterized by Unlabeled Use of
one or more seizures with a relatively high recurrence risk (ie, 60% or greater Products/Investigational
likelihood). The implication of this definition for therapy is that antiepileptic drug Use Disclosure:
Drs St. Louis and Cascino
therapy may be initiated following a first seizure in certain situations. report no disclosures.
EEG remains the most commonly used study in the evaluation of people with * 2016 American Academy
epilepsy. Routine EEG may assist in diagnosis, classification of seizure type(s), of Neurology.
identification of treatment, and monitoring the efficacy of therapy. Video-EEG
monitoring permits seizure classification, assessment of psychogenic nonepileptic
seizures, and evaluation of candidacy for epilepsy surgery. MRI is pivotal in eluci-
dating the etiology of the seizure disorder and in suggesting the localization of
seizure onset.
Summary: This article reviews the new International League Against Epilepsy practical
clinical definition for epilepsy and the differential diagnosis of other physiologic
paroxysmal spells, including syncope, parasomnias, transient ischemic attacks, and
migraine, as well as psychogenic nonepileptic seizures. The initial investigational
approaches to new-onset epilepsy are considered, including neuroimaging and
neurophysiologic investigations with interictal and ictal video-EEG. Neurologists should
maintain a high index of suspicion for epilepsy when children or adults present with a
single paroxysmal spell or recurrent episodic events.

Continuum (Minneap Minn) 2016;22(1):15–37.

INTRODUCTION The initial diagnostic approach to

Epilepsy is one of the most common the patient with epilepsy and related
and disabling public health problems, episodic disorders has importance for
affecting approximately 3 million both long-term prognosis and treat-
Americans and an estimated 50 million ment, including the determination of
people around the world.1 Modern
whether treatment is necessary and
diagnostic testing and evolving thera-
the type(s) of therapy to be consid-
pies have transformed care for people
with epilepsy. All neurologists need to ered. When evaluating a patient with
be intimately familiar with epilepsy possible epilepsy, the basic approach
because of its high prevalence, its is as follows: Is this epilepsy, and, if so,
variable and diverse clinical mani- is it focal or generalized? Once a
festations, and the current use of seizure is determined to be a manifes-
antiepileptic drugs (AEDs) for neuro- tation of epilepsy, a diagnostic workup
psychiatric disorders. must be performed to understand the
Continuum (Minneap Minn) 2016;22(1):15–37 www.ContinuumJournal.com 15

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Diagnosis of Epilepsy

KEY POINTS
h All neurologists need to underlying cause(s) and epilepsy syn- clinical, electroencephalographic, or neu-
be intimately familiar with drome type when possible. These basic roimaging tests that a heightened risk [at
epilepsy because of its considerations then determine which least 60%] exists for future seizures over
high prevalence, its diagnostic investigations are needed and the next 10 years), or when an epilepsy
variable and diverse the subsequent therapeutic approach. syndrome is diagnosed.2 This new defi-
clinical manifestations,
The basic goals of treatment for epilepsy nition recognizes the practical impor-
and the current use of tance of treating some patients after a
antiepileptic drugs for
are to help the patient achieve freedom
single seizure, since they may also ex-
neuropsychiatric disorders. from further seizures without adverse
perience the consequences of epilepsy,
h Seizures are typically effects of therapies, or at least minimize such as lower quality of life, loss of psy-
paroxysmal and the frequency of disabling or potentially chosocial functioning, and injury.3
episodic, resulting in a injurious seizure types when seizure The principal clinical symptoms and
suddenly occurring but freedom is not achieved, and to address signs of epilepsy include ictal (during a
transient behavioral, any relevant interictal comorbidities of seizure), postictal (immediately following
somatosensory, motor, epilepsy to maximize quality of life for seizure termination), and interictal (be-
or visual symptom or
people with epilepsy. Thus, these goals tween seizure episodes) manifestations.
sign, and caused by
abnormally excessive should guide the diagnostic approach Behavioral alterations accompanying epi-
cortical neuronal activity. to people with epilepsy for overall suc- leptic seizures are diverse, ranging from
cessful management. subjective feelings reported by the pa-
h The International
tient to objectively witnessed behavioral
League Against Epilepsy
adopted a new practical PRACTICAL DEFINITION OF arrest, unresponsiveness, or involuntary
definition for epilepsy EPILEPSY movements. The nature of the ictal
as a disease with either Seizures are typically paroxysmal and behavioral disturbance depends upon
recurrent seizures episodic, resulting in a suddenly occur- the location of seizure onset in the brain
(ie, two or more ring but transient behavioral, somato- and its rate and pattern of propagation
unprovoked seizures sensory, motor, or visual symptom or involving neuronal networks in neigh-
occurring at least sign, and caused by abnormally exces- boring or distant brain regions.
24 hours apart) or a sive cortical neuronal activity. Seizures
heightened tendency
may be provoked by certain influences DIAGNOSIS OF SEIZURE TYPE
toward recurrent AND EPILEPSY SYNDROME
(eg, trauma, brain hemorrhage, meta-
unprovoked seizures
bolic dyscrasias, or drug exposures) or A seizure is a symptom resulting from an
(ie, a single seizure,
occur spontaneously without provo- underlying brain lesion or dysfunction
accompanied by evidence
that a heightened risk cation. Some individuals may have that is not specific for a particular etio-
for future seizures exists), recurrent provoked seizures without logic cause. Diverse causative pathologies
or when an epilepsy having epilepsy, which instead re- can result in similar ictal behaviors and
syndrome is diagnosed. quires that a heightened tendency EEG manifestations. The prognosis and
h The principal clinical toward spontaneous recurrent seizures treatment of a person with epilepsy are
symptoms and signs of is present. Provoked seizures do not directed by the diagnosis of his or her
epilepsy include ictal recur when provoking factors are al- epilepsy syndrome (Case 1-1). Seizure
(during a seizure), tered or corrected. type and epilepsy syndrome diagnosis
postictal (immediately In 2014, the International League are based on a description of seizure
following seizure Against Epilepsy (ILAE) adopted a new behavior and EEG manifestations, fur-
termination), and practical definition for epilepsy as a ther aided by neuroimaging and genetic
interictal (between seizure disease with either recurrent unprovoked investigations in some cases.
episodes) manifestations. seizures (ie, two or more unprovoked Traditionally, epilepsy syndromes
seizures occurring at least 24 hours apart) have been classified as partial, general-
or a heightened tendency toward recur- ized, or unknown (based on predomi-
rent unprovoked seizures (ie, a single nant seizure type[s]), with parallel
seizure, accompanied by evidence from terminology concerning the epilepsy
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 Case 1-1
A 19-year-old man with a family history of epilepsy in his father and paternal first cousin presented following
a first apparent seizure. He had just completed his firstYsemester final examinations as a college freshman and
for 2 weeks had been repeatedly sleep deprived. After his last examination, he spent the night celebrating
with friends and drank four beers, although his custom was to have only one or two alcoholic beverages per
week. He awoke the following morning with a slight headache but no other symptoms. After his morning
shower, his roommate said he fell, then stiffened, and his body convulsed for 1 or 2 minutes. He had bitten
his tongue and lost control of his bladder. He remembered nothing until recovering in the emergency
department 2 hours later. Noncontrast head CT was normal, as were serum electrolytes and complete blood
count. He was not started on any specific therapy and was released to home after recovery with a prompt
neurologic consultation arranged. One week later, he was seen in the neurology clinic. Further history was
elicited, and he mentioned a 3-year history of intermittent arm jerking episodes after awakening in the
morning. When he was 15 years old, after arising earlier than usual to deer hunt with his father, he dropped his
rifle when his arm involuntarily jerked, and several times a year, he would twitch and spill his breakfast coffee.
EEG (Figure 1-1) showed generalized atypical spike-and-wave discharges. The patient was diagnosed with
juvenile myoclonic epilepsy and started on divalproex sodium 500 mg 2 times a day. On this regimen,
he remained seizure free and without recurrence of morning arm jerking episodes 1 year later.

FIGURE 1-1 EEG, showing generalized atypical spike-and-wave discharges, of the patient in Case1-1, who had myoclonic
seizures and a first tonic-clonic seizure consistent with juvenile myoclonic epilepsy. Average referential montage.

Continued on page 18

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 Diagnosis of Epilepsy

Continued from page 17

Comment. This patient presented following an apparent first generalized tonic-clonic seizure.
His presentation during teenage years, history of other subtler habitual clinical myoclonic seizures,
provocation by recent sleep deprivation and alcohol binge, and generalized epileptiform EEG pattern
were all features consistent with an epilepsy syndrome diagnosis of juvenile myoclonic epilepsy. It is
important to take a thorough history to understand whether patients may have a history of other
spells that signify previous seizures, enabling an earlier diagnosis of epilepsy and prompt treatment of
this lifelong epilepsy syndrome.

KEY POINTS etiology as either idiopathic (having an even many epilepsy practitioners.8
h The prognosis and unknown but often presumed to be ge- Therefore, familiarity with both classifi-
treatment of a person netic cause), cryptogenic (unknown, but cation schemes is preferred until a de-
with epilepsy are directed with a likely causative pathology that finitive classification system is accepted.
by the diagnosis of his or
has not yet been identified), or symp- Differentiating seizure types is often
her epilepsy syndrome.
tomatic (the etiology is known, and the difficult in new-onset seizures. Many
h In the 2010 revised brain is disordered or diseased before partial/focal seizures present clinically as
International League or between seizure episodes). generalized tonic-clonic seizures without
Against Epilepsy
However, in 2010, a revision in sei- apparent focal features, and patients
classification scheme,
zure classification was proposed.4,5 Over- may present after a single seizure or a
seizures are divided into
focal (involving brain
all, the newer proposed nosology is quite limited number of seizures, so the full
networks confined to similar to the traditional 1981 seizure6 range of seizures and related behaviors
one hemisphere) or and 1989 epilepsy7 classification schemes enabling diagnosis in a patient may have
generalized (beginning and reflects advancements in the un- not fully evolved or developed.
in bilaterally distributed derstanding of epilepsy as a brain net- In the traditional terminology, partial
networks synchronously work disorder demonstrated by basic seizures are further classified as simple,
in both hemispheres science, neuroimaging, neurophysiol- complex, or secondarily generalized. Sim-
from onset). ogy, and genetic research.4,5 In the 2010 ple partial/focal seizures do not impair
revised ILAE classification scheme, sei- consciousness and may involve very small
zures are divided into focal (involving volumes of brain tissue with limited
brain networks confined to one hemi- network involvement, equivalent to the
sphere) or generalized (beginning in older term aura but involving a range of
bilaterally distributed networks syn- possible symptoms depending on loca-
chronously in both hemispheres from tion of onset so that autonomic, cogni-
onset).4,5 Some of the proposed termi- tive, emotional, somatosensory, visual,
nology, however, is cumbersome (eg, or involuntary motor activity can occur.
focal dyscognitive seizures instead of TemporalY or extratemporalYonset com-
the older term complex partial seizures, plex partial/focal seizures typically in-
meant to reflect alteration of conscious- volve impaired or altered consciousness
ness in association with a focal/partial and can cause behavioral arrest; staring;
seizure type). A modification of the and oral or manual limb automatisms
proposed classification uses the term such as chewing or swallowing, lip
focal seizure with loss of awareness smacking, vocalization, and aimless
for this seizure type. The specific ictal fumbling hand movements; they are
behavior should also be included in usually accompanied by amnesia. As the
the seizure classification (eg, focal mo- seizure propagates, head turning and
tor seizure). The newer classification limb posturing are frequent. Head turn-
may not be well understood by people ing is most often toward the seizure
with epilepsy, neurology trainees, or focus initially (ipsiversive), followed by

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head or body/trunk deviation away from
the seizure focus late in the course TABLE 1-1 Typical Partial/Focal
(versive turning).9 Limb posturing may Seizure Characteristics
(if Present) According to
be asymmetric, involving a still and dys- Region of Seizure Onset
tonic hand posture contralateral to the
seizure focus and a hand/arm with mo- Partial/Focal
bile automatisms ipsilateral to the focus. Region of Seizure
Extratemporal focal seizures more often Onset Characteristics
have prominent axial and proximal limb Frontal Focal clonic
movements, leading to patient mobiliza- motor
tion, possible falls, and bizarre violent Hypermotor
limb movements that may be misdiag- behavior
nosed as psychogenic (so-called hyper-
Temporal
kinetic or hypermotor seizures), and
more frequently arise from the sleep Mesial Autonomic
state. Variability in behavioral character- Dysmnesic
istics is seen both within and across in-
Déjà vu
dividuals with seizure behaviors. Focal
seizures may secondarily generalize, with Jamais vu
the arm contralateral to the side of sei- Gustatory
zure onset extending while the ipsilat- Olfactory
eral arm is often held flexed at the elbow,
making a figure 4 sign.9 Table 1-1 sum- Lateral/ Auditory
posterior
marizes characteristics of partial/focal sei- neocortical
Complex
zures. Infants may also display a range of visual
other potential seizure types, including Dysphasia
spasms (myoclonic/astatic attacks result-
Parietal Somatosensory
ing in head nodding and axial flexion or
collapse, frequently with arm extension) Occipital Simple visual
and other behaviors.10,11 For more in-
formation on pediatric seizures, refer to
the article “Infantile, Childhood, and muscles, usually with preserved con-
Adolescent Epilepsies” by Elaine Wirrell, sciousness. Massive myoclonus involv-
MD,12 in this issue of Continuum. ing the trunk may lead to falls and
The range of generalized seizure types injury. Tonic seizures involve sustained
includes absence, atonic/astatic, tonic, abnormal posturing of the extremities
myoclonic, clonic, or tonic-clonic sei- caused by cocontraction of agonist and
zures. Absence seizures, frequently pre- antagonist musculature, usually less than
viously called petit mal seizures, are brief 15 seconds in duration, with or without
(less than 10 seconds in duration) epi- vocalization, apnea, and falling. Atonic
sodes involving behavioral arrest, staring seizures (also known as astatic seizures)
with unresponsiveness, and automa- cause loss of muscle tone and falling.
tisms, but unlike focal seizures they Clonic seizures are repetitive jerking
lack any premonitory aura symptoms movements, and generalized tonic-clonic
or postictal state. Frequently, absence seizures involve an initial tonic posturing
attacks may be precipitated in the office phase followed by clonic limb move-
or EEG laboratory by hyperventilation. ments lasting 1 to 3 minutes, usually
Myoclonic seizures involve sudden brief followed by several minutes of postictal
jerks or twitching of limb or axial stupor, confusion, and language or motor

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 Diagnosis of Epilepsy

KEY POINTS
h The most common dysfunction (often called Todd paralysis quent compared to epileptic seizures.
non-neurologic disorder [or Todd paresis] when lateralized or Cardiogenic causes of syncope result
mimicking epilepsy localized weakness of limbs is present, from bradyarrhythmia or tachyarrhyth-
is syncope. which can mimic an acute stroke when mia and less frequently involve long
h Several paroxysmal individuals present following an unwit- prodromes. Orthostatic hypotension re-
neurologic disorders can nessed seizure event). Loss of bladder sults from a fall in blood pressure fol-
be confused with or bowel continence and tongue lacer- lowing a positional change to standing
epilepsy, including ation from biting are frequent. from a recumbent position and is a fre-
nonepileptic behavior in quent cause of syncope in patients who
cognitively impaired DIFFERENTIAL DIAGNOSIS OF are elderly or diabetic with autonomic
individuals, transient SEIZURES AND RELATED neuropathy. EEG during a syncopal
ischemic attacks from EPISODIC DISORDERS event most often shows generalized
cerebrovascular disease, The differential diagnosis of epilepsy is slowing or suppression if cerebral blood
delirium, migraines, wide, since several paroxysmal disorders flow is substantially interrupted for a
and movement and
may closely mimic an epileptic seizure. period of 20 to 30 seconds, often re-
sleep disorders.
Table 1-2 details common nonepileptic sulting when asystole occurs during
paroxysmal spells and the seizure types severe vasovagal attacks.
they most closely resemble by behav-
ioral characteristics, duration, and usual Neurologic Differential Diagnoses
EEG findings. Nonepileptic spells can be Several paroxysmal neurologic disorders
divided into two basic categories, phys- can be confused with epilepsy, including
iologic and psychogenic. Physiologic nonepileptic behavior in cognitively im-
nonepileptic spells include a diversity of paired individuals, transient ischemic
non-neurologic and neurologic etiologies. attacks (TIAs) from cerebrovascular dis-
ease, delirium, migrainous events, and
Non-neurologic Differential movement and sleep disorders. Individ-
Diagnosis uals who are cognitively impaired are
The most common non-neurologic dis- especially prone to be overdiagnosed
order mimicking epilepsy is syncope. with epilepsy or to have nonepileptic
Syncope most frequently results from behavioral spells complicating true epi-
cardiogenic, vasovagal (often called sim- lepsy. Examples of nonepileptic behav-
ple faints), or hypotensive causes.13 ioral spells in this patient population
Vasovagal/neurocardiogenic syncope is include staring with unresponsiveness
the most common of these and is a and movements mistaken for epileptic
generally benign form of syncope char- automatisms (eg, stereotypies, manner-
acterized by prodromal subjective isms, or tardive dyskinesia). When be-
symptoms of lightheaded dizziness, havior presumed to be seizure related
diaphoresis, and nausea, often provoked fails to respond to AED treatment,
by triggers such as positional change, video-EEG monitoring may be neces-
physical exertion, Valsalva maneuvers sary to classify nonepileptic and epilep-
(eg, lifting, toileting), or strong emo- sy-related behaviors. Patients with drug-
tional triggers (eg, the sight of blood). resistant epilepsy (ie, refractory to two
Loss of consciousness is often brief, or more AEDs) should also undergo
lasting seconds to a few minutes. Con- epilepsy monitoring for classification
vulsive movements are frequent dur- and possible surgical localization.
ing syncopal attacks, leading to further Cerebrovascular disease. Cerebro-
diagnostic confusion with epilepsy. Con- vascular disorders also can present with
fusion and loss of continence following paroxysmal cerebral dysfunction resem-
recovery of consciousness are infre- bling seizures. Clinical characteristics
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TABLE 1-2 Differentiating Seizures From Nonepileptic Spells

Type of
Paroxysmal Premonitory Spell Usual Postspell
Event Symptoms Characteristics Duration Symptoms
Absence seizure None Staring, G10 seconds None
automatisms
Focal seizure with Variable aura Staring, 30Y180 seconds Common;
loss of awareness or brief automatisms, amnesia,
(complex partial (10Y30 seconds) variably preserved aphasia,
seizure) sensory march posture sleepiness,
confusion,
variable
incontinence
Tonic-clonic Aura variable Brief tonic 1Y3 minutes Requisite;
seizure posturing, amnesia,
ensuing clonic sleep,
movements incontinence,
tongue
biting/injury
Psychogenic Variable Variable Often prolonged Variable,
spell/attack responsiveness, (95Y10 minutes) often none
nonstereotyped,
unusual movements
Syncope Frequent: Falling, eye closure, 1Y5 minutes Variable,
lightheaded, variable movements often none
dizziness
Migraine Prolonged sensory Often “positive” 20Y60 minutes Headache
march (minutes) symptoms (eg,
paresthesia,
photopsia)
Transient Rapid sensory march Often “negative” G60 minutes None
ischemic attack (1Y10 seconds) symptoms (eg, dead
numbness, weakness)
Parasomnia None Vocalization, Minutes Amnesia,
confusion, confusion
ambulation
Cataplexy Emotional Muscle atonia, Seconds to None
provocation preserved minutes
consciousness or
sleep attack

depend on the duration of ischemia radiographic evidence for infarction.

and the arterial territory involved, and, Cerebrovascular disorders more fre-
as with seizures, a diversity of clinical quently cause “negative” symptoms,
symptoms may result depending on such as numbness, weakness, visual
anatomic localization. TIAs typically loss, or aphasia, compared to epileptic
last from minutes to 1 hour, although seizures. Epileptic seizures more often
prolonged TIAs are likely to show involve “positive” symptoms and signs

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 Diagnosis of Epilepsy

during the ictal event, although post- resulting in further diagnostic confu-
ictal “negative” signs, including aphasia sion. In delirious patients, EEG most
and hemiparesis, frequently complicate often shows diffuse nonspecific non-
seizures, leading to diagnostic confu- epileptiform background slowing or
sion with stroke. However, repetitive even epileptiform-appearing patterns
limb-shaking convulsive movements such as diffuse triphasic waves.
(so-called limb-shaking TIAs); other Migraine. Clinical manifestations of
abnormal movements such as hemi- migraine and epilepsy are often similar,
ballismus, chorea, or dystonia; or even involving visual, sensory, and cognitive
symptomatic seizures from irritation symptoms. Migrainous headaches often
of neighboring cerebral cortical tissue follow epileptic seizures, and seizures
may all follow acute ischemia, leading following a primary migraine may oc-
to diagnostic uncertainty in some cur. However, in most patients, despite
cases.14 Ictal video-EEG monitoring similar clinical characteristics, migraine
is sometimes helpful in differentiating and epilepsy have distinct mechanisms.
TIAs from seizures, since focal cerebral During a migraine attack, EEG demon-
slowing or normal findings are seen on strates focal or generalized slowing, as
EEG during TIAs or stroke (typically poly- opposed to partial seizures, which may
morphic delta activity), distinguished show focal evolving rhythmic activity.
from the focal evolving rhythmic activity Movement disorders. Movement dis-
accompanying most partial seizures. orders, including paroxysmal dystonias
Encephalopathy. Delirium (enceph- and dyskinesias and some tremor dis-
alopathy) is a state of generalized confu- orders, may also resemble epileptic sei-
sion caused by a systemic disorder, often zures. EEG is invariably normal during
occurring when a vulnerable patient subcortically generated movement dis-
with an underlying mild cognitive im- orders. Careful observation of clinical
pairment or dementia is subjected to phenomenology is necessary to distin-
a procedure; change in medication; or guish these episodes from seizures, since
new acute change associated with sys- simple partial motor seizures may also
temic infection, inflammation, or expo- demonstrate stereotyped movements
sure to toxins or a metabolic disturbance, lacking an EEG change.
such as acute evolving hepatic or renal Sleep disorders. Nocturnal events
impairment.15 The hallmarks of deliri- confused with sleep epilepsies include
um are disorientation and inattention; the nonYrapid eye movement (REM)
patients are acutely disoriented, unable parasomnias (disorders of arousal) and
to accurately name their current loca- REM sleep behavior disorder.16 Non-
tion or the date, and incapable of con- REM parasomnias involve a spontaneous
centrating well enough to execute serial arousal from non-REM sleep, usually
calculations or spell words backward. from N2 or N3 (slow-wave) sleep, with
The clinical phenomena of confusion in nonstereotyped confused behavior
a delirious state may closely resemble with or without vocalization or sleep-
ictal or postictal behavior associated walking behavior. EEG may show no
with a complex partial/focal seizure, in- change other than arousal but oc-
volving staring with disorientation, inat- casionally shows generalized or frontal
tention, and variable responsiveness; dominant rhythmic delta or theta pat-
stupor with reduced vigilance; and un- terns lasting a few seconds following
usual movements, including myoclonic the arousal. REM sleep behavior disor-
jerks. Encephalopathic patients may also der is characterized by complex motor
have acute symptomatic seizures, behavior paralleling dream content,
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 KEY POINT
causing enactment of the dream. Be- duration (ie, often much longer than h Psychogenic nonepileptic
haviors are often violent as patients may 1 minute). Typical features of PNES may seizures are behavioral
dream of being attacked or chased, and closely resemble actual epileptic seizures, events closely resembling
while in their dream they are defending including unresponsiveness, abnormal epileptic seizures
themselves, they may injure themselves movements, and postictal-type behavioral but lacking the
or a bed partner by punching, kicking, alteration. However, PNES can be distin- typical clinical and
or falling out of bed. Polysomnography guished by eye closure during the spell electrophysiologic
is necessary for diagnosis, showing (which may rarely be seen in true epileptic features of true epilepsy.
frequent rapid phasic muscle jerks and seizures as well) and often bizarre volun-
heightened chin and limb muscle tone tary movements, including “yes-yes” type
during REM sleep. head nodding or “no-no” type side-to-side
In distinction, nocturnal seizures head shaking, prominent pelvic thrust-
demonstrate highly stereotyped com- ing, or atypical nonanatomic spread of
plex motor behavior, frequently with movements (eg, clonic-type move-
oral, limb, or trunk automatisms. Sei- ments that may begin in a leg, spread
zures of temporal lobe origin show to the head, then to an arm, features
prominent focal evolving rhythmic activ- that also may occur in true epilepsy).
ity, while frontal lobe seizures often Moreover, individual PNES lack stereo-
show little demonstrable ictal EEG typy across different events. The hall-
change that is often obscured by muscle mark of PNES is the lack of an ictal
and movement artifact; diagnosis relies epileptiform EEG discharge. However,
upon observation of stereotyped typical caution and considerable experience are
hypermotor behaviors. Cataplexy accom- necessary to accurately diagnose PNES,
panying narcolepsy may occasionally be as epileptic seizures may share many
difficult to distinguish from astatic sei- similar atypical clinical characteristics
zures but is usually easily distinguished by and lack an EEG change. When diagnos-
characteristic emotional provocation, es- tic confusion remains, patients should
pecially following laughter or anger. undergo ictal video-EEG monitoring to
Diagnosis can be made with confidence ensure an accurate diagnosis, which can
upon observing an episode and demon- be accomplished in most cases within
strating reversible loss of knee muscle 2 to 3 days of admission to an epilepsy
stretch reflexes during an attack, followed monitoring unit. For more information
by recovery of reflexes between attacks. on PNES, refer to the article “Diagnosis
Nonepileptic behavioral events. and Treatment of Nonepileptic Seizures”
Psychogenic nonepileptic seizures by David K. Chen, MD, and W. Curt
(PNES) are frequent sources of confu- LaFrance Jr, MD, MPH, FAAN, FANPA,
sion with epileptic seizures.17,18 PNES DFAPA,19 in this issue of Continuum.
are behavioral events closely resem-
bling epileptic seizures but lacking the INVESTIGATION OF THE PATIENT
typical clinical and electrophysiologic WITH SEIZURES AND SPELLS
features of true epilepsy. PNES are espe- The emphasis for patients with new-onset
cially common presentations in epilepsy seizures or spells is prompt diagnosis and
monitoring unit practices, accounting an evaluation to determine the underlying
for 30% to 50% of admissions. Ictal etiology. Diagnostic tests also help deter-
video-EEG telemetry remains the gold mine the epilepsy syndrome diagnosis
standard for diagnosis. Patients with and help determine the prognosis for
PNES are less likely to have abnormal future seizure recurrence. After a detailed
EEGs or MRI scans prior to admission history is taken from the patient and any
and more often have prolonged spell available collateral historians, investigation
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 Diagnosis of Epilepsy

KEY POINTS
h When the EEG shows an with EEG and neuroimaging is essential or spike-wave discharges that are dis-
epileptiform discharge to consider in the evaluation of most tinct from the normal background
after a single seizure, patients presenting with seizures or spells activity and indicate an increased sei-
treatment may be and is an expected consideration within zure tendency. The spike discharges
considered even before a the American Academy of Neurology are predominantly negative transients
diagnosis of epilepsy (AAN) Epilepsy Quality Guidelines.20 with steep ascending and descending
is established. limbs and a duration of 20 ms to 70 ms.
h The sensitivity of a single Electroencephalography A sharp wave is a broader potential with
EEG study to record an The EEG is the most commonly a duration of 70 ms to 200 ms. The
epileptiform abnormality performed diagnostic study in people epileptiform discharges should be dis-
may be 50% or less in with epilepsy. The first EEG performed tinct from the normal background activity,
people with epilepsy. on a person was recorded by Hans involve more than one scalp electrode,
Berger in 1924, and the importance of and have a physiologic field, and a voltage
EEG in the evaluation of patients with gradient should be present. Knowledge
epilepsy was confirmed by several in- about the patient’s age, coexistent medi-
vestigators in the 1930s. The EEG has cation uses, state of consciousness, and
enhanced our understanding of the patho- medical history are needed to appro-
physiology of seizures and has been an priately interpret the EEG study. The
invaluable diagnostic tool in the evalua- conceptual age of the patient is impor-
tion and treatment of seizure disor- tant for neonatal recordings. An epilep-
ders.20,21 Early observations concerning tiform pattern seen on EEG after a
the use of EEG in epilepsy validated the first-time seizure often predicts recur-
basic tenets outlined by J. Hughlings rence of seizures based on studies in
Jackson and his colleagues in the 19th both adults and children, with recur-
century regarding cortical excitability and rence rates that range from 30% to 70%
hypersynchrony in focal seizures.22 in the first year.24 Therefore, when the
The routine awake and asleep EEG EEG shows an epileptiform discharge
recording may be obtained on an outpa- after a single seizure, treatment may be
tient or inpatient basis and includes considered even before a diagnosis of
activating procedures, such as eye open- epilepsy is established.
ing and eye closure, hyperventilation, The clinical applications of EEG in-
and photic stimulation. The importance clude diagnosis of epilepsy, selection of
of sleep deprivation and the performance AED therapy, evaluation of response to
of the EEG recording during sleep in treatment, determination of candidacy for
patients with epilepsy have been empha- drug withdrawal, and surgical localization.
sized.23 In selected patients, the epilep- Sensitivity and specificity. The sen-
tiform discharges may only be present sitivity of a single EEG study to record
during the sleep EEG recording. The an epileptiform abnormality may be
AAN recommends EEG in diagnosing 50% or less in people with epilepsy.23Y25
epilepsy in adults and children, with The diagnostic yield increases to 80% to
inclusion of photic stimulation, hyper- 90% if three or more serial EEGs are
ventilation, and sleep deprivation in performed.26 Patients with childhood
adults as part of the protocol.20 EEG epilepsy are more likely to have abnor-
studies may reveal interictal epilepti- mal epileptiform EEG recordings than
form abnormalities. Repetitive EEGs adult patients. The timing of the EEG in
may be of diagnostic importance and relationship to a clinical seizure also in-
may evaluate the patient’s response to creases the likelihood of recording a
therapy. Epileptiform abnormalities specific epileptiform pattern.20,21 The
usually appear as spikes, sharp waves, presence of an epileptiform discharge
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 KEY POINT
suggests a significant epileptogenic po- barriers to recording the EEG include h Normal interictal EEG
tential and indicates a high specificity CSF, dura, bone, and scalp, and these studies do not exclude
for these paroxysmal findings. Normal noncerebral tissues intervening between the presence of a
interictal EEG studies do not exclude the brain’s surface and recording elec- seizure disorder.
the presence of a seizure disorder. Ulti- trodes produce a marked attenuation of
mately, epilepsy is a clinical diagnosis spontaneous cortically generated EEG
and the EEG serves to provide support- activity. Extracranial (scalp) EEG records
ing evidence; in other words, you treat activity in only approximately one-third
the patient and not the EEG. Interictal of the cerebral cortex. Scalp EEG may
epileptiform discharges are seen rare- not record potentially epileptiform dis-
ly in adults or children without epilepsy charges in basal regions, sulci, medial
(0.2% to 3%).27 Epileptiform abnormali- temporal lobe, and interhemispheric
ties were detected very uncommonly in regions. Simultaneous extracranial and
healthy airline personnel who under- intracranial EEG recordings show that
went EEG studies.28 Other factors that only 10% to 15% of intracranial spikes
may affect the diagnostic yield of EEG in are detected with scalp EEG studies.29
patients with epilepsy include: (1) the Routine EEG conventionally samples
age of the patient (children often have a narrow bandwidth of frequencies
more frequent interictal spiking or re- (0.5 Hz to 70 Hz); brain frequency ac-
corded seizures); (2) seizure classifica- tivity is much broader.
tion and epileptic syndrome diagnosis The presence of artifacts is a con-
(patients with primary generalized sei- stant concern in the interpretation of
zures and epilepsies usually have higher the EEG. These may include electrode
yield of diagnostic interictal changes popping, high electrode impedance,
on EEG); (3) presence of AED therapy and other technical and environmen-
(which can decrease the yield for tal factors. Physiologic changes associ-
interictal discharges); and (4) proximity ated with head movement, tremor, eye
of the EEG recording to seizure activity opening and closure, sweating, nystag-
(since patients with more recent sei- mus, and myogenic activity may be
zures more frequently have diagnostic difficult to differentiate from epilepti-
EEG recordings). form discharges. The EEG study is usually
The presence of an epileptiform brief, approximately 20 to 40 minutes,
abnormality does not always indicate a and may fail to identify epileptiform
seizure disorder. Occipital spikes have alterations in people with epilepsy. At
been observed in blind people, and least 6 cm2 of cerebral cortex must be
generalized spikes have been reported involved to generate a scalp-recorded
in relatives of patients with genetic gen- epileptiform discharge.29
eralized epilepsies. Interictal epilepti- When EEG alterations are seen, the
form discharges may also be seen in routine EEG study almost invariably re-
patients receiving bupropion, cefepime, cords interictal EEG alterations because
clozapine, lithium, and tramadol, and in of the paroxysmal nature of the sei-
individuals with certain metabolic disor- zures.20,21,23 Recognition of the ictal
ders such as patients with renal failure EEG pattern (ie, during the seizure)
or an acute encephalopathy. may be necessary to confirm the diag-
Limitations. The limitations associ- nosis of a seizure disorder and to sug-
ated with routine EEG are significant gest seizure type(s). In many patients,
and have been known since the initial interictal epileptiform activity may prove
studies of this diagnostic tool in people sufficient to select the appropriate treat-
with epilepsy (Table 1-3). Physiologic ment. The sensitivity and specificity of
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 Diagnosis of Epilepsy

TABLE 1-3 Diagnostic Use of EEG Recordings

Factors Beneficial Features Limitations

Duration of study Brief (G60 minutes) Low to moderate diagnostic
sensitivity given limited
recording duration and single
sampling point in time
Location Outpatient or inpatient None
Patient age Children or adults Maturational effects of EEG
may be difficult to interpret,
patient cooperation
required for EEG
Video monitoring Outpatient or inpatient availability, Higher cost, inpatient
actual spell recording with concomitant recordings require intensive
video-recorded behavior and ictal EEG resources and expose patient
is the gold standard for diagnosis of to temporary danger if
spell/seizure type when clinical history antiepileptic drugs
and/or interictal EEG is unclear are discontinued
EEG interpretation Reproducible results, study findings Overinterpretation of
can be compared to prior EEGs, nonspecific findings, normal
highly specific patterns paroxysmal alterations (eg,
drowsiness), benign variants,
medication effects, and
artifacts can be mistaken for
abnormal epileptiform activity

EEG = electroencephalogram.

ictal EEG, however, is superior to mal variants in EEG (eg, benign sporadic
interictal EEG as a diagnostic tool. sleep spikes or wicket waves during
Interictal EEG alone may lead to errors drowsiness or “build-up” slow waves
in diagnostic classification that result in with intermixed spiky components dur-
an ineffective treatment strategy. The ing hyperventilation) may also be in-
routine EEG may be persistently normal correctly identified as epileptiform
in an individual with epilepsy, even discharges that suggest the diagnosis
with drug-resistant seizure disorders of epilepsy.30 These paroxysmal alter-
(Case 1-2). Paroxysmal alterations (ei- ations are not associated with an in-
ther nonspecific or potentially epilep- creased epileptogenic potential.
tiform discharges) may be identified in Electroencephalography and focal
a patient with nonepileptic behavioral seizures. Focal seizures are the most
events (PNES). The interictal EEG pat- common seizure type in patients with
tern also may be an unreliable indica- epilepsy. The most epileptogenic region
tor of the classification of seizure type. or zone (the area likely to be associated
For example, generalized spike-and-wave with seizures) is the medial temporal
discharges may be present in a patient lobe, including the amygdala and hip-
with a focal seizure disorder; general- pocampus. The majority of patients
ized paroxysmal abnormalities may be with extratemporal focal seizures (ie,
present without well-defined focal alter- seizures emanating outside the tempo-
ation(s). Nonspecific benign and nor- ral lobe) have seizures of frontal lobe

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 Case 1-2
A 33-year-old man presented with two recent unprovoked nocturnal
tonic-clonic seizures during sleep in the last 3 months. During one seizure,
he lacerated the lateral aspect of his tongue and had probable urinary
incontinence. The seizures were witnessed by his spouse. The patient
had no history of remote symptomatic neurologic disease. There was no
family history of seizures. The patient’s medical history was essentially
unremarkable and did not suggest an etiology for his seizures. He was
receiving no medications and denied a history of alcohol or substance
abuse. Neurologic examination was normal. Both a CT and an MRI of
his brain were normal. An awake-asleep EEG with standard activating
procedures was unremarkable.
Comment. This patient would be an appropriate candidate for
antiepileptic drug therapy despite the normal EEG recording. The
probability of a third seizure is sufficiently high to justify empiric therapy
in the absence of a determined etiology or an epileptiform EEG finding.
It is best to “treat the patient and not the EEG” in this setting.

origin. An extratemporal region of sei- reveal epileptiform discharges.31 The

zure onset can be confirmed in 10% to interictal EEG finding in the patient
30% of patients with focal seizures. with focal seizures is the focal-spike or
Extratemporal seizures are more likely sharp-wave discharge identifying the
associated with EEG studies that do not irritative zone (Figure 1-2). Focal spikes

FIGURE 1-2 EEG of a patient with focal seizures of right frontal lobe origin that reveals right superior frontal (F4) and
midfrontal (Fz) spike discharges during sleep.

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 Diagnosis of Epilepsy

KEY POINT
h The sensitivity and or sharp waves are usually asymmetric
and may be bilaterally synchronous, TABLE 1-4 Epileptogenic
specificity of the routine Potential of
EEG in focal epilepsy often followed by a slow wave. They Paroxysmal Discharges
depends on the generally have a radial dipole (formed
localization of the when current flow is perpendicular b High (990%)
epileptic brain tissue, to the scalp). The field of distribution
Anterior temporal lobe spikes
duration of the recording, on a scalp recording depends on the
use of supplementary location of the irritative zone. They Vertex spikes
electrodes, frequency of occur singly but in some cases can be Generalized paroxysmal
seizure activity, and focal polyspikes, and the state during fast activity
timing of the study in
which they appear (ie, awake or asleep) Generalized slow spike
relationship to the most
can vary with the epilepsy syndrome. and wave
recent seizure.
Another interictal EEG pattern is tem- Hypsarrhythmia
poral intermittent rhythmic delta ac-
tivity (TIRDA). The interictal EEG b Moderate (50Y90%)
alterations suggest an increased epilep- Frontal lobe spikes
togenic potential. Epileptiform changes Central-midtemporal spikes
during a routine EEG recording may
Occipital spikes
confirm the classification of the seizure
disorder and suggest the region of Generalized atypical spike
seizure activity in the brain. The most and wave
common interictal EEG finding in adult Photoparoxysmal discharge
patients with focal seizures is the ante- b None
rior temporal lobe spike discharge. The
anterior temporal lobe epileptiform Benign variants
discharge is highly epileptogenic, and Normal sleep activity
80% to 90% of these patients have a Photic driving
seizure disorder (Table 1-4). The sen-
Hyperventilation-induced
sitivity and specificity of the routine
changes
EEG in focal epilepsy depends on the
localization of the epileptic brain tissue Drowsy bursts
(with EEG in patients with temporal
lobe seizures having higher diagnostic
yield than extratemporal seizures), du- poral spikes may not be identified
ration of the recording, use of supple- during routine scalp-recorded EEG
mentary electrodes, frequency of studies. Supplemental scalp electrodes
seizure activity, and timing of the study may prove useful to localize the topog-
in relationship to the most recent sei- raphy of the irritative zone. The diag-
zure. Patients with focal seizures may nostic yield of the EEG in patients with
have generalized or bihemispheric focal seizures depends on multiple
spike discharges that are widely distrib- factors, including the localization of
uted without lateralization, or bilateral the epileptogenic zone.20,21,23Y26 In pa-
independent temporal lobe epilepti- tients with temporal lobe epilepsy, 80%
form alterations. Secondary bilateral to 90% will have predominantly tem-
synchrony has been observed in pa- poral lobe epileptiform discharges.
tients with focal seizures of mesial Bitemporal spike discharges may be
frontal lobe origin. identified in 25% to 33% of patients
Diagnostic yield of electroencepha- with temporal lobe epilepsy. Only ap-
lography in focal seizures. Mesial tem- proximately one-half of patients
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 KEY POINT
with extratemporal seizures will have Generalized seizures. The pre-
h Approximately 10% to
interictal epileptiform discharges local- dominant routine EEG abnormality in 30% of patients with
ized to the correct lobe of seizure patients with a genetic generalized focal seizures of
origin. Approximately 10% to 30% of epilepsy is the widely distributed and extratemporal origin
patients with focal seizures of extra- bisynchronous alteration referred to have no interictal
temporal origin have no interictal epi- as the generalized spike-and-wave dis- epileptiform discharges
leptiform discharges on repetitive charge (Figure 1-1).32 The interictal on repetitive routine
routine EEG recordings. A lateralized, epileptiform pattern may be most EEG recordings.
but not localized, interictal abnormality prominent in the anterior or posterior
is the most common routine EEG alter- head region. The epileptiform dis-
ation in patients with extratemporal charge shows no significant lateraliza-
seizures. Patients with mesial frontal tion. Activation of the epileptiform
lobe regions of seizure onset may have abnormality may occur in response to
bisynchronous spike discharges with- selected provocative maneuvers (eg,
out obvious asymmetry. In patients hyperventilation or photic stimula-
with temporal lobe epilepsy, the EEG tion). Typically, absence seizures
pattern is a more reliable indicator of are activated with hyperventilation,
the epileptogenic zone. although epileptiform discharges in
The care and management of pa- focal epilepsies may be activated as
tients with focal seizures is deter- well. Photic stimulation is a useful
mined by the response to therapy method of activating epileptiform dis-
and not necessarily the presence of charges primarily in patients with a
interictal epileptiform discharges after genetic generalized epilepsy, but also
therapy is initiated (Case 1-3). The in those with focal seizures. Photic
use of routine EEG to select candi- driving of a posterior rhythm is a
dates for AED discontinuance is con- normal response, and a photomyogenic
troversial. Other factors, including response that consists of brief repetitive
seizure type, history of remote symp- muscle activity, such as eye blinks seen
tomatic neurologic disorders, difficulty in anterior electrodes that increase in
attaining seizure remission, and seizure- amplitude with flash frequency and
free duration may be more predic- cease when stimulation stops, is a
tive determinants of the success of normal variant. A photoparoxysmal re-
AED discontinuance. sponse (Figure 1-3) that consists of

Case 1-3
A 42-year-old man had a history of recurrent focal seizures. He was seizure
free on a single antiepileptic drug (AED) for over 1 year. The patient was
highly compliant with his medical regimen. He denied drug adverse
effects. He was employed and operating a motor vehicle without difficulty.
A routine EEG that was performed while he was on AED therapy showed
intermittent right temporal interictal epileptiform discharges during sleep.
Comment. This patient has a seizure disorder in remission on AED
therapy. The presence of an interictal epileptiform discharge would not
require a change in medical therapy or an increase in the dose of medication.
The patient’s performance on his AED therapy (seizure freedom and
without adverse effects) is the best indicator of medication response.
The abnormal interictal EEG study would also not require a change in
his ability to operate a motor vehicle.

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 Diagnosis of Epilepsy

FIGURE 1-3 EEG during photic stimulation of a patient with a generalized seizure disorder showing a photoparoxysmal
response. Ipsilateral ear reference montage.

KEY POINT generalized spike-wave or polyspike- types, including myoclonic, generalized

h Seizure type(s), frequency, and-wave discharges, which may be tonic-clonic, and atonic seizures. The
and specific epilepsy anterior or posterior dominant and that interictal EEG pattern in these patients
syndrome are important may or may not be associated with loss reveals “slow” spike and wave, which
determinants of the of awareness or myoclonic jerks, is an occurs at 1.5 Hz to 2.5 Hz. Patients with
diagnostic yield of
abnormal response often associated pervasive developmental delay may
routine EEG studies in
with epilepsy, especially if it outlasts have increased diffuse slow-wave activ-
patients with a genetic
generalized epilepsy.
the duration of the photic stimulation. ity and disorganization of the EEG
Photoparoxysmal responses are most background. These individuals may have
often seen in genetic generalized epi- Lennox-Gastaut syndrome, associated
lepsies, such as childhood absence epi- with a chronic global encephalopathy,
lepsy with or without eyelid myoclonia, multiple seizure types, and generalized
juvenile absence epilepsy, and juvenile spike-and-wave discharges (Figure 1-4).
myoclonic epilepsy.33 Almost invariably, patients with this un-
Seizure type(s), frequency, and spe- favorable epilepsy have tonic seizures
cific epilepsy syndrome are important with generalized paroxysmal fast activity
determinants of the diagnostic yield of bursts during slow-wave sleep. Patients
routine EEG studies in patients with a with juvenile myoclonic epilepsy and
genetic generalized epilepsy.30 Patients generalized tonic-clonic seizures upon
with childhood absence epilepsy may awakening usually have a normal EEG
have a normal EEG background with the background with intermittent general-
emergence of 2.5-Hz to 3.5-Hz general- ized spike-and-wave discharges and
ized spike-and-wave discharges. Individ- polyspikes (3.5 Hz to 6 Hz).32 These in-
uals with atypical absence seizures are terictal EEG alterations are more likely
more likely to have developmental to occur upon arousal after sleeping
delay and experience multiple seizure and during photic stimulation.

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FIGURE 1-4 EEG revealing generalized slow spike-and-wave discharges and diffuse slowing in a patient with
Lennox-Gastaut syndrome. Ipsilateral ear reference montage.

Video-Electroencephalography cal center.34 The studies may be par- KEY POINTS

Recordings ticularly important in neurocritical care h Indications for video-EEG
units in the assessment of encephalopa- studies include the
Video-EEG monitoring may be used to
evaluation of spells,
evaluate patients with presumed seizure thy and nonconvulsive status epilepticus.
seizure classification,
disorders. In a minority of people with An estimated 25% to 33% of patients
seizure quantification,
epilepsy, video-EEG monitoring is nec- admitted to an epilepsy monitoring unit assessment of seizure-
essary for correct diagnosis prior to AED have nonepileptic behavioral events precipitating factors,
therapy (Figure 1-5). Indications for (PNES) (Figure 1-6).35,36 Spell symp- and surgical localization
these EEG studies include the evaluation tomatology, patient examination by in drug-resistant
of spells, seizure classification, seizure monitoring personnel during the event, focal epilepsy.
quantification, assessment of seizure- and lack of electrographic seizure activity h Spell symptomatology,
precipitating factors, and surgical local- are used to render the diagnosis of a patient examination by
ization in drug-resistant focal epilepsy. nonepileptic disorder. Correct classifi- monitoring personnel
Video-EEG monitoring can be performed cation of a nonepileptic disorder will during the event, and
on an outpatient or inpatient basis or in permit discontinuance of AED therapy lack of electrographic
a specially designed epilepsy monitor- and institution of appropriate medical seizure activity are used
ing unit. Ambulatory studies are now treatment. Only about 9% to 15% of pa- to render the diagnosis
of a nonepileptic disorder.
available that provide digital video-EEG tients with psychogenic events have co-
monitoring at sites remote from a medi- existent seizure disorders.35 Repeat

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 Diagnosis of Epilepsy

FIGURE 1-5 Scalp-recorded EEG change during a habitual event showing the onset of a left temporal lobe seizure. This
study was performed in the epilepsy monitoring unit with video-EEG recording. Bipolar montage.

KEY POINTS video-EEG monitoring may be necessary is considered essential in patients under-
h Only about 9% to 15% of if the initial evaluation is indeterminate.37 going a presurgical evaluation.
patients with psychogenic Inpatient video-EEG has several
events have coexistent Magnetic Resonance Imaging
limitations. First, patients may not
seizure disorders.
have a typical or habitual clinical spell The rationale for neuroimaging studies
h Focal seizures without during their inpatient stay. However, a in people with epilepsy includes iden-
loss of awareness, long-term EEG study is still potentially tification of the pathologic findings
especially when of
valuable. Over 80% of people with associated with focal or generalized
extratemporal origin,
epilepsy will have interictal epilepti- seizures, localization of the epilepto-
may not be associated
with a scalp-recorded
form discharges present during 3 days genic zone, and determination of sur-
seizure discharge. of EEG recording. Second, focal sei- gical localization in drug-resistant focal
zures without loss of awareness, espe- epilepsy (Figure 1-7 and Figure 1-8)
h All individuals with
cially when of extratemporal origin, (Case 1-4).38 MRI is the structural
seizures should undergo
an MRI study unless the
may not be associated with a scalp- neuroimaging procedure of choice in
patient has a confirmed recorded seizure discharge. Individuals people with epilepsy.38Y43 Neuroimag-
genetic generalized with supplementary motor area seizures, ing studies are increasingly important
epilepsy syndrome however, typically will have sleepYrelated for the evaluation of patients with recur-
(eg, childhood absence hypermotor seizures. Finally, the cost of rent paroxysmal symptoms suggesting a
epilepsy) or a these studies is substantial. The cost- seizure disorder in the presence of un-
contraindication exists effectiveness of video-EEG monitoring as remarkable or indeterminate routine
that does not permit a diagnostic tool is more difficult to assess EEG studies. All individuals with seizures
this imaging procedure than is the relevant information obtained should undergo an MRI study unless
to be done safely. using these studies. Inpatient monitoring the patient has a confirmed genetic

32 www.ContinuumJournal.com February 2016

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FIGURE 1-6 EEG during a psychogenic nonepileptic seizure. A, EEG during psychogenic nonepileptic seizure revealing a
prominent artifact related to muscle activity and movement during the “convulsive” behavior. B, EEG
immediately after the motor activity has ceased showing a normal awake background without epileptiform
activity. The patient appeared unresponsive at this time. This study was performed in the epilepsy monitoring unit with
video-EEG recording. Bipolar montage.

generalized epilepsy syndrome (eg, Importantly, 12% of patients in one

childhood absence epilepsy) or a con- series of 1013 patients with a first
traindication exists that does not per- seizure had an abnormal MRI head
mit this imaging procedure to be done (specific pathologic alteration) in the
safely. Even individuals with single presence of a normal CT head.39 MRI is
seizure episodes may benefit from an a reliable indicator of selected underly-
MRI study because 29% of these pa- ing pathologies with varying degrees
tients may have abnormal imaging.39 of sensitivity and specificity that are
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 Diagnosis of Epilepsy

FIGURE 1-7 Coronal fluid-attenuated inversion recovery (FLAIR)

MRI sequence showing increased signal in the right
hippocampal region. Pathology following epilepsy
surgery revealed mesial temporal sclerosis.

FIGURE 1-8 Sagittal MRI using the double inversion recovery

sequence showing a focal signal change consistent
with “bottom-of-sulcus dysplasia” (arrow).
Pathology revealed focal cortical dysplasia.

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 Case 1-4
A 25-year-old man had a history of recurrent
focal seizures beginning in childhood. He had
nocturnal seizures during sleep associated with
hypermotor activity. His neurologic examination
was normal. Routine EEG revealed only mild
diffuse nonspecific slowing. Video-EEG monitoring
showed a bifrontal ictal discharge that was
lateralized to the right hemisphere. Brain MRI
showed a transmantle sign seen in the
oblique-coronal fluid-attenuated inversion
recovery (FLAIR) sequence (Figure 1-9). The
patient underwent chronic intracranial EEG
monitoring that confirmed the concordance
between the area of seizure onset and the
MRI-identified structural abnormality. The
pathologic findings were consistent with focal
cortical dysplasia. The patient was seizure
free following a focal cortical resection.
Comment. The imaging finding of a
transmantle sign is a specific alteration
that has been shown to be consistent with FIGURE 1-9 Imaging of the patient in Case 1-4. Coronal
focal cortical dysplasia and is associated fluid-attenuated inversion recovery (FLAIR)
MRI sequence showing a focal lesion in the
with a favorable operative outcome in right frontal lobe consistent with the “transmantle sign.”
patients with drug-resistant focal epilepsy. Pathology revealed focal cortical dysplasia.
MRI was pivotal in this patient to suggest
the area of seizure onset, the underlying
pathology, and an operative strategy.

associated with focal seizures, includ- sclerosis defined on histopathology

ing tumor, vascular malformation, (Figure 1-7). Studies demonstrated that
posttraumatic changes, mesial tempo- more sophisticated methods of image
ral sclerosis, and malformations of corti- reconstruction from 3-D acquisitions
cal development.40Y43 allow a better evaluation of patients with
The optimal MRI technique in adult discrete structural lesions (eg, focal
patients with focal seizures includes use cortical dysplasia) (Figure 1-8).40Y43
of a 3-tesla study in the coronal or
oblique-coronal, axial, and sagittal planes CONCLUSION
using T1-weighted, T2-weighted, and Epilepsy is a clinical diagnosis that is
fluid-attenuated inversion recovery often based on medical history alone as
(FLAIR) sequences. MRI epilepsy proto- health care providers rarely personally
cols should include a three-dimensional observe the patient’s seizure activity.
(3-D) T1-weighted volumetric acquisi- EEG is the most important diagnostic
tion with isotropic voxel size of 1 mm or tool that may assist in diagnosis, seizure
1.5 mm to enable the reconstruction classification, and monitoring response
of images in any plane.38Y41 FLAIR to treatment. Importantly, individuals
imaging sequences have shown an with normal routine EEG recordings
accuracy of 97% for detecting abnor- and recurrent seizures may be appro-
malities associated with mesial temporal priate candidates for AED therapy.

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 Diagnosis of Epilepsy

Video-EEG monitoring may be neces- results. Epilepsia 2015;56(3):340Y343.

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 Review Article

Management of a
Address correspondence to
Dr Gregory K. Bergey, Johns
Hopkins School of Medicine,
600 North Wolfe Street, Meyer
2-147, Department of Neurology,
Baltimore, MD 21287,
[email protected].
First Seizure
Relationship Disclosure: Gregory K. Bergey, MD, FAAN
Dr Bergey has received
personal compensation for
serving as an associate editor
of Neurotherapeutics and has ABSTRACT
received research support
from the National Institutes Purpose of Review: Assessment of the patient with a first seizure is a common and
of Health. important neurologic issue. Less than 50% of patients who have a first unprovoked
Unlabeled Use of seizure have a second seizure; thus, the evaluation should focus on determining the
Products/Investigational
Use Disclosure:
patient’s risk of seizure recurrence.
Dr Bergey reports no disclosure. Recent Findings: A number of population studies, including some classic reports,
* 2016 American Academy have identified the relative risk factors for subsequent seizure recurrence. The 2014
of Neurology. update of the International League Against Epilepsy definition of epilepsy incorporates
these findings, and in 2015, the American Academy of Neurology published a guide-
line that analyzed the available data.
Summary: Provoked or acute symptomatic seizures do not confer increased risk for
subsequent unprovoked seizure recurrence. Multiple seizures in a given 24-hour
period do not increase the risk of seizure recurrence. Remote symptomatic seizures, an
epileptiform EEG, a significant brain imaging abnormality, and nocturnal seizures are
risk factors for seizure recurrence. Antiepileptic drug therapy delays the time to second
seizure but may not influence long-term remission.

Continuum (Minneap Minn) 2016;22(1):38–50.

INTRODUCTION of 2014, the International League

Patients presenting with a first seizure, Against Epilepsy (ILAE) defines epi-
whether as a child or adult, are often lepsy as at least two unprovoked sei-
quite distressed. When one considers zures occurring more than 24 hours
that about 10% of the population will apart, one unprovoked seizure and a
have a seizure at some time in their probability of further seizures similar
lives but less than half of these patients to the general recurrence risk (approx-
will have multiple seizures, the impor- imately 60% or more) over the subse-
tance of proper assessment is brought quent 10 years after two unprovoked
into focus. The article “Diagnosis of Epi- seizures, or the diagnosis of an epilep-
lepsy and Related Episodic Disorders” tic syndrome.2 The components of this
by Erik K. St. Louis, MD, MS, FAAN, and definition are drawn from published
Gregory D. Cascino, MD, FAAN,1 in this studies that are discussed in this article.
issue of Continuum discusses the Accurately making an early assess-
process of making the diagnosis and ment avoids unnecessary treatment of
proper evaluation, so for the purpose patients unlikely to have a second un-
of this article, it will be assumed that provoked seizure. Indeed, because of
the patient has had an epileptic seizure the importance of this early evaluation,
(either convulsive or nonconvulsive), a number of epilepsy centers have es-
and the evaluation will only be men- tablished first seizure clinics. In these
tioned in the context of findings that clinics, patients who have experienced
influence the risk of seizure recurrence. a first seizure are seen promptly by an
It is worth repeating, however, that as experienced epileptologist with the

38 www.ContinuumJournal.com February 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINTS
hope that this early expert assessment seizures. Seizures due to a preexisting h The diagnosis of
will more appropriately guide treat- brain abnormality or disorder (eg, trau- epilepsy is appropriately
ment. Decisions about treatment after a matic brain injury [TBI]) are considered used even after a single
single seizure include considerations of remote symptomatic seizures. While some unprovoked seizure
the chance of having a second seizure, authors6 group provoked and acute if the risk of a
the consequences of having a second symptomatic seizures together, some second unprovoked
seizure, efficacy of medications in pre- benefit exists in separating these two seizure is significant
venting future seizures, and the poten- categories, as will be discussed further. (approximately 60%
tial toxicity of antiepileptic drugs (AEDs). Sometimes a first seizure and the asso- or more).
The chance of seizure recurrence is one ciated EEG findings allow a syndromic h A very important part
of the most important determinations classification that indicates likely recur- of the history from
that will guide treatment decisions. rence. Obviously, not all patients fit into patients with a “first
While one must still deal with proba- these categories; in some, the cause of the seizure” is determining
bilities, fortunately, a number of pop- seizures is unknown even after evaluation. whether they have,
in fact, had other
ulation studies exist that can assist in In assessing the patient with a “first”
unrecognized seizures.
this determination. Of more than 180 seizure, the neurologist must also de-
practice parameters published by the termine whether the patient has actually
American Academy of Neurology (AAN), had multiple seizures. It is common for
six deal with initiation of AED therapy, patients to seek medical care after the
including evaluation of a first seizure in first generalized tonic-clonic seizure,
children,3 treatment of the child with a but they may not have appreciated the
first unprovoked seizure,4 assessment of significance of myoclonic jerks after
a first seizure in adults,5 and the 2015 awakening, nocturnal tongue biting,
guideline for the management of an un- or brief staring spells (absence or focal
provoked first seizure in adults.6 The seizures with dyscognitive features). A
2015 guideline is the most relevant to careful history will often determine that
the discussion in this article. (Refer to many patients with newly diagnosed
Appendix A for a summary of the AAN seizures have actually had multiple
evidence-based guideline for clinicians.) events. This is particularly true in pa-
In framing the discussion, it is worth- tients with complex partial seizures and
while to review the classification of a children with absence seizures.
first seizure (Table 2-1). Provoked sei- If the patient has had multiple
zures are due to identifiable causes, seizures, it is important to determine
such as medications, drugs of abuse, when these seizures occurred over
or metabolic causes. Seizures resulting time. In a study by Kho and colleagues,7
from acute brain processes (eg, enceph- 72 patients with multiple seizures in
alitis) are classified as acute symptomatic a 24-hour period as their first seizure

TABLE 2-1 Classification of a First Seizure

b Provoked seizure (eg, seizure caused by toxin, medication, or metabolic factors)

b Acute symptomatic seizure (seizure cause by acute illness such as stroke,
traumatic brain injury, encephalitis/meningitis)
b Remote symptomatic seizure (seizure caused by preexisting brain injury)
b Seizure associated with epileptic syndrome (eg, juvenile myoclonic epilepsy)
b Other unidentified

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 Management of a First Seizure

KEY POINTS
h Multiple unprovoked presentation were compared with 425 after a first unprovoked seizure, the
seizures within a 24-hour patients presenting with a single sei- overall risk for a second seizure was
period should be zure. The recurrence rate overall was only 33%. After a second seizure, how-
considered a single 38% (28% provoked, 38% idiopathic, ever, the risk of a third unprovoked
event, and this by itself 53% remote symptomatic); however, seizure rose to 76%. This recurrence
does not establish the those presenting with multiple seizures risk is incorporated into the ILAE de-
diagnosis of epilepsy. in a 24-hour period were no more likely finition. Most recurrences are within
h After two unprovoked to have seizure recurrence than those 1 year of the second or third seizure.
seizures separated by presenting with a single seizure, irre- After a second symptomatic seizure,
more than 24 hours spective of etiology or treatment the risk of a third seizure over 5 years
occur, the risk of (Figure 2-1). The 2014 ILAE definition was 87%, compared to 64% recurrence
additional seizures is incorporates these findings by stipulat- risk for idiopathic or cryptogenic sei-
high (more than 60%), ing “at least two unprovoked seizures zures. In another study in children, the
the diagnosis of epilepsy occurring more than 24 hours apart.”2 risk of a third seizure after a second
(seizure disorder) is
One might still elect to begin AED ther- seizure was 72%.9
present, and antiepileptic
apy (eg, for remote symptomatic sei-
drug therapy is
zures), but this decision to treat should ANTIEPILEPTIC DRUG
often warranted.
not be influenced by multiple seizures PROPHYLAXIS
in a 24-hour period. The only evidence supporting AED
After two unprovoked seizures (more prophylaxis is in patients with high-risk
than 24 hours apart), the risk of sub- head injury in the early posttraumatic
sequent seizures increases dramatically. period10; this is addressed in an AAN
In a study by Hauser and colleagues8 guideline.11 No evidence exists for AED
that prospectively followed 204 patients treatment of patients with brain tumors,12

FIGURE 2-1 Data showing no difference in cumulative chance of seizure recurrence whether
patients presented with a single seizure (n = 425) or multiple seizures (n = 72).
7
Reprinted with permission from Kho LK, et al, Neurology. www.neurology.org/content/67/6/1047.
B 2006 American Academy of Neurology.

40 www.ContinuumJournal.com February 2016

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINTS
cerebral cavernous hemangiomas, cere- seizures may recur if the patient is ex- h Except for during the
brovascular events, or craniotomy13 be- posed again to the provocative agent. first week after severe
fore a first seizure occurs. Obviously, if one could accurately head trauma, no
predict who would and who would not evidence exists to
ANTIEPILEPTIC DRUG have a second unprovoked seizure, then support administration
TREATMENT INITIATION specific recommendations could be pro- of antiseizure medication
After a first seizure occurs, the fol- vided for all patients. In reality, only to prevent a first
lowing factors should be considered predictions of probabilities of seizure unprovoked seizure.
in deciding whether or not to start recurrence can be made. For example, h Patients with provoked
AED treatment. the young child with a single convul- seizures do not have
sion and no risk factors (eg, normal epilepsy and do not
Provoked Versus Unprovoked examination, EEG, and imaging) has a need seizure medication
Seizures relatively low risk of seizure recurrence. if the provoking cause
The ILAE definition defines epilepsy as can be eliminated.
unprovoked seizures. Table 2-2 is a Type of Seizure
partial list of some of the more com- Simple partial (focal) seizures with only
mon causes of provoked seizures. While sensory or focal motor symptoms with-
on occasion hypoglycemia can produce out alteration of consciousness are less
focal neurologic findings, in general, disabling than complex partial seizures
provoked seizures are generalized with alteration of awareness. The deci-
convulsive events, not focal seizures. sion to treat these simple partial (focal)
Alcohol-provoked seizures, either due minor seizures without alteration of
to intoxication or withdrawal, will not awareness should be individualized.
be focal seizures, recognizing that in- The 8-year-old with a focal motor sei-
toxication may lower seizure thresh- zure of the mouth and an EEG showing
old in the patient with focal brain centrotemporal spikes consistent with
injury. Therefore, a patient presenting benign rolandic epilepsy can reason-
with symptoms suggesting either focal ably be left off medication unless gen-
seizures (eg, focal motor activity, tran- eralized tonic-clonic seizures occur or
sient confusion) or focal seizures with recurrent focal seizures produce psy-
secondary generalization should be chosocial distress. In contrast, the
treated as having an unprovoked sei- 23-year-old with a frontal cortically
zure. Provoked seizures usually do not based cavernous hemangioma with a
warrant AED therapy. In some instances, surrounding hemosiderin ring and a
prescribed medication is essential yet focal motor seizure clinically similar
is a cause of provoked seizures in that to that of the 8-year-old may warrant
patient. AED therapy may be justified for therapy because of the risk of second-
a period of time. Of course, provoked ary generalization and the fact that

TABLE 2-2 Examples of Provoked Seizures

b Alcohol withdrawal
b Barbiturate or benzodiazepine withdrawal
b Metabolic (eg, hyponatremia, hypocalcemia, hypoglycemia, hyperglycemia)
b Drugs of abuse (eg, cocaine, amphetamines, phencyclidine)
b Medications (eg, tramadol, imipenem, theophylline, bupropion)

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 Management of a First Seizure

KEY POINTS
h Patients over the age the consequences of a disabling sei- on this small group was undetermined
of 60 with a new zure (eg, focal with altered awareness, but certainly may have delayed the time
unprovoked seizure secondarily generalized seizure) would to second seizure. Of the 48 patients,
should be considered be much greater in this active adult and five were lost to follow-up before 1 year
symptomatic (often because of the symptomatic nature of and 16 died before 1 year, confound-
cerebrovascular disease) the focal seizure. Febrile seizures are ing analyses. Many first unprovoked
even if the evaluation another seizure type that typically does seizures in older adults can be consid-
is unrevealing. not require therapy. Refer to the article ered remote symptomatic seizures. Treat-
h Patients with acute “Febrile Seizures” by Ajay Gupta, MD,14 ment decisions in this age group should
symptomatic seizures in this issue of Continuum. also include the living and lifestyle
are much less likely situation of the patient (eg, active and
to have subsequent Patient Age driving versus long-term care resident).
seizures than are The question of whether the elderly
patients with remote patient with a single unprovoked sei- Acute Versus Remote
symptomatic seizures. Symptomatic Seizures
zure warrants different consideration
h Patients with acute from a child is not fully resolved. The It is important to consider acute symp-
symptomatic seizures incidence of new-onset epilepsy is tomatic seizures separately from re-
do not need long-term highest in children and the older adult.15 mote symptomatic seizures. A study by
antiepileptic drug
Elderly patients with unprovoked sei- Hesdorffer and colleagues18 compared
therapy after the
zures do not have idiopathic seizures. 262 patients with acute symptomatic
period of acute illness
unless a subsequent
Even if imaging is unrevealing or non- seizures with 148 patients with a first
seizure occurs. specific, these seizures, while classi- unprovoked seizure due to a static brain
fied as due to unknown etiology, may lesion (ie, remote symptomatic). They
be due to an undefined cause rather defined acute symptomatic as within
than being idiopathic. Cerebrovascu- 7 days of stroke or TBI and during the
lar disease is the most common cause active infection for central nervous sys-
of seizures in the elderly.16 Unprovoked tem (CNS) infections. Patients with a
seizures in elderly patients should be first acute symptomatic seizure were
considered focal, with or without sec- 8.9 times more likely to die within 30 days
ondary generalization, even if the pre- compared to those with a first unpro-
sentation is one of only a generalized voked seizure. After 30 days, the 10-year
convulsive seizure. A study of all pa- risk of mortality did not differ between
tients in Marshfield, Wisconsin, over the two groups. Over a 10-year period,
age 50 who experienced a first seizure individuals with a first acute symptom-
between 1996 and 1998 identified 48 atic seizure were 80% less likely to ex-
patients (incidence 162 per 100,000 perience a second unprovoked seizure
patient years).17 Of these, 12 had re- compared to individuals with a first un-
current unprovoked seizures (ie, epi- provoked seizure due to a remote symp-
lepsy), 14 had a single seizure and tomatic cause (Figure 2-2). The etiologies
abnormal EEG or imaging, and 22 had of acute symptomatic seizures in this
a single seizure with normal studies. study were stroke (34.7%), TBI (34.7%),
During a 12-month follow-up, 6 of the and CNS infection (30.6%). The etiol-
22 patients (27%) with a single seizure ogies of the first unprovoked remote
and a normal evaluation had a second symptomatic seizure were stroke
seizure. Interestingly, none of the 14 (68.2%), TBI (25%), and CNS infection
patients with abnormal tests had a sec- (6.8%). Patients 65 years of age or older
ond seizure in the 12-month follow-up accounted for 31.7% of the patients
period, but most of these patients (87.5%) with the first acute symptomatic seizure
were treated; the influence of treatment but almost half (48.7%) of those with a
42 www.ContinuumJournal.com February 2016

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 KEY POINT
h Patients with an
unprovoked remote
symptomatic seizure
have a high risk of
seizure recurrence and
often fulfill the
International League
Against Epilepsy criteria
for the diagnosis
of epilepsy.

FIGURE 2-2 Risk of subsequent seizure over 10 years after acute symptomatic seizure during
acute illness (eg, stroke, central nervous system infection, traumatic brain injury)
compared with risk of subsequent seizure in patients with remote symptomatic
unprovoked seizure (ie, previous stroke, central nervous system infection, traumatic brain injury).
18
Reprinted with permission from Hesdorffer DC, et al, Epilepsia. onlinelibrary. wiley.com/doi/10.1111/j.1528-1167.2008.
01945.x/full. B 2009 International League Against Epilepsy.

first unprovoked seizure, with many of tomatic seizures are not epilepsy. This
this second group being the patients is why these acute symptomatic seizures
with cerebrovascular etiologies. In the are sometimes grouped with provoked
Hesdorffer study,18 the risk of a sub- seizures as in the 2015 AAN guideline.6
sequent seizure after a stroke was only While this is appropriate from the
33% if the seizure was acute symptom- standpoint of implications for treat-
atic, but 71.5% if unprovoked remote ment, some rationale exists for separat-
symptomatic. In TBI patients, the risk ing acute symptomatic seizures from
of seizure recurrence was 13.4% if acute other provoked seizures (eg, metabolic,
symptomatic and 46.6% if remote medications, drugs) since the former
symptomatic, and with CNS infections, can produce cerebral injury and chronic
the risk was 16.6% if acute symptomatic changes (eg, gliosis, encephalomalacia)
and 63.5% if remote symptomatic. The that may be associated with later remote
authors of the study concluded that symptomatic seizures, whereas other
the prognosis of a first acute symptom- provoked seizures do not. Case 2-1
atic seizure differs from that of a first provides an example of these consid-
unprovoked seizure when the etiology erations in clinical practice.
is stroke, TBI, or CNS infection. Acute
symptomatic seizures have a higher STUDIES OF RISK OF
mortality in the first month and lower RECURRENCE
risk for subsequent seizures than re- All of the above considerations per-
mote symptomatic seizures, and the taining to the significance of a first sei-
authors appropriately concluded that zure essentially revolve around the idea
the evidence suggests that acute symp- of risk of recurrence. Some of the best
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 Management of a First Seizure

KEY POINT
h An idiopathic seizure Case 2-1
with an EEG pattern of
A 27-year-old man presented to the emergency department after an
spike-wave discharges is
episode of right leg jerking that progressed to secondary generalization
likely to recur and
with tongue biting. His past medical history was significant for a history of
may represent an
a depressed skull fracture 2 years previously. He was treated with prophylactic
epileptic syndrome.
antiepileptic drugs (AEDs) at the time of the trauma but he had no seizures,
and his levetiracetam had been discontinued shortly thereafter.
His neurologic examination was normal. Brain MRI showed an area of
increased cortical and subcortical signal in the anterior left frontal lobe
consistent with his previous injury. EEG revealed no epileptiform activity,
but some mild focal slowing was seen in the left frontocentral region.
He acknowledged he had been drinking (four beers) while watching a
sporting event on television with his friends 36 hours prior to the seizure.
Comment. This patient has experienced a first seizure. The remote
alcohol intake was probably not enough to produce an alcohol-withdrawal
seizure, and, in any case, his seizure had focal features and provoked
seizures are not focal. His initial treatment at the time of his high-risk
(depressed skull fracture) head injury was appropriate since prophylactic
AEDs can reduce the risk of early (but not late) posttraumatic seizures.
His treating physicians at that time were correct in not continuing his
levetiracetam after the acute period since no evidence exists that AEDs
prevent late posttraumatic epilepsy. Now, however, he has had a remote
symptomatic seizure due to the previous head injury. His MRI documents
this previous injury. That his EEG is nonspecific (ie, not epileptiform) does
not alter the fact that his risk now of seizure recurrence is significant, and the
patient should now be placed on long-term AED therapy. This patient
embodies the considerations of risk factors addressed in the text of a remote
symptomatic seizure resulting from a previous high-risk head injury.

epidemiologic studies regarding the risk tain the risk of a subsequent seizure,
of seizure recurrence are now over and the cumulative risks of recurrence
25 years old and predate MRI tech- for the entire cohort were 16%, 21%,
nology. Nevertheless, the findings from and 27% at 12, 24, and 36 months,
these studies remain relevant today, respectively. If the seizures were
and, indeed, these studies were very deemed idiopathic, only 17% had a
important in drafting the 2015 AAN recurrence at 20 months, rising to 26%
guideline. The lack of imaging with by 36 months. If the seizures were
MRI in these earlier studies served to idiopathic with spike-wave discharges
underrepresent the group with remote on EEG, however, the risk of seizure
symptomatic seizures, so the conclu- recurrence was 50% at 18 months. If
sions in this highest-risk group remain the seizure was idiopathic and the pa-
valid, and the risk of patients with a tient had a sibling with seizures, the
negative evaluation (including MRI) risk of seizure recurrence was 29% at
today might be even lower than re- 4 months. Age at first seizure, seizure
ported. In the landmark study by type, and onset with status were not
Hauser and colleagues,19 244 patients risk factors in this study. It is interesting
of all ages who presented with a first that, in this study and others, whether
unprovoked seizure were followed an individual had partial (focal) or gen-
for a median of 22 months to ascer- eralized seizures did not influence the

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chance of later recurrence. One might zures. Again, treatment was administered
hypothesize that since focal seizures in 80% of patients, but no evidence
are often remote symptomatic, they showed that treatment favorably af-
would be more likely to recur, but fected seizure recurrence. A history of
this has not been demonstrated, per- a previous neurologic insult (ie, remote
haps because many primary general- symptomatic) was associated with a
ized seizures have high recurrence 2.5-fold increased risk of recurrence.
rates and some patients with general- In this report, risk factors for seizure
ized seizures may have unrecognized recurrence in patients with idiopathic
partial onset. seizures were: (1) a sibling with epilepsy,
In the 1982 Hauser study,19 patients (2) generalized spike-wave discharges
with remote symptomatic seizures had on EEG, and (3) a history of acute symp-
a risk of seizure recurrence of 34% over tomatic seizures. The latter two risk factors
36 months, but all of these seizures oc- increased the risk of seizure recurrence
curred in the first 20 months. In patients to 60% or more.
with head trauma, who comprised 37% Status epilepticus, prior acute symp-
of the remote symptomatic group, the tomatic seizures, or a Todd paralysis
recurrence risk was 40% at 12 months increased the risk of seizure recurrence
and 46% at 20 months. Most of these in those patients with remote symp-
patients (69%) were treated after the tomatic seizures. These analyses pro-
first seizure; no difference in recurrence vide additional support for separating
was noted between those treated and provoked seizures due to drugs or
the small number of untreated patients. substances that have no influence on
Overall, a prior neurologic insult was recurrence risk of later unprovoked sei-
the most powerful predictor found. A zures from acute symptomatic seizures.
spike-wave pattern on EEG was also a As discussed, acute symptomatic sei-
risk factor; a spike-wave pattern could zures have a low risk of seizure recur-
suggest the possibility of an epileptic rence (less than 25%), and chronic
syndrome (eg, juvenile myoclonic epi- AED treatment is often not warranted.
lepsy) with a known high risk of seizure But once the patient has a subsequent
recurrence. Interestingly, a focal EEG unprovoked seizure, a history of a pre-
abnormality was not a predictor in this vious acute symptomatic seizure in-
study by Hauser and colleagues.19 A creases the risk of seizure recurrence to
positive family history was also an inde- 60% or more.
pendent risk factor in these patients.
These initial 1982 studies were ex- SEIZURE RECURRENCE IN
tended to longer follow-up that was CHILDREN
subsequently published in 1990.20 These Interestingly, no population studies have
208 patients were followed for a mean demonstrated age as an independent
duration of 4 years after their first un- risk factor for seizure recurrence. Sei-
provoked seizure. Overall recurrence zures that begin in childhood are much
risks were 14%, 29%, and 34% at 1, 3, more likely to be idiopathic than in adults,
and 5 years, respectively, following the and children are more likely to be diag-
first episode. In the 149 patients with nosed with epileptic syndromes. Both
idiopathic seizures, the recurrence risks of these factors can influence the chance
were 10%, 24%, and 29%, compared to of seizure remission, a topic that will not
recurrence risks of 26%, 41%, and 48% be addressed here. As mentioned, the
at 1, 3, and 5 years, respectively, for AAN has a separate guideline for treat-
patients with remote symptomatic sei- ment of the child with a first unprovoked
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 Management of a First Seizure

KEY POINT
h Risk factors for seizure seizure.4 This is reasonable since the mal EEG. Interestingly, in children with
recurrence in children causes of unprovoked seizures in chil- symptomatic unprovoked seizures (eg,
are similar to those in dren are different than those in adults. structural lesions), an abnormal EEG
adults, with epileptiform While children may bike, swim, and was not associated with increased risk;
EEG and remote climb trees, they are not going to be that is, the increased risk was conferred
symptomatology being driving, and the risks of injury due to by the structural lesion. Risk factors are
important factors. a second seizure may be less than for similar for early or late seizure recur-
an adult. Sudden unexpected death in rence.21 In another study by the same
epilepsy (SUDEP) is a concern for pa- group,22 the 5-year recurrence risk for
tients of all ages; no evidence exists that children having a first unprovoked
treatment after a first unprovoked sei- seizure was only 21% if the seizures
zure reduces this risk. Although many were idiopathic/cryptogenic and the
of the second- and third-generation EEG was normal. Only 3% of children
AEDs have better cognitive profiles had a second seizure after 5 years from
than the first-generation agents, medi- the first.
cations can still have effects on learn-
ing, and the taking of daily medication EFFECT OF TREATMENT ON
may be stigmatizing to the otherwise RISK OF RELAPSE
healthy young child in school. In assessing the risk of a second seizure,
Shinnar and colleagues9,21 have con- treating physicians are trying to deter-
ducted very thorough studies of sei- mine when to start AED therapy. It is
zure recurrence in children. In one study hoped that AED therapy will provide
of 407 children followed a mean of seizure control or at least reduce the
6.3 years after an unprovoked seizure, risk of a second seizure. As mentioned,
42% had subsequent seizures, with the no evidence has shown that prophylac-
cumulative risk of 29% at 1 year rising tic AED therapy prevents the develop-
to 37% at 2 years and 42% at 3 years.9 ment of epilepsy. Does AED therapy
Risk factors for seizure recurrence in reduce the risk of a second seizure in
this group included remote symptom- patients who have already had their first
atology, abnormal EEG, seizures occur- unprovoked seizure?
ring during sleep, history of prior febrile Two randomized trials have attempted
seizures, and a Todd paralysis. An to answer that question. The First Seizure
epileptiform EEG was more predictive Trial (FIR.S.T) Group studied 397 pa-
of seizure recurrence than an EEG that tients, 2 to 70 years of age, 193 of whom
was abnormal but nonspecific. The risk were randomly assigned to delayed
of seizure recurrence with a normal treatment.23 The risk of recurrence in the
EEG was less than 30% over 5 years. untreated cohort was 18% at 3 months,
This risk rose to 45% with a nonep- 28% at 6 months, and 51% at 24 months.
ileptiform abnormal EEG and to over Among the treated cohort, the risk of
60% with an epileptiform EEG. Focal relapse was 25% in the first 24 months,
slowing was also associated with a high suggesting that treatment does lead to
risk of seizure recurrence in these significant reduction of risk.
studies, in contrast to the studies by The European Multicenter Epilepsy
Hauser and colleagues.19 In the studies and Single Seizure Study (MESS) was
of Shinnar and colleagues,9,21 the EEG an unmasked multicenter randomized
was the most important predictor in study of immediate versus deferred
patients with idiopathic first seizures. AED treatment in 1847 patients with
Symptomatic first seizures were more single seizures or early infrequent un-
commonly associated with an abnor- provoked seizures.24 Of the 408 patients
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 KEY POINTS
in MESS who were randomly assigned ural history of patients receiving treat- h Antiepileptic drug
to deferred treatment, 26% had recur- ment. In one large series of over 1000 therapy after a first
rence at 6 months and 39% at 2 years, patients, 37% achieved early (within unprovoked seizure
similar to the FIR.S.T results. At 5 years, 6 months of initiation of therapy) sus- increases the time to
51% of the untreated MESS cohort had tained seizure freedom, and 22% second seizure.
a recurrence of seizures; those patients achieved delayed (after 6 months of h Seizure recurrence in
followed for 8 years had a 52% recur- initiation of therapy) seizure freedom adults presenting with a
rence rate. In this later study by Marson on AED monotherapy.26 The chance first unprovoked seizure
and colleagues,24 immediate AED ther- of achieving seizure freedom declines is greatest in the first
apy increased the time to first seizure, dramatically from the first to third drug 2 years (21% to 45%
second seizure, and first tonic-clonic regimen, particularly in patients with for all patients).
seizure, as well as significantly reduced focal epilepsy for whom therapy has
the time to achieve a 2-year remission failed because of lack of efficacy, not
of seizures, but at 5-year follow-up, 76% side effects.26,27
of the patients in the immediate treat-
ment group and 77% of those in the AMERICAN ACADEMY OF
deferred treatment group were seizure NEUROLOGY PRACTICE
free, indicating that immediate AED GUIDELINES AND PRACTICE
treatment did not reduce the long-term PARAMETERS
remission rate in individuals who had In 2015, the AAN published an evidence-
infrequent or single seizures. based guideline on the management of
Kim and colleagues25 further ana- an unprovoked first seizure in adults.6
lyzed the MESS patient cohort. Using (Refer to Appendix A for a summary of
the 1443-patient cohort, they developed the AAN evidence-based guideline for
a prognostic model. The hazard ratio for clinicians.) As is required with these
seizure recurrence in the untreated arm evidence-based guidelines, the authors
was 1.35 for remote symptomatic seizures did an exhaustive review. They identi-
and 1.54 for an abnormal EEG. In de- fied 2613 articles and selected 281 for
veloping their model, they assigned two full review. A number of the studies they
points for three or four seizures prior to used in their analyses have been dis-
presentation and one point each for an cussed above, but the reader is referred
abnormal EEG, a neurologic disorder, to the guideline for the complete anal-
or two or three seizures prior to pre- ysis. Drawing from the best available
sentation. The low-risk group included published information (Class I and
those patients with only a single seizure. Class II studies), they found that risk
The high-risk group was more than of recurrence was greatest in the first
three seizures or two or more risk 2 years and was 21% to 45% for the un-
factors. The remaining patients were selected patients (Figure 2-3). Patients
classified as medium risk. There was with a prior brain lesion or insult (re-
little benefit to immediate treatment in mote symptomatic), an EEG with epi-
the low-risk group, but potential benefit leptiform abnormalities, a significant
in the medium- and high-risk groups. brain imaging abnormality, or nocturnal
Other studies have looked at pat- seizures were at increased risk of seizure
terns of treatment response in newly recurrence (Table 2-3). Two Class II
diagnosed epilepsy in which all patients studies supported the increased risk of
were treated with AEDs. While these nocturnal seizures; certain seizures (eg,
studies do not fulfill the requirements frontal lobe focal seizures) have a pre-
of evidence-based assessment, they do disposition to occur at night. The au-
provide information regarding the nat- thors found evidence that immediate
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Management of a First Seizure

KEY POINT
h Delay in antiepileptic
drug initiation until
after the second
unprovoked seizure
does not influence
the chance of
long-term remission.

FIGURE 2-3 Percentage of patients with first seizure

experiencing a recurrent seizure over time.
6
Reprinted with permission from Krumholz A, et al, Neurology.
www.neurology.org/content/84/16/1705.full. B 2015 American Academy
of Neurology.

AED therapy was likely to reduce the In 2003, the AAN published a
risk of a second unprovoked seizure practice parameter on the treatment
by about 35% over the next 2 years but of the child with a first unprovoked
that delay in initiating therapy until seizure.4 Their analyses used only
after a second unprovoked seizure did studies that included children, but
not influence the chance of long-term the authors acknowledged that few
remission. The MESS reports discussed good studies limited to children
above addresses these issues.24,25 The existed. Having said this, it should be
guidelines state that the risk for ad- mentioned that age has not been
verse events from AEDs was 7% to shown to be an independent variable
31%, but the authors acknowledged in multiple studies. Their conclusion
that a number of the studies employed was that treatment with an AED is not
first-generation AEDs and that selected indicated for the prevention of epi-
second- or third-generation AEDs could lepsy. Although treatment after a first
be better tolerated. unprovoked seizure appears to decrease

TABLE 2-3 Patients at Increased Risk for Seizure Recurrence After

First Seizure: American Academy of Neurology
Guideline Analysisa

b Patients with prior brain lesion or insult (remote symptomatic)

b Epileptiform EEG abnormality
b Significant brain-imaging abnormality
b Nocturnal seizure
EEG = electroencephalogram.
a
Data from Krumholz A, et al, Neurology.6 www.neurology.org/content/84/16/1705.full.

48 www.ContinuumJournal.com February 2016

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American Academy of Neurology and the
authors stressed that treatment deci- Practice Committee of the Child Neurology
sions should be based on a risk-benefit Society. Neurology 2003;60(2):166Y175.
assessment and individualized to take doi:10.1212/01.WNL.0000033622.27961.B6.
into account specific medical, social, 5. Krumholz A, Wiebe S, Gronseth G, et al. Practice
and family issues. parameter: evaluating an apparent unprovoked
first seizure in adults (an evidence-based
review): report of the Quality Standards
CONCLUSION Subcommittee of the American Academy of
After it has been determined that a Neurology and the American Epilepsy Society.
Neurology 2007;69(21): 1996Y2007.
patient has indeed had an epileptic doi:10.1212/01.wnl.0000285084.93652.43.
seizure, the evaluation of the patient
6. Krumholz A, Wiebe S, Gronseth GS, et al.
with a first seizure should focus on as- Evidence-based guideline: management of
sessing the risk for subsequent seizures, an unprovoked first seizure in adults: report
recognizing that many patients will of the Guideline Development Subcommittee
of the American Academy of Neurology
not have a second seizure. A careful and the American Epilepsy Society. Neurology
history should focus on identifying 2015;84(16):1705Y1713. doi:10.1212/
possible provoking or acute causes or WNL. 0000000000001487.
unrecognized previous seizures, con- 7. Kho LK, Lawn ND, Dunne JW, Linto J. First
vulsive or nonconvulsive. This should seizure presentation: do multiple seizures
within 24 hours predict recurrence?
be supplemented by good imaging Neurology 2006;67(6):1047Y1049.
(MRI preferred) and EEG to help iden- doi:10.1212/01.wnl.0000237555.12146.66.
tify those patients with remote symp- 8. Hauser WA, Rich SS, Lee JR, et al. Risk of
tomatic causes or epileptic syndromes. recurrent seizures after two unprovoked
This information can then be used to seizures. N Engl J Med 1998;338(7): 429Y434.
doi:10.1056/NEJM199802123380704.
identify those patients at high risk
for seizure recurrence. The 2015 AAN 9. Shinnar S, Berg AT, O'Dell C, et al. Predictors
of multiple seizures in a cohort of children
guideline provides an excellent criti- prospectively followed from the time of
cal review of these risk factors that their first unprovoked seizure. Ann Neurol
can be extremely useful in guiding 2000;48(2):140Y147. doi:10.1002/1531-8249.

therapy, recognizing that the decision 10. Temkin NR, Dikmen SS, Wilensky AJ, et al. A
randomized, double-blind study of phenytoin
to start AED therapy depends also for the prevention of post-traumatic
upon the patient and his or her spe- seizures. N Engl J Med 1990;323(8):497Y502.
cific life situation. doi:10.1056/NEJM199008233230801.

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 Management of a First Seizure

11. Chang BS, Lowenstein DH; Quality Standards first unprovoked seizure. N Engl J Med
Subcommittee of the American Academy of 1982;307(9):522Y528. doi:10.1056/
Neurology. Practice parameter: antiepileptic NEJM198208263070903.
drug prophylaxis in severe traumatic brain
20. Hauser WA, Rich SS, Annegers JF, Anderson VE.
injury: report of the Quality Standards
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seizure: an extended follow-up. Neurology
Neurology. Neurology 2003;60(1):10Y16.
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doi:10.1212/01.WNL.0000031432.05543.14.
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12. Glantz MJ, Cole BF, Forsyth PA, et al. Practice
21. Shinnar S, Berg AT, Moshe SL, et al. The risk
parameter: anticonvulsant prophylaxis in
of seizure recurrence after a first unprovoked
patients with newly diagnosed brain
afebrile seizure in childhood: an extended
tumors. Report of the Quality Standards
follow-up. Pediatrics 1996;98(2 pt 1):216Y225.
Subcommittee of the American Academy
of Neurology. Neurology 2000;54(10): 22. Berg AT, Shinnar S. The risk of seizure recurrence
1886Y1893. doi:10.1212/WNL.54.10.1886. following a first unprovoked seizure: a
quantitative review. Neurology 1991;41
13. Wu AS, Trinh VT, Suki D, et al. A prospective
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randomized trial of perioperative seizure
prophylaxis in patients with intraparenchymal 23. Randomized clinical trial on the efficacy
brain tumors. J Neurosurg 2013;118(4): of antiepileptic drugs in reducing the risk
873Y883. doi:10.3171/2012.12.JNS111970. of relapse after a first unprovoked
tonic-clonic seizure. First Seizure Trial
14. Gupta A. Febrile seizures. Continuum
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15. Faught E, Richman J, Martin R, et al.
24. Marson A, Jacoby A, Johnson A, et al.
Incidence and prevalence of epilepsy among
Immediate versus deferred antiepileptic
older U.S. Medicare beneficiaries. Neurology
drug treatment for early epilepsy and single
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seizures: a randomised controlled trial.
WNL.0b013e3182477edc.
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16. Rowan AJ, Ramsay RE, Collins JF, et al. New doi:10.1016/S0140-6736(05)66694-9.
onset geriatric epilepsy: a randomized study
25. Kim LG, Johnson TL, Marson AG,
of gabapentin, lamotrigine, and carbamazepine.
Chadwick DW; MRC MESS Study group.
Neurology 2005;64(11):1868Y1873. doi:10.1212/
Prediction of risk of seizure recurrence
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after a single seizure and early epilepsy:
17. Ruggles KH, Haessly SM, Berg RL. Prospective further results from the MESS trial.
study of seizures in the elderly in the Lancet Neurol 2006;5(4):317Y322.
Marshfield Epidemiologic Study Area (MESA). doi:10. 1016/S1474-4422(06)70383-0.
Epilepsia 2001;42(12): 1594Y1599. doi:10.
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Patterns of treatment response in newly
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seizure. Epilepsia 2009;50(5):1102Y1108.
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McRoberts SM. Seizure recurrence after a NEJM200002033420503.

50 www.ContinuumJournal.com February 2016

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 Review Article

Febrile Seizures
Address correspondence to
Dr Ajay Gupta, Cleveland
Clinic Lerner College of
Medicine, Cleveland Clinic
Ajay Gupta, MD Foundation, 9500 Euclid
Avenue, Cleveland OH 44195,
[email protected].
Relationship Disclosure:
ABSTRACT Dr Gupta has served on the
Purpose of Review: This article provides an update on the current understanding advisory board of Lundbeck
and has received research
and management of febrile seizures. Febrile seizures are one of the most common support from the Tuberous
age-related epileptic convulsions that lead to outpatient consultations, emergency Sclerosis Alliance for the Natural
department visits, and hospital or intensive care admissions. History Database Study.
Unlabeled Use of
Recent Findings: The Consequences of Prolonged Febrile Seizures in Childhood Products/Investigational
(FEBSTAT) study, an ongoing multicenter prospective longitudinal study, is providing Use Disclosure:
valuable insights into the subset of patients who develop febrile status epilepticus, the Dr Gupta discusses the
unlabeled/investigational use
most life-threatening type of febrile seizures with potential long-term consequences. of benzodiazepines for the
Mutations in voltage-gated ion channels and neurotransmitter receptor genes have treatment of febrile seizures.
been shown to result in familial occurrence of febrile seizures and epilepsy. Acute * 2016 American Academy
abortive treatment of febrile seizures using a commercially available rectal delivery kit of Neurology.
has gained widespread use by nonmedical caregivers as a first-line treatment at home.
Summary: Most febrile seizures are self-limiting episodes with low risk of injury,
death, and long-term neurologic consequences. Most fevers and infections that cause
febrile seizures are relatively benign and do not require extensive testing or procedures.
Long-term management requires thorough assessment and risk stratification to devise
a customized plan for each child, paying attention to the caregiver situation at home
and day care. Most important treatment efforts are directed at caregiver education
and, when appropriate, on effective use of abortive seizure treatment at home.

Continuum (Minneap Minn) 2016;22(1):51–59.

INTRODUCTION criteria for other acute symptomatic

Febrile seizures are one of the most seizures.2 While the two operational
commonly encountered acute neuro- definitions differ in the age range and
logic conditions in children. A consensus specifications of the exclusion criteria,
development conference of the National on a practical level both emphasize a thor-
Institutes of Health (NIH) first formalized ough history, physical examination, and
the definition of a febrile seizure as “an judiciously selected laboratory tests to
event in infancy or childhood, usually rule out intracranial infection, trauma, and
occurring between three months and metabolic causes (such as hypoglycemia,
five years of age, associated with fever hyponatremia, or dehydration) before
but without evidence of intracranial making a diagnosis of a febrile seizure.3
infection or defined cause.”1 In 1993,
the International League Against Epi- EPIDEMIOLOGY AND
lepsy (ILAE) proposed another definition TRIGGERING FACTORS
of a febrile seizure as a seizure occurr- The incidence of febrile seizures in the
ing in childhood after age 1 month, white population is reported to be 2%
associated with a febrile illness not to 5%.4 A few studies quote a higher
caused by an infection of the central incidence of 8% to 10% in the Asian
nervous system (CNS), without previ- population.5,6 The age range for febrile
ous neonatal seizures or a previous seizures in the literature is perplexingly
unprovoked seizure, and not meeting variable and ranges from 1 month up

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 Febrile Seizures

KEY POINTS
h The peak age for the to 8 years. A national cohort study (GEFS+). GEFS+ is reported to be caused
occurrence of febrile reported that 90% of children had their by mutations in the subunit genes
seizures is 18 to first febrile seizure before the age of (SCN1A, SCN2A, and SCN1B) that com-
24 months, and the 3 years, with the peak age being 18 to pose the neuronal voltage-gated sodium
majority of children with 24 months.4,7 Only 6% of febrile sei- channel. The GEFS+ phenotype has
febrile seizures continue zures occur before 6 months of age also been reported due to mutations
to have normal growth and 4% after 3 years of age, indicating in the GABA-A receptor subunit gene
and development. that the age of onset is a critical consid- (GABRG2).11 These conditions may re-
h Mutations in eration in further evaluation of children sult in a clinical presentation of febrile
voltage-gated sodium with febrile seizures. The majority of seizures, febrile seizures that persist
channel subunits and children with febrile seizures have nor- beyond early childhood, and even fe-
GABA receptor gene mal growth and development. Febrile brile seizures with coexisting epilepsy
subunits explain family seizures show no clear sex predilection. (afebrile spontaneous seizures) of vari-
history of febrile Most febrile seizures occur at or around able severity and seizure types. Dravet
seizures and epilepsy
the onset of fever. The fever of febrile syndrome is the most severe form of
in some patients.
seizures is commonly due to self-limiting voltage-gated sodium channelYrelated
viral infections affecting ear, nose, and epileptic encephalopathy, with febrile
throat or respiratory or gastrointestinal seizures, febrile status epilepticus, the
systems, and the risk of CNS infection is development of intractable generalized
low.3,8 However, recent studies further epilepsy, and severe cognitive impair-
specify viral strains in children who ment. Vast intrafamilial and interfamilial
have prolonged febrile seizures or fe- variation exists in the clinical course of
brile status epilepticus. In the Conse- genetic epilepsies, and genotype-
quences of Prolonged Febrile Seizures phenotype characterization is complex
in Childhood (FEBSTAT) study, febrile and poorly understood. It is important
status epilepticus was associated with to keep in mind that the majority of
the presence of human herpesvirus children with febrile seizures do not
(HHV) 6B DNA and RNA in serum (but have a family history of them, and ge-
not HHV-6A or HHV-7), suggesting acute netic testing is not routinely warranted.
HHV-6B viremia. Overall, HHV infec- Other pathophysiologic triggering
tions were found in 30% of all patients factors, such as rate of rise of fever, peak
with febrile status epilepticus in the body temperature during the illness, vac-
FEBSTAT study, suggesting an HHV-6B cinations (mainly diphtheria-pertussis-
infection as a specific trigger of febrile tetanus and measles-mumps-rubella),
status epilepticus.9 Despite this new find- low birth weight and in utero growth
ing, routine use of viral studies cannot retardation, respiratory alkalosis, and
be recommended in febrile seizures at systemic release of proinflammatory cy-
this time as they do not have direct tokines have been reported. These trig-
clinical or prognostic implications. gers remain a matter of much debate
Genetics seem to play a major role in and are not helpful in directing clinical
febrile seizures. As many as 25% to 40% management.12Y17
of children with febrile seizures have a Febrile infectionYrelated epilepsy syn-
family history of febrile seizures.10 Re- drome (FIRES) is controversial but touted
cently, a robust relationship has been as a distinct entity and reported in the
demonstrated between familial febrile literature. FIRES is a catastrophic epi-
seizures and genetically determined leptic encephalopathy that is clinically
epilepsies. The most established is the characterized by recurrent febrile sei-
clinically defined syndrome of genetic zures and febrile status epilepticus in
epilepsy with febrile seizures plus the acute phase during infancy, followed
52 www.ContinuumJournal.com February 2016

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 KEY POINT
by intractable epilepsy and intellec- than one event within 24 hours or the h Between 20% and 30%
tual impairment. The etiopathogenesis same illness, a duration longer than of all febrile seizures
is unknown, and whether FIRES repre- 15 minutes, or focal symptomatology. may be complex febrile
sents a unique disease is still a matter It is estimated that about 20% to 30% seizures, defined as
of controversy.18 of all febrile seizures may be complex more than one seizure
febrile seizures.12,20,21 Febrile status within 24 hours or
TYPES OF FEBRILE SEIZURES epilepticus is a subset of complex febrile the same illness, a
Because most febrile seizures occur at seizures that is most severe and poten- duration longer than
home and provoke acute caregiver anx- tially life threatening. 15 minutes, or
iety, scant data exist on accurate symp- focal symptomatology.
tomatology, duration, and the clinical DIAGNOSTIC WORKUP AND
circumstances surrounding them. While, ACUTE TREATMENT OF
on interview, the majority of caregivers FEBRILE SEIZURES
report a convulsive seizure, a history of Prompt bedside history and examina-
tonic body stiffening, apnealike episodes, tion are key to establishing the diagno-
limpness with pallor or cyanotic hue, and sis, distinguishing complex from simple
trembling (like shivering) with altered febrile seizures, considering differential
awareness are not uncommon descrip- diagnoses, and initiating acute treat-
tions of febrile seizures, and sometimes ment (Case 3-1).
it remains undetermined whether the Although rare, a child may still be
event was indeed a seizure. seizing or in febrile status epilepticus
In an attempt to stratify the risk of when first seen. Prompt attention
developing epilepsy in the future, fe- should be given to airway, breathing,
brile seizures are classified into two types: and circulation, and IV anticonvulsant
simple febrile seizures and complex fe- agents should be administered. Acute
brile seizures.19 Simple febrile seizures abortive treatment of prolonged febrile
are defined as solitary events during an seizures or frank febrile status epilep-
illness, usually in the form of nonfocal ticus is no different from any other
convulsions of fewer than 15 minutes in status epilepticus. Caution is warranted
duration. Complex febrile seizures are in children with a known diagnosis of so-
defined as events that do not meet the dium channelopathies (voltage-gated so-
criteria of simple febrile seizures, ie, more dium channelYrelated epilepsies) where

Case 3-1
A 22-month-old boy was referred for an office consultation after a
recent emergency department visit. His mother witnessed whole-body
convulsions that lasted for 2 minutes during a fever of 38.9-C (102-F).
The child had a runny nose for 2 days before he had the fever, which
was later determined to be due to an ear infection. By the time the
child was transported to the emergency department, he had fully
recovered. With temperature control, he became cheerful again and
had good oral intake in the emergency department. His examination
raised no concerns. The child’s history had no red flags, and he had
normal growth and development. He was fully immunized.
Comment. This child had a simple febrile seizure. His history is typical
for a febrile seizure that is most likely predicted to have a benign course.
No further tests are warranted. The mother should be educated and
counseled about this condition.

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 Febrile Seizures

KEY POINT
h Brain imaging, EEG, sodium channel blockers such as infection rather than a consequence of
and blood testing are fosphenytoin may be relatively contrain- febrile seizures or febrile status epilepti-
indicated only dicated because of the potential for cus. A 2012 study showed that even in
infrequently in selected worsening of seizures. febrile status epilepticus, CSF pleocy-
children with febrile Gradually reducing high fever with tosis is rarely a result of febrile status
seizures, and their antipyretics and gentle measures is gen- epilepticus.22 The American Academy
widespread use should erally recommended. It is not known if of Pediatrics established guidelines for
be discouraged. such measures impact the duration of lumbar CSF testing in children presenting
febrile seizures or the chance of recur- with febrile seizures (Table 3-1).3
rence of another febrile seizure. Neuroimaging, brain CT or MRI, is
Finding and treating the cause of generally not indicated unless clinical
the fever presenting with febrile sei- suspicion of an acute neurologic condi-
zures is key. CNS infection and acute tion or a history of focal hemiconvulsions
metabolic/toxic derangement are the suggesting a structural substrate exists.3,23
two most important causes that must EEG is of limited use during febrile
be ruled out. A good history and physical seizures or in the postacute state. Up
examination as well as rapid and full to one-third of patients with febrile
postictal recovery in febrile seizures may seizures, whether simple or complex,
establish the often self-limiting nature may show transient EEG abnormalities
of febrile illness without the need for during the postacute state; however,
further tests. Monitoring of vital signs EEG alone seldom dictates manage-
and close observation of neurologic status ment of febrile seizures.24,25 EEG may
following the febrile seizure are essential be justifiable in a subset of patients, as
in all children, and other laboratory tests, shown by the FEBSTAT study, an ongo-
including lumbar puncture (for CSF anal- ing multicenter prospective longitudinal
ysis), should be selectively considered study on consequences of prolonged
depending on each clinical scenario. febrile seizures.26 In this study, EEGs
Until proven otherwise, any finding of were performed within 72 hours of fe-
CSF pleocytosis, even without remark- brile status epilepticus. Focal slowing or
able changes in glucose and protein, attenuation on the EEG was highly as-
should be considered as an evidence of sociated with acute hippocampal injury

TABLE 3-1 Key Action Statements on the Indications of Lumbar Puncture a(Cerebrospinal Fluid
Examination) in a Child Who Presents With Seizure and Fever

In Any Child Who Presents With a Seizure and Fever,

a Lumbar Puncture: Level of Evidence
1a: Should be performed if the child has meningeal signs and symptoms B (Overwhelming evidence
or history or examination raises a possibility of meningitis or from observational studies)
intracranial infection
1b: Is an option in an infant 6Y12 months of age when the child is considered D (Expert opinion, case reports)
deficient in Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae
immunizations or when immunization status cannot be determined
1c: Is an option when the child has been pretreated with antibiotics, D (Reasoning from clinical
because antibiotic treatment can mask the signs and symptoms experience, case series)
of meningitis
a
Data from Subcommittee on Febrile Seizures; American Academy of Pediatrics, Pediatrics.3

54 www.ContinuumJournal.com February 2016

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 KEY POINTS
on the brain MRI. The study concluded seizure, the higher the risk of febrile h Caregivers often
that EEG may be a sensitive, reliable, seizure recurrence. One study showed confuse febrile seizures
and noninvasive marker of acute injury febrile seizure recurrence in 50% of with epilepsy. It is
associated with febrile status epilepti- patients who were younger than 1 year important that
cus and, hence, a potential marker for of age at the time of the first febrile physicians clearly
long-term consequences after febrile seizure. In comparison, only 20% had differentiate between the
status epilepticus.26 febrile seizure recurrence when the two while counseling.
age at the time of the first febrile seizure h Age at the time of the
POSTACUTE MANAGEMENT, was older than 3 years.30 Other risk fac- first febrile seizure is
RISK ASSESSMENT, AND tors identified in various studies include cited as the most
COUNSELING history of febrile seizure in first-degree important risk factor for
relatives, relatively low-grade fever dur- recurrence of a febrile
Caregivers of children with febrile sei-
ing the febrile seizure, and occurrence seizure. The younger
zures often express a sense of anxiety the age at the time of
after witnessing a seizure at home. State- of the febrile seizure at the inception
the first febrile
ments such as “I felt as if my child were (sometimes before recognition) of
seizure, the higher the
dying” and “I felt powerless to help my fever/illness.21,28Y30 Ironically, whether
risk of recurrence.
child” are commonly used to express the first febrile seizure was simple or
complex did not seem to affect the h Less than 5% of
parental concern. Experience tells us that children with
the caregivers often confuse terms such febrile seizure recurrence risk, nor did
febrile seizures will
as febrile seizures and epilepsy. It is im- the duration of the first febrile seizure.31
develop epilepsy.
portant that physicians clearly differenti- However, subsequent febrile seizures
can be prolonged if the initial seizure h Risk factors for
ate febrile seizures from epilepsy while epilepsy in a child with
discussing treatment goals during counsel- was prolonged.32
a febrile seizure are
ing. Parents of children with febrile sei- developmental delay or
RISK OF EPILEPSY
zures usually ask four questions, which abnormal neurologic
are answered consecutively in the sec- The risk of developing unprovoked sei- examination, complex
tions that follow: zures after a febrile seizure is estimated febrile seizures, and a
to be 2% to 5%.33 This risk is approx- first-degree relative
& Can this occur again? imately 2 to 3 times the risk of epilepsy with epilepsy.
& Is this epilepsy or will it become in the general population; however, it
epilepsy?
is still low enough to warrant judicious
& Does this cause brain damage? evaluation in only a few selected chil-
& What can I do to stop it next time? dren who are at high risk. The most
important predictive risk factors for the
RISK OF RECURRENCE OF development of epilepsy are develop-
FEBRILE SEIZURES mental delay or an abnormal neuro-
A second febrile seizure is likely to logic examination before the onset of
occur in about one-third of patients. A the febrile seizure, a history of complex
third febrile seizure is reported in about febrile seizures (including febrile status
half of the patients who had a second epilepticus), and a first-degree relative
febrile seizure, ie, only 15% of the en- with epilepsy (Case 3-2). Prolonged febrile
tire febrile seizure cohort will have three seizures and febrile status epilepticus
febrile seizures. More than three febrile are increasingly being recognized as
seizures are rare and seen in less than 5% potential risk factors for epilepsy.19,34Y36
of the febrile seizure cohort.21,27Y29 Mechanisms for the development of
Age at the time of the first febrile epilepsy after a febrile seizure are unclear;
seizure is cited as the most important however, these risk factors could possibly
risk factor for recurrence. The younger suggest a preexisting congenital, perina-
the age at the time of the first febrile tal, or metabolic-genetic vulnerability to
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 Febrile Seizures

Case 3-2
A 7-month-old infant was referred for consultation 2 weeks after she was
discharged from a hospital. She was admitted for a prolonged convulsive
seizure. Her parents were unaware of the fever or illness until after the
convulsion. The seizure apparently lasted 35 minutes and only stopped
after administration of IV lorazepam in the emergency department. Later,
a fever of 37.8-C (100-F) was noted, and a viral upper respiratory infection
was diagnosed. Blood biochemistry was normal. On further questioning,
the parents reported she had a history of previous febrile seizures at the
age of 3 months and 5 months that were 15 to 20 minutes in duration but
stopped before arriving at the emergency department. The infant was fully
immunized. Concerns regarding hypotonia and delayed motor milestones
were previously noted and confirmed at this office visit. On examination,
truncal ataxia and a few body jerks suggestive of myoclonia were noted.
Comment. This child had complex febrile seizures. In fact, the last episode
was febrile status epilepticus, the most severe form of febrile seizure. She
had many red flags, including early age of onset, the duration of seizures,
low fever or lack of documented fever at the onset of seizures, delayed
development, and abnormal neurologic examination. Her clinical scenario is
consistent with a possibility of an epileptic encephalopathy, such as Dravet
syndrome or other genetic epilepsy. Counseling may be difficult in such
situations when the family is expecting a benign diagnosis of febrile seizures.
Further diagnostic workup, such as EEG and genetic testing, is warranted
to confirm the diagnosis. This child is likely a candidate for initiation of
appropriate long-term anticonvulsant treatment. Also, she is at risk for future
prolonged convulsions, and it is prudent to devise a rescue plan, including
a prompt call to emergency medical services. Longitudinal follow-up is
critical in this child.

seizures that manifests with the second in these patients. There has been a long-
hit of fever/illness followed by enduring standing observation of the association
epilepsy. In a prospective FEBSTAT MRI of febrile status epilepticus, hippocam-
study of children presenting with acute pal sclerosis, and mesial temporal lobe
febrile status epilepticus, acute hip- epilepsy37; however, the cause-and-
pocampal injury due to febrile status effect relationship is yet to be confirmed
epilepticus was commonly seen. It was and may perhaps be more complex than
found that children with febrile status previously hypothesized.
epilepticus (defined as a seizure dura- While confirming the risk factors dis-
tion longer than 30 minutes) and acute cussed above, a 2013 study also identi-
hippocampal injury commonly had con- fied two other risk factors in multivariate
genital hippocampal malformations/ analyses: the occurrence of four or more
malrotations that could contribute to febrile seizures in a child and late age
the development of febrile status of febrile seizure onset (older than
epilepticus.34 Long-term follow-up of 3 years).38 This finding may need be
the febrile status epilepticus cohort is replicated in other larger studies. How-
ongoing to understand the possible ever, as discussed earlier, it makes sense
development of hippocampal sclero- as less than 5% of children with febrile
sis and mesial temporal lobe epilepsy seizures will have more than four seizures

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 KEY POINTS
or have their first febrile seizure after as soon as fever is recognized to help h The risk of developmental,
the age of 3 years. comfort the child. Prompt attention to behavioral, and
diagnose the cause of the fever is es- academic disability in
RISK OF FEBRILE STATUS sential. A few studies have reported ben- children with febrile
EPILEPTICUS efit from intermittent benzodiazepines seizures is no greater
Only a small number of patients with during fever for preventing febrile sei- than in the
febrile seizures present with febrile zures and reducing emergency depart- general population.
status epilepticus either as the first or ment visits and hospital admissions. A h Febrile status
subsequent seizure episode. In a case- 2- to 3-day course of oral diazepam or epilepticus is the most
control study that compared children clobazam was used successfully to pre- severe and potentially
with a first febrile seizure, febrile status vent recurrences.42,43 Such use of ben- life-threatening form of
epilepticus was associated with younger zodiazepines in children is not approved febrile seizures, with
age, lower body temperature, longer dura- by the US Food and Drug Administration long-term consequences;
tion of unrecognized fever before febrile (FDA). In addition, benzodiazepines can it must be emergently
treated just as any other
seizure, female sex, documented struc- cause sedation, can interfere with hydra-
status epilepticus.
tural temporal lobe abnormalities on a tion and feeding, and may delay the
previous brain MRI, and a first-degree recognition of a serious illness.
relative with febrile seizures. When such Rectal diazepam is available in the
risk factors exist alone or in combina- United States as an acute abortive treat-
tion, it may be prudent to develop an ment of an ongoing seizure and has been
acute seizure intervention at home, fol- successfully used in febrile seizures. Care-
lowed by initiating an emergency med- givers should be educated in the timing
ical services call for early and effective and technique of administering the med-
treatment of potential febrile status epi- ication as well as close monitoring after
lepticus. Delayed treatment and the de- its use. Using rectal diazepam at home is
velopment of febrile status epilepticus an attractive option in the hands of savvy
in a child is a risk factor for acute brain caregivers but may provide a false sense
injury, the development of epilepsy, and of security. Caregivers should be cau-
long-term neurocognitive disability.31 tioned that if the convulsion continues
after rectal diazepam (total duration
RISK OF INTELLECTUAL DISABILITY longer than 5 minutes) or sensorium
Longitudinal studies suggest that the does not recover, emergency medical
risk of developmental, behavioral, and services should be immediately con-
academic disability in children with fe- tacted for treatment of potential fe-
brile seizures is no greater than in the brile status epilepticus. A 2014 study
general population.21,39Y41 This infor- concluded that once established, febrile
mation should be emphasized when status epilepticus rarely stops sponta-
developing an individualized plan for neously, and it is fairly resistant to anti-
each child. However, one should keep epileptic medications. Earlier onset of
in mind that a subset of children with effective treatment results in shorter
prolonged febrile seizures or febrile total seizure duration. In this study, even
status epilepticus could develop long- the subjects who received medication
term neurologic consequences.31 prior to emergency department arrival
seized for a median of 81 minutes. Un-
TREATMENT OF FEBRILE SEIZURES fortunately, 19% of them had suboptimal
Antipyretic medications and measures dosing of benzodiazepines before arrival
remain controversial in preventing to the emergency department. Therefore,
febrile seizures, but they are generally it may be prudent to suggest administra-
recommended to caregivers at home tion of rectal diazepam at the onset of
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Febrile Seizures

KEY POINT
h Long-term daily febrile seizures in children who are at 5. Tsuboi T. Epidemiology of febrile and
afebrile convulsions in children in Japan.
anticonvulsants are not risk of febrile status epilepticus.44
Neurology 1984;34(2):175Y181.
usually indicated No justification exists for the use of
6. Hackett R, Hackett L, Bhakta P. Febrile seizures
in children with daily anticonvulsant medications. Phe- in a south Indian district: incidence and associations.
febrile seizures. nobarbital and valproate are touted Dev Med Child Neurol 1997;39(6):380Y384.
to successfully reduce the recurrence 7. Steering Committee on Quality Improvement
of febrile seizures; however, they may and Management, Subcommittee on Febrile
not reduce the ultimate risk of devel- Seizures American Academy of Pediatrics. Febrile
seizures: clinical practice guideline for the
oping epilepsy. Long-term treatment with long-term management of the child with simple
daily anticonvulsants may be justifiable febrile seizures. Pediatrics 2008;121(6):1281Y1286.
only in a small subset of children with doi:10.1542/peds.2008-0939.
complex febrile seizures and febrile status 8. Kimia AA, Capraro AJ, Hummel D, et al.
epilepticus with multiple risk factors Utility of lumbar puncture for first simple
febrile seizure among children 6 to
that portend a high risk of epilepsy. 18 months of age. Pediatrics 2009;123(1):
No guidelines exist for initiation of daily 6Y12. doi:10.1542/peds.2007-3424.
anticonvulsants in febrile seizures, and 9. Epstein LG, Shinnar S, Hesdorffer DC, et al.
it remains a matter of clinical judgment.7 Human herpesvirus 6 and 7 in febrile
A customized febrile seizure action plan, status epilepticus: the FEBSTAT study.
Epilepsia 2012;53(9):1481Y1488.
surveillance on febrile seizure recurrences, doi:10.1111/j.1528-1167.2012.03542.x.
and monitoring physical and developmen-
10. Hauser WA, Annegers JF, Anderson VE,
tal behavioral milestones are critical in Kurland LT. The risk of seizure disorders
the management of febrile seizures. among relatives of children with febrile
convulsions. Neurology 1985;35(9):1268Y1273.
CONCLUSION
11. Scheffer IE, Berkovic SF. Generalized
Febrile seizures are a common neuro- epilepsy with febrile seizures plus. A genetic
logic emergency in children. It is im- disorder with heterogeneous clinical
phenotypes. Brain 1997;120(pt 3):479Y490.
portant to recognize this condition and
offer a customized evidence-based plan 12. Verity CM, Butler NR, Golding J. Febrile
convulsions in a national cohort followed up
of care to each family. The majority of from birth. IIVmedical history and intellectual
children can be managed by application ability at 5 years of age. Br Med J (Clin Res Ed)
of the essential clinical principles outlined 1985;290(6478):1311Y1315.
in this article. 13. Barlow WE, Davis RL, Glasser JW, et al.
The risk of seizures after receipt of
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 Review Article

Infantile, Childhood, and

Address correspondence to
Dr Elaine Wirrell, Mayo Clinic,
200 1st St SW, Rochester,
MN 55905, wirrell.elaine@
mayo.edu.
Relationship Disclosure:
Dr Wirrell receives royalties
Adolescent Epilepsies
from UpToDate, Inc, and Elaine Wirrell, MD
research support from the
American Epilepsy Society
Infrastructure Award and the
Dravet Syndrome Foundation. ABSTRACT
Unlabeled Use of
Product/Investigational
Purpose of Review: Infantile, childhood, and adolescent epilepsies comprise a
Use Disclosure: diverse group of entities. Careful characterization of epilepsy into a specific electro-
Dr Wirrell reports no disclosure. clinical syndrome or etiology assists greatly in understanding both the natural history of
* 2016 American Academy the seizure disorder (pharmacoresistant versus pharmacoresponsive and self-limited
of Neurology.
versus lifelong) and the best therapeutic options for the child.
Recent Findings: Tremendous growth has been seen in the understanding of both
genetic factors predisposing to epilepsy and neuroimaging techniques. Additionally,
a number of studies have focused on the efficacy of certain therapies in specific
syndromes or etiologies.
Summary: This article reviews both common epilepsy syndromes (including benign
focal epilepsy of childhood, absence epilepsy, and juvenile myoclonic epilepsy) and
the rarer syndromes with associated management implications (eg, Dravet syndrome,
progressive myoclonic epilepsy, and mitochondrial disorders) and addresses genetic
and metabolic investigations.

Continuum (Minneap Minn) 2016;22(1):60–93.

INTRODUCTION many children have a specific elec-

Epilepsy is one of the most common troclinical syndrome, defined as “a
neurologic disorders of childhood, with complex of signs and symptoms that
an estimated incidence of 40 to 50 per define a unique epileptic condition.”3
100,000 persons per year.1 The inci- Such syndromes denote specific clinical
dence is highest in the first year of life, seizure types, EEG findings, characteris-
becoming lower in later childhood and tic clinical features (eg, age at onset and
adolescence. Approximately 20% to associated neurologic and psychological
25% of cases are pharmacoresistant, findings), and underlying pathophysio-
resulting not only in disabling seizures logic or genetic mechanisms. Identify-
but also profound consequences on ing the underlying cause of epilepsy or
cognitive development, behavior, emo- specific electroclinical syndrome is crit-
tional well-being, and quality of life. ical to understanding its natural history
Additionally, children with pharma- and best treatment options.
coresistant seizures are at greater risk This article highlights the clinical
of injury and death due to accidents, characteristics, appropriate neuroim-
status epilepticus, and sudden unex- aging, genetic and metabolic evalua-
pected death in epilepsy (SUDEP). tions, and management of the most
The impact of pharmacoresistant epi- common syndromes as well as the less
lepsy on development appears most common syndromes that have associ-
severe in early life.2 ated management implications. Epi-
Epilepsy in children is due to a lepsies are organized based on the
diverse group of etiologies. Additionally, usual ages at presentation.

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 KEY POINTS
INFANTILE-ONSET EPILEPSIES in all infants who do not have a clear h Pediatric epilepsy is
The following epilepsy syndromes etiology. As cortical dysplasia may be pharmacoresistant 20%
begin in the first 2 years of life. difficult to detect in infancy, an MRI to 25% of the time, and
may be repeated at 6-month intervals the impact of intractable
West Syndrome and certainly after age 24 to 30 months seizures on development
West syndrome is the most common in cases with persisting seizures. In is most profound early
epileptic encephalopathy with an inci- those without a known cause after MRI, in life.
dence of 3 to 4.5 per 10,000 live births. further investigations are warranted.4 h A focal pathology
Clinical features. West syndrome Genetic studies are higher yield than should be suspected in
comprises a triad of (1) epileptic extensive metabolic testing, unless children with asymmetric
spasms, (2) hypsarrhythmia, and (3) imaging suggests an inborn error of spasms or those with
arrest or regression of psychomotor metabolism. A comparative genomic focal seizures coinciding
development. Typical onset is from 3 hybridization array and, if this is with spasms.
to 12 months of age. Epileptic spasms nondiagnostic, an epilepsy gene panel
consist of sudden flexion, extension, or should be considered. Whole exome
mixed flexion-extension movements sequencing should be considered if
that last 1 to 2 seconds in the proximal the etiology remains unknown and
and truncal muscles and occur in clus- seizures persist or developmental de-
ters that last several minutes often lay is evident. Initial metabolic studies
shortly after waking. Typically, clusters should include serum lactate, amino
are seen several times per day. Spasms acids, and urine organic acids to
may be symmetric, asymmetric, or evaluate for mitochondrial disorders,
unilateral and occasionally can be clini- aminoacidopathies, and organic acidurias.
cally subtle. Focal seizures may precede Further metabolic testing can in-
or follow spasms and should suggest an clude !-aminoadipic semialdehyde
underlying focal pathology. (pyridoxine-dependent epilepsy),
Many children with West syndrome CSF for pyridoxal 5¶-phosphate
have a history of perinatal complica- (pyridoxal 5¶-phosphateYdependent
tions and developmental delay. Im- epilepsy), neurotransmitters (neuro-
paired visual attention is often seen transmitter disorders), lactate (mito-
and can worsen after spasm onset. chondrial disorders and glucose
Abnormal findings on motor examina- transporter deficiency), and glucose
tion or microcephaly are common. A (glucose transporter deficiency). This
Wood’s lamp may assist in visualizing testing could be undertaken if the
cutaneous findings of neurocutaneous initial studies are negative.
disorders such as tuberous sclerosis. Hypsarrhythmia, the classic finding
Organomegaly, unusual odor, or dys- on interictal EEG, is characterized by
morphic features would suggest a very high-amplitude asynchronous slow
metabolic or genetic etiology. waves, multifocal spikes, and polyspikes
Investigations. A clear etiology is (Figure 4-1A). It is most prominent
evident in approximately half of infants during quiet sleep, often attenuated
after initial clinical examination and during wakefulness, and may be absent
neuroimaging and in three-fourths fol- in rapid eye movement (REM) sleep.
lowing further genetic and metabolic Absence of hypsarrhythmia in a
investigations. Structural etiologies, in- child with a suspicious history does
cluding cortical malformations, tuber- not exclude West syndrome. Such
ous sclerosis, and perinatal brain cases should be considered for
injury, are most common, and brain prolonged EEG to record spasms.
MRI is a necessary initial investigation During spasms, the EEG shows a
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 Pediatric Epilepsy

FIGURE 4-1 EEG of a 7-month-old boy with West syndrome. A, High-amplitude and excessively slow background with
multifocal discharges characteristic of hypsarrhythmia. B, During an actual spasm, there is a high-amplitude,
generalized spike-wave complex followed by generalized attenuation.

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 KEY POINT
high-voltage, often generalized, sharp or Prognosis. Most children with West h The usual antiepileptic
slow wave followed by an electro- syndrome have intellectual disability at drugs have limited
decrement (Figure 4-1B). follow-up, and underlying etiology is efficacy in West
Treatment. First-line treatments in- the most critical predictor of develop- syndrome. First-line
clude adrenocorticotropic hormone mental outcome. A recent meta-analysis therapies include
(ACTH), prednisolone, or vigabatrin.5 documented good neurodevelopmental adrenocorticotropic
Vigabatrin is the treatment of choice in outcome in 54% of infants with cryp- hormone, prednisolone,
infantile spasms due to tuberous scle- togenic spasms versus only 12.5% or vigabatrin.
rosis, with seizure cessation being seen with symptomatic spasms.7 Relatively
in 95% of cases, and also appears favorable symptomatic etiologies in-
effective in focal cortical dysplasia. Lim- clude Down syndrome, neurofibro-
iting treatment duration to 6 months matosis type 1, preterm infants with
minimizes the risk of retinal toxicity. periventricular leukomalacia, and neo-
ACTH may have greater short-term natal hypoglycemia. Additional factors
efficacy than vigabatrin once infants predictive of outcome include shorter
with tuberous sclerosis are excluded. treatment lag; favorable response to
Although one large study reported initial therapy; absence of other seizure
similar short-term efficacy of ACTH and types prior to spasms; and absence of
high-dose oral prednisolone (40 mg/d to atypical spasms, focal seizures, or asym-
60 mg/d),6 at present insufficient evi- metric EEG abnormalities.
dence exists that other steroids are as Infantile spasms are age dependent
effective as ACTH. and typically resolve by the early
In children with focal cortical struc- preschool years. However, 50% to
tural abnormalities, expedient referral 90% of patients evolve to other syn-
for possible surgical therapy is indicated dromes, most commonly Lennox-
if both hormonal therapy and vigabatrin Gastaut syndrome, focal epilepsy, or
fail to control spasms (Case 4-1). multifocal epilepsy.

Case 4-1
A 25-month-old girl presented with epileptic spasms that had been
occurring since she was 7 months of age. She was the product of a healthy
pregnancy and delivery and appeared developmentally normal prior to
spasm onset. Her EEG at diagnosis confirmed hypsarrhythmia, and she was
treated with high-dose adrenocorticotropic hormone (ACTH). Spasms
resolved for 6 weeks but then recurred and remained refractory to a
second course of ACTH, vigabatrin, topiramate, and pyridoxine and a trial
of the ketogenic diet. Her initial MRI was normal at 8 months of age, and
extensive genetic and metabolic evaluations were unrevealing. Around 18
months of age, her development plateaued. She underwent video-EEG
monitoring, and clusters of asymmetric spasms were recorded, with right
eye deviation and greater involvement of her right upper extremity. A
repeat MRI showed a region of T2 hyperintensity in the left frontal region,
which was consistent with a focal cortical dysplasia (Figure 4-2). She
underwent surgical resection of this region and exhibited postoperative
transient right upper extremity weakness, which markedly improved with
therapy. At 6 years of age, she was seizure free, off antiepileptic drugs, and
doing well at school, although she received resource help with reading.
Continued on page 64

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 Pediatric Epilepsy

KEY POINT
h Dravet syndrome should
Continued from page 63
be suspected in a child
with recurrent prolonged
focal febrile seizures
beginning before
18 months of age.

FIGURE 4-2 Imaging of the patient in Case 4-1. Coronal

fluid-attenuated inversion recovery (FLAIR)
MRI shows a region of T2 hyperintensity
in the left frontal region (arrow), suggestive of focal
cortical dysplasia.

Comment. The asymmetric manifestations of this child’s clinical seizures

suggested focal pathology, as was ultimately found on imaging. Such cases
may be amenable to surgical therapy if spasms are refractory to medical
treatment, and earlier intervention may maximize cognitive development.

Children with West syndrome have by fever or hyperthermia. Classically,

an elevated risk of death, with a seizures switch sides, starting on the
mortality rate of 10% by age 3 years right with some events and the left with
and 18% by age 10 years in one study.8 others; this alternating pattern is highly
suggestive of Dravet syndrome. Seizures
Dravet Syndrome may be falsely generalized, meaning that
Dravet syndrome (previously called se- there are either bilateral EEG changes
vere myoclonic epilepsy of infancy) is a but focal clinical events or bilateral EEG
relatively rare intractable childhood epi- changes at onset that become asymmet-
lepsy syndrome with an estimated prev- ric as the seizure evolves. The ictal EEG
alence of 1 in 40,900 live births.9 Boys may also show topographic change with
and girls are equally affected. a seizure starting in a specific focus,
Clinical features. Epilepsy onset is spreading to one or both hemispheres,
before age 18 months with prolonged and ending focally.
hemiconvulsive seizures (with or with- In the early preschool years, other
out secondary generalization), triggered seizure types emerge, including

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 KEY POINT
myoclonic, atypical absence, and focal cating in 50% (mostly nonsense, h SCN1A testing in Dravet
seizures. Tonic seizures are unusual. frameshift, splice site, or missense syndrome should
Obtundation status, in which the child mutations, with the latter predomi- include sequencing,
appears poorly responsive for several nantly affecting the pore-forming re- and, if negative, testing
hours, has erratic myoclonus predom- gion of the SCN1A sodium channel).9 for large-scale
inantly affecting the fingers and Intragenic deletions or whole gene duplications and
orobuccal muscles, and discrete inter- deletions account for 2% to 3% of deletions is required.
spersed massive myoclonic jerks that cases; duplications and amplifications
may interfere with sleep, may also be are rare. Testing should, therefore,
seen. Typically, obtundation status is include SCN1A sequencing, and, if
noted on awakening, and convulsive negative, testing for large-scale duplica-
seizures may initiate, occur during, or tions and deletions is required. Rarely,
terminate this status. Reflex seizures other gene mutations can be seen in
are also frequent with provoking fac- children with a Dravet phenotype.
tors, including hyperthermia (eg, EEG findings in Dravet syndrome
caused by fever, immersion in hot are not specific. The background is
water, intense physical exercise, or normal at epilepsy onset, but by 1 to
high ambient temperature), photosen- 2 years of age, most patients show
sitivity, or pattern sensitivity. Most diffuse background theta slowing.
commonly, reflex myoclonic jerks are Epileptiform discharges (usually gen-
noted; however, convulsive or focal eralized) are seen in approximately
seizures may also be triggered. Some one-fourth of patients at epilepsy
patients may self-trigger seizures by onset. Between the ages of 2 and
rapid eye blinking while staring at a 5 years, an increase in paroxysmal
bright source or pattern. abnormalities (which can be general-
Development is normal at epilepsy ized, focal, or multifocal) is seen. Photic
onset but slows around the time of stimulation and eye closure may elicit
onset of myoclonus and nonconvulsive discharges in up to one-fourth of cases
seizures. The degree of intellectual (Figure 4-3). In older children and
disability varies markedly from border- adults, multifocal and focal interictal
line to severe impairment. More severe discharges are most common, and
impairment has been linked to higher discharges may be absent in approxi-
frequency of both convulsive and non- mately 25% of patients.
convulsive seizures. The neurologic Neuroimaging studies are typically
examination is typically normal at epi- normal, although scans done later in life
lepsy onset; however, ataxia, slight pyra- may show mild atrophy, hippocampal
midal signs, and a crouch gait (increased sclerosis, or loss of gray-white definition.
knee and hip flexion and ankle dorsi- Treatment. Dravet syndrome is
flexion, often with a mild flexible extremely pharmacoresistant. The goals
kyphosis) may develop over time. of treatment are to avoid prolonged
Investigations. SCN1A mutations status epilepticus, reduce frequency of
are found in 80% of patients. De novo briefer seizures, and avoid problematic
mutations account for 95% of cases; adverse effects of multiple antiepileptic
however, 5% of patients show familial drugs (AEDs) used at high doses.10
mutations in which affected relatives Sodium channel blocking agents, in-
have a much milder clinical picture with cluding carbamazepine, oxcarbazepine,
genetic epilepsy with febrile seizures lamotrigine, and phenytoin, should be
plus (GEFS+) phenotypes. SCN1A mu- avoided as they exacerbate seizures.
tations in Dravet syndrome are trun- First-line therapy typically involves
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 Pediatric Epilepsy

FIGURE 4-3 EEG of a 2-year-old girl with Dravet syndrome showing a generalized spike-wave discharge triggered by
photic stimulation.

KEY POINT valproic acid or clobazam, although add-on fenfluramine in a small study in
h Sodium channel agents topiramate, levetiracetam, and possibly which 7 of 12 patients achieved seizure
should be avoided in zonisamide may also have efficacy. freedom for at least 1 year after 1 to
Dravet syndrome.
Stiripentol is often considered if first- 19 years of treatment.13 Clinical trials
Valproic acid or clobazam
line therapy is ineffective and has been are currently under way to deter-
are first-line agents.
shown in a prospective randomized mine efficacy of cannabinoids. Vagus
placebo-controlled study to result in a nerve stimulation has been tried with
69% reduction of seizures.11 It also limited effectiveness.
reduces status epilepticus, need for Given patients’ predisposition to-
rescue medications, hospitalizations, ward recurrent prolonged seizures,
and emergency department visits.12 caregivers of children with Dravet
However, stiripentol is not currently syndrome should be taught to admin-
US Food and Drug Administration ister a home dose of rescue benzodi-
(FDA)Yapproved and, in the United azepine. Additionally, a treatment plan
States, must be obtained through an for management of prolonged seizures
Investigational New Drug (IND) appli- should be provided to the family and
cation to the FDA. The ketogenic diet their nearest emergency department.
also has documented efficacy with Prognosis. While seizures remain
sustained seizure reduction in one- medically refractory in most pa-
half to two-thirds of children. Remark- tients, prolonged seizures and status
able efficacy was also documented with epilepticus become much less frequent

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in mid to late childhood. Absences and With the exception of rare cases on
myoclonic seizures either markedly the severe end of the phenotypic
reduce or resolve by early adulthood, spectrum, children with GEFS+ are
and brief nocturnal generalized tonic- typically neurologically and developmen-
clonic seizures are the main seizure tally normal. Antecedent birth and devel-
type. Temperature sensitivity persists in opmental histories are unremarkable.
up to half of patients, but photic and Investigations. GEFS+ is usually
pattern sensitivity typically resolve by inherited in an autosomal dominant
adulthood. Developmentally, most pa- manner with incomplete penetrance. It
tients with Dravet syndrome have mod- remains a clinical diagnosis, and genetic
erate to severe disability and cannot live testing is not required. While numerous
independently as adults.14 genes have been implicated in GEFS+
Several studies have reported an (eg, SCN1A, SCN1B, SCN2A, GABRG2,
increased mortality rate in children and GABRD), mutations are identified
with Dravet syndrome, with approxi- in only a minority of affected families
mately 15% dying by early adulthood overall. This suggests that GEFS+ most
due to status epilepticus, SUDEP, or likely follows complex inheritance and
accidental death.14Y18 that more than one gene is involved,
including possible modifying genes,
Genetic Epilepsy With Febrile with environmental contribution.
Seizures Plus An EEG is not indicated in simple
GEFS+ is a common familial electro- febrile convulsions. It is typically
clinical syndrome in which two or more obtained in children with afebrile
family members have symptoms consis- seizures, and the findings in GEFS+
tent with this diagnosis.19 Phenotypes are heterogeneous and depend on
range from mild to severe, and phe- seizure type. The background and
notypic heterogeneity is usual. Age at sleep patterns are typically normal,
onset is between 6 months and 6 years, although diffuse slowing may be seen
and boys and girls are equally affected. in individuals on the severe phenotyp-
Clinical features. At the mildest ic end of the spectrum with either
end of the phenotypic spectrum are myoclonic-atonic epilepsy or Dravet
children with febrile seizures alone, syndrome. In individuals with general-
which may be recurrent, prolonged, ized seizures, the interictal recording
focal, or clustered. Other children have typically shows generalized discharges,
febrile seizures plus, in which febrile which can become fragmented and
seizures either continue beyond the age may appear focal or multifocal in sleep.
of 6 years or afebrile seizures coexist In those with temporal lobe epilepsy,
with febrile seizures. Most commonly, focal discharges are seen.
afebrile seizures are brief generalized Neuroimaging is generally not re-
convulsive events; however, other types quired; if done, it is typically normal.
of generalized (typical absence, myo- Rarely, hippocampal sclerosis can be
clonic, myoclonic-atonic, or atonic) or seen in patients with GEFS+ and
focal seizures may also be seen. At the temporal lobe epilepsy.
severe end of the spectrum are individ- Treatment. Prophylactic AEDs are
uals with either myoclonic-atonic epi- not indicated for simple febrile seizures.
lepsy or Dravet syndrome. Some If they are prolonged or clustered, a
individuals may also present with tem- home dose of rescue benzodiazepine
poral lobe epilepsy with or without therapy could be administered. Prophy-
hippocampal sclerosis. lactic antiepileptic therapy for afebrile
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 Pediatric Epilepsy

KEY POINT
h Panayiotopoulos seizures should be geared toward the and familial hemiplegic migraine.
syndrome should be seizure type. Benzodiazepines (such Seizures are pharmacoresponsive and
suspected in a a s clobazam and clonazepam), self-limited.
previously well late levetiracetam, valproic acid and its de-
preschool or early rivatives, and topiramate are usually CHILDHOOD-ONSET EPILEPSIES
school-aged child who effective in the treatment of GEFS+. The following epilepsies typically have
presents with a Because many mutations in GEFS+ their onset in the childhood years.
nocturnal seizure with may alter sodium channel function,
pronounced autonomic sodium channel blockers such as phe- Panayiotopoulos Syndrome
features such as ictal nytoin, carbamazepine, oxcarbazepine, (Early-Onset Benign Occipital
vomiting or retching. Epilepsy)
and lamotrigine may potentially be
more problematic. Panayiotopoulos syndrome accounts
Prognosis. Generally, most seizures for 1% to 2% of pediatric focal epilepsy
in GEFS+ are pharmacoresponsive cases with a peak age at onset of 5 years.
and self-limited, in most cases resolv- The condition is slightly more common
ing before puberty. Development re- in girls and affects neurologically nor-
mains normal. mal children.
Clinical features. Seizures are char-
Familial and Nonfamilial acterized by prominent autonomic
Benign Focal Epilepsies features (eg, nausea, retching, and
Benign focal epilepsies affect develop- vomiting) and usually occur at night.
mentally normal infants and may be Tonic eye deviation is common, but
familial or nonfamilial.20 visual hallucinations are rare. Seizures
Benign epilepsy in infancy is a often become dyscognitive and may
nonfamilial syndrome that presents at evolve to hemiconvulsions or general-
a peak age of 4 to 6 months, most ized convulsions. Duration can be
typically with a cluster of focal seizures prolonged; up to one-third develop
consisting of behavioral arrest, automa- focal status epilepticus, but seizure
tisms, and mild convulsive movements. frequency is low with 33% of patients
Seizures may progress to secondary having only a single seizure.
generalization. The interictal EEG is It has been speculated that Panayi-
typically normal, as is neuroimaging. otopoulos syndrome is the result of a
Seizures are pharmacoresponsive but combination of multifocal cortical hy-
may occur in another cluster weeks to perexcitability and an unstable auto-
months later. As malformations of cor- nomic nervous system. The syndrome
tical development can be challenging to is an age-specific epilepsy syndrome,
see on MRI in young infants, careful and no causal gene has been identified.
follow-up is needed to confirm the Investigations. The interictal EEG
benign nature of the epilepsy. shows high-amplitude, frequent, focal,
Various familial benign neonatal or multifocal spikes that typically
and infantile epilepsies have also increase in sleep and may show
been described with a number of fixation-off sensitivity, in which activa-
implicated genes, including KCNQ2, tion of discharge is seen when the
KCNQ3, and PRRT2. These are typically patient is not actively looking at some-
inherited as autosomal dominant thing. Location is often, but not always,
conditions with incomplete pene- in the occipital region; the centrotemporal
trance, and families may also have and parietal regions are also common
other neurologic disorders, inclu- foci. Spikes often shift in focus on
ding paroxysmal choreoathetosis subsequent recordings. Ictal recordings
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 KEY POINT
are rare; however, rhythmic theta or delta vals. Frequent seizures are seen in only h Benign epilepsy with
activity with intermixed spikes that 6%, while 13% to 21% will have only a centrotemporal spikes
usually start posteriorly have been single event. Postictal Todd paresis is should be suspected in
reported. Uncommonly, Panayiotopoulos seen in 7% to 16% and may suggest previously well
syndrome can evolve to continuous focal onset in those presenting with a school-aged children
spike and wave in slow sleep. generalized nocturnal seizure. who present with focal
If the history and EEG are typical, Affected children are usually neuro- seizures affecting the
neuroimaging is not required. However, developmentally normal, although 16% lower face or with early
MRI should be considered with atypi- will have a history of febrile seizures. morning generalized
cal features. A genetic component consistent tonic-clonic seizures.
The EEG shows
Treatment. Prophylactic AED treat- with complex inheritance has been
high-amplitude
ment may not be needed if seizures shown, but a causal gene has not
centrotemporal
are infrequent. If treatment is started, been found. Acquired or environmen- sharp waves.
levetiracetam, oxcarbazepine, and car- tal factors are likely necessary for
bamazepine are frequent choices; no expression of the seizure disorder.
particular AED has been shown to be Investigations. The EEG shows
superior. Intermittent use of benzodi- high-amplitude, diphasic, unilateral or
azepines should be considered for the bilateral, centrotemporal spikes or
child with prolonged events. sharp waves, which have a character-
Prognosis. Remission of active epi- istic horizontal dipole (maximal nega-
lepsy typically occurs within 1 or 2 years tivity in centrotemporal and positivity
from onset, and children can then dis- in frontal regions) and are followed by
continue prophylactic medications. Cog- aftercoming slow waves (Figure 4-4).
nitive and social outcome is excellent. Discharges are markedly activated in
drowsiness and non-REM sleep, and
Benign Epilepsy With the background is normal. Few re-
Centrotemporal Spikes ports of recorded rolandic seizures
(Benign Rolandic Epilepsy) exist, but two unique features are
Benign epilepsy with centrotemporal noted: (1) dipole reversal of ictal
spikes accounts for 6% to 10% of all discharge with electropositivity in the
childhood epilepsies and has a peak age centrotemporal region and negativity
at onset of 7 to 8 years, resolving by age in the frontal area and (2) absence of
16. Boys are more commonly affected. postictal slowing.
Clinical features. Focal seizures with Approximately 0.7% of children
clonic or tonic activity of one side of the with no seizure history show typical
lower face or tongue; paresthesia of the rolandic discharges on their awake
tongue, lips, gum, and cheek; drooling; recording. Thus, this EEG finding
and dysarthria are classic features of the should be considered incidental if
condition. Hemiconvulsions are more clinical symptoms are not suggestive
common in young children, and evolu- of benign epilepsy of childhood with
tion to bilateral convulsive activity is centrotemporal spikes.
frequent in sleep. Seizures typically Imaging is not required in a neuro-
occur shortly after falling asleep or logically normal child with a charac-
before awakening; however, 15% of teristic clinical history and EEG. MRI is
patients have seizures in both sleep usually normal but may show hippo-
and wakefulness and 20% to 30% in the campal asymmetry, white matter ab-
waking state alone. Seizures are typ- normalities, or developmental lesions
ically brief and often occur in clusters in a minority of cases. MRI should be
interspersed by long seizure-free inter- considered with atypical features.
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 Pediatric Epilepsy

FIGURE 4-4 EEG of a developmentally normal 8-year-old boy who presented with an early morning generalized
tonic-clonic seizure. EEG shows prominent independent left and right centrotemporal discharges in sleep
characteristic of benign epilepsy of childhood with centrotemporal spikes.

KEY POINT Treatment. Prophylactic medication Electrical Status Epilepticus in

h Children with benign may not be required for children with Slow Sleep
epilepsy with infrequent nocturnal focal seizures. If ESES comprises two similar but dis-
centrotemporal spikes
recurrent generalized or diurnal seizures tinct syndromes: continuous spike
achieve remission,
occur, or if they are sufficiently disturb- and wave in slow sleep (CSWS) and
most often by early
adolescence, and
ing to the child or the family, treatment Landau-Kleffner syndrome.
can discontinue is generally started. AEDs prescribed for Clinical features. In both CSWS
antiepileptic drugs. focal seizures have equivalent efficacy, and Landau-Kleffner syndrome, marked
with 50% to 65% of patients having no fur- activation of epileptiform discharges
ther seizures once medication is started. occurs during non-REM sleep to the
Prognosis. Remission occurs in point that they become nearly continu-
essentially all children: 50% by age ous (Figure 4-5).22 In association with
6 years, 92% by age 12 years, and the EEG change, children experience
99.8% by age 18 years.21 Although developmental regression, which is
learning and behavior problems may more global in CSWS and predomi-
be seen in the acute phase, long-term nantly affects receptive language in
psychosocial outcome is excellent Landau-Kleffner syndrome. The cause
with no increase in psychiatric or of CSWS is heterogeneous; how-
personality problems and excellent ever, approximately half of cases have
occupational status. Rarely, this syn- early developmental lesions, including
drome evolves atypically to electrical malformations of cortical develop-
status epilepticus in slow sleep (ESES). ment or vascular insults (particularly
Such deterioration has been infre- involving the thalamus), and a signifi-
quently reported with carbamazepine, cant minority have various genetic ab-
phenobarbital, and lamotrigine. normalities (Case 4-2). In distinction,

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FIGURE 4-5 EEG of a 5-year-old boy with a history of seizures, developmental regression, and hyperactivity showing nearly continuous,
bilaterally synchronous discharges in sleep characteristic of a diagnosis of electrical status epilepticus in slow sleep.

Case 4-2
A 5-year-old girl with a history of perinatal stroke and right hemiparesis (Figure 4-6A) presented with two
prolonged right hemiconvulsive seizures occurring during an intercurrent illness. Her awake EEG showed
frequent spikes from the left frontal and temporal regions, and she was started on oxcarbazepine. When
she presented for follow-up 2 months later, although she had no further prolonged seizures, brief
right-sided seizure activity persisted, and she had a marked decline in her behavior and learning. She
often appeared vacant and had poor ability to sustain attention on a task. She had several falls with
injury. A repeat EEG showed nearly continuous left-sided discharge during sleep (Figure 4-6B), consistent
with electrical status epilepticus in slow sleep (ESES). She also had recorded atypical absence seizures that
correlated with her vacant spells. Her oxcarbazepine was stopped, and she was started on levetiracetam
without significant benefit. She was then treated with high-dose diazepam (0.5 mg/kg at bedtime) with
marked improvement in her cognition, resolution of falls, and fewer vacant episodes. A repeat sleep EEG
4 weeks later showed only occasional left-sided discharges.
Comment. Children with perinatal thalamic injury are at high risk of developing ESES. Certain
medications, including oxcarbazepine, may also increase this risk. A history of developmental regression,
particularly of language, as well as worsening nonconvulsive seizures (absences and atonic events) should
suggest the diagnosis, which is confirmed by sleep EEG recording.
Epilepsy associated with continuous spike and wave in slow sleep is polymorphic and severe, with many
patients having multiple daily events, including generalized tonic-clonic, atypical absence, myoclonic,
atonic, and focal seizures. In distinction, seizures in Landau-Kleffner syndrome are much less frequent and
are focal or secondarily generalized.
Continued on page 72

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 Pediatric Epilepsy

Continued from page 71

FIGURE 4-6 Imaging and EEG of the patient in Case 4-2. A, Axial T2-weighted fluid-attenuated inversion recovery (FLAIR)
MRI showing a remote left middle cerebral artery infarction. T2 hyperintensity is also seen in the left
thalamus. B, EEG shows nearly continuous left-sided discharge during sleep.

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 KEY POINTS
Landau-Kleffner syndrome is seen in affects otherwise neurologically nor- h Electrical status
children with normal imaging and re- mal children. epilepticus in slow
flects one end of the epilepsy-aphasia Clinical features. Typical absence sleep presents with
spectrum. Additionally, GRIN2A muta- seizures are the only seizure type at developmental
tions have been identified to play a presentation and characteristically regression along with
role in a significant minority of epilepsy- occur very frequently (often 10 to nearly continuous
aphasia spectrum disorders.23 50 times per day). Generalized tonic- epileptiform discharges
Treatment. In a child with ESES clonic seizures may develop in 30% to on sleep EEG. Most
and documented regression, treatment 40% of patients but usually do not antiepileptic drugs are
goals include both improved seizure begin before adolescence. Absences poorly efficacious, and
high-dose diazepam
control and reduction of interictal EEG are brief (less than 20 to 30 seconds),
or steroids are
abnormalities to maximize learning abrupt in onset, and triggered by
often needed.
and memory.24 Medications that can hyperventilation. Mild facial myoclo-
exacerbate such activity, including nus is common, but prominent eyelid h Childhood absence
epilepsy presents in
oxcarbazepine and carbamazepine, or perioral myoclonia or massive my-
neurologically normal
should be discontinued. Selected AEDs, oclonus of the limbs or head should
school-aged children
including valproate, ethosuximide, leve- suggest an alternative diagnosis. with absence seizures as
tiracetam, lamotrigine, and sulthiame Investigations. The EEG back- the only seizure type.
(which is not FDA approved in the ground is usually normal but may show Ethosuximide is
United States), have been reported to posterior bilateral rhythmic delta activ- first-line treatment.
be potentially beneficial in small case ity, consisting of 3-Hz high-voltage slow
series but not consistently. High-dose activity in the parietooccipital regions
benzodiazepines or steroids are often that is attenuated by eye opening and
used as first-line agents. Surgery can often enhanced by hyperventilation.
also be considered, particularly in The ictal EEG shows generalized 3-Hz
children with CSWS with neuroimag- spike-wave (Figure 4-7), and during
ing abnormalities. sleep, discharges often become more
Prognosis. Seizures ultimately re- fragmented. Photosensitivity may be
solve or markedly decrease in frequency seen; however, prominent photosensi-
by puberty, even in cases with symp- tivity and polyspike discharges suggest
tomatic etiologies. The electrographic greater likelihood of progression to
pattern of ESES also resolves in pu- juvenile myoclonic epilepsy. Etiology
berty. However, the neuropsycholog- is presumed to be genetic, and imag-
ical prognosis is more worrisome with ing is not required.
less than half of children achieving Treatment. Ethosuximide is consid-
normal intelligence and language ered first-line treatment of childhood
function. Factors predictive of poorer absence epilepsy, with valproic acid and
outcome include earlier onset of ESES lamotrigine considered second-line.25
and longer duration until effective Most cases of childhood absence epi-
therapy is initiated, which under- lepsy are pharmacoresponsive. Carba-
scores the need for maintaining a high mazepine, oxcarbazepine, tiagabine,
level of suspicion of this diagnosis. vigabatrin, and possibly phenytoin
may exacerbate absence seizures and
Childhood Absence Epilepsy should be avoided.
Childhood absence epilepsy presents Prognosis. Over two-thirds of chil-
at a peak age of 5 to 7 years and dren with childhood absence epilepsy
accounts for 5% to 10% of all epilepsies will achieve seizure control with their
beginning in childhood. The condition first or second AED, and medication
is slightly more common in girls and should be weaned after a seizure-free
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 Pediatric Epilepsy

FIGURE 4-7 EEG of a 7-year-old girl with staring spells shows abrupt onset of 3-Hz generalized spike-wave discharge with
staring, consistent with an absence seizure.

period of 1 to 2 years if the EEG family history is frequently positive for

normalizes. While most cases ultimately either epilepsy (15% to 37%) or febrile
remit and do not require medication seizures (50%). Myoclonic-atonic epi-
into adulthood, a minority evolve to lepsy is one of the syndromes that can
juvenile myoclonic epilepsy in late ado- be seen in GEFS+ families.
lescence or early adulthood, or patients Clinical features. The initial pre-
may continue to have brief, often infre- sentation of myoclonic-atonic epilepsy
quent, absence seizures in adulthood. is usually with febrile or afebrile gen-
Even with remission of epilepsy, social eralized tonic-clonic seizures, followed
outcomes can be problematic with by other generalized seizures after weeks
academic and behavioral concerns to months.26 The myoclonic-atonic sei-
persisting into adulthood. zure is characteristic, seen in nearly all
cases, consists of a brief generalized
Myoclonic-Atonic Epilepsy myoclonic jerk affecting proximal mus-
(Doose Syndrome) cles, and is followed by an atonic com-
Myoclonic-atonic epilepsy, or Doose ponent that can be very subtle (head
syndrome, is a rare syndrome (1% to nod) or more prominent (abrupt fall)
2% of childhood epilepsy) that has (Figure 4-8). Myoclonic, atonic, atypi-
onset between 2 and 5 years of age cal absences, and, rarely, tonic seizures
and has a male preponderance. Most may also occur. One or more periods
children are developmentally normal of nonconvulsive status epilepticus can
prior to the onset of seizures, and be seen in 40% of patients and may be

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FIGURE 4-8 EEG of a 3-year-old boy with myoclonic-atonic epilepsy who presented with sudden onset of staring and falls
showing a generalized spike-wave discharge in association with a head drop. Some head drops are
preceded by a brief jerk and minor vocalization, consistent with myoclonic-atonic seizures.

induced by inappropriate AEDs such Prognosis. Outcome is variable in

as carbamazepine. patients with myoclonic-atonic epilepsy.
Investigations. The initial EEG back- Seizures remit in 54% to 89% of cases,
ground is normal, but over time, cen- and half of children have normal devel-
troparietal theta rhythms emerge, opment long term or only mild cogni-
amplitude increases, and a 2-Hz to 3-Hz tive delay.27 However, other cases fare
generalized spike, polyspike, and wave poorly, with persisting seizures and cog-
discharge is seen interictally, which nitive regression. Poorer outcome is
increases with sleep. Photosensitivity predicted by prolonged or recurrent
is common. nonconvulsive status epilepticus and
Treatment. Medications that may be by the presence of tonic seizures.
beneficial in myoclonic-atonic epilepsy Myoclonic-atonic epilepsy is impor-
include valproic acid, ethosuximide, tant to differentiate from Lennox-Gastaut
lamotrigine, topiramate, levetiracetam, syndrome. Useful distinguishing features
zonisamide, and, in refractory cases, include family history of epilepsy (often
ACTH. However, seizures are frequently positive in myoclonic-atonic epilepsy ver-
pharmacoresistant, and the ketogenic sus usually negative in Lennox-Gastaut
diet is one of the most efficacious ther- syndrome), past history of neuro-
apies, providing a greater than 50% re- developmental delay (usually absent in
duction in seizures in 55% of cases and myoclonic-atonic epilepsy versus often
seizure freedom in 18%. present in Lennox-Gastaut syndrome),

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 Pediatric Epilepsy

KEY POINTS
h Myoclonic-atonic presence of tonic seizures (uncommon 3 years, frequent seizures, and recurrent
epilepsy is important and usually late in the course of nonconvulsive status epilepticus. Hyper-
to distinguish from myoclonic-atonic epilepsy versus the kinetic behaviors, autistic features, and
Lennox-Gastaut prominent seizure type in Lennox- perseverative behaviors are common.
syndrome, as Gastaut syndrome), and interictal EEG Investigations. Interictally high-
myoclonic-atonic pattern (2-Hz to 3-Hz generalized spike- amplitude 1.5-Hz to 2.5-Hz general-
epilepsy usually has a wave with 4-Hz to 7-Hz centroparietal ized and multifocal polyspike and
much more benign rhythms in myoclonic-atonic epilepsy spike-wave discharges on a slow back-
long-term prognosis. versus 1-Hz to 2-Hz generalized spike- ground are seen, which increase dur-
h Lennox-Gastaut wave and fast anterior rhythms in ing sleep (Figure 4-9A). However, this
syndrome typically affects Lennox-Gastaut syndrome). pattern may take months to evolve
neurodevelopmentally and is present in less than 30% of
abnormal children with Lennox-Gastaut Syndrome patients early on. Low-voltage frontally
characteristic features, Lennox-Gastaut syndrome is a relatively predominant greater than 10-Hz gen-
including tonic and
rare epilepsy syndrome with an inci- eralized paroxysmal fast activity is seen
atonic seizures. Interictal
dence of 1.9 to 2.1 per 100,000 children in slow-wave sleep (Figure 4-9B) and is
EEG shows both slow
spike-wave discharge
but accounts for approximately 6% to suggestive of the diagnosis of Lennox-
and characteristic 7% of children with intractable epilepsy. Gastaut syndrome, even if other EEG
generalized paroxysmal Onset is typically in the preschool years, features have not yet fully evolved.
fast activity in sleep. and males are preferentially affected. Treatment and prognosis. The
Two-thirds of cases occur in children seizures in Lennox-Gastaut syndrome
with preexistent brain abnormalities, are pharmacoresistant. Valproic acid
one-third of whom have a history of and its derivatives are commonly used,
West syndrome. and lamotrigine, topiramate, rufinamide,
Clinical features. Lennox-Gastaut clobazam, and felbamate have all been
syndrome typically evolves over months shown to be superior to placebo in
to include a triad of symptoms: (1) randomized controlled studies.28 Carba-
multiple generalized seizure types, in- mazepine may lessen tonic seizures but
cluding tonic, atonic, myoclonic, and worsen atypical absences. Ethosuximide
atypical absence; (2) an interictal EEG may be helpful for refractory atypical
pattern of diffuse slow spike-wave com- absences. Given the poor response to
plexes; and (3) cognitive dysfunction.26 AEDs, the ketogenic diet should be
Nocturnal tonic events are most considered early in the course of
characteristic of Lennox-Gastaut syn- Lennox-Gastaut syndrome.29 Approxi-
drome but are often subtle and diffi- mately half of children experience
cult to recognize without video-EEG significant seizure reduction with rare
recording. Daytime tonic and atonic cases achieving seizure freedom.
seizures often lead to problematic Children with Lennox-Gastaut syn-
falls. Nonconvulsive status epilepticus drome are generally not candidates for
is also common but often difficult to resective surgery. Corpus callosotomy
detect in a timely manner. is a possible treatment for intractable
Intellectual disability ultimately af- drop seizures. Section of only the
fects nearly all children with Lennox- anterior two-thirds limits severity of
Gastaut syndrome but is not always disconnection symptoms compared
evident early in the course. Factors pre- to complete callosotomy but is less
dictive of poorer cognitive outcome effective. Retrospective studies have
include delayed development prior to demonstrated vagus nerve stimulation
seizure onset, history of infantile spasms, to reduce seizures by approximately
onset of symptoms before the age of 50% in nearly half of children.29
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FIGURE 4-9 EEG of a 5-year-old boy with a remote history of West syndrome, global developmental delay, and multiple
seizures. A, Interictal EEG shows high-amplitude frontally predominant slow spike waves characteristic of
Lennox-Gastaut syndrome. B, Generalized paroxysmal fast activity is shown during sleep.

ADOLESCENT-ONSET EPILEPSIES Juvenile Absence Epilepsy

The following syndromes have their on- Juvenile absence epilepsy, one of the
set in adolescence or young adulthood. less-common genetic generalized

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 Pediatric Epilepsy

KEY POINT
h While a generalized epilepsies, accounts for 1% to 2% of which they attributed to nervousness
tonic-clonic childhood epilepsy. or clumsiness. Of patients with juve-
seizure is the most Clinical features. Juvenile absence nile myoclonic epilepsy, 30% to 40%
common seizure type epilepsy presents in otherwise healthy have a history of brief and infrequent
leading to diagnosis of children at a peak age of 10 to 12 years absences that were often disregarded.
juvenile myoclonic with relatively infrequent absences (of- Investigations. The interictal EEG
epilepsy, most patients ten less than daily). Generalized tonic- usually shows paroxysmal generalized
have a history clonic seizures occur in approximately 4-Hz to 6-Hz polyspike-and-wave dis-
of early morning 80% of patients, usually after onset of charge and irregular spike-and-wave
myoclonic jerks, the absences, and minor myoclonic jerks on a normal background (Figure 4-10).
significance of which
may coexist in 20% of cases. Focal changes and a photoparoxysmal
had gone unrecognized.
Investigations. While the EEG is response are each seen in up to half of
similar to childhood absence epilepsy, cases. The characteristic ictal finding is
spike-wave frequency is slightly faster a frontally predominant polyspike-
(greater than or equal to 3.5 Hz), and and-wave discharge that correlates with
polyspikes may be seen. Discharges are a myoclonic jerk.
commonly induced by hyperventilation; Treatment and prognosis. Although
however, photosensitivity is unusual. most cases are pharmacoresponsive,
Treatment and prognosis. First-line remission is rare and lifelong therapy is
medications include valproic acid or usually needed.30 Valproic acid has ex-
lamotrigine. While ethosuximide may be cellent efficacy, but the potential adverse
efficacious for absences, monotherapy is effects of weight gain, polycystic ovary
not advised as it is ineffective for gener- syndrome, teratogenicity (neural tube
alized tonic-clonic seizures. Juvenile ab- defects in up to 6% of pregnancies),
sence epilepsy is usually a lifelong and cognitive concerns in offspring
condition. Approximately 60% of patients limits its use in women of childbearing
achieve complete seizure control with age. Lamotrigine is often the therapy of
medication, while the remainder have first choice, although it rarely may
ongoing infrequent generalized tonic- exacerbate myoclonic seizures. Other
clonic or absence seizures. therapeutic options include topiramate,
levetiracetam, and zonisamide. Carba-
Juvenile Myoclonic Epilepsy mazepine, phenytoin, and vigabatrin
Juvenile myoclonic epilepsy is the most should be avoided as they typically
common of the genetic generalized worsen seizures. Counseling regarding
epilepsies, accounting for approximately avoidance of common provoking fac-
5% to 10% of all epilepsies. It most tors, such as sleep deprivation, exces-
commonly begins between 12 and sive alcohol use, and exposure to photic
18 years of age in neurodevelop- stimulation, should be provided.
mentally normal individuals and has a
slight female predilection (60%). VARIABLE-ONSET EPILEPSIES
Clinical features. Patients with ju- The following syndromes may present
venile myoclonic epilepsy typically at a variety of ages.
present with a generalized tonic-
clonic seizure (often provoked by Focal Epilepsy of Unknown Cause
sleep deprivation, alcohol ingestion, Nonlesional focal epilepsy that does not
exposure to flashing lights, or stress), meet criteria for a known electroclinical
but most patients have had myoclonic syndrome comprises approximately
jerks (predominantly early morning) 20% to 30% of new-onset epilepsy in
often triggered by sleep deprivation, children.31 In these children, a variety
78 www.ContinuumJournal.com February 2016

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FIGURE 4-10 EEG, showing generalized polyspike and atypical spike-wave discharge, of a developmentally normal 16-year-old
boy who presented with a single early morning generalized tonic-clonic seizure triggered by photic
stimulation. The patient also has a history of myoclonus, exacerbated by sleep deprivation. These findings
are characteristic of juvenile myoclonic epilepsy.

of focal-onset seizures are seen, and Lesional Focal Epilepsy KEY POINT
the majority are developmentally and Lesional focal epilepsy also accounts for h Focal epilepsy of
neurologically normal. These epilep- unknown cause in
approximately 20% to 30% of new-onset
sies have an overall benign course, neurodevelopmentally
epilepsies in children and can present at
with a much better seizure prognosis normal children
any age. Common lesional causes in-
accounts for 20% to
than those with lesional focal epilepsy; clude malformations of cortical devel- 30% of all pediatric
approximately two-thirds will remit and opment, tuberous sclerosis, perinatal epilepsy and overall has
be able to discontinue AEDs, while brain injury or other remote brain a very benign course.
only 7% to 13% will develop intractable insult, hippocampal sclerosis, develop-
epilepsy. Although terminal remission mental tumors, or vascular causes.
rates are high, many children go Pharmacoresistant epilepsy is a signifi-
through a relapsing and remitting cant concern in this group, and only
pattern before achieving that state. approximately one-third will achieve
Despite their relatively mild epilepsy, long-term seizure remission. For those
many have social concerns and with intractable seizures, resective sur-
comorbidities, including school, behav- gery should be strongly considered in
ior, and psychiatric concerns that can eligible cases once pharmacoresistance
persist into adulthood. has been established.

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 Pediatric Epilepsy

Important Genetic and includes a summary of several of the

Metabolic Causes currently recognized more frequent
Genetic etiologies are being recognized causal genes. Important metabolic etiol-
as causal for many early-onset epileptic ogies, including treatable causes, are
encephalopathies (Case 4-3).32 Table 4-1 listed in Table 4-2.

Case 4-3
A 34-month-old boy presented with a history of intractable generalized epilepsy that began at 12 months
of age. He had myoclonic-atonic seizures as well as isolated myoclonic, atypical absence, and atonic
events. His EEG showed mild slowing of the background, bursts of generalized polyspike, and spike-wave
discharges as well as recorded seizures with a generalized correlate (Figure 4-11). Seizures had been
medically intractable to levetiracetam, lamotrigine, oxcarbazepine, and valproic acid. His development was
mildly delayed, and he had just started combining words. His neurologic examination was unremarkable,
and head circumference was concordant with weight and height. On further investigation, he had low CSF
glucose (35 mg/dL), low CSF-to-plasma glucose ratio (36.8%), and a borderline low CSF lactate (1.2 mEq/L).
Genetic testing revealed a pathogenic mutation in the glucose transporter gene (SLC2A1), and he was
initiated on the ketogenic diet with resolution of seizures and improvement in his developmental trajectory.

FIGURE 4-11 EEG of the patient in Case 4-3 showing a recorded myoclonic-absence seizure. Further metabolic evaluation
revealed low CSF glucose, and a diagnosis of glucose transporter deficiency was made. His seizures resolved
on the ketogenic diet.

Continued on page 81

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 Continued from page 80
Comment. Significant phenotypic heterogeneity is present in disorders of glucose transport. This
diagnosis should be considered in cases of early-onset epilepsy (particularly early-onset absence epilepsy)
with mild to severe developmental delay with or without microcephaly. Expedient diagnosis and
treatment with a ketogenic diet allows the child to maximize his or her developmental potential.

TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies

Gene or Other Clinical Interictal EEG

Syndrome Chromosome Findings Seizure Type Findings Course
SCN1A 2q24.3 Severe cases: Severe cases: Generalized or Severe cases:
Developmental Dravet syndrome focal/multifocal Medically
delay, crouch with prolonged discharges intractable,
gait, ataxia, hemiconvulsive lifelong
Photoparoxysmal
pyramidal signs seizures triggered epilepsy
response may
by fever prior to
be seen Mild cases:
18 months of age;
Remission
later on, other
generalized and
focal seizures
Mild cases: Genetic
epilepsy with
febrile seizures
plus (GEFS+) with
febrile seizures
and generalized
or focal seizures
Wolf- Partial Prenatal growth Focal, myoclonic, High-voltage Severity
Hirschhorn monosomy 4p failure, severe generalized spike wave or slow decreases
syndrome delay, cleft lip tonic-clonic, or waves or sequences with time
or palate, atypical absence of sharp waves in
beaked nose, seizures the centroparietal
hypertelorism, or occipital regions
low-set ears
HCN1 5p12 Mild to severe Onset of febrile Multifocal or Medically
intellectual or afebrile generalized intractable
disability, autistic generalized or discharges
features, behavior focal seizures in
disturbances, first year of life,
ataxia followed by
absence or
myoclonic
seizures
STXBP1 9q34.1 Severe to Early-onset tonic Suppression-burst Seizures often
profound delay, seizures, spasms, or hypsarrhythmia intractable
MRI may show or tonic-clonic although
hypomyelination, seizures rarely remit;
global atrophy, severe to
or thinning of profound
the corpus developmental
callosum delay
Continued on page 82

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 Pediatric Epilepsy

TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies Continued from page 81

Gene or Other Clinical Interictal EEG

Syndrome Chromosome Findings Seizure Type Findings Course
SPTAN1 9q33Y9q34 Progressive Spasms, Hypsarrhythmia Medically
microcephaly, generalized intractable
spastic quadriplegia, seizures
severe intellectual
disability,
hypomyelination
and diffuse brain
atrophy on MRI
DNM1 9q34 Hypotonia Infantile spasms Hypsarrhythmia, Severe to
evolving to slow spike wave profound
Lennox-Gastaut intellectual
syndrome disability,
intractable
epilepsy
SLC25A22 11p15.5 Hypotonia, Myoclonic Suppression-burst, Medically
microcephaly, seizures, spasms hypsarrhythmia intractable
abnormal
electroretinogram
Trisomy 12p 12 Severe delay, short Myoclonic or 3-Hz spike and Seizures often
neck, prominent myoclonic polyspike respond to
forehead, absence, antiepileptic drugs
flat occiput, generalized
hypertelorism, tonic-clonic
micrognathia, seizures
low-set ears
SCN8A 12q13.1 Movement disorder Clusters of focal Multifocal or Often intractable
or generalized generalized
seizures discharges
triggered by
fever, spasms
Ring 14 Severe delay, Symptomatic Multifocal or Often intractable
chromosome microcephaly, generalized generalized
14 narrow face, epilepsy with discharges
high-arched onset in first
palate, short year of life
palpebral
fissures, flat nasal
bridge, retrognathia,
ocular anomalies
FOXG1 14q11Y14q13 Severe delay without Focal and Slowing of Often refractory
microcephaly, generalized background,
“congenital Rett” seizures focal and
multifocal
discharge

Continued on page 83

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TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies Continued from page 82

Gene or Other Clinical Interictal EEG

Syndrome Chromosome Findings Seizure Type Findings Course
Inversion- 15 Moderate to Epileptic Hypsarrhythmia, Often
duplication severe delay, encephalopathy slow spike wave refractory
15 syndrome autism, microcephaly, resembling West
mild occasional syndrome or
dysmorphic features Lennox-Gastaut
syndrome,
occasional focal
seizures
Angelman Partial Ataxia, tremor, Atypical High-amplitude, Valproic
syndrome monosomy 15q minimal speech, absence, symmetric, acid and
severe delay, myoclonic, synchronous benzodiazepines
happy demeanor tonic-clonic, notched 2-Hz helpful
unilateral polyphasic slow
clonic, focal waves or Seizure severity
dyscognitive slow and decreases
seizures sharp waves, over time
particularly
during slow-
wave sleep
POLG1 15q24 Cerebral atrophy, Myoclonic, Multifocal Refractory
liver dysfunction other focal and discharge
generalized with slowing
seizures
CHD2 15q26 Intellectual Fever-sensitive Generalized Mild to severe
disability, may generalized polyspike- intellectual
have microcephaly tonic-clonic and-wave disability
seizures usually discharges
after age 1; later initially, later
with prominent on may see
myoclonus focal or
and atypical multifocal
absences discharge
GRIN2A 16p13.2 Intellectual Focal seizures Centrotemporal Seizures resolve
disability, affecting the spikes, which around puberty,
speech delay lower face or may be nearly but intellectual
secondarily continuous disability and
generalized in sleep speech delays
seizures from may persist
sleep; onset in
late preschool
to early
school years

Continued on page 84

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 Pediatric Epilepsy

TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies Continued from page 83

Gene or Other Clinical Interictal EEG

Syndrome Chromosome Findings Seizure Type Findings Course
Miller-Dieker 17p13.3 Four-layered In first weeks Prominent fast Seizures are
syndrome deletion lissencephaly; to months, activity, although refractory
microcephaly; massive slowing is
bitemporal myoclonus and common in the
narrowing; small, epileptic spasms first year of life
anteverted nose; are seen; over
micrognathia; time, focal and
high forehead; tonic seizures
cardiac, renal, emerge as
and sacral predominant
anomalies seizure types
KCNQ2 20q13.33 Usually normal Severe cases: Severe cases: Most cases are
infants but Early-onset Suppression-burst mild with
rarely may have tonic spasms, or hypsarrhythmia self-limited
moderate to focal seizures, seizure disorder
profound delay; myoclonic Mild cases: and normal
severely affected seizures Normal or focal development
infants may have discharges
reversible T2 Mild cases: Rarely, may
signal changes in Focal epilepsy present as
the thalami and in infants a severe
basal ganglia early-onset
epileptic
encephalopathy
with refractory
seizures
Ring 20 Mild to moderate Runs of atypical Ictal: High-voltage, Seizures are
chromosome delay, restlessness, absence or 2-Hz to 3-Hz refractory and
20 aggression, myoclonic slow activity with do not remit
nondysmorphic status superimposed spikes with age
epilepticus maximal over
frontal regions

Interictal: Normal
or mild slowing/
sharp waves
DEPDC5 22q12.3 Autosomal Focal epilepsy Focal or multifocal Heterogeneous:
dominant (often frontal discharges Some cases have
inheritance with or temporal) well-controlled
incomplete epilepsy, others
penetrance (50% are intractable
to 82%); may be
associated with Rarely, individuals
cortical dysplasias, may have
often bottom of intellectual
the sulcus disability, autism,
and psychiatric
features
Continued on page 85

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TABLE 4-1 Selected Genetic Causes of Epileptic Encephalopathies Continued from page 84

Gene or Other Clinical Interictal EEG

Syndrome Chromosome Findings Seizure Type Findings Course
CDKL5 Xp22 More common in Generalized Interictal EEG Intractable
girls but also seen tonic seizures normal early on, generalized
in boys, severe beginning then see slowing seizures
developmental in first 10 weeks, of background
delay with followed by and modified
hypotonia, acquired spasm, atypical hypsarrhythmia
microcephaly absences, and
in some cases, myoclonic
impaired eye seizures
contact, gaze
avoidance
PCDH19 Xp22.1 Girls only, intellectual Generalized Generalized or Intellectual
disability, autism tonic-clonic or focal discharge disability,
focal seizures, autism
typically occurring
in clusters with Seizures
febrile illness often
medically
intractable
Rett Xq28 Normal early Generalized Slowing of Often
syndrome development tonic-clonic background with refractory
(MECP2) followed by seizures, other multifocal and
acquired generalized generalized
microcephaly, and focal epileptiform
autistic features, seizures discharge
lack of purposeful
hand movement
with characteristic
hand wringing
ARX Xp22.3 Severe developmental Spasms, other Suppression-burst, Usually
delay and seizures generalized hypsarrhythmia refractory
in boys; often seizures
associated cerebral
malformations
including
lissencephaly,
agenesis of corpus
callosum; may
have dystonia,
spasticity
SLC35A2 Xp11.23-p11.22 Moderate to Spasms, Hypsarrhythmia, Often
severe intellectual focal electrical status intractable
disability, language epilepsy epilepticus in
impairment, slow sleep
early pubertal onset
EEG = electroencephalogram; MRI = magnetic resonance imaging.

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 86
TABLE 4-2 Selected Metabolic Causes of Epileptic Encephalopathies

Metabolic Age at Clinical

Disorder Onset Presentation Diagnostic Test Prognosis Treatment
Pyridoxine Birth to Refractory seizures Increased Variable, depending Pyridoxine 50Y200 mg/d
dependency33,34 1 year that may begin in !-aminoadipic on duration of IV or orally
utero, progressive semialdehyde in CSF, symptoms prior to
encephalopathy, serum, and urine; supplementation

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clinical and EEG confirm with ALDH7A1
response to pyridoxine genetic analysis
Pyridoxal phosphate Neonatal Refractory seizures, Low pyridoxal Variable, depending Pyridoxal 5¶-phosphate
dependency33,34 often in preterm 5¶-phosphate on duration of 30 mg/kg/d orally
infant, encephalopathy, in CSF; confirm with symptoms prior to
clinical and EEG response PNPO genetic analysis supplementation
to pyridoxal phosphate
Folinic acidYresponsive Neonatal Refractory seizures, Increased Variable, depending Folinic acid 3Y5 mg/kg/d
seizures33,34 encephalopathy, clinical !-aminoadipic on duration of orally
and EEG response to semialdehyde in CSF symptoms prior to
folinic acid, incomplete and increased supplementation
Pediatric Epilepsy

response to pyridoxal serum pipecolic acid,

phosphate and abnormal peaks on
pyridoxine CSF neurotransmitter
analysis
Serine deficiency Neonatal and Microcephaly, cognitive Decreased serine in Variable, depending Serine 500Y700 mg/kg/d
disorders33,34 childhood disability, failure to thrive, CSF and plasma on duration of with or without glycine
spasticity, hypomyelination amino acids symptoms prior to supplementation orally
and brain atrophy on MRI, supplementation
neonatal or absence seizures
Creatine deficiency33 Neonatal and Developmental delay, Screen with urine testing Poor, majority with Creatine monohydrate
infancy seizures, autistic features, for creatine and GAA, moderate to severe 5Y20 g/d orally
movement disorder, followed by definitive developmental
poor growth genetic testing for disability
AGAT, GAMT, or

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creatine transporter
Untreated Neonatal and Growth failure, Increased phenylalanine Good if diagnosed Phenylalanine-restricted
phenylketonuria infancy microcephaly, seizures, in plasma amino acids and treated early diet, consider
developmental delay, tetrahydrobiopterin trial to
mousy odor rule out deficiency

February 2016
 Urea cycle Neonatal, later Vomiting, lethargy, Increased serum Variable, depending Removal of
disorders if partial coma, seizures, ammonia, abnormal on severity ammonia with dialysis
enzyme developmental delay, serum amino acids and duration (if hyperammonemic
deficiency protein avoidance, and urine organic acids of symptoms crisis); treat with
diffuse white matter sodium benzoate,
changes on MRI sodium phenylacetate,
arginine supplementation,
high-carbohydrate and
low-protein diet with
provision of essential

Continuum (Minneap Minn) 2016;22(1):60–93

amino acids
Nonketotic Neonatal and Lethargy, hypotonia, Increased CSF and Poor, death Sodium benzoate
hyperglycinemia33 infancy hiccups, intractable plasma glycine with usually within 250Y750 mg/kg/d orally
seizures, apnea CSF/plasma glycine the first year and dextromethorphan;
90.08 avoid valproate
and vigabatrin
GABA transaminase Neonatal and Intractable seizures, lethargy, Increased GABA Poor, death Symptomatic only
deficiency infancy irritability, severe delay, in serum and CSF usually within
hypotonia, hyperreflexia, the first 5 years
accelerated growth
Sulfite oxidase Neonatal and Intractable seizures, Elevated sulfite Poor Some patients
deficiency and infancy progressive neurocognitive levels in fresh urine; may improve with
molybdenum decline, acquired low plasma vigabatrin or
cofactor deficiency33 microcephaly, MRI homocysteine; dextromethorphan;
demonstrating confirm with specific some may improve
leukoencephalomalacia enzyme analysis with dietary restriction
and atrophy; later-onset of fibroblasts of methionine
forms may present with
encephalopathy, focal
findings, and seizures
after a febrile illness
Peroxisomal Neonatal and Hepatic disease, Abnormal very long Variable, depending Symptomatic only
disorders33 infancy developmental delay, chain fatty acids or on phenotype
retinopathy, deafness, phytanic acid
seizures, cortical

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migration defects

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Continued on page 88

87
 88
TABLE 4-2 Selected Metabolic Causes of Epileptic Encephalopathies Continued from page 87

Metabolic Age at Clinical

Disorder Onset Presentation Diagnostic Test Prognosis Treatment
Menkes disease33 Infancy Developmental regression; Low serum copper Poor, with Copper histidine
seizures, particularly and ceruloplasmin; progression supplementation
spasms; hypopigmentation confirm with ATP7A to death typically and supportive
of skin and hair; mutation analysis within 5 years treatment
hypothermia; characteristic
“kinky” hair

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Glutaricaciduria type 1 Infancy and Macrocephaly; Increased urinary Poor, although Low-protein
childhood acute neurologic glutaric acid detection and diet (low lysine
decompensation with treatment prior to and tryptophan)
infection or febrile decompensation may with carnitine
illness, characterized by improve outcome supplementation
hypotonia, opisthotonic
posturing, dystonia or
dyskinesia; seizures;
encephalopathy; MRI
shows widening of
sylvian fissures
Pediatric Epilepsy

Biotinidase deficiency33 Neonatal through Seizures, hypotonia, Low serum biotinidase Outcome can be Biotin
childhood developmental delay, good if diagnosed supplementation
ataxia, dermatitis, and treated early 5Y40 mg/d
hair loss, autistic
behavior, optic atrophy
Succinic semialdehyde Infancy and Developmental delay, Increased GABA in Variable, Symptomatic
dehydrogenase childhood ataxia, hypotonia, seizures, urine; confirm with treatment targeted
deficiency hyperactivity, behavior enzymatic analysis at symptoms
problems; increased or ALDH5A1
T2 signal in globus pallidus, gene sequencing
dentate nucleus, and
subthalamic nucleus with
cerebral atrophy
Congenital Infancy and Epilepsy, Postprandial Outcome can be Protein restriction,

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hyperinsulinism childhood intellectual disability hypoglycemia, good if diagnosed diazoxide
and hyperammonemia hyperammonemia; and treated early
confirm by mutation
analysis in glutamate
dehydrogenase gene

February 2016
 Tetrahydrobiopterin 2 to 12 months Cognitive regression, Elevated phenylalanine Outcome can be Tetrahydrobiopterin
deficiencies34 microcephaly, in plasma amino acids, good if diagnosed supplementation;
generalized seizures, abnormal pterins and and treated early may need additional
irritability, dystonia, neurotransmitters supplementation with
rash, basal ganglia in CSF neurotransmitter
calcifications precursors based on type
Glucose transporter Birth to early Seizures (infantile- Low CSF/plasma glucose Variable, Ketogenic diet
deficiency33Y35 childhood onset focal or with normal or low depending
generalized, or lactate; confirm with on duration of
early-onset absence SCL2A1 genetic testing symptoms prior
epilepsy), microcephaly, to treatment with
developmental ketogenic diet

Continuum (Minneap Minn) 2016;22(1):60–93

delay, acquired ataxia,
paroxysmal dyskinesia
Cerebral folate Childhood to Intractable epilepsy, Low CSF Variable, Folinic acid
deficiency adolescence intellectual disability methyltetrahydrofolate; depending supplementation
or regression, further testing requires on exact etiology 0.5Y5 mg/kg/d orally
microcephaly, mutation analysis in and duration of
dyskinesias, autism FOLR1 gene, assessment symptoms prior
for antibodies to folate to treatment
receptors, and if these
are negative, a workup
for secondary causes of
cerebral folate deficiency
should be undertaken
Mitochondrial Infancy to Focal or generalized Elevated plasma Variable, Avoid valproate; treat
disorders33 adulthood seizures, spasms, and CSF lactate; may depending with mitochondrial
deafness, myopathy, have evidence of on specific type cocktail (L-carnitine,
lactic acidosis, cardiac, renal, or coenzyme Q, riboflavin);
ataxia, optic atrophy, hepatic dysfunction; ketogenic diet may be
hepatic dysfunction elevated lactate peak on MR helpful in some conditions
spectroscopy, muscle biopsy,
and specific genetic analysis
Congenital Infancy to Developmental Abnormalities in Variable Symptomatic
disorders of childhood delay, hypotonia, carbohydrate deficient depending
glycosylation failure to thrive, transferrin analysis; on cause

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multisystem disease, confirm with specific
inverted nipples or genetic analysis

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abnormal fat pads,
cerebellar hypoplasia
CSF = cerebrospinal fluid; EEG = electroencephalogram; GABA = ,-aminobutyric acid; MR = magnetic resonance; MRI = magnetic resonance imaging.

89
 Pediatric Epilepsy

TABLE 4-3 Progressive Myoclonic Epilepsy Syndromes

Disease or Age at Clinical

Condition Onset Presentation Investigations Prognosis
Tay-Sachs disease 4Y9 months Exaggerated Hexosaminidase Death in 2Y4 years
and Sandhoff startle reflex, A deficiency
disease developmental (Tay-Sachs disease)
regression, visual loss, and hexosaminidase
cherry red spot A and B deficiency
(Sandhoff disease)
Tetrahydrobiopterin 2Y12 months Cognitive regression, Urine for pterins May respond to
deficiencies microcephaly, tetrahydrobiopterin
generalized seizures,
irritability
Alpers disease 0Y5 years Progressive cognitive Genetic: POLG1 Death, usually
deterioration, mutation due to hepatic
peripheral neuropathy, failure or status
recurrent status epilepticus
epilepticus and
epilepsia partialis
continua,
hepatic failure
Juvenile Huntington 5Y20 years Myoclonic tremor, Genetic: expanded Slow progression
disease chorea, cognitive trinucleotide to death in
regression, CAG repeat on 10Y20 years
behavior change chromosome 4p16.3
Neuronal ceroid Infancy to Progressive seizures, Skin, rectal, conjunctival, Death within
lipofuscinosis adulthood, ataxia, myoclonus, or brain biopsy 1Y15 years,
depending dementia, visual loss demonstrating depending
on subtype with some subtypes, characteristic on subtype
cerebral atrophy, ultrastructural
pyramidal and pathology; genetic
extrapyramidal signs diagnosis available
for many subtypes
Sialidosis type 1 8Y15 years Decreased vision, !-Neuraminidase Profound impairment
cherry red spot, from myoclonus,
Urine
burning extremity death in third or
oligosaccharides
pain, progressive fourth decade
myoclonus, cognition
mildly impaired
Sialidosis type 2 0Y10 months Coarse features, !-Neuraminidase Often severe
in infantile visual deficits,
form or cherry red spot, Urine
adolescence generalized seizures, oligosaccharides
in juvenile burning extremity
form pain, dementia
Unverricht- 6Y18 years Ataxia, mild cognitive Genetic: EPM1 (21q22.3) Slow progression
Lundborg deterioration, with tendency
disease generalized to stabilize
tonic-clonic seizures in adulthood

Continued on page 91

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TABLE 4-3 Progressive Myoclonic Epilepsy Syndromes Continued from page 90

Disease or Age at Clinical

Condition Onset Presentation Investigations Prognosis
Lafora disease 6Y19 years Generalized tonic-clonic Genetic: EMP2A Rapidly
and occipital seizures, or EMP2B progressive to
rapid cognitive Axillary skin biopsy death within
regression 2Y10 years
Myoclonic epilepsy 3Y65 years Partial or generalized Genetic testing of Variable
with ragged seizures, deafness, mitochondrial DNA
red fibers myopathy, lactic
Muscle biopsy for
acidosis, ataxia,
ragged red fibers
optic atrophy
Gaucher disease Childhood to Supranuclear gaze Glucocerebrosidase Variable but
early adulthood palsy, generalized deficiency often more
or partial seizures, severe if
rigidity, ataxia, younger onset
cognitive regression,
splenomegaly
Dentatorubral- 6Y69 years Choreoathetosis, CAG expansion Variable
pallidoluysian dementia, psychosis, at 12p13
atrophy (DRPLA) ataxia
DNA = deoxyribonucleic acid.

Progressive Myoclonic Epilepsy new-onset epilepsy and epilepsy syndromes

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progressive medically intractable myoc- cognitive outcomes: a prospective cohort
lonus, and slowing of the EEG back- study. Neurology 2012;79(13):1384Y1391.
ground. Specific etiologies that should doi:10.1212/WNL.0b013e31826c1b55.
be considered in childhood are listed 3. Berg AT, Berkovic SF, Brodie MJ, et al.
in Table 4-3. Revised terminology and concepts for
organization of seizures and epilepsies:
report of the ILAE Commission on Classification
CONCLUSION and Terminology, 2005-2009. Epilepsia
Epilepsy in children is due to a diverse 2010;51(4):676Y685. doi:10.1111/j.
group of disorders. Careful delinea- 1528-1167.2010.02522.x.
tion of the etiology and electroclinical 4. Gaillard WD, Chiron C, Cross JH, et al.
syndrome will improve yield and cost- Guidelines for imaging infants and children
with recent-onset epilepsy. Epilepsia 2009;50(9):
effectiveness of investigations, aid in 2147Y2153. doi:10.1111/j.1528-1167.2009.02075.x.
the selection of more efficacious ther-
5. Go CY, Mackay MT, Weiss SK, et al.
apies, and allow a clearer picture of Evidence-based guideline update: medical
prognosis for both seizure control and treatment of infantile spasms. Report of the
long-term remission. Guideline Development Subcommittee of
the American Academy of Neurology and
the Practice Committee of the Child
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 Review Article

Adult Focal Epilepsies

Address correspondence to
Dr Christopher T. Skidmore,
Thomas Jefferson University,
901 Walnut Street, 4th Floor,
Philadelphia, PA 19107, Christopher T. Skidmore, MD
christopher.skidmore@
jefferson.edu.
Relationship Disclosure:
Dr Skidmore serves as a ABSTRACT
consultant for Upsher-Smith Purpose of Review: Focal epilepsy is the most common type of epilepsy in
Laboratories, Inc, and has
received research support from adulthood. This article discusses the seizure symptomatology, EEG findings, and
NeuroPace, Inc. imaging findings of the various forms of focal epilepsy. The majority of the article
Unlabeled Use of focuses on temporal and frontal lobe epilepsy as these represent the majority of
Products/Investigational
Use Disclosure:
focal epilepsies.
Dr Skidmore reports Recent Findings: While significant overlap exists in the clinical symptomatology of
no disclosure. the focal epilepsies, detailed seizure descriptions can often provide useful clinical
* 2016 American Academy evidence to help establish an accurate diagnosis. EEG and MRI continue to serve as
of Neurology.
the main diagnostic tools for the diagnosis of focal epilepsy.
Summary: The various forms of focal epilepsy generate seizure presentations that
are dependent on the anatomic structures that are involved in the seizure. By
understanding the symptoms typically generated in each region of the brain, a
better understanding of the possible seizure localizations can be made. Most forms
of epilepsy have clear changes on EEG that permit accurate localization, but several
pitfalls exist, which are discussed in this article. Imaging has revolutionized our
ability to accurately identify lesions associated with epilepsy and increased our
ability to localize seizures in the brain.

Continuum (Minneap Minn) 2016;22(1):94–115.

INTRODUCTION Other acquired causes, such as in-

This article focuses on focal (partial- fections or trauma, can be associated
onset) epilepsy since it is the most with acute or remote onset of epilepsy.
common form of epilepsy to be Obtaining a detailed epilepsy risk
diagnosed during adulthood. Certainly factor history from patients, including
patients with idiopathic generalized a history of pregnancy complica-
epilepsy, especially juvenile myoclonic tions, learning or physical disabilities/
epilepsy, can have onset in early milestone delay, febrile seizures, sig-
adulthood, but the clinical history nificant head trauma, central nervous
and diagnostic workup are the same system infections, and a family history
as for childhood-onset epilepsy and of epilepsy, is important to help guide
are discussed in the article “Infantile, the clinical workup.
Childhood, and Adolescent Epilep- This article outlines the typical
sies” by Elaine Wirrell, MD,1 in this presentation of various forms of focal
issue of Continuum. epilepsy and highlights the typical
Focal epilepsy can develop at any seizure symptomatology, interictal and
point in life, and the etiologies associ- ictal scalp EEG, and potential etiologies.
ated with it vary by age. In general
terms, congenital abnormalities or TEMPORAL LOBE EPILEPSY
Supplemental digital content: genetic triggers are often associated The temporal lobe is one of the most
Direct URL citations appear in with earlier onset, while stroke and common localizations for focal epilepsy,
the printed text and are provided
in the HTML, PDF, and app neurodegenerative disorders are asso- and it is important to recognize the
versions of this article. ciated with an older age of onset. common presentations to ensure that
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 KEY POINT
an accurate diagnosis is established. The factor for the development of hippo- h Mesial temporal lobe
features of temporal lobe epilepsy can be campal sclerosis,2 which is a common epilepsy is the most
broken down into two broad categories: cause of mesial temporal lobe epi- common form of
mesial and lateral (neocortical) onset. lepsy. Hippocampal sclerosis is char- temporal lobe epilepsy,
acterized by atrophy and gliosis of and the most common
Mesial Temporal Lobe Epilepsy the hippocampus, which may be pathology associated
Mesial temporal lobe epilepsy is one of unilateral or bilateral (Figure 5-1 with mesial temporal
the most well-defined forms of epilepsy and Figure 5-2). Other etiologies that lobe epilepsy is
in the literature. It often begins during may be seen in the mesial temporal hippocampal sclerosis.
late adolescence or early adulthood. lobe include cavernous hemangiomas,
Clinical features. Prolonged febrile gliosis/encephalomalacia secondary to
seizures are believed to be a risk prior injury, and tumors such as

FIGURE 5-1 Right mesial temporal sclerosis. A, B, Coronal T1-weighted MRIs demonstrate a
smaller right hippocampus. C, D, Coronal fluid-attenuated inversion recovery
(FLAIR) MRIs demonstrate increased signal in the right hippocampus consistent
with gliosis.

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 Adult Focal Epilepsies

FIGURE 5-2 Bilateral mesial temporal sclerosis. Coronal

fluid-attenuated inversion recovery (FLAIR)
MRI demonstrates bilateral increased signal
in the hippocampus consistent with gliosis.

dysembryoplastic neuroepithelial tumors with nondominant temporal lobe sei-

(Case 5-1). zures include ictal spitting, vomiting,
Many patients with mesial temporal and urinary urge.6
lobe epilepsy experience auras, which The seizures typically last 60 to
can include psychic sensations (déjà vu 90 seconds and are often followed by
and jamais vu), a gastric rising sensa- a period of confusion/disorientation,
tion, a sensation of “butterflies” in their more prominent in patients with dom-
stomach, fear, or olfactory symptoms inant temporal lobe seizures. After
(usually an unpleasant chemical or dominant temporal lobe seizures,
burning smell). The aura is typically prominent postictal symptoms may be
followed by loss of consciousness/ attributed to involvement of the lan-
awareness with prominent oral and guage centers in the ictal discharge.
manual automatisms in patients with Seizures from the mesial temporal
dominant temporal lobe seizures, while region rarely secondarily generalize, but
nondominant temporal lobe seizures when they do, it is typically very late
may have preserved awareness with into the seizure in contrast to neo-
oral and manual automatisms (Case 5-1).5 cortical temporal lobe or extratemporal
Dystonic limb posturing during the ictus lobe epilepsy, which frequently second-
has been described and is very predic- arily generalizes earlier in the seizure.
tive of seizure onset starting in the Several clinical features help to lateral-
mesial temporal lobe contralateral to ize the seizure focus to the ipsilateral
the dystonic limb. It is not uncommon temporal lobe regardless of dominance.
for the patient to have manual autom- These include postictal nose wiping,
atisms in the hand ipsilateral to the ictal unilateral eye blinking (Case 5-2),
seizure focus. Symptoms associated and ictal piloerection.6 The hand that

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 KEY POINT
wipes the nose first after a seizure is very focal fields, and, without the h Anterior temporal
typically ipsilateral to the seizure focus. addition of extra anterior temporal discharges may often
A delay often exists in diagnosing electrodes (T1, T2), an interictal spike have a limited field, and
nondominant temporal lobe seizures may be missed (Supplemental Digital additional electrodes
because of preserved awareness and Content 5-2, links.lww.com/CONT/ (T1 and T2) may aid
minimal postictal symptoms. Often the A158). The interictal epileptiform activ- in the detection of
patient is unaware of the ictal automa- ity is typically bilateral,5 even in pa- epileptiform activity.
tisms, and until an observer witnesses a tients with unilateral seizures, but
seizure, the symptoms are often mini- typically one side has a preponderance
mized or ignored by the patient. How- (Supplemental Digital Content 5-3,
ever, once patients are made aware of links.lww.com/CONT/A159). Sleep
the symptoms, they typically can reli- deprivation can often activate focal
ably report their seizures. epileptiform discharges; therefore,
EEG findings. In mesial temporal an EEG with sleep recording is
lobe epilepsy, the interictal EEG is recommended during the diagnostic
associated with anterior temporal workup. The presence of mid or
spikes/sharp waves that are maximum posterior temporal spikes may suggest
in electrodes T1/F7 or T2/F8 (FT9/FT10 a more widespread epileptogenic net-
in the 10/10 system) (Supplemental work even in the presence of clear mesial
Digital Content 5-1, links.lww.com/ temporal pathology. The ictal EEG is
CONT/A157). Often the spikes can have typically characterized by rhythmic

Case 5-1
A 35-year-old woman presented for evaluation after having a seizure associated with loss of
consciousness that resulted in a minor car accident. She did not sustain any injuries during the accident.
Upon questioning, she stated that she first developed a sense of fear and then a butterfly sensation in
her stomach. Ten seconds later, she lost awareness. She reported that she had experienced the aura
sporadically over the last 5 years, and it had increased in frequency over the last 6 months. She denied
prior spells with loss of awareness. According to her partner, when she reported this sensation she
often had oral automatisms; she was able to converse during the events, but her responses were slightly
delayed. Typically, these spells were 45 seconds in duration.
Based on the history of a single complex partial seizure and multiple simple partial seizures
associated with a fear/abdominal aura and oral automatisms with preserved awareness, a diagnosis
of epilepsy was made. To try to define an etiology, an MRI of the brain with and without contrast was
obtained, which demonstrated findings most consistent with a right temporal dysembryoplastic
neuroepithelial tumor (DNET) (Figure 5-3). A routine EEG was obtained, which revealed right anterior
temporal sharp waves (Figure 5-4A). The patient was treated with lamotrigine 150 mg 2 times a day.
Despite maintaining therapeutic blood levels, she continued to experience seizures and was
transitioned to levetiracetam 500 mg 2 times a day and weaned off lamotrigine. She had an initial
seizure-free period of 3 months on levetiracetam monotherapy, but her seizures recurred and she
continued to have four seizures per month.
She was admitted to an epilepsy monitoring unit and underwent continuous video-EEG
monitoring. Her habitual seizures were recorded, and the EEG revealed a right temporal ictal
discharge (Figure 5-4B, 5-4C, and 5-4D). Based on the concordance of her clinical symptomatology,
interictal and ictal EEG, and imaging, a right anterior temporal lobe resection was recommended and
performed. Pathology of the resected lesion showed a DNET. She remained seizure free after the
surgery and was eventually taken off her antiepileptic drugs.
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 Adult Focal Epilepsies

Continued from page 97

FIGURE 5-3 Imaging of the patient in Case 5-1 showing characteristics consistent with right temporal dysembryoplastic
neuroepithelial tumor (DNET). Coronal T1 (A) and fluid-attenuated inversion recovery (FLAIR) (B) and axial
FLAIR (C) MRIs demonstrate a mass lesion in the region of the right amygdala.

FIGURE 5-4 EEGs of the patient in Case 5-1 demonstrating right temporal lobe epilepsy. A, EEG
demonstrates right anterior to midtemporal spikes. Panels BYD reveal a typical right
temporal ictal EEG discharge. The ictal discharge starts with low-amplitude rhythmic
delta activity that evolves on panel C to high-amplitude rhythmic theta before stopping around
the fourth second of panel D.

Continued on page 99

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 Continued from page 98

FIGURE 5-4 EEGs of the patient in Case 5-1 demonstrating right temporal lobe epilepsy. A, EEG
demonstrates right anterior to midtemporal spikes. Panels BYD reveal a typical
right temporal ictal EEG discharge. The ictal discharge starts with low-amplitude
rhythmic delta activity that evolves on panel C to high-amplitude rhythmic theta before stopping
around the fourth second of panel D.

Continued on page 100

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 Adult Focal Epilepsies

Continued from page 99

FIGURE 5-4 EEGs of the patient in Case 5-1 demonstrating right temporal lobe epilepsy. A, EEG
demonstrates right anterior to midtemporal spikes. Panels BYD reveal a typical
right temporal ictal EEG discharge. The ictal discharge starts with low-amplitude
rhythmic delta activity that evolves on panel C to high-amplitude rhythmic theta before stopping
around the fourth second of panel D.

Comment. The clinical symptomatology in this patient was consistent with seizures emanating
from the mesial temporal region, and, based on the clinical history alone, a diagnosis of focal
epilepsy could be established. EEG and MRI confirmed the clinical diagnosis and better defined the
location and potential cause of her epilepsy. In this case, the patient had the typical mesial temporal
EEG patterns and imaging consistent with a common benign tumor associated with temporal lobe
epilepsy. In this patient, trials of two therapeutic antiepileptic drugs had failed, therefore fulfilling the
definition of drug-resistant epilepsy.3 The likelihood of long-term seizure freedom with medical
therapy was low at that point (less than 5%), and she was referred for consideration of epilepsy
surgery, which led to successful seizure control.3,4

alpha or theta activity that evolves into ceded by an initial sharp wave or
higher-amplitude rhythmic delta or suppression of the normal EEG
theta activity that may be sharply patterns or epileptiform activity that
contoured or contain discrete spikes was occurring immediately before the
(Supplemental Digital Content 5-4, ictus. Other patterns at onset include
links.lww.com/CONT/A160). Often, rhythmic delta with or without spikes
the initial ictal discharge may be pre- (Supplemental Digital Content 5-5,

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 Case 5-2
A 40-year-old man presented for evaluation of persistent seizures. The patient began to have seizures
at age 22. He stated that his seizures always started with a burning sensation in his stomach that often
rose up through his chest. This occurred over 10 to 15 seconds, after which he lost awareness.
Observers had noted that he stared blankly, was unresponsive to questions, and had oral and manual
automatisms and unilateral left eyelid blinking during the seizure. The seizures typically lasted for
60 to 90 seconds and were followed by postictal fatigue and confusion that lasted for up to 1 hour.
He had three seizures per month. He was being treated with zonisamide 300 mg/d, and previous
treatments with levetiracetam, carbamazepine, lamotrigine, phenytoin, and topiramate had failed.
He continued to work as a math teacher in a junior high school, but needed rides to and from work
because of his inability to drive. He admitted to mild depression in the past that had not required
treatment, but he denied ever considering suicide. He wished to consider alternative treatment
options since medical therapy had failed.
An MRI of the brain was obtained (Figure 5-5A and 5-5B) and was consistent with left mesial
temporal sclerosis. The patient was admitted to the epilepsy monitoring unit for video-EEG
monitoring (Figure 5-6). The interictal EEG revealed frequent left anterior temporal delta slowing
(Figure 5-6A) and left anterior temporal sharp waves (Figure 5-6B) that were maximal at the T1
electrode in the transverse chain and F7 in the anterior-posterior chain of electrodes. The ictal EEG
revealed a left temporal seizure pattern (Figure 5-6C, 5-6D, 5-6E, and 5-6F). Neuropsychological
evaluation revealed normal visual memory and reduced, but still average, verbal memory.

FIGURE 5-5 Imaging of the patient in Case 5-2 showing left mesial temporal lobe sclerosis. Coronal fluid-attenuated inversion
recovery (FLAIR) (A) and T1 (B) MRIs demonstrate increased signal on T2-weighted imaging and atrophy on
T1-weighted imaging of the hippocampus. Coronal T2 MRI demonstrates postoperative encephalomalacia in the
mesial temporal lobe that was created using a minimally invasive laser thermal ablation technique (C).

Comment. Based on the patient’s seizure symptomatology, interictal and ictal EEG, and imaging, he
was diagnosed with mesial temporal lobe epilepsy secondary to hippocampal sclerosis. He was felt to be a
very good candidate for a left anterior temporal lobectomy, but his reduced verbal memory and need to
function as a math teacher were concerns. The patient underwent a new minimally invasive approach
utilizing stereotactic thermal ablation for the treatment of mesial temporal sclerosis7,8 and has remained
seizure free for 2 years since the operation (Figure 5-5C). He remained on zonisamide 300 mg/d and was
back working as a math teacher 2 weeks after the surgery. Follow-up neuropsychological testing
demonstrated no decline when compared to his preoperative data, and he reported no subjective
cognitive concerns.
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 Adult Focal Epilepsies

Continued from page 101

FIGURE 5-6 EEGs of the patient in Case 5-2 demonstrating left mesial temporal lobe
epilepsy. A, Interictal focal slowing in the left anterior temporal region. B,
Frequent left anterior temporal spikes. Panels CYF reveal a left temporal lobe
seizure that begins with moderate-amplitude rhythmic delta and evolves to higher-amplitude
delta rhythmic spiking, which ceases 12 seconds into panel F.

Continued on page 103

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 Continued from page 102

FIGURE 5-6 EEGs of the patient in Case 5-2 demonstrating left mesial temporal lobe epilepsy.
A, Interictal focal slowing in the left anterior temporal region. B, Frequent left
anterior temporal spikes. Panels CYF reveal a left temporal lobe seizure that
begins with moderate-amplitude rhythmic delta and evolves to higher-amplitude delta rhythmic
spiking, which ceases 12 seconds into panel F.

Continued on page 104

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 Adult Focal Epilepsies

Continued from page 103

FIGURE 5-6 EEGs of the patient in Case 5-2 demonstrating left mesial temporal lobe epilepsy.
A, Interictal focal slowing in the left anterior temporal region. B, Frequent left
anterior temporal spikes. Panels CYF reveal a left temporal lobe seizure that begins
with moderate-amplitude rhythmic delta and evolves to higher-amplitude delta rhythmic spiking,
which ceases 12 seconds into panel F.

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 KEY POINTS
links.lww.com/CONT/A161 and Supple- are normal, and the disease course is h Imaging of the mesial
mental Digital Content 5-6, links.lww. benign for most patients. The exact temporal lobe requires
com/CONT/A162). genetic mutation is not known.10 thin-cut coronal
The seizure discharge may remain imaging with T1- and
limited to the mesial temporal struc- Lateral/Neocortical Temporal T2-weighted images to
tures, but often spreads to the remain- Lobe Epilepsy properly visualize the
der of the ipsilateral hemisphere and Lateral/neocortical temporal lobe epi- key structures.
contralateral temporal lobe. During lepsy is less common than mesial tem- h The symptomatology
the postictal state, unilateral temporal poral lobe epilepsy and less well-defined. associated with
lobe slowing that is typically ipsilateral Because of the rich connections to other neocortical temporal
to the seizure onset may be seen. regions of the brain and the larger total lobe epilepsy is quite
Imaging. An MRI of the brain with- cortical area available to generate seizures, varied and dependent
out contrast is recommended in the the symptomatology, EEG findings, and on the location of the
evaluation of a patient with suspected associated pathologies are varied. seizure onset.
mesial temporal lobe epilepsy. An Clinical features. Seizures originat- h Auditory auras and
enhanced MRI may be used dependent ing from the temporal pole or anterior aphasic seizures are
on local imaging protocols and basal temporal surface often display very suggestive of
suspected etiologies. It is preferable auras and other clinical features that neocortical temporal
to include coronal T1- and T2-weighted lobe epilepsy.
are similar to mesial temporal lobe
images with thin cuts (less than 3 mm) epilepsy as described earlier. This is
through the temporal lobes to properly most likely secondary to early spread
evaluate the hippocampus. Key imag- of the ictal electrographic discharge to
ing characteristics to evaluate for hip- the mesial temporal lobe structures.
pocampal sclerosis are asymmetric size Lateral and perisylvian seizure foci
(smaller on the affected side) and often have features that involve the
increased T2 signal in the hippocam- eloquent cortex in that region, such as
pus consistent with gliosis. Inclusion of aphasic seizures in the dominant tem-
gradient echo imaging may assist in the poral lobe and auditory auras due to
identification of vascular etiologies. involvement of the primary and second-
Fluorodeoxyglucose positron emission ary auditory cortex.6 Seizure onsets near
tomography (FDG-PET) scan imaging the temporooccipital junction may be
has been extensively studied in pa- associated with vertiginous symptoms
tients undergoing presurgical evalua- or visual auras at the onset of the sei-
tion, and unilateral temporal lobe zures. The auras often evolve to bland
hypometabolism ipsilateral to the sei- staring and unresponsiveness followed
zure focus is a positive predictor of a by rapid secondary generalization. As
good outcome after epilepsy surgery.9 the seizures begin to generalize and
FDG-PET scanning is reserved only activate the motor cortex, it is not
for patients who are being consi- uncommon to have unilateral (contra-
dered for epilepsy surgery since the lateral to the seizure focus) clonic
presence or absence of temporal lobe jerking of the face or upper extremity.11
hypometabolism does not impact EEG findings. The interictal and
medical treatment. ictal EEG patterns in lateral/neocortical
Genetic considerations. Familial lobe epilepsy can be similar to those
forms of mesial temporal lobe epi- seen in mesial temporal lobe epilepsy;
lepsy have been described. The ma- however, patients with lateral or
jority of reports describe families with perisylvian foci may have more mid to
psychic auras and simple or complex posterior temporal foci involving elec-
partial seizures. The imaging studies trodes T4/T3 and T6/T5. The activity
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 Adult Focal Epilepsies

the same MRI techniques described

for mesial temporal lobe epilepsy. The
pathologies associated with this form
of epilepsy can include, but are not
limited to, malformations of cor-
tical development, vascular malfor-
mations, encephalomalacia secondary
to trauma, and tumors (Figure 5-7,
Figure 5-8, and Figure 5-9).11 FDG-PET
scans may show hypometabolism
in the lateral temporal neocortex,
but again, this imaging technique is
reserved for patients undergoing a
presurgical evaluation.
Genetic considerations. Two forms
of genetic lateral temporal lobe epilepsy
have been identified. The familial
form is referred to as autosomal dom-
inant lateral temporal lobe epilepsy or
autosomal dominant partial epilepsy
with auditory features. The sporadic
form is referred to as idiopathic partial
epilepsy with auditory features. Both
FIGURE 5-7 Temporal malformation of cortical forms are associated with partial-onset
development. Coronal T1-weighted MRI
demonstrating a transmantle cortical dysplasia seizures, often with auditory auras, but
in the left mesial temporal region (black arrow) and a they may also have other sensory auras,
periventricular nodular heterotopia in the right mesial
temporal region (white arrow). as described earlier, and frequent sec-
ondary generalization. Imaging is typi-
cally negative, and the EEG findings are
KEY POINT often rapidly propagates to other supportive of a lateral temporal neo-
h Two genetic forms of lobes, and spread to the contralateral cortical focus. The most common
lateral temporal lobe hemisphere typically occurs earlier mutation found in patients with the
epilepsy have been when compared to mesial temporal familial form of the disorder is in
identified: autosomal
lobe epilepsy.11 Foldvary and col- the leucine-rich, glioma inactivated
dominant partial
epilepsy with auditory
leagues12 described a lateralized poly- 1 (LGI1) gene. The familial form has a
features and idiopathic morphic delta pattern in patients with penetrance of approximately 70% to
partial epilepsy with neocortical temporal lobe epilepsy, 80%. How this mutation causes
auditory features. and paroxysmal fast/beta onset activity epilepsy remains unclear at this time.
has also been reported (Supplemental The medical treatment of these pa-
Digital Content 5-7, links.lww.com/ tients is no different than that of
CONT/A163 and Supplemental Digital patients with other forms of tem-
Content 5-8, links.lww.com/CONT/ poral lobe epilepsy, but they typi-
A164). Occasionally the onset is poorly cally have a more benign prognosis
defined but eventually evolves into a and their seizures can be controlled
lateralized temporal lobe ictal dis- with medication.13
charge (Supplemental Digital Content
5-9, links.lww.com/CONT/A165). FRONTAL LOBE EPILEPSY
Imaging. Imaging in lateral/neocortical Frontal lobe epilepsy is the second most
epilepsy should be obtained with common type of focal epilepsy. The

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 KEY POINT
h Frontal lobe seizures are
typically brief and
associated with various
motor symptoms.

FIGURE 5-8 Posttraumatic encephalomalacia. Coronal fluid-attenuated inversion recovery

(FLAIR) (A) and T1-weighted (B) MRIs demonstrating extensive areas of
encephalomalacia within the right frontal and temporal lobe (blue arrows).
A smaller region of encephalomalacia and gliosis is also noted in the left lateral temporal
lobe (red arrows).

seizure symptomatology associated with volve motor symptomatology, and oc-

frontal lobe epilepsy varies depending cur more often from sleep. The
on the location of the seizure onset zone postictal period is often characterized
within the frontal lobe.14 Compared to by a quick return to normal cognition
temporal lobe seizures, frontal lobe but is occasionally associated with sub-
seizures are often shorter, usually in- tle paresis or frank paralysis of the

FIGURE 5-9 Right temporal cavernous hemangioma. Coronal fluid-attenuated inversion

recovery (FLAIR) (A) and T1-weighted (B) MRIs demonstrate a mass lesion in the
anterior temporal pole, consistent with a cavernous hemangioma.

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 Adult Focal Epilepsies

involved motor region that resolves frontal lobe regions. Several of the
over time. Frontal lobe seizures can more common presentations are
often appear unusual or bizarre to the discussed later in the article.
untrained observer, and many patients Focal clonic or tonic seizures affecting
are misdiagnosed with psychogenic a limb or region of the trunk without loss
nonepileptic seizures or parasomnias. of consciousness or awareness are highly
suggestive of a seizure focus within the
Clinical Features perirolandic cortex or dorsolateral cor-
With respect to seizures, the frontal tex. Seizures of the perirolandic cortex
lobe can be divided into primary are typically clonic movements limited
motor, supplementary sensorimotor, to one region of the motor homunculus
orbitofrontal, dorsolateral, frontopolar, (eg, face or hand) but can spread to
and opercular regions. Most frontal adjacent regions; this spreading is re-
regions are associated with prominent ferred to as the jacksonian march.
motor phenomena because of the Bilateral asymmetric tonic seizures,
presence of premotor and motor cor- which are described as tonic flexion of
tices within the frontal lobe. However, one arm and extension of the other with
frontopolar and orbitofrontal seizures or without tonic leg involvement, are
can have bland symptomatology, with associated with activation of the supple-
staring, unresponsiveness, and late mentary sensorimotor area located in
motor manifestations (complex autom- Brodmann area 6 on the mesial or dorsal
atisms or versive head or eye move- aspect of the frontal lobe. These seizures
ment) that can be confused with are also referred to as “fencing seizures”
temporal lobe epilepsy. Table 5-1 out- because of the position of the arms.
lines the clinical features that can be They are considered simple partial sei-
seen with seizures from the various zures since patients retain awareness

a
TABLE 5-1 Clinical Manifestations of Frontal Lobe Syndromes

Location Ictal Behavior

Perirolandic or Focal motor seizures with or without jacksonian march,
primary motor speech arrest or dysphasia, vocalization
Supplementary Focal asymmetric tonic posturing, versive movements of head
sensorimotor and eyes, speech arrest, vocalization
Dorsolateral Focal tonic or clonic activity, versive movements of head and
eyes, speech arrest or dysphasia
Orbitofrontal Complex motor automatisms, olfactory hallucinations
and illusions, autonomic features
Anterior Versive movements of head and eyes, forced thinking, initial
frontopolar loss of contact or “absencelike,” speech or motor arrest
Opercular Mastication, salivation, swallowing, laryngeal symptoms;
speech arrest or dysphasia; epigastric aura, fear; autonomic
features; facial clonic activity; gustatory hallucinations
Cingulate Fear, vocalization, emotional or mood changes, complex
motor automatisms, autonomic features
a
Reprinted with permission from Bagla R, Skidmore CT, Neurologist.14 journals.lww.com/
theneurologist/Abstract/2011/05000/Frontal_Lobe_Seizures.1.aspx. B 2011 Lippincott Williams
& Wilkins, Inc.

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 KEY POINT
despite the bilateral motor manifesta- movement, contralateral to the sei- h The supplementary
tions (Case 5-3). The presence of this zure focus. Occasionally, the entire sensorimotor area has
seizure type is often associated with a body will turn with the head and eyes, bilateral sensory and
mesial frontal or dorsolateral seizure and the patient may spin around the motor representation,
focus that preferentially spreads to long axis of his or her body several and seizures generated
activate the supplementary sensorimo- times. Involvement of the Broca re- from this region have
tor area. Seizures associated with large gion can result in an aphasic seizure, bilateral motor
vigorous proximal muscle movements, and activation of the negative motor symptoms with
such as bicycling movements of the legs cortex, located on the posterior aspect preserved awareness.
or windmilling of the arms, are often of the inferior frontal gyrus or near the
associated with activation of the supplementary sensorimotor area, can
frontopolar or orbitofrontal region. These produce seizures during which the
seizures have also been described in patient is unable to move a limb or
the literature as hypermotor or hyper- body part.14,15
kinetic seizures. Activation of other
specific structures in the frontal lobe EEG Findings
can produce very specific seizure symp- The interictal EEG associated with fron-
toms. For example, activation of the tal lobe epilepsy can vary depending
frontal eye field located in the premotor on the location of the seizure focus.
cortex results in forced head and eye Overall, in a large surgical series, in-
version, unnatural upward and lateral terictal epileptiform activity was within

Case 5-3
A 25-year-old man presented for evaluation after having a generalized tonic-clonic seizure at home. He was
previously diagnosed with psychogenic nonepileptic seizures (PNES) at age 23. When asked to describe his
events, he stated that he often woke up from sleep and had tonic posturing of his arms and legs. He
specifically stated that his right arm was extended and his left arm was flexed toward his chest. At the end of
the seizure, he had several clonic jerks of his entire body. He stated that he is fully aware throughout the
events but cannot speak because he cannot control his mouth. A typical seizure lasted for approximately
20 seconds, and he often had clusters with 5 to 10 seizures per cluster. Immediately following the event, he
felt weak, but within 30 to 60 seconds, he felt normal. He had been evaluated at a local hospital and had a
normal EEG during one of these events. Based on the fact that he recalled the events despite having
bilateral motor manifestations and a negative EEG during one of the events, a diagnosis of PNES had been
made, and he was treated by a behavioral psychologist after that diagnosis, without relief.
Comment. The symptomatology described in the case is consistent with a bilateral asymmetric tonic
(fencing) seizure. These seizures are common for mesial frontal lobe epilepsy with activation of the
supplementary motor cortex. The supplementary motor cortex has bilateral motor and sensory
representation that has somatotopic organization. Therefore, a unilateral ictal discharge could cause
bilateral motor manifestations without impairing consciousness. Because of the limitations of scalp EEG, it is
not uncommon for patients, such as this patient, with mesial frontal lobe epilepsy to have normal EEGs.
A montage that included electrodes Fz, Cz, and Pz could have increased the diagnostic yield of the EEG. Even
in the face of a normal EEG, the stereotyped brief events are not typical of PNES, and PNES should
always remain a diagnosis of exclusion.
This patient was admitted to an epilepsy monitoring unit for continuous EEG monitoring, and
had an MRI of the brain that revealed a small cortical dysplasia in the left mesial frontal region
(Figure 5-10). During his admission, 15 stereotyped seizures were captured as described earlier. The
EEG revealed the onset of rhythmic beta in the central region, maximum at electrode Cz (Figure 5-11).
The patient was started on carbamazepine and was seizure free at last follow-up.
Continued on page 110

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 Adult Focal Epilepsies

Continued from page 109

FIGURE 5-10 Imaging of the patient in Case 5-3 showing left frontal cortical dysplasia.
Coronal fluid-attenuated inversion recovery (FLAIR) MRIs demonstrate an area
of increased cortical thickness in the mesial aspect of the superior frontal gyrus
(A, red arrow) and an associated tail of abnormality that extends toward the ventricle (B, blue
arrow). These findings are consistent with a cortical migrational abnormality.

FIGURE 5-11 EEG of the patient in Case 5-3 demonstrating mesial frontal seizure. During the third second of the EEG, a
paroxysmal fast discharge develops at electrode Cz (arrow). This finding was reproducible with all seizures
and always preceded clinical onset.

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 KEY POINT
the frontal lobe in 65% of patients, unilaterally before the “generalized” h The interictal and ictal
outside the frontal lobe in 37%, contra- discharge, which, if stereotyped, pro- EEG associated with
lateral to the seizure focus in 17%, and vides a clue to the lateralization of the frontal lobe epilepsy can
generalized in 24%.16 Dorsolateral and epileptiform activity. Paroxysmal fast be challenging from a
frontopolar epilepsies are most likely to (beta frequency) activity is also a technical perspective
show focal epileptiform activity since the feature of the interictal EEG that has because of movement
typical scalp EEG electrodes are imme- been associated with frontal lobe epi- artifact and the limited
diately over these locations. However, lepsy (Supplemental Digital Content ability of scalp
even in these regions, epileptiform 5-10, links.lww.com/CONT/A166).18 electrodes to record
activity may not be recorded with scalp The ictal EEG is also challenging from seizure locations
(basal frontal,
electrodes because of the size of the in frontal lobe epilepsy. In the sur-
interhemispheric, and
cortical region involved. Based on gical series published by Jeha and
opercular regions) and
simultaneous scalp and intracranial re- colleagues, 16 the ictal discharge in cases with limited
cordings, an area of at least 6 cm2 must was localized to the frontal lobe in cortical involvement.
fire simultaneously to generate a depo- 51% of cases, unilateral in 14%, and
larization that can be recorded reliably generalized in 21%. Because of the
with scalp electrodes.17 This technical prominent motor manifestations asso-
limitation is further exacerbated when ciated with frontal lobe seizures, ictal
the distance between the generator and recordings are often obscured by
the recording electrode is increased, muscle artifact (EMG). This makes it
such as with foci involving the inter- difficult to see the initial ictal onset
hemispheric region, orbitofrontal cortex, and spread even after the digital EEG
or frontal opercular cortex. The addi- is filtered. Other challenges include
tion of extra 10-10 electrodes, in partic- the technical limitations mentioned
ular over the midline region, may earlier with respect to recording
increase the likelihood of recording ictal epileptiform activity from deeper
interictal epileptiform discharges and foci and simple partial seizures that
ictal EEG changes. Because of the rich may involve a limited amount of
connections to and location near the cortex. These limitations are not
temporal lobe, orbitofrontal epilepsy unique to frontal lobe epilepsy and
can be associated with epileptiform apply to all forms of focal epilepsy.
activity in the anterior temporal elec- Despite these technical limitations,
trodes. The overlap between the clinical several patterns have been associated
symptomatology and interictal EEG with frontal lobe epilepsy, includ-
between orbitofrontal lobe epilepsy ing diffuse electrodecrement, focal
and temporal lobe epilepsy must be rhythmic fast activity, and bilateral
considered, especially in patients with hypersynchrony.18 An example of a
nonlesional epilepsy. frontal ictal discharge can be seen in
Bilateral secondary hypersynchrony Supplemental Digital Content 5-11,
has been described in patients with links.lww.com/CONT/A167.
frontal lobe epilepsy and is character-
ized by the rapid spread of the interictal Imaging
spike between the two hemispheres. MRI of the brain without contrast
These epileptiform discharges often should be obtained in the coronal and
appear as generalized spikes, poly- axial plane and should include thin
spikes, or spike and wave, and it is slices (less than 3 mm). As described
important not to misdiagnose a patient for mesial temporal lobe epilepsy, the
with generalized epilepsy. Often an MRI should include T1- and T2-
initial spike/sharp wave can be seen weighted images, and the use of
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 Adult Focal Epilepsies

KEY POINTS
h MRI scans should contrast will vary depending on poten- lobe epilepsy had regions of hypo-
include thin-cut T1- and tial etiology and local protocols. In two metabolism identified. This compared
T2-weighted images surgical series, malformations of corti- to 67% for temporal lobe epilepsy and
in the axial and cal development were the most com- 61% for nontemporal and nonfrontal
coronal planes. mon etiology associated with frontal lobe epilepsies. In the frontal lobe cases with
h Malformations of epilepsy (40% to 58%) (Figure 5-12), hypometabolism, the findings were on-
cortical development compared to tumor (10% to 19%), ly helpful in making a surgical decision
are the most common vascular (3% to 7%), and encephalo- in 38% of cases.20 In the frontal lobe
etiology associated with malacia (10% to 12%) (Figure 5-8). surgical series mentioned earlier, when
frontal lobe seizures in Based on imaging or pathology, 10% PET was performed, the results were
large surgical series. to 31% of patients had no identifiable abnormal in 25% of the patients in the
h Autosomal dominant etiology. MRI scans were nonlesional in Lazow and colleagues series19 and in
nocturnal frontal lobe 26% to 45% of patients.16,19 Use of 76% of the patients in the Jeha and
epilepsy is associated FDG-PET imaging for presurgical plan- colleagues series.16
with a genetic mutation ning is less likely to reveal a deficit in
in the neuronal nicotinic patients with frontal lobe epilepsy com- Genetic Considerations
acetylcholine receptor. pared to patients with temporal lobe Autosomal dominant nocturnal frontal
epilepsy. However, in a 2012 series of lobe epilepsy is a well-described genetic
194 patients (34% with frontal lobe frontal lobe epilepsy syndrome. It is
epilepsy), 51% of patients with frontal characterized by brief motor seizures that
are stereotyped and occur multiple times
per night and is associated with normal
intelligence and a normal neurologic
examination between attacks. A family
history of similar seizures often exists,
although patients are often misdiagnosed
as having parasomnias, and a detailed
history regarding family members is
needed. The most commonly associated
abnormality with this disorder is in the
neuronal nicotinic acetylcholine recep-
tor, and the penetrance is variable, 29%
to 100% in the literature.21

PARIETAL AND OCCIPITAL

LOBE EPILEPSY
Epilepsy associated with the parietal and
occipital lobes is much less common
than temporal or frontal lobe epilepsy.
Due to the rich connections between
the parietal and occipital lobes and the
frontal and temporal lobes, it can often
be challenging to reliably identify these
patients without the use of invasive
FIGURE 5-12 Left frontal malformation of cortical
development. Coronal T1-weighted MRI
techniques. Visual auras are more com-
demonstrates a large malformation of mon in occipital lobe epilepsy and are
cortical development in the left frontal region typically elemental auras. Other symp-
(arrow). Associated enlargement of the left lateral
horn is seen. toms may include ictal blindness,
blinking, and ocular movement.22 More

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 KEY POINTS
complex visual scenes or objects may lepsy. In studies that reviewed occipital h Occipital lobe epilepsy is
be seen in occipital lobe epilepsy and and parietal lobe epilepsy, malforma- often associated with a
suggest spread of the seizure discharge tions of cortical development and tu- visual aura as the first
to the temporooccipital region. Sei- mors were more common in occipital clinical sign.
zure foci below the calcarine sulcus will lobe epilepsy,25 while tumors were the h Parietal and occipital
preferentially spread to the temporal most common etiology for parietal lobe epilepsies
region and may generate complex lobe epilepsy.24,26 frequently spread to
partial seizures with symptomatology adjacent cortical regions
and ictal EEG typical for temporal lobe INSULAR AND CINGULATE and may have features
epilepsy.23 Foci above the calcarine LOBE EPILEPSY of seizures commonly
sulcus preferentially spread to the Focal epilepsy involving the insular associated with temporal
parietal and frontal lobes. cortex and cingulate is uncommon. or frontal seizures.
Parietal lobe epilepsy is often associ- Insular seizures should be suspected h Parietal lobe epilepsy is
ated with somatosensory auras that are in patients who present with seizure often associated with a
typically contralateral to the seizure symptoms involving contraction or a somatosensory aura as
focus but can be bilateral.24 Often choking sensation of the oropharynx/ the first clinical sign.
patients with parietal lobe epilepsy will larynx or a painful somatosensory h Insular and cingulate
display symptoms associated with aura.27,28 Cingulate epilepsy is very lobe epilepsy are rare
spread to the motor cortex, premotor difficult to differentiate clinically from and should be carefully
regions, or temporooccipital region. the other focal epilepsies. Because of considered in patients
Because of the rapid spread of the ictal the rich anatomic connections to the with nonlesional
discharge to distant regions, it is very frontal and temporal regions, cingulate epilepsy since the
symptomatology often
important to take a detailed history to seizures often mimic seizures originat-
overlaps with other
try to identify if the first symptom is a ing from these structures.13 In the
types of focal epilepsy.
somatosensory aura. absence of a clear lesion on MRI, these
The EEG findings in occipital and cases often require invasive EEG mon-
parietal lobe epilepsy can be challeng- itoring to confirm an ictal onset in the
ing. It is possible to see focal interictal cingulate or insular region.
spikes and ictal onsets, but it is also
common to see interictal and ictal CONCLUSION
patterns localizing to the temporal The focal epilepsies are very common
and frontal regions because of the rich in adulthood, and, while overlap in
synaptic connections. With midline clinical presentations often exists, each
parietal or occipital foci, the possibility region of the cortex often has several
exists for false localization to the distinct clinical presentations, EEG
wrong hemisphere because of the findings, or imaging findings that may
orientation of the electrical dipole aid in establishing an accurate diagno-
pointing to the contralateral hemi- sis. The clinical history of the seizure
sphere. In addition, the possibility of event either as reported by the patient
bilateral hypersynchrony, described or observers, or through watching a
earlier for frontal lobe epilepsy, also video of the event, is extremely impor-
exists. An example of the onset of a tant. The terms complex partial and
left parietal seizure that was associated simple partial are certainly helpful in
with a cortical dysplasia is shown in defining whether a patient has lost
Supplemental Digital Content 5-12, awareness or consciousness or not,
links.lww.com/CONT/A168. but do not reflect the details that
The causes of parietal and occipital permit a more accurate diagnosis.
lobe epilepsies are similar to those Imaging and EEG are critical in
mentioned earlier for frontal lobe epi- evaluating patients with focal epilepsy,
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Adult Focal Epilepsies

but one must be cautious to ensure American Epilepsy Society 68th Annual Meeting;
December 5Y9. 2014; Seattle, Washington.
that the study is properly designed to
ensure that common pathologies or 9. LoPinto-Khoury C, Sperling MR, Skidmore C,
et al. Surgical outcome in PET-positive,
EEG findings are not missed inadver- MRI-negative patients with temporal lobe
tently. This includes properly imaging epilepsy. Epilepsia 2012;53(2):342Y348.
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and obtaining a thin-cut MRI for all 10. Crompton DE, Scheffer IE, Taylor I, et al.
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benign epilepsy syndrome showing complex
dard MRI used for stroke imaging is inheritance. Brain 2010;133(11):3221Y3231.
not sufficient since epileptogenic le- doi:10.1093/brain/awq251.
sions may often be subtle and missed 11. Kennedy JD, Schuele SU. Neocortical
on an MRI with thicker cuts. The temporal lobe epilepsy. J Clin Neurophysiol
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WNP.0b013e31826bd78b.
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12. Foldvary N, Lee N, Thwaites G, et al. Clinical
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accurate diagnosis. neocortical temporal lobe epilepsy. Neurology
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24. Salanova V, Andermann F, Rasmussen T, et al. (5):385Y391. doi:10.1097/WNP.
Parietal lobe epilepsy. Clinical manifestations 0b013e31826bd82e.
and outcome in 82 patients treated surgically 28. Montavont A, Mauguière F, Mazzola L, et al.
between 1929 and 1988. Brain 1995;118(pt 3): On the origin of painful somatosensory
607Y627. seizures. Neurology 2015;84(6):594Y601.

Continuum (Minneap Minn) 2016;22(1):94–115 www.ContinuumJournal.com 115

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Review Article

Diagnosis and Treatment

Address correspondence
to Dr W. Curt LaFrance Jr,
Rhode Island Hospital, Brown
University, 593 Eddy Street,
Providence, RI 02903,
william_lafrance_jr@brown.
edu.
of Nonepileptic Seizures
Relationship Disclosure: David K. Chen, MD; W. Curt LaFrance Jr, MD, MPH, FAAN, FANPA, DFAPA
Dr Chen reports no disclosure.
Dr LaFrance serves on the
Epilepsy Foundation
Professional Advisory Board; ABSTRACT
has served as a clinic
development consultant for Purpose of Review: This article details the evaluation process involved in the diagnosis
the Cleveland Clinic, Emory of psychogenic nonepileptic seizures (PNES). The psychological underpinnings, prog-
University, Spectrum Health, nostic factors, and recent treatment advances of PNES are also reviewed.
and the University of Colorado
Denver; and has provided Recent Findings: The diagnosis of PNES is determined based on concordance of
expert medicolegal testimony. the composite evidence available, including historical and physical examination
Dr LaFrance receives royalties findings, seizure symptoms and signs, and ictal/interictal EEG. No single clinical data
from Cambridge University
Press and Oxford University point is definitively diagnostic of PNES. The diagnosis of PNES can be challenging
Press and has received research at times, such as when seizure documentation on video-EEG cannot be readily
support from the American obtained. Yet, delayed diagnosis of PNES portends poor outcome. A multicompo-
Epilepsy Society, the Epilepsy
Foundation, the Matthew Siravo nent approach to the diagnosis of PNES, with use of an aggregate of available evi-
Memorial Foundation Inc, the dence, may facilitate diagnosis and then care of patients with PNES. Emerging evidence
National Institutes of Health, supports the effectiveness of cognitive-behavioralYbased therapy in the treatment of
and Rhode Island Hospital.
Unlabeled Use of
these patients.
Products/Investigational Summary: The diagnosis of PNES can be made reliably, and evidence-based treatment
Use Disclosure: now exists. Continued efforts remain necessary to enhance prompt recognition and
Drs Chen and LaFrance report
no disclosures.
interdisciplinary management for patients with PNES.
* 2016 American Academy
of Neurology. Continuum (Minneap Minn) 2016;22(1):116–131.

INTRODUCTION convulsive syncope, cataplexy, or alcohol-

Nonepileptic seizures are episodes of withdrawal seizure) (Table 6-15). Treating
altered movement, sensation, or expe- the underlying pathology of physiologic
rience distinguished from epileptic sei- nonepileptic events addresses the event.
zures by the lack of associated ictal In contrast, psychogenic nonepileptic
abnormal electrical brain discharges. seizures (PNES) represent physical mani-
About one-quarter of patients referred festations derived from psychological
to specialist centers for apparent “drug- underpinnings. In epilepsy specialty
resistant epilepsy” are found to be mis- centers, 88% of patients with nonepilep-
diagnosed.1 After an average delay of tic seizures are deemed to have a psy-
about 1 to 7 years to establish the correct chogenic etiology for their events.6
diagnosis,2,3 patients with nonepileptic This review therefore focuses primar-
seizures will frequently have taken higher ily on the diagnosis and management
Supplemental digital content:
doses of antiepileptic drugs (AEDs), uti- of PNES.
Videos accompanying this ar- lized greater health care resources, and
ticle are cited in the text as sustained more iatrogenic adverse ef- DIAGNOSIS OF PSYCHOGENIC
Supplemental Digital Content.
Videos may be accessed by fects than patients with epilepsy.4 NONEPILEPTIC SEIZURES
clicking on links provided in the Nonepileptic seizures are further cat- The diagnosis of PNES can be challeng-
HTML, PDF, and app versions of
this article; the URLs are pro- egorized as physiologic or psychogenic ing. When comprehensive neurologic
vided in the print version. Video in origin. Physiologic nonepileptic events and psychiatric assessment and video-
legends begin on page 128.
result from systemic alterations or dis- EEG are not available in one setting, an
ease states that produce an ictus (eg, iterative assessment process over time

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 KEY POINTS
history are useful in raising the suspicion h About one-quarter of
TABLE 6-1 Physiologic Causes for PNES. The seizure burden of patients patients referred to
of Nonepileptic with PNES is generally more pronounced
Seizuresa specialist centers for
than that of those with epilepsy, in terms apparent drug-resistant
of both seizure frequency8 and du- epilepsy (ie, failing to
b Syncope
ration.9 While stimuli-specific reflex epi- respond to adequate
Vasovagal lepsies exist, the endorsement of more trials of two or more
Cardiogenic pedestrian triggers, such as certain light- antiepileptic drugs) are
ing level conditions, body movements, found to have physiologic
b Neurologic or psychogenic
sounds, or foods, would be unusual for
Cerebrovascular nonepileptic seizures
epilepsy and should raise suspicion for
rather than epilepsy.
Migraine PNES, especially if the reported associ-
ation is strikingly consistent. Of note, sei- h After an average delay
Vertigo of about 1 to 7 years to
zure exacerbation by emotional stressors
Cataplexy establish the correct
is not pathognomonic for PNES. Studies
diagnosis, patients with
Parasomnias have shown that similar stressors can
nonepileptic seizures
Movement disorders also provoke epileptic seizures.10 will frequently have
Over the lifetime of patients with taken higher doses of
b Metabolic
PNES, about half have been diagnosed antiepileptic drugs,
Hypoglycemia with depression, about half have co- utilized greater health
Electrolyte disturbances morbid posttraumatic stress disorder care resources, and
(PTSD), and about two-thirds have sustained more
Toxicity (eg, drugs and alcohol)
personality disorders.11 The presence iatrogenic adverse
a
Modified with permission from Mellers JD, of psychogenic disorders is a strong risk effects than patients
Postgrad Med J.5 pmj.bmj.com/content/ with epilepsy.
81/958/498.full. B 2005 British Medical factor for other forms of comorbid or
Journal Publishing Group. future psychosomatic symptoms.12 Ac- h In epilepsy specialty
cordingly, about 70% of patients with centers, a predominant
PNES endorse comorbid experiences majority (about 88%)
with medically unexplained symptoms, of patients with
may be necessary to establish the diag-
such as intractable pain.13 nonepileptic seizures
nosis of PNES.7 Habitual seizures of in-
are deemed to have a
terest, especially in patients with multiple psychogenic etiology
independent event types, are sometimes Clinical Features Differentiating
for their events
not captured during an initial video-EEG Psychogenic Nonepileptic
(ie, psychogenic
monitoring study. Long-term video-EEG Seizures and Epileptic Seizures
nonepileptic seizures).
monitoring is also not readily available Key elements in the evaluation of PNES
h The diagnosis of
in some locations. Appreciating these include the recognition of ictal features
psychogenic nonepileptic
diagnostic challenges and the importance that are: (1) suggestive of a psychogenic seizures can be
of prompt recognition of this disorder, process and (2) not in favor of an epi- challenging, hence
this article first details relevant features leptic source (Table 6-25,14). Each of contributing to the
from clinical history, symptoms and these two elements should be consid- frequent time delay
signs, and video-EEG evaluations that ered separately. An important caveat is (an average of 1 to 7 years)
support the PNES diagnosis and differ- that the features described by the pa- before patients with
entiate it from epilepsy. tient and witnesses poorly correspond psychogenic nonepileptic
with the observed PNES documented seizures are
Historical Features Differentiating during video-EEG monitoring.15 There- correctly diagnosed.
Psychogenic Nonepileptic fore, ictal features described by patients’
Seizures and Epileptic Seizures or witnesses’ report alone should be in-
At the outset, a number of peculiar fea- terpreted with less diagnostic certainty
tures uncovered from a carefully elicited than those visually documented from
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 Nonepileptic Seizures

TABLE 6-2 Clinical Signs and Examination Findings Used to Help Distinguish Psychogenic
Nonepileptic Seizures From Epileptic Seizuresa,b

Signs Examination Findings

Psychogenic nonepileptic Long duration, fluctuating course, asynchronous Resists eyelid opening, guarding
seizures movements, pelvic thrusting, side-to-side head of hand dropping over face,
or body movement, ictal eye closure, ictal evidence of visual fixationc
crying/weeping, memory recall for period
of unresponsiveness
Epileptic seizures Occurrence from EEG-confirmed sleep, postictal Very severe tongue biting,
obtundation/confusion, stertorous impaired corneal reflex, extensor
breathing postictally plantar response
EEG = electroencephalogram.
a
Data from Avbersek A, Sisodiya S, J Neurol Neurosurg Psychiatry,14 jnnp.bmj.com/content/81/7/719.abstract; Mellers JD, Postgrad
Med.5 pmj.bmj.com/content/81/958/498.full.
b
No single sign distinguishes psychogenic nonepileptic seizures from epileptic seizures.
c
Visual fixation can be elicited by placing a mirror in front of the patient or rolling the patient from one side to the other.

KEY POINTS video-EEG monitoring and, to a lesser clonic PNES may demonstrate unchang-
h Over the lifetime extent, home video recording. ing frequency and variable amplitude
of patients with In distinguishing PNES from epileptic throughout the ictus.17 Some PNES
psychogenic nonepileptic seizures, clinical features are generally show poorly discernible ictal onset from
seizures, about half
more specific than sensitive,14 and no a setting of apparent sleep, during
have been diagnosed
individual feature is definitively diag- which EEG activity discordantly corre-
with depression, about
half have comorbid
nostic of PNES.15 Instead, the degree of lates with wakefulness or light drows-
posttraumatic stress diagnostic confidence correlates with iness.18 On the other hand, paroxysms
disorder, and about concordant features favoring PNES. For with clear-cut emergence from EEG-
two-thirds have example, assessment of the characteris- documented sleep would have a high
personality disorders. tic seizure temporal evolution is often likelihood of being physiologic in origin
h The diagnosis of helpful. Ictal vocalization in epileptic (ie, epileptic seizures or parasomnias).
psychogenic nonepileptic seizures is usually restricted to the PNES have been classified into dis-
seizures requires the beginning of the seizure, primitive in tinct groups according to the predom-
demonstration of ictal nature (laryngeal sound), and highly inant clinical features. These groupings
features that favor a stereotyped. In PNES, the vocalization include rhythmic motor, hypermotor,
psychogenic process; are may be present not only at the begin- complex motor, dialeptic (impaired
not consistent with ning of the seizure but may persist or awareness), subjective, and mixed.19
epilepsy; and occur even intensify through the course of the
in the context of While such categorization can contrib-
ictus. Vocalization in PNES can be more ute to pattern recognition useful in the
supportive historical,
complex, with affective content re-
physical examination, evaluation of PNES, it is presently uncer-
flecting somatic expression of emo-
and ictal/interictal tain whether such categorization is
video-EEG findings.
tional distress (eg, weeping, moaning,
and coughing).16 The generalized tonic- useful to distinguish psychological un-
h Patients’ and witnesses’ clonic epileptic features can inform di- derpinnings or inform prognosis. Fur-
descriptions of the thermore, unlike stereotyped epileptic
agnosis, where ictal features evolve
ictal features have seizures arising from a singular epilep-
been known to
through an organized fashion such that
clonic frequency progressively declines togenic substrate, the ictal features of
correlate poorly with
observed features while amplitude increases through the patients with PNES can often change,
of video-EEGY course of the convulsion. In contrast, the transforming into other clinical presen-
captured seizures. convulsive activity in generalized tonic- tations or unrelated somatic symptoms.20

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 KEY POINTS
Distinguishing Syncope From and EEG documentation of the habitual h No feature in itself is
Other Causes of Drop Attacks seizures of interest. In the setting of an definitively diagnostic
The mean duration of vasovagal syn- unconscious patient, physiologic causes of psychogenic
cope (the most common mechanism for can be excluded by concurrent presence nonepileptic seizures.
syncope) from the moment of event of an intact alpha rhythm on the EEG h Assessing the
onset to recovery of full consciousness (a neurophysiologic correlate of alert- characteristics of the
has been shown to be 41.4 seconds.21 ness). In other scenarios, the absence temporal evolution of a
Therefore, paroxysms of swoons that of an epileptiform ictal EEG correlate seizure can frequently
last longer than 1 minute should raise before, during, or after the seizure in- yield helpful clues in
suspicion for other etiologies. It has dicates that the captured event is likely differentiating
been suggested that patients with re- nonepileptic in origin but does not nec- psychogenic nonepileptic
current “syncope of unknown origin” essarily distinguish a psychogenic versus seizures from
physiologic etiology. Consideration of epileptic seizures.
despite a thorough evaluation (about
20% to 30% of patients with syncope) a psychogenic etiology requires the h The EEG during syncope
should undergo video-EEG monitoring demonstration of PNESYconsistent proceeds through a
as some of them may, in fact, have clinical event features in the context stereotyped pattern,
beginning with theta
PNES.22 Contrasting with the absence of supportive historical and ictal/
peri-ictal physical examination find- slowing, then delta
of significant EEG background change
slowing followed
for PNES, the EEG during syncope pro- ings (Table 6-2). A concordant impres-
by suppression.
ceeds through a stereotyped pattern, sion from each of these data elements
beginning with theta slowing, then delta with the video-EEG provides the diag- h In the setting of an
unconscious patient,
slowing followed by suppression.22 nostic gold standard with high levels
physiologic causes
The presence of convulsionlike mo- of certainty as well as excellent inter-
can be excluded by
tor accompaniments does not preclude rater reliability.15
concurrent presence
the consideration of syncope. In a study Nuances of video-EEG interpretation. of an intact alpha
involving video analysis of 42 episodes For some patients with PNES who rhythm on the EEG
of syncope, 38 (90%) of the episodes experience dense amnesia for the details (a neurophysiologic
were associated with motor symptoms. of their seizures, any recorded event correlate of alertness).
The most commonly observed move- should be confirmed by an eyewitness h Upon demonstrating
ment pattern in this study was multi- to be typical of the habitual seizures of psychogenic nonepileptic
focal arrhythmic jerks in both proximal interest. Otherwise, the clinical relevance seizureYconsistent clinical
and distal muscles, usually lasting only a of the recorded event remains uncertain. event features in the
few seconds.23 The motor symptoms of If the patient’s historical features sug- context of supportive
syncope terminate when the patient as- gest more than one type of event, then historical and physical
sumes a horizontal position that facili- an occurrence of each type should be examination findings,
tates cerebral perfusion, whereas those recorded, as independent event types video-EEG offers a
may reflect distinct etiologies. If not, the diagnostic gold standard
of epileptic seizures would not be in-
etiology of the nondocumented event with high levels of
fluenced by body position.
certainty and reliability.
type should be diagnosed with a more
Confirming the Diagnosis of cautious level of certainty. Indeed, ap-
Psychogenic Nonepileptic Seizures proximately 10% of patients with PNES
Diagnostic tools used to help support also have an independent diagnosis of
the diagnosis of PNES include inpatient epilepsy.24 For patients with a learning
video-EEG monitoring, ambulatory EEG disability, further diagnostic caution is
recording, and home video recording of warranted as the percentage of mixed
habitual seizures. PNES with epilepsy cases can be up to
Video-EEG. Video-EEG entails pro- 30%.25 Focal epileptic seizures with pre-
longed continuous monitoring of the served consciousness and rather restricted
patient, allowing for simultaneous video motor, autonomic, or sensory/psychic
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 Nonepileptic Seizures

KEY POINTS
h Only 21% of simple components (simple partial symptom- EEG activation procedures (hyperven-
partial epileptic seizures atology) may arise from only a small pool tilation and photic stimulation) with-
have been shown to of neuronal tissue. As such, only 21% out placebo. Asking the patient or
correlate with ictal EEG of simple partial epileptic seizures have family if they know of a trigger that
epileptiform changes, been shown to correlate with ictal epi- can be reproduced in the unit is fre-
while some frontal lobe leptiform changes on scalp EEG.26 Some quently helpful (eg, scrolling on a com-
epileptic seizures can frontal lobe epileptic seizures arise from puter screen). Comparable success rates
demonstrate very subtle, deep-seated foci (eg, orbitofrontal or in- have been demonstrated between PNES
falsely lateralizing, or terhemispheric regions) such that ictal activation procedures with placebo ver-
undiscernible ictal EEG epileptiform discharges can conduct/ sus without placebo.32
epileptiform correlates.
distribute over a widespread area bilat- Ambulatory EEG and home video
h When confronted with erally, demonstrate a contralateral max- recordings. Some patients with PNES
enigmatic paroxysms of imum, or become obscured by copious may not experience seizures in a hospital
uncertain etiologies, artifacts related to hypermotor activity. setting that secludes patients from ha-
the demonstration
Therefore, ictal EEG epileptiform cor- bitual stressors of their indigenous mi-
of inducibility (ie,
relates of some frontal lobe epileptic lieu. Under such circumstances, outpatient
provocative induction)
would strongly (but not
seizures can be very subtle, falsely lat- ambulatory EEG (sometimes with con-
entirely) support a eralizing, or undiscernible. current video recordings) can be useful.
psychogenic etiology. Within 2 days after admission for Because of less-standardized recording
video-EEG monitoring, the majority of settings and greater susceptibility to arti-
patients with PNES will have experienced facts, the qualities of the ambulatory
a spontaneous and characteristic seizure EEG and video data can be quite var-
of interest.27 For those who do not ex- iable. For cases in which supportive clin-
perience spontaneous seizures, use of ical or historic contexts are not available,
suggestion techniques (ie, provocative ambulatory EEG should be interpreted
inductions) can improve the rate of sei- with caution.
zure capture28 and shorten the duration The frequency of some patients’ PNES
of video-EEG admission.29 The success may be too rare to be practically captured
rate of induction is higher among pa- during limited time frames of video-EEG
tients who demonstrate preinduction or ambulatory EEG recordings. Consid-
characteristics of hypermotor ictal symp- ering the common availability of mobile
tomatology, prevalent self-reporting devices that can record video, home
of uncommon cognitive and affective video documentation of some patients’
symptoms, and absence of prior induc- infrequent seizures may be able to pro-
tion exposure.30 Moreover, when con- vide useful diagnostic data. Video data
fronted with enigmatic cases for which
alone (without EEG) have been shown to
frontal lobe epileptic seizures, simple
provide reasonably robust sensitivity and
partial epileptic seizures, or other phys-
specificity in distinguishing epileptic sei-
iologic nonepileptic events have not
zures from PNES.33 A key interpretive
been conclusively excluded, the dem-
onstration of inducibility would strongly caution is that home video recordings
(but not entirely) support a psychogenic may frequently miss the moment of sei-
etiology. Ethical concerns are raised by zure onset and instead capture the mid-
the use of placebos during induction dle or recovery phase of the seizure.
(eg, saline injection or alcohol wipes), Moreover, the neurobehavioral man-
which inherently reflect a deceptive in- ifestations during the postictal recov-
tervention to the patient.31 Such con- ery phase of epileptic seizures can highly
cerns can be circumvented by performing resemble the ictal symptomatology of
induction techniques that utilize routine some PNES.
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 KEY POINT
Levels of Certainty in the available aforementioned data reflec- h Psychogenic nonepileptic
Diagnosis of Psychogenic tive of scenarios commonly encoun- seizures are a subtype of
Nonepileptic Seizures tered in clinical practice, a diagnosis of conversion (somatoform)
In acknowledging that video-EEG is not PNES can be made with several levels disorder in which
readily available to every patient world- of diagnostic certainty, the highest level psychological conflicts
wide and that it may not always capture being “documented” (Table 6-3). With are manifested with
seizures characteristic of the patient’s this approach, the task force aims to symptoms resembling
single or multiple independent event provide greater clarity regarding the epileptic seizures.
types, the Nonepileptic Seizure Task evaluation process for PNES, facili-
Force of the International League tate prompt recognition of this dis-
Against Epilepsy (ILAE) delineated a order, and enhance care of patients
staged approach to PNES diagnosis.7 with PNES worldwide.
The ILAE task force recognized that dif-
ferent settings may not have access to PSYCHOPATHOLOGY
video-EEG, so different levels of diag- PNES are most commonly conceptual-
nostic certainty were delineated based ized as a subtype of conversion disorder
on the available data. in which psychological conflicts are mani-
The clinical data utilized in this fested as symptoms resembling epileptic
staged approach include patients’ his- seizures. The Diagnostic and Statisti-
torical presentation, witness accounts, cal Manual of Mental Disorders, Fifth
and clinicians’ observation in person Edition (DSM-5)34 provides revised diag-
or via review of video recordings during nostic criteria for conversion disorder
ictus, interictal EEG, and video-EEG. in accordance with updated insights
Based on varying combinations of the regarding this disorder. Whereas the

TABLE 6-3 Overview of Proposeda Diagnostic Levels of Certainty for Psychogenic

Nonepileptic Seizures

Diagnostic Level History Witnessed Event EEG

Possible + By witness or self-report/description No epileptiform activity in routine
or sleep-deprived interictal EEG
Probable + By clinician who reviewed video No epileptiform activity in routine
recording or in person, showing or sleep-deprived interictal EEG
semiology typical of psychogenic
nonepileptic seizures (PNES)
Clinically established + By clinician experienced in diagnosis No epileptiform activity in routine
of seizure disorders (on video or in EEG or ambulatory ictal EEG,
person), showing semiology typical capturing a typical ictusb
of PNES, while not on EEG
Documented + By clinician experienced in diagnosis No epileptiform activity immediately
of seizure disorders, showing before, during, or after ictus
semiology typical of PNES, while captured on ictal video EEG with
on video EEG typical PNES semiology
EEG = electroencephalogram; + = history characteristics consistent with PNES.
a
Modified with permission from LaFrance WC Jr, et al, Epilepsia.7 onlinelibrary.wiley.com/doi/10.1111/epi.12356/full. B 2013 International
League Against Epilepsy.
b
Captured ictus should not resemble types of epileptic seizures that may not show ictal epileptiform correlate on EEG (eg, simple partial
epileptic seizures).

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 Nonepileptic Seizures

KEY POINT
h Whereas DSM-IV Diagnostic and Statistical Manual of surgeries/anesthesia37Y39) can provoke
approached conversion Mental Disorders, Fourth Edition conversion symptoms and may involve
disorder as a diagnosis (DSM-IV) required the presence of psy- processes that are physiologic as much
of exclusion, the chological factors to precede or exac- as psychological (Case 6-1).
updated DSM-5 guides erbate conversion symptoms, such DSM-IV approached conversion dis-
users to make a positive requirement has been relegated to a order as a diagnosis of exclusion from
conversion disorder note in DSM-5.34,35 The reason for this other pathophysiologic conditions. To
diagnosis based on change is that while psychological fac- circumvent this problem, DSM-5 guides
inclusion of clinical tors are important in the evolution of users to make a positive conversion
features that are conversion disorders, they are not always disorder diagnosis based on inclusion
incongruent to known
immediately apparent from the history. of clinical findings that are incongruent
anatomy, physiology,
Some patients’ readiness to discuss psy- to known anatomy, physiology, or dis-
or disease.
chological factors may depend on the eases (Table 6-2). The criterion on exclud-
strength of the clinician-patient alliance. ing other pathophysiologic conditions
Even when psychological factors are has been revised to a criterion that re-
readily identified, it may not be clear quires that the symptom in question is
that they are etiologically relevant to “not better explained by another dis-
the symptoms at hand.36 Moreover, evi- ease.” This revision encourages clinical
dence exists that physical factors (such investigation for an alternative medical/
as traumatic brain injuries, undergoing neurologic explanation for the symptom,

Case 6-1
A 57-year-old man presented with a 10-year history of seizures involving
abrupt loss of awareness with falls, followed by postictal disorientation/
confusion. Considering his known left frontal encephalomalacia from a
stroke that also occurred about 10 years ago, he had been treated for
(presumed) epilepsy with antiepileptic drugs. Since some of his paroxysms
were preceded by coughing fits, posttussive syncope was within the
differential diagnosis. However, he continued to experience frequent
seizures, despite trials of three antiepileptic drugs and measures to treat
his obstructive airway disease. He was referred for video-EEG monitoring,
which confirmed the diagnosis of psychogenic nonepileptic seizures (PNES)
(Supplemental Digital Content 6-1, links.lww.com/CONT/A169). This seizure
was induced by routine activation procedures that included photic stimulation
and provocation with verbal suggestion, but no placebo. PNES was
supported by the documented features of suggestibility (increasing seizure
intensity with higher photic frequency), ictal eye closure at ictal onset,
side-to-side head movements, illness-affirming behaviors (retching cough,
semifetal posture), and incongruence of intact EEG alpha rhythm (a
neurophysiologic correlate of alertness) during dialeptic symptomatology
with clinical unresponsiveness.
Comment. While strokes are associated with epilepsy and epileptogenic
foci, this case illustrates that the emotional affliction from significant
health-related adverse events should not be overlooked. Moreover,
evidence exists that physical factors (such as brain injuries) can provoke
conversion symptoms and may involve processes that are physiologic as much
as psychological. This case also exemplifies the importance of considering a
wide differential diagnosis in patients with paroxysmal disorders, which
includes epilepsy, physiologic nonepileptic events, and PNES.

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but also allows for a conversion dis- distress is expressed somatically, rather
order diagnosis even if a potentially than in a healthy verbal manner.
related disease is present. The other
notable change for conversion disorder BORDER ZONES OF PSYCHOGENIC
in DSM-5 is that the former require- NONEPILEPTIC SEIZURES
ment for exclusion of feigning has been (PSYCHIATRIC DIFFERENTIAL
abandoned. In clinical practice, such DIAGNOSIS)
requirement is problematic, as exclu- Border zones of PNES represent neuro-
sion of malingering may be difficult behavioral paroxysms with psychologi-
to validate with absolute certainty cal underpinnings but are not considered
without surveillance or forensic evalu- to be conversion disorders, as described
ation.40 Volitionally feigned symptoms, above. Panic attacks can be the paroxys-
as in the cases of malingering or fac- mal manifestation of panic disorder or
titious disorders, are not PNES (ie, not other conditions associated with anxiety.
psychogenic), and are rare, present Symptoms of tremulousness, shaking,
mostly in at-risk groups. derealization, or depersonalization can
Several etiologic models have been be quite prominent in some panic at-
proposed in the effort to explain the tacks, hence showing a notable parallel
inception and evolution of conversion to seizures. Careful exploration of the
disorder manifesting as PNES.41 One overall presentation should uncover
model stipulates two main types of other key features meeting DSM-5 crit-
psychological difficulties that underlie eria for panic attacks, in which intense
PNES: posttraumatic and developmen- fear is accompanied by at least four of
tal.42 Posttraumatic PNES develop in
the following symptoms: palpitations,
response to psychological or physical
diaphoresis, shortness of breath, chest
trauma(s) that the patient struggles
discomfort, nausea and abdominal dis-
to adequately process or integrate. In
comfort, dizziness, and the aforemen-
the face of “unspeakable dilemmas,”
tioned seizurelike symptoms. Similar to
some authors postulate that PNES re-
panic attacks, behavioral manifestations
flects an automatic cutoff phenomenon
of PTSD frequently entail derealization,
in response to spontaneous intrusion
depersonalization, or affective numbing,
into consciousness of such intolerable
memories.43 Developmental PNES de- all of which can resemble seizure activ-
rives from difficulties coping with com- ities. In fact, the DSM-5 designates a
plex life tasks and milestones along the PTSD subtype with prominent dissocia-
patient’s continuum of psychosocial de- tive symptoms. Upon careful evaluation,
velopment in an environment of emo- if the patient’s overall symptomatology
tional privation (eg, relational neglect). can be better explained by PTSD per
Studies have shown that some patients DSM-5 criteria, then the additional di-
with PNES rely on avoidant coping agnosis of conversion disorder should
responses (denial and repression) to not be made. Some authors contend that
perceived threats,44 hence hindering the presentation of exclusively subjective
appropriate maturation of psychosocial sensory symptoms (albeit neurologic
development. For some patients with symptoms, such as paresthesia or numb-
PNES, both posttraumatic and devel- ness) are not sufficiently reliable in them-
opmental types of psychological etiol- selves to meet the criteria for PNES.40
ogies may coexist. In essence, PNES Most of these cases likely represent anx-
(and other conversion disorders) are a ious misinterpretation of common non-
disorder of communication, where specific paroxysmal symptoms of everyday

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 Nonepileptic Seizures

KEY POINTS
h An important prognostic life, including transient dizziness, limb approach to PNES diagnosis may be
factor of psychogenic numbness, or head sensations that may beneficial in prompting earlier discus-
nonepileptic seizures is briefly disrupt attention. The misinter- sion regarding potential psychological
the duration of illness, in pretation of benign symptoms as being contributions to seizures, as soon as
which the prognosis more pathologic may be more common minimum criteria for the diagnosis of
worsens the longer the in patients who have had personal expe- PNES have been met. Deferring such
patient’s illness has been riences with seizures or who have other discussions until video-EEGYdocumented
mistreated as epilepsy. neurologic/medical conditions. Another diagnostic certainty may lead to sig-
h In children with scenario that falls within the border zones nificant delay, considering the afore-
psychogenic nonepileptic of PNES is the purposeless and repetitive mentioned diagnostic challenges and
seizures, serious behavioral mannerisms (learned behav- limited video-EEG availability in some
psychosocial issues (eg, locations. Factors that may prognosti-
ior) that occur not infrequently in some
physical or sexual abuses) cate better outcomes among adults
can be ongoing at the
cognitively impaired patients.45
include higher level of education; youn-
time of presentation and PROGNOSIS ger age at both time of seizure onset
should be explored in
When considering the overall popula- and time of diagnosis; seizures with
every case.
tion of patients with PNES, seizure less- dramatic symptomatology; fewer
cessation is reported to occur in about additional psychosomatic symptoms;
40% of patients over time. About one- and neuropsychological measures sup-
third of patients experience seizure porting lower dissociative, inhibitive,
reduction, while the remaining approx- emotional dysregulating, and compul-
imately one-third of patients undergo a sive tendencies.50,51
chronically intractable course.46 A com-
prehensive assessment of PNES out- PSYCHOGENIC NONEPILEPTIC
comes should encompass not only SEIZURES IN CHILDREN
seizure burden, but also the state of While much of the earlier discussions
psychosocial comorbidities, functionality, regarding PNES in adults also apply to
and overall quality of life.47 Upon pursu- children, some differences are notable
ing a more complete outcome assess- in light of varying psychosocial elements
ment of PNES as such, one study showed across developmental stages in children.
the following observations: 44% of pa- PNES can emerge in children as young
tients were not seizure free and re- as 5 years old, and their frequency in-
mained dependent (poor outcome); creases with age, becoming the most
40% of patients were either seizure free common type of nonepileptic seizure in
but dependent or not seizure free but adolescents.52 Conversely, comorbid
independent (intermediate outcome); epilepsy (mixed disorder) is more prev-
and 16% of patients were seizure free alent in younger children with PNES
and independent (good outcome).48 than in older children or adolescents
The above results suggest that patients with PNES.52 Compared to adults with
with PNES, in general, may have a poorer PNES, differences in psychiatric comor-
course than those with newly diag- bidities include lower rates of mood
nosed epilepsy.48 disorders (32%) and PTSD (10%) and a
Several patient-specific characteristics higher rate of significant family stressors
are identified as influencing the disease (44%) for children with PNES.53 Impor-
course of PNES. An important prognos- tantly, serious psychosocial issues (eg,
tic factor is duration of illness, in which physical or sexual abuses) can be on-
the prognosis worsens the longer the going at the time of presentation and
patient’s illness has been mistreated as should be explored in every case. Risk
epilepsy.49 Correspondingly, a staged factors for pediatric PNES are noted,
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 KEY POINT
including somatopsychic and adversity who continue to use the outdated pe- h The neurologist’s
components related to maladaptive jorative terminology of “pseudoseizures,” explanation of the
coping.54 The clinical outcome of PNES with connotations of being false or fake, diagnosis of psychogenic
is better in children than adults, per- create a distance between patients and nonepileptic seizures
haps contributed to in part by a gen- clinicians. Legitimization and confirma- is vital and should be
erally briefer duration of illness or that tion of PNES through these efforts can communicated to the
dysfunctional patterns have become enhance the patient’s acceptance of patient via a tactful,
less engrained.55 the subsequent diagnostic explanation empathetic, and
(Case 6-2). In turn, the patient’s ac- unequivocal approach.
MANAGEMENT OF PSYCHOGENIC ceptance of the PNES diagnosis has
NONEPILEPTIC SEIZURES been shown to be associated with sei-
Management of patients with PNES be- zure improvement.57
gins with a comprehensive evaluation Hence, the neurologist’s explanation
(ie, seizure history, psychosocial assess- of this diagnosis is vital, and should be
ment, video-EEG), which includes a de- communicated to the patient via a tact-
velopmental history and review of past ful, empathetic, positive, nonpejorative,
trauma and abuse in the intake neuro- and unequivocal approach.58 Provision
logic assessment.56 Many times, patients of supplementary written information
have been dismissed in prior emergency may help consolidate (and further legit-
department and neurologic encounters, imize) the PNES diagnosis.59 Commu-
so conveying to the patient that the nication with family and the referring
seizures in PNES are just as real as those physician regarding this diagnosis can
in epilepsy is essential. Neurologists also augment the uniformity of diagnostic

Case 6-2
A 27-year-old man presented with near-daily seizures that involved diffuse
shaking with varying degree of unconsciousness. Given his high seizure
frequency, a brief 23-hour inpatient video-EEG was able to capture his
habitual seizure, and he received the diagnosis of psychogenic nonepileptic
seizures (PNES). He then sought additional referrals, endorsing the
frustration that, “My family thinks it’s all in my head,” and “It has to come
from something else.” During a subsequent video-EEG monitoring course,
efforts were made to capture the full spectrum of the patient’s seizures.
The diagnosis of PNES was explained to the patient and family members,
emphasizing PNES as a real, albeit nonepileptic, type of seizure. This
explanation of the diagnosis took place across two inpatient visits to allow
the patient and his family the opportunity to process their understanding
and ask questions. An explanation letter (addressed to the patient) and PNES
brochures were encouraged to be shared with other clinicians or individuals
pertinent to the patient’s care.
Comment. For patients with PNES, establishing the correct diagnosis is the
first step of treatment. Optimal management begins with comprehensive
evaluation (ie, neurologic and psychiatric assessment, description of the
events and psychosocial history taking, video-EEG monitoring). The
clinician-patient rapport and legitimization of PNES established through
these efforts can enhance the patient’s acceptance of diagnosis. In this
sense, neurologists can be a factor not only in the diagnosis, but also in the
initial treatment of patients with PNES as they prepare patients for
collaborative care with a mental health professional.

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 Nonepileptic Seizures

KEY POINTS
h Medications do not fully insight across the patient’s milieu. Not more open-mindedness toward accep-
treat psychogenic providing the diagnosis with patient or tance of this diagnosis.64,65 Because
nonepileptic seizures. providers has been shown to be associ- driving is an issue for patients with
Moreover, antiepileptic ated with no improvement or even seizures, barriers to treatment delivery
drugs may worsening of symptoms.60 Likewise, are being overcome with computer
make psychogenic merely sharing the diagnosis (without video telemedicine, which is being used
nonepileptic seizures further dedicated therapeutic efforts) is in the US Department of Veterans Af-
worse. Selective frequently insufficient, as other somatic fairs to provide live-remote therapy for
serotonin reuptake and affective symptoms often develop veterans with either epileptic seizures
inhibitors (SSRIs) help the if the core issues are not addressed.13 or PNES.66
comorbidities (eg,
Letting the patient and family know that The working relationship between
depression and anxiety)
they are not alone in that many people the neurologist and patient should not
but do not
stop psychogenic
have the same disorder; that treatment abruptly end after a diagnosis of PNES
nonepileptic seizures. involves addressing predisposing, pre- has been established, for several reasons.
cipitating, and perpetuating factors; and For some patients with PNES, especially
h Targeted psychotherapy
that effective treatment is available pro- those who have been chronically mis-
appears to be the
mainstay of treatment
vides hope to patients and empowers diagnosed as having epileptic seizures,
for psychogenic treating clinicians to engage.50 a proper understanding of the diagnosis
nonepileptic seizures. The mainstay of effective treatment may not be achievable with a “one-shot”
To date, two pilot for PNES is psychotherapy directed at disclosure. Instead, iterative explanation
randomized controlled the known pathologies in the population. of the diagnosis via a supportive/
trials for psychogenic Pharmacologic interventions are used to noncoercive tone across serial visits may
nonepileptic seizures address common comorbidities (eg, se- gradually foster the patient’s acceptance
have shown clinically lective serotonin reuptake inhibitors for mental health treatment referrals.
meaningful results using [SSRIs] for depression and anxiety). Once the transition to mental health
either traditional However, psychotropics may reduce care is complete, then discussion can
cognitive-behavioral
seizures but do not lead to seizure commence regarding the patient’s dis-
therapy or a
cessation in PNES.3,61 Among psycho- charge from the neurologist’s practice.
seizure-treatment
workbook based
therapeutic approaches for patients with If a specific AED has no alternative
on a multimodality PNES, cognitive-behavioral therapy has beneficial indication (eg, mood stabili-
cognitive-behavioral the most substantial body of controlled zation or migraine prophylaxis), then a
therapyYinformed efficacy data. To date, two pilot random- timely taper of the drug is advisable.
psychotherapy for ized controlled trials for PNES have Early, as opposed to delayed, AED
psychogenic nonepileptic shown clinically meaningful results. One withdrawal portends greater beneficial
seizures and for epilepsy. study used conventional cognitive- effects on a range of clinical out-
behavioral therapy,62 while the other comes.57 Patients with normal video-
study used a multimodality cognitive- EEG findings should be followed by a
behavioral therapyYinformed psycho- neurologist for at least 6 months after
therapy3 based on a workbook used discontinuing AEDs. This consideration
by therapists and patients to treat is because of the small but ever-present
both epileptic seizures and PNES possibility of coexisting epilepsy and
(Table 6-4).63 Some patients may con- the fact that breakthrough epileptic
tinue to maintain some ambivalence re- seizures can occur several months
garding the nature of the PNES diagnosis after discontinuation of AEDs. Patients
and express reluctance toward in-depth with PNES who also have known
individual psychotherapies. In such cases, interictal or ictal epileptiform abnormal-
group psychoeducational approaches ities on their video-EEG should continue
have been shown to consolidate patients’ to be followed by a neurologist. Patients
understanding of PNES and promote with mixed epilepsy/PNES should be
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TABLE 6-4 Cognitive-Behavioral Approaches Evaluated in Randomized Controlled Trials for
Psychogenic Nonepileptic Seizures

Goldstein et al, 201061 LaFrance et al, 20143

Therapeutic Based on traditional cognitive-behavioral therapy Based on CBT-informed psychotherapy model
approach (CBT) and fear escape-avoidance model: initially aimed to enhance self-control of
Psychogenic nonepileptic seizures (PNES) as epileptic seizures: PNES as the somatic
dissociative responses to cues associated with manifestations of maladaptive core beliefs
extremely distressing or life-threatening (negative schemas) that have been derived
experiences. These experiences are, in turn, linked chronically from life experiences and traumas.
to unbearable feelings of fear and distress.
Main topics include seizure-directed Main topics include healthy communication,
techniques; attention refocusing; relaxation; support seeking, and goal setting; conducting
dealing with avoidance behaviors, negative a functional behavioral analysis; aura
cognitions, and other factors key toward identification; linking triggers, negative
engendering PNES. states, and target symptoms; relaxation;
examining external stressors and internal
conflicts; promotion of ongoing health
and wellness.
Outcomes CBT group experienced fewer seizures than When compared to before treatment,
the control group at the end of treatment. CBT-informed psychotherapy workbook
group showed significant seizure reduction
and improvement in depression,
anxiety, quality of life, and global
functioning measures.
During the last 3 months of a 6-month follow-up When compared to baseline, the treatment
period, between-group differences in seizure as usual/standard medical care control group
frequency were not significant, although the CBT showed no significant difference in seizure
group was 3 times more likely to be seizure free. frequency or any secondary outcome measures.

treated with the lowest effective AED a positive conversion disorder diagnosis KEY POINT
dose for the epilepsy, noting that AEDs based on identifying incongruent exam- h For the 10% of patients
do not treat PNES, and behavioral in- ination and laboratory findings in rela- with mixed epilepsy/
psychogenic nonepileptic
terventions should target the PNES. tion to known anatomy or physiology.
seizures, use the lowest
Continued follow-up by the neurologist Neurologists can work collaboratively with
effective antiepileptic drug
during the transition to mental health mental health providers to adequately dose for the epileptic
providers mitigates repeat workups with address the psychological underpinnings seizure and use mental
other providers. of these challenging patients. This team health treatments for
approach highlights the importance of the psychogenic
CONCLUSION interdisciplinary dialogue and transition nonepileptic seizures.
Conversion disorder is usually not diag- in the care of patients with PNES. To
nosed by the mental health provider this end, better communication by neuro-
alone; the neurologist is integral in the logists can overcome past diverging in-
evaluation and diagnosis. Indeed, patients terdisciplinary perspectives regarding
with conversion disorder frequently pres- PNES, with psychiatrists frequently be-
ent to neurologists first in search of a ing uncertain about the accuracy of video-
neurologic explanation to their symp- EEG.68 Further efforts are necessary to
toms.67 As such, neurologists have ac- augment this vital interdisciplinary part-
quired substantial experience in making nership. Recent diagnostic and treatment

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 Nonepileptic Seizures

studies have shown momentum in shift- 6. Benbadis SR, O’Neill E, Tatum WO, et al.
Outcome of prolonged video-EEG monitoring
ing PNES to a neuropsychiatric inter- at a typical referral epilepsy center. Epilepsia
disciplinary (shared-care) model with 2004;45(9):1150Y1153. doi:10.1111/j.
a mind/brain perspective.66 As research 0013-9580.2004.14504.x.
in PNES advances, cognizance of and, 7. LaFrance WC Jr, Baker GA, Duncan R, et al.
hence, empathy for patients with this Minimum requirements for the diagnosis of
psychogenic nonepileptic seizures: a staged
challenging condition can advance,
approach: a report from the International
in parallel. League Against Epilepsy Nonepileptic